NO900132L - AROMATIC OR HETEROCYCLIC OXAZEPINES AND THIAZEPINERIC PROCEDURES FOR PREPARING THEREOF. - Google Patents

Description

The present invention relates to new aromatic 2,3-dihydro-1,4-oxazepin-5-(4H)-ones and sulfur analogues thereof, and in particular aromatic 2,3-dihydro-1,4-oxazepin-5(4H)-ones and sulfur analogues thereof which have the aromatic component condensed in the oxazepine or thiazepine ring and are substituted in the 2-position with short-chain aminoalkyl radicals, and which exhibit antihistamine and anti-allergy activity, and a new process and new intermediates for their production.

3-aryl-1,4-benzoxazepin-5(4H)-ones substituted on the oxazepine nitrogen with an aminoalkyl radical have been described by Schenker, K. in Swiss Patent 505,850 (CA. 75, 98600s).

Conversion of flavones to benzoxazepinones substituted in the 2-position with a phenyl radical has been described by Levai,' A. a"nd Bognar, R., Top. Flavnoid Chem. Biochem. Proe. Hung. Bioflavonoid Symp. 4th Ed. 1973 (Pub . 1975)

119 - 123 (CA. 85, 79098n). Thione derivatives were obtained by treatment with phosphorus pentasulphide.

Certain chemical intermediates, 1-substituted-3-substituted phenoxypyrrolidines exemplified by 1-methyl-3-(2-carbamoylphenoxy)pyrrolidine,

1-benzyl-3-(2-carbamoylphenoxy)pyrrolidine, and

1-methyl-3-(2-carboxyphenoxy)pyrrolidine

in an otherwise new class of compounds is described in US patent 3,577,415.

Oxazepine and the thiazepine derivatives according to the invention which exhibit antihistamine activity have the formula:

wherein A represents an aromatic ring with two of its carbon atoms mutually held together with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene, or a pyridine in any of its four positions, and wherein any of the rings may be optionally substituted with one or two Y radicals selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl; B and E are selected from oxygen or sulfur and may be the same or different; R is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl or phenyl-lower alkyl, where phenyl may optionally be substituted with one or two radicals selected from halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl; n is 1, 2 or 3; 1 2 Z is selected from the group consisting of -NR R , 1H-pyrazol-1-yl or 1H-imidazol-1-yl; R 1 and R 2 are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl and phenyl-lower alkyl, which phenyl group may optionally be substituted with 1 or 2 radicals selected from halogen, lower alkyl, lower alkoxy, 1 2 nitro, trifluoromethyl or cyano, or where R and R together with the adjacent nitrogen atom can form a heterocyclic residue selected from the group consisting of 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1,yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl, 4- substituted piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4-substituted piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl and pharmaceutically acceptable salts thereof, provided that when R = H is Z never a primary or secondary amine, and provided that when n = 3, Z is not 1H-pyrazol-1-yl-1H-iraidazol-1-yl, 2,5-dimethylpyrrolidin-1,yl, 2-methylpyrrolidin-1, yl or 1,2,3,6-tetrahydropyridin-1-yl.

The new oxazepine and thiazepine precursors leading to the compounds of formula I have the formula:

wherein A, B, E, R and Y are as defined in formula I with the exception that R is not hydrogen, n is 1 or 2 and X is chlorine, bromine or cyano, and acid addition salts thereof.

Other chemical intermediates in the preparation of the compounds of formula II are new and have the formula:

wherein A, E, R, n and Y are as defined under formula II and X is chlorine or bromine.

Still other chemical intermediates leading to the compounds of formula IVb have the formula:

wherein A, E, R, n and Y are as defined in formula II, and Q is selected from CN or

3

wherein R is H, alkali-

metal ion or an esterifying radical. Compounds of formula IVa are novel except where A is phenyl or substituted phenyl and E is oxygen.

In the further definition of the symbols in the formulas, and where these may be found in the present description and claims, the expressions have the following meaning: The expression "lower alkyl" as used here includes straight-chain and branched radicals with up to 8 carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals. The term "lower alkoxy" has the formula -O-lower alkyl.

The term "cycloalkyl" as used herein primarily includes cyclic alkyl radicals containing 3-9 carbon atoms and includes such groups as cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and the like.

The terms "halo" or "halogen" include fluorine, chlorine, bromine and iodine unless otherwise indicated.

"Pharmaceutically acceptable salts" include acid addition salts, hydrates, alcoholates and quaternary salts of the compounds of formula I, which are physiologically compatible in warm-blooded animals. The acid addition salt can be formed by either strong or weak acids. Examples of strong acids are hydrochloric acid, sulfuric acid and phosphoric acid. Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid, cyclohexanoic acid and the like.

Suitable quaternary salts include lower alkyl halides and lower alkyl sulfates.

By "sulphurizing agent" is meant any agent

or mixture of agents which will convert ox- and thiazepinones to ox- and thiazepine thiones, such as 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide or a mixture of phosphorus pentasulfide and alkali metal sulfide or a mixture of phosphorus pentasulfide in pyridine.

The compounds according to the invention exhibit antihistamine activity in guinea pigs. The test method is a modification of the procedure described by Tozzi et al (Agents and Actions, Vol. 4/4, 264-270, 1974) as follows: Guinea pigs were fasted for 18-24 hours in individual cages. Water is available ad lib. On the test day, animals in groups of 3 are injected intraperitoneally with 30 mg/kg of the test compound prepared in a suitable carrier. 30 minutes later, histamine is injected at a dose level of 1.2 mg/kg (= 2 x LDgg) into a marginal ear vein. Survival of guinea pigs within 24 hours is positive evidence of antihistamine activity. If the vehicle used for the test compound is different from water, its effect is determined by testing an equal amount as a control. The dose that protects 50% of the animals (PDj-q) from death can be determined from dose-response curves.

The new method according to the invention includes the following steps:

Step 1) Halogenation of a compound of formula

wherein A represents an aromatic ring selected from benzene, naphthalene or a pyridine in any of its 4-positions, optionally substituted with one or two Y radicals selected from halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl;

E is oxygen or sulphur;

R is selected from the group consisting of lower alkyl, cycloalkyl or phenyl-lower alkyl, in which the phenyl group may optionally be substituted with one or two radicals selected from halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl;

R^ is hydrogen or an acid-neutralizing ion, and n is one or two,

while forming a compound of the formula:

or its free base wherein X is chlorine or bromine and A, E, R,

Y and n have the previously stated meanings. Suitable halogenating agents include:

a) thionyl halides

b) triphenylphosphine and a carbon tetrahalide

c) phosphorus pentahalides

d) phosphorus trihalides and

e) triphenylphosphine dihalide,

where the thionyl halides are preferred.

Step 2) Neutralization if necessary, and condensation of the carboxylic acid halide derivative prepared in step 1 to form an oxazepinone or a thiazepinone of the formula:

wherein A, E, R, X, Y and n have the meanings given in step 1, and wherein A now has two of its carbon atoms mutually held together with the oxazepine or thiazepine moiety.

Step 3) Optional reaction of the compound prepared in step 2) with a sulfurizing agent to form an oxazepine thione or a thiazepine thione of the formula:

in which A, E, R, X, Y and n have the meanings given in step 2.

Step 4) A compound prepared in step 2) is reacted, if necessary, with an alkali metal cyanide to form a compound of the formula:

where A, E, Y and R are as defined in step 2.

Step 5) Reaction of a halogen compound prepared in step 2 or 3 with a compound of the formula ZH in which Z is selected from -NR 1 R 2 , 1H-pyrazol-1-yl or 1H-imida-1 2

zol-1-yl, and in which R and R are selected from hydrogen, lower alkyl, cycloalkyl and phenyl-lower alkyl in which phenyl may optionally be substituted with 1 or 2 radicals selected from halogen, lower alkyl, lower alkoxy, nitro, trifluoromethyl or cyano, or where R 1 and R 2 together with the adjacent nitrogen atom can form a heterocyclic residue selected from the group consisting of 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl, 4-substituted-piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4-substituted-piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl, forming a compound of the formula:

wherein A, E, R, n and Y are as defined in step 2, Z is the same as in the ZH compound, and B is an oxygen or sulfur atom.

Step 6) Optional reaction of a compound prepared in step 5 in which B is an oxygen atom with a sulfurizing agent, preferably phosphorus pentasulfide in pyridine to form a compound of the formula:

where A, E, R, n, Y and Z are as defined in step 5.

Step 7) Reduction of a cyano compound (Formula lic) prepared in step 4 to a primary amine of the formula:

where A, E, Y and R are as defined in steps 2 and 4.

Step 8) If necessary reaction of a primary amine prepared in step 5 or 7 of the formula:

wherein A, E, Y and R are as defined in step 2 (R is not hydrogen) with one of the following reactants or sets of reactants a) formaldehyde and formic acid to form a tertiary dimethylamine, b) a dihalide to form a heterocyclic amine, c) a dialdehyde and sodium cyanoborohydride to form a heterocyclic amine, d) equimolar amounts of aldehyde or ketone, sodium cyanoborohydride with a large excess of

the above-mentioned primary amine below

formation of a secondary amine,

e) equal molar amounts of the primary amine and sodium cyanoborohydride with at least two equivalents of aldehyde or ketone, f) in sequence trifluoroacetyl chloride, alkyl or phenyl alkyl halide, potassium hydride and potassium hydroxide,

since all products are covered by the formula

where A, E, Y and R are as defined in step 2 (note: R is

12 12

not hydrogen) and Z is -NR R in which R and R are lower alkyl, cycloalkyl and phenyl-lower alkyl where phenyl is optionally substituted with halogen, lower alkyl, lower alkoxy, nitro,

1 2

trifluoromethyl or cyano or R and R together with the adjacent nitrogen atom may form a heterocyclic residue selected from 1-pyrrolidinyl, 1-piperidinyl, 4-substituted piperidin-1-yl, 4-morpholinyl, 1-piperazinyl-1-yl or 1, 2,3,6-tetrahydropyridin-1-yl, and optionally sulphurisation of the azepinone or thiazepinone to form the corresponding thione as in step 6.

Step 9) if necessary, reacting a benzyl or substituted benzyl compound obtained in step 5, 6 or 8 wherein Z is tertiary amino, pyrazolyl or imidazolyl of the formula

wherein A, E and Y are as defined in step 2, and wherein Z is any radical taken from the definition of Z under formula I, and with the same caveats as stated therein, and with sodium and ammonia to form a compound of the formula

wherein A, E and Y are as defined in step 2, n is 1 to 3 and Z is as defined under formula I with the limitations indicated there.

Step 10) Any turnover of the free base of

any compound prepared in steps 5-9 with a pharmaceutically acceptable acid or quaternary forming halide or sulfate to form a pharmaceutically acceptable salt.

The compounds of formula I wherein n is 2 are preferred because of their antihistamine activity. The method which includes steps 1-3, 5, 6 and 10 in which the prepared compounds have a methyl or ethyl side chain (n = 1 or 2) represents a preferred method corresponding to a sequence of steps A-F as indicated in the following.

The compounds of formula I.,, I, , I. , to I -,,

a' b c-1 x-7

Ic_^a, Id, Ig, If are all covered by formula I and the compounds of formula <H>a/-^b'IIc'IId and IIe are all covered by formula II.

Steps 1-4 also represent a new method for preparing compounds of formula Ha/IIc', all of which are covered by formula II.

It is thus a goal of the present invention

to provide certain new aromatic 2,3-dihydro-1,4-oxazepin-5(4H)-ones (and sulfur analogs thereof) substituted in the 2-position with short-chain aminoalkyl radicals, which compounds have antihistaminic activity.

Another objective is to provide certain new aromatic 2,3-dihydro-1,4-oxazepin-5(4H)-ones (and sulfur analogs thereof) substituted in the 2-position with alkyl halogen or alkyl cyano radicals which are chemical intermediates.

A further aim is to provide a new method for the preparation of aromatic 2,3-dihydro-1,4-oxazepin-5(4H)-ones (and sulfur analogues thereof) substituted in the 2-position with short-chain alkyl halogen or alkyl cyano or alkyl amino radicals.

Further aims and advantages of the present invention will be apparent from the subsequent description of the best way to practice the invention, and from the subsequent claims.

The present invention comprises the new oxazepine and thiazepine derivatives as indicated in Formula I and II, and certain new compounds of Formula III, IVa and IVb as such, and a method for the preparation of a compound of Formula I, II and III.

Reaction schemes I and II illustrate the preparation of all intermediate products. R is never hydrogen.

Reaction scheme III illustrates reaction sequences for the production of end products in which R is different from hydrogen and n is 1 or 2.

Reaction core IV illustrates the preparation of compounds with ethyl and propyl radicals in the 2-position, omega-substituted with primary amine (-NH^). R is never hydrogen.

Reaction core V illustrates methods for converting the omega-NH2-substituted ethyl and propyl compounds into secondary and tertiary amines. This is an alternative method for the production of the ethyl secondary and tertiary amines. R is never hydrogen.

Reaction core VI illustrates the preparation of compounds in which R is hydrogen.

Preparations 1-23 illustrate the synthesis of compounds of Formula IVa, IVb or certain starting materials thereof. Intermediates 1-36 (see also Table 1) illustrate the preparation of compounds covered by Formula II, which are atomic 2,3-dihydro-1,4-oxazepin-5(4H)-ones (and sulfur analogues thereof) substituted in 2- position with alkyl halogen or alkyl cyano radicals. The compounds of Formula III are formed in the reaction mixtures usually without isolation. Examples 1-71 (see also Table 2) illustrate the preparation of compounds covered by Formula I. However, the scope of the invention is not limited to the following preparations, intermediate products and examples.

With reference to the method and procedural steps according to the invention as stated above as they relate to the preparation of compounds of formula I, II and III, the following description applies.

In step 1, starting compounds of formula IV^ (see Reaction nucleus I) bearing a carboxylic acid or an acid-neutralizing ion such as an alkali metal salt thereof on the A ring ortho to the ether bond are treated as a substantially pure unit or preferably derived in a reaction mixture resulting from hydrolysis of precursors bearing in the same ortho position carbamoyl, cyano or carboxylic acid ester functions without substantially isolating the carboxylic acid

(or salt) from the reaction mixture, with a suitable halogenating agent such as those described above, preferably thionyl chloride or triphenylphosphine and carbon tetrachloride. The halogenation is carried out in a suitable organic solvent, preferably a refluxing organic solvent or a refluxing halogenating agent such as the preferred thionyl chloride. Temperatures for the chlorination can be used over a wide range, for example from room temperature

to 100°C or above, however, temperatures of 50-80°C are preferred, which temperatures include refluxing chloroform or thionyl chloride. When the excess of halogenating agent such as thionyl chloride has been used as a carrier, this is preferably evaporated. When a solvent such as chloroform is used, this can be evaporated away but need not be. In each case, a solution comprising a solvent and compounds of Formula III or a residue comprising compounds of Formula III, all of which are confirmed by infrared analysis, is available for use in the next step.

In step 2, the halogenated compounds of Formula III, prepared in step 1, if they are not already present in a solvent, are dissolved in an organic solvent, preferably chloroform, and usually neutralized or preferably made basic with a tertiary amine such as triethylamine, and is then heated to a temperature and for a time sufficient to effect a condensation of the carbonyl with the basic nitrogen and cleavage of the cyclic amine and formation of 2-(2-alkylchloro or bromo)oxazepine or thiazepine compounds of Formula IIa, for example in refluxing triethylamine. If the tendency to condense is sufficiently great, the neutralization and basification can be eliminated. The compounds of Formula IIa can be isolated in a known manner, for example by partitioning between a suitable organic solvent or mixture of solvents and aqueous acid or base, followed by drying and evaporation of the organic layer and recrystallization of the residue from a suitable solvent.

In step 3, the compounds of Formula Ila can optionally be converted to oxazepine thione or thiazepine thione (Ilb) by heating together with a sulphurising agent in a suitable organic solvent such as toluene. Thionet (IIb) can be isolated in a known manner, preferably by partitioning between an organic solvent and dilute alkali metal base, and crystallization from a suitable solvent such as ethanol.

In step 4, an oxazepinone or thiazepinone (Ila) is reacted with potassium cyanide in a warm protic solvent

using a phase transfer catalyst such as tetrabutylammonium bromide. The resulting cyano compound is then extracted into a suitable solvent such as ethyl acetate, and the solution is dried and evaporated. The residue is then recrystallized from a suitable solvent such as a mixture of methyl acetate and isopropyl ether or ethyl acetate alone. As will be understood, the prepared compounds have methyl and ethyl cyanoside chains (n = 1 or 2) leading to side chain extension to aminopropyl n = 3 or as an alternative starting material for extension of a methyl chain to aminoethyl.

In step 5, the oxazepinone and thiazepinone (Ila) obtained in step 2 or the oxazepinthione and thiazepinthione (Ilb) obtained in step 3 are reacted with pyrazole, imidazole or

12 12

with an amine of formula NHR R in which R and R have the meanings indicated under formula I, forming compounds of formula Ia and Ib. The latter reaction is preferably carried out in an excess of amine such as e.g. volatile methyl-

amines. The free bases of the products of formulas Ia and Ib

is isolated in a known manner by removing the volatile constituents and partitioning between dilute aqueous alkali metal base and a solvent such as chloroform or methylene chloride, followed by evaporation. The free base can be converted to a pharmaceutically acceptable salt with a suitable acid and, in the case of a quaternary salt, with a lower alkyl halide or sulfate and recrystallization in known manner. The free bases can be recovered from the acid addition salts, usually in a purer form, by redistributing the salt between aqueous base and a suitable solvent, followed by evaporation. As will be understood and as appears from Reaction Core I,

the side chain of the produced intermediate is limited to aminomethyl and aminoethyl (n = 2).

In step 6, when this is desired, a compound prepared in step 5 in which B is oxygen is sulphurised, preferably by refluxing in dry pyridine together with phosphorus pentasulphide for several hours. The resulting thione is isolated by cooling the solution and partitioning between a suitable solvent such as chloroform and an aqueous base, and evaporation of the organic phase and isolation in a known manner.

In step 7, a cyano compound (lic) prepared in step 4, which is an oxazepinone and thiazepinone, is reduced preferably with hydrogen using Raney nickel catalyst at ca. 60° C. The primary aminoethyl or aminopropyl compound formed (n = 2 or 3) is isolated in a known manner, preferably as an acid addition salt which can be converted back to the free base by partitioning between a suitable solvent and an aqueous base with subsequent drying and evaporation of the organic layer.

In step 8 (see Reaction Core V) a primary amine is converted into a secondary or tertiary amine depending on the choice of reactants.

The method provides a reaction route to secondary and tertiary amino compounds of Formula I with n = 3 which is not given by step 5, and which additionally provides an alternative reaction route to secondary and tertiary amino compounds of Formula I in which n = 1 or 2. Preparation of dimethyl- amino derivatives by reaction of primary amine with formaldehyde and formic acid is a conventional method for the preparation of tertiary dimethylamines such as reaction of a dihalide to form a heterocyclic amine such as 1-pyrrolidino, piperidino or 4-morpholino. The alternatives using sodium cyanoborohydride follow the procedures described by R.F. Borch et al, J. Amer. Chem. Soc. 93, 2,908

(1971). The procedure using conversion to trifluoroacetamide is described by J.E. Norlander et al, Tetrahedron Letters, 1978 (50) pp. 4987-4990.

In step 9, a 4-benzyloxyazepinone or thiazepinone derivative (R = benzyl) under formula I excluding primary or secondary amines is converted to the corresponding 4-unsubstituted (R = H) oxazepinone or thiazepinone by reaction with sodium and ammonia, and which can be isolated as illustrated in Example 68.

Step 10 is optionally dependent on whether the compound of formula I is already in the form of a pharmaceutically acceptable salt or whether it is desirable to convert this into another salt or whether the free base is desired. To obtain the free base from any addition salt of formula I, the salt is partitioned between a suitable organic solvent such as chloroform and a dilute aqueous base. The organic layer is dried and condensed to form the free base which is then, if desired, reacted with an acid as described above to form the desired salt.

As indicated above, the preferred steps for the formation of the preferred compounds with an ethyl side chain in the 2-position include steps 1-3, 5, 6 and 10 of the general process for the preparation of all compounds of formula I. As the compounds having a methyl side chain can be produced by the same process, compounds in which n = 1 are included in the preferred process. These steps of a preferred process are indicated by A to F corresponding to the numbered steps of the general process with the restriction that n = 1 or 2 and R is different from hydrogen as follows:

Production 1

2-(1-benzyl-3-pyrrolydinyloxy)benzamide

To a suspension of 4.3 g (0.11 mol) of sodium amide

in 60 ml of dry toluene was added 19.3 g (0.11 mol) of 1-benzyl-3-pyrrolidinol at a rate sufficient to maintain a temperature of 35° C. Stirring was continued at room temperature for 3 hours. 19 g (0.1 mol) of o-toluenesulfonyl chloride were added to the mixture by rapid dropwise cooling with ice bath cooling to keep the temperature at 20 - 30° C. Stirring was continued at room temperature for 2.5 hours and the mixture was allowed to stand overnight. The toluene was washed twice with water, dried with sodium sulfate and concentrated.

To a suspension of 5.4 g (0.1 mol) of sodium methoxy in 50 ml of dimethylformamide in another vessel was added 13.6 g (0.1 mol) of salicylamide in 75 ml of dimethylformamide at a rate sufficient to maintain a temperature of 50° C. After stirring for 15 minutes, the sulfonate prepared above in 25 ml of dimethylformamide was added dropwise and the solution was boiled under reflux for 5 hours. The material was partitioned between 500 ml of ethyl acetate and 500 ml of water. The ethyl acetate was extracted with dilute hydrochloric acid, the acid made basic with dilute sodium hydroxide and extracted with ethyl acetate. The organic layer was dried, concentrated and the residue crystallized twice from isopropyl ether-ethyl acetate. The yield of product was 12.5 g (4 2 %), m.p. 120.5 - 122° C.

Analysis: Calculated for C^<gH>2<Q>N2O2=

C 72.95 H 6.80 N 9.46

Found : C 73.23 H 6.78 N 9.56

Manufacturing 2

2-(1-methyl-3-pyrrolidinyloxy)benzamide

To 85.6 g (2.2 mol) of sodium amide in 1.5 liters of dry toluene was added 202 g (2 mol) of 1-methyl-3-pyrrolidinol so that the temperature did not exceed 50° C. The mixture was then heated to 70° C for 4.5 hours. The mixture was cooled and 381 g (2 mol) of o-toluenesulfonyl chloride was added by rapid dropwise addition while maintaining the temperature at 20-30°C by means of an ice bath. The mixture was stirred at room temperature for 2.5 hours and was washed with water. The toluene solution was dried with sodium sulfate and concentrated. The residue dissolved in 500 ml of dimethylformamide was added to a reaction mixture prepared by adding 119 g (2.2 mol) of sodium methoxide and 2 74 g (2.0 mol) of salicylamide to 1 liter of dimethylformamide, and the mixture was worked up as described in Preparation 1. The yield of the product was 170 g (38%),

sm.p. 116 - 118° C.

Analysis: Calculated for cj2<Hl>6<N>2°2:

C 65.43 H 7.32 N 12.72

Found: C 65.28 H 7.28 N 12.77

Manufacturing 3

2-[3-(1-benzyl)pyrrolidinyloxy]benzoic acid

To a solution of 20.3 g (0.52 mol) sodium hydroxide

to 600 ml of ethanol and 400 ml of water was added 150 g (0.51 mol) of 2-[3-(1-benzyl)pyrrolidinyloxy]benzamide and the mixture was stirred under reflux for 48 hours. The mixture was concentrated on a rotary evaporator to half the volume and the residue was extracted with ethyl acetate to remove unreacted amide. The aqueous layer was filtered and the pH of the filtrate was adjusted to 6.5 with hydrochloric acid. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in isopropyl alcohol.

The resulting mixture was filtered and the filtrate concentrated. The residue, 85.7 g, was composed mainly of the title compound.

Manufacturing 4

3- [( l- methyl- 3- pyrrolidinyl) oxy]- 2- naphthalenecarboxamide

To a cooled solution of 68 g (0.67 mol) of 1-methyl-3-pyrrolidinol and 74 g (0.73 mol) of triethylamine in 700 ml of dry benzene, 74 g (0.63 mol) of methanesulfonyl chloride were added dropwise. After stirring at room temperature for 45 minutes, the mixture was filtered and the filtrate concentrated under reduced pressure and dissolved in 100 ml of dimethylformamide.

To a cooled suspension of 10.8 g (0.45 mol) of sodium hydride in 75 ml of dimethylformamide in another vessel was added dropwise 84 g (0.45 mol) of 3-hydroxy-2-naphthalenecarboxamide dissolved in 400 ml of dimethylformamide. The sulfonate solution prepared above was added dropwise and the reaction mixture was stirred and heated under reflux for 16 hours. The cooled solution was diluted with 1000 ml water and was extracted twice with 500 ml portions of chloroform. The chloroform was washed with water and extracted twice with 500 mL portions of 3N hydrochloric acid. The aqueous extracts were basified with 50% sodium hydroxide and extracted three times with 500 mL portions of chloroform. After drying over magnesium sulfate, the chloroform was evaporated under reduced pressure to give 27.4 g (22%) of a pale yellow solid. The product was recrystallized from ethyl acetate, mp 128 - 130°C.

Analysis: calculated for C^^H^g^C^:

C 71.09 H 6.71 N 10.36

Found: C 70.88 H 6.68 N 10.37

Manufacturing 5

3-[(l- methyl- 3- pyrrolidinyl) oxy]- 2- naphthalene- carboxylic acid oxalate [ 2:1]

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 to reflux for 16 hours and after cooling the pH was adjusted to 6.8 with concentrated hydrochloric acid. The resulting solid was separated by filtration and the pH of the filtrate was adjusted to 6.02. The filtrate was concentrated under reduced pressure and the residue boiled in 200 ml of isopropyl alcohol and filtered. The filtrate was again concentrated under reduced pressure to give 69 g (94%) of an amorphous solid. A sample was dissolved in isopropanol and treated with oxalic acid. The oxalate salt was recrystallized from

ethanol/water, m.p. 20 9 - 212° C.

Analysis: Calculated for ci7H^8N05:

C 64.55 H 5.74 N 4.43

Found: C 63.86 H 5.68 N 4.37

Preparation 6

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

To a stirred suspension of 6.4 g (0.13 mol) of 50% sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mol) of 1-methyl-3-pyrrolidinol. During the addition, the temperature rose from 25 to 31° C. After 10 minutes, a solution of 10 g (0.063 mol) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise which caused the temperature to rise. When the temperature reached 55? C it was maintained there by alternating use of ice baths until the addition had been completed. The mixture was then heated to 55-60°C for 1.5 hours, cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetate-methanol. The yield of the product was 5 g with a decomposition point of 240° C. The NMR analysis showed that the compound contained 1/3 mol of sodium acetate as impurity.

Analysis: Calculated for C^-^H^2N2^3Na " l/^C^H-^C^Na :

C 51.62 H 5.20 N 10.32

Found: C 51.81 H 5.15 N 10.3 9

Manufacturing 7

4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide

To a solution of 55.5 g (0.55 mol) of triethylamine in 500 ml of dry benzene, 50.5 g (0.50 mol) of 1-methyl-3-pyrrolidinol was added dropwise at such a rate that the temperature was maintained at 25 - 30° C. To the mixture, kept at 20 - 50° C, 57 g (0.50 mol) methanesulfonyl chloride was added dropwise. After stirring for 1 hour at room temperature, the mixture was filtered and the precipitate was washed with 250 ml of hot benzene. The filtrate and washings were combined and concentrated under reduced pressure and the residue was dissolved in 200 ml of dimethylformamide.

To a cooled suspension of 19.6 g (0.41 mol) of sodium hydride in 100 ml of dimethylformamide in another vessel was added dropwise a solution of 70 g (0.41 mol) of 4-chlorosalicylamide in 200 ml of dimethylformamide at such a rate that the temperature was maintained at 20° C. To the resulting reaction mixture was added dropwise the sulfonate salt prepared above, and the mixture was heated to reflux for 19 hours. The reaction mixture was cooled and diluted with 1 liter of water. The diluted mixture was extracted three times with 300 mL portions of chloroform. The chloroform extracts were combined and extracted with two 500 ml portions of 3N hydrochloric acid. The combined aqueous extract was made alkaline with 50% sodium hydroxide and extracted three times with 500 mL portions of ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate and concentrated under reduced pressure to give 46.5 g (45%)

of a beige solid material. The solid was recrystallized from ethyl acetate, m.p. 122 - 123° C.

Analysis: Calculated for C12H15N2C102:

C 56.58 H 5.94 N 10.99

Found: C 56.4 8 H 5.96 N 10.84

Manufacturing 8

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

To a cooled solution of 101 g (1.0 mol) 1-methyl-3-pyrrolidinol, 111 g (1.1 mol) triethylamine in 1000 ml dry benzene, 114 g (1.0 mol) methanesulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and was filtered. The filtrate was concentrated under reduced pressure and was dissolved in 100 ml of dimethylformamide.

To a cooled suspension of 30 g (0.63 mol) of sodium hydride in 100 ml of dimethylformamide in another vessel was added dropwise 5-bromosalicylamide (137 g, 0.63 mol) dissolved in 750 ml of dimethylformamide. The sulfonate prepared above was added dropwise and the reaction mixture was heated to reflux for 18 hours. The cooled solution was diluted with 1000 ml of water and was extracted three times with 500 ml<1>s portions of chloroform. The chloroform extracts were washed with water and extracted four times with 500 mL portions of 3N hydrochloric acid. The aqueous layer was made alkaline with 50% sodium hydroxide and extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 52 g (28%) of a yellow solid. The solid was recrystallized from ethyl acetate/chloroform, m.p. 160 - 162° C. Analysis: Calculated for C, ~H, ,-N-BrO-,:

lz lb2.2.

C 48.18 H 5.05 N 9.36

Found: C 48.02 H 5.01 N 9.22

Production 9

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

To a cooled suspension of 2.4 g (0.41 mol) of sodium hydride in 50 ml of dimethylformamide, 17 g (0.1 mol) of 5-chlorosalicylamide dissolved in 50 ml of dimethylformamide was added dropwise at such a rate that the temperature did not exceed 20°C . After the addition of the salicylamide was complete, 16.7

g (0.1 mol) 3-bromo-1-methylpyrrolidine dissolved in 50 ml dimethylformamide added dropwise. The reaction mixture was stirred and heated to reflux for 19 hours. The cooled solution was diluted with 250 ml of water and extracted twice with 250 ml<1>s portions of chloroform. The chloroform was extracted three times with 500 ml<1>s portions of 3N hydrochloric acid. The aqueous extracts were made alkaline with 50% sodium hydroxide and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate under reduced pressure gave 6 g (2 3%) of product as a beige solid. The solid was recrystallized from ethyl acetate, m.p. 126 - 128° C.

Analysis: Calculated for C24<H>32<N>4<C>^2°5<:>

C 54.65 H 6.11 N 10.62

Found: C 54.87 H 6.12 N 10.69

Production 10

1-[(1-methyl-3-pyrrolidinyl)oxy]naphthalene-carboxamide

A solution of 118 g (0.63 mol) of 1-hydroxy-2-naphthalenecarboxamide in 250 ml of dimethylsulfoxide was added dropwise to a suspension of 27.6 g (0.69 mol) of 50% sodium hydride (mineral oil) in 250 ml of dimethylsulfoxide. The reaction was exothermic and the temperature rose to 60°C.

In another vessel, 79 g (0.69 mol) methanesulfonyl chloride was added dropwise to a solution of 69.7 g (0.69 mol) 1-methyl-3-pyrrolidinol and 77 g (0.76 mol) triethylamine in 500 ml dry benzene while cooling with an ice bath. The mixture was stirred for 15 minutes and filtered. The filter cake was washed with 500 ml of benzene and the benzene filtrates were combined and concentrated on a rotary evaporator to approx. 200 ml. The residue was added dropwise to the above-prepared dimethyl sulfoxide solution containing the sodium salt of 1-hydroxy-2-naphthalenecarboxamide while stirring at 75° C. The temperature was maintained at 75° C. for 18 hours by means of external heat. The resulting solution was cooled and an equal volume of water was added. The mixture was extracted with three portions of chloroform. The washing solutions were combined and concentrated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was basified with sodium hydroxide and extracted twice with ethyl acetate. The ethyl acetate washes were combined, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-isooctane. The yield of the solid material was 55 g (32%). A portion was recrystallized twice from ethyl acetate-isooctane, m.p.

122 - 129° C.

Analysis: Calculated for C^g^ig1^^ :

C 71.11 H 6.71 N 10.36

Found: C 70.96 H 6.71 N 10.31

Production 11

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

To a solution of 151 g (1.5 mol) of 1-methyl-3-pyrrolidinol and 166 g (1.6 mol) of triethylamine in 1500 ml of dry benzene, 171 g (1.5 mol) of methanesulfonyl chloride were added dropwise while cooling. The reaction mixture was stirred at room temperature for 1 hour and was filtered. The filtrate was concentrated under reduced pressure to give an orange colored oil.

In another vessel, the sulfonate prepared above and 139 g (0.93 mol) of 5-methoxy-salicylamide dissolved in 600 ml of dimethylformamide under cooling. The reaction mixture was heated to reflux for 14 hours. After cooling, the reaction mixture was diluted with 1000 ml of water and was extracted three times with 700 ml portions of chloroform.

The combined chloroform extracts were washed three times

with water and was extracted three times with 500 ml portions of 3N hydrochloric acid. The aqueous layer was made alkaline and extracted with chloroform. The chloroform extracts were washed three times with water, dried over magnesium sulfate and evaporated under reduced pressure to give a viscous brown oil. Vacuum distillation of this material gave a viscous orange oil which was dissolved in chloroform, extracted into acid, made alkaline and extracted into chloroform again. Evaporation of the solvent gave a dark brown oil which solidified under reduced pressure. Three recrystallizations from ethyl acetate gave 10 g of white crystals (4%), m.p. 85 - 87° C.

Analysis: Calculated for ci3HigN2°3:

C 62.38 H 7.25 N 11.19

Found: C 62.47 H 7.26 N 11.20

Production 12

3-[(l- methyl- 3- pyrrolidinyl) oxy]- 4- pyridine-carbonitrile-fumarate [1:2]

A solution of 55 g (0.55 mol) of 1-methyl-3-pyrrolidinol in 55 ml of dry dimethylformamide was added dropwise to a suspension of 22 g (0.58 mol) of 60% sodium hydride/40% mineral oil in 300 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour and 73 g (0.53 mol) of 3-chloro-4-cyano-pyridine in 200 ml of dimethylformamide was added dropwise with gentle cooling to maintain the temperature at 30 - 40°C The solution was stirred for 3 hours and an equal volume of water was added. The solution was acidified with dilute hydrochloric acid and was extracted with isopropyl ether. The aqueous layer was basified with sodium hydroxide and extracted five times with chloroform. The extracts were combined, dried over sodium sulfate and concentrated. The residue was treated with 50 g of fumaric acid in 400 ml of isopropyl alcohol and 40 ml of water. The resulting crystals (51 g, 21%) were collected. A 2 g sample was recrystallized from methyl isobutyl ketone. Yield of the product was 1.5 g, m.p. 172 - 174° C.

Analysis: Calculated for ci9H21<N>3°<9:>

C 52.42 H 4.86 N 9.65

Found: C 52.40 H 4.90 N 9.68

Production 13

1- [( l- methyl- 3- pyrrolidinyl) oxy]- 2- naphthalene- carbonitrile-oxalate

A solution of 29 g (0.11 mol) of 1-[(1-methylpyrrolidinyl)oxy-2-naphthalenecarboxamide and 38 g (0.32 mol) of thionyl chloride in 150 ml of chloroform was heated to reflux for 6 hours. The solution was poured into ice water and made basic with sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and concentrated. The residue was dissolved in hot isooctane. The solution was treated with bone charcoal, filtered and concentrated. The residue was dissolved in isopropyl alcohol and oxalic acid was added. The precipitate was crystallized from isopropyl alcohol-water. Yield of the product was 11.5 g (31%), m.p. 176 - 184° C.

Analysis: Calculated for C^8<H>18<N>2°5:

C 63.15 H 5.30 N 8.81

Found: C 63.00 H 5.29 N 8.15

Production 14

3, 5- diiodo- methyl salicylate

To 1 liter of absolute methanol was added 150 g (0.39 mol) of 3,5-diiodosalicylic acid. Hydrogen chloride was dissolved through the reaction mixture with stirring and was refluxed for 3 hours. The reaction mixture became cloudy and suddenly a large volume of white crystals precipitated. The mixture was filtered and after drying gave 136 g (83%) of product with a melting point of 198 - 202°C.

Production 15

2- hydroxy- 3, 5- diiodobenzamide

A stainless steel bomb, cooled with dry ice-acetoht, was filled with excess liquid ammonia, 3,5-diiodomethylsalicylate and a catalytic amount of sodium hydride. The bomb was sealed and shaken at room temperature for 16 hours. After cooling, the contents of the bomb were poured out and excess ammonia was allowed to evaporate at room temperature. The product melted at 190 - 195° C during cleavage. Mass spectrum analysis determined

Production 16

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

Following the procedure described in Preparation 2, but using 2-hydroxy-3,5-diiodobenzamide instead of salicylamide, the title compound was prepared.

Production 17

Sodium- 2-[(l- methyl- 3- azetidinyl) oxy]- 3- pyridine- carboxylate

The title compound was prepared by following the procedure described in Preparation 6, but using 1-methyl-3-azetidinol instead of 1-methyl-3-pyrrolidinol. Production 18

4-[(l- methyl- 3- pyrrolidinyl) oxy]- 3- pyridine- carboxylic acid sodium salt

4-Chloropyridine was reacted with diisopropyllithium amide and carbon dioxide to form the lithium salt of 3-carboxy-4-chloropyridine which was then reacted with 1-methyl-3-pyrrolidinol as described in Preparation 6.

Production 19

3-[(1-methyl-3-pyrrolidinyl)oxy]-2-pyridinecarbonitrile fumarate 2-carboxamide-3-hydroxypyridine was reacted with

Cl

j?-P=o using 2-cyano-3-chloropyridine as then

Cl

was reacted with 1-methyl-3-pyrrolidinol as described in Preparation 12 to form the title compound. Production 2 0

l- methyl- 3- pyrrolidinethioacetate (ester) ethanedioate

To a solution of 101 g (1 mol) 1-methyl-3-pyrrolidinol and 110 g (1.1 mol) triethylamine in 700 ml dry benzene, 115 g (1 mol) methanesulfonyl chloride was added dropwise while stirring and while cooling with ice bath. The resulting mixture was stirred for 1/2 hour and was filtered. The filtrate was concentrated on a rotary evaporator to approx. 200 ml, taking care that no overheating occurred. The residue was dissolved in 150 ml of ethanol.

In a separate vessel, 25.3 g (1.1 mol) of sodium were dissolved in 800 ml of ethanol under a nitrogen purge.

After dissolution was complete, 83.6 g (1.1 mol) of thiolacetic acid was added slowly and the resulting solution was stirred for an additional 10 minutes.

The above-prepared ethanolic solution of methanesulfonate was added, and the resulting solution was heated to 60°C for 20 hours. The mixture was cooled to 25°C and filtered, and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in isopropyl ether and the mixture was filtered to remove a small amount of solid material. The filtrate was concentrated and the residue distilled to give 70 g of the free title ester base, m.p. 95 - 105/15 mm.

A 7 g portion of the free base was treated with 4 g of oxalic acid in isopropyl alcohol, and the resulting salt was recrystallized from isopropyl alcohol to give 8.4 g of the title compound, m.p. 108 - 111° C.

Production 21

1- methyl- 3- pyrrolidinethiol oxalate

A solution of 62 g (0.39 mol) of 1-methyl-3-pyrrolidinethiolacetate (ester) in 200 ml of absolute methanol was treated with a 2 mm ball of sodium, and the resulting solution was distilled at 1 atmosphere of pressure at a pan temperature of 100° C. Vacuum was switched on and the pressure was slowly set to 100 mm. The residue was distilled at a temperature of 130°C to give 25 g (56%) of distillate with a boiling point of 95-100°C/100mm which was the free base of the title compound. A 4 g sample was treated with oxalic acid in isopropyl alcohol, forming 5.5 g of the oxalate salt with a melting point of 80 - 82°C.

Production 22

2- [(l- methyl- 3- pyrrolidinyl) thio]- 3- pyridine- carboxylic acid

To a stirred suspension of 80 g (2 mol) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylformamide, the whole heated to 60° C and using nitrogen as the purge gas, was added dropwise one solution of 157.0 g ( 1 mol) of 2-chloronicotinic acid and 117 g (1 mol) of 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a rate sufficient to maintain a temperature of 60-67°C. The mixture was heated to 65°C in 6 hours and was allowed to stand

overnight at room temperature and was then filtered.

The collected solid was suspended in 1 liter of isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a pH of 6.2 was achieved. The mixture was brought to a boil and was filtered. The solid material was dissolved in 2 liters of water and extracted with isopropyl ether. The pH was adjusted to 6.0 and the solution was concentrated to a volume of 800 ml and placed in a refrigerator. The resulting solid (95 g) collected by filtration was a mixture consisting of approx. 85% of the title compound and 15% sodium chloride. A sample of this was crystallized once from ethanol and twice from isopropyl alcohol-water. The recrystallized product was cleaved at approx. 225°C.

Production 23

Sodium 2-[(l-cyclohexyl-3-azetidinyl)oxy]- 3- pyridinecarboxylate

A solution of 105 g (0.68 mol) 1-cyclohexyl-3-azetidinol and 106 g (0.68 mol) 2-chloronicotinic acid in 400 ml dry dimethylformamide was added by rapid dropwise addition to 52 g (1.35 mol) 60 % sodium hydride/mineral oil suspended in 400 ml of dry dimethylformamide at 60° C. Mild exothermic reaction was observed. After stirring for 2 hours at 60°C, the mixture was filtered. The filter cake was washed with ethyl acetate and dried at 80°C/2 mm to give 174 g (86%) of the crude title compound.

Intermediate 1

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

To 54 g (1.35 mol) of sodium hydroxide in 800 ml of water was added 148 g (0.67 mol) of 2-[(1-methyl-3-pyrrolidinyl)oxy-benzamide, and the mixture was refluxed for 18 hours. The pH was adjusted to 7 with hydrochloric acid and the solution was filtered and concentrated. The residue was boiled with 400 ml of isopropanol and was filtered. The filtrate was concentrated and the residue (as crystallized) was boiled under reflux in 300 ml of thionyl chloride for 1/2 hour and was concentrated in vacuo. The residue was dissolved in 300 ml of chloroform and the solvent was evaporated off in vacuo. The residue was redissolved in chloroform, 150 ml of triethylamine was added and the mixture was refluxed for 1 hour. The solution was concentrated in vacuo and the residue was distributed between 400 ml of ethyl acetate, 400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. The organic layer was washed twice with water and once with dilute sodium hydroxide, dried with sodium sulfate and concentrated. The residue was crystallized from isopropanol-water. The yield of the product was 75 g (47%), m.p. 97 - 107° C.

Analysis: Calculated for C-^H-^NC^Cl:

C 60.13 H 5.89 N 5.84

Found : C 60.35 H 5.91 N 5.65

Intermediate product 2

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

To 85.7 g (0.29 mol) of 2-[(1-benzyl-3-pyrrolidinyl)-oxy]-benzoic acid was added 150 ml of thionyl chloride. The solution was allowed to stand for 15 minutes and was then refluxed for 30 minutes and concentrated in vacuo. The residue was treated twice with 250 ml of chloroform and was concentrated in vacuo. The residue was dissolved in 500 ml of chloroform and 101 g (1 mol) of triethylamine was slowly added with stirring. The solution was refluxed for 1 hour and concentrated in vacuo.

The residue was partitioned between 50% ethyl acetate-50% isopropyl ether and dilute hydrochloric acid. The organic layer was washed with dilute sodium hydroxide and concentrated. The residue was crystallized five times from isopropyl ether-ethyl acetate. The yield of the product was 23.8 g (26%), m.p. 145 - 147° C.

Analysis: Calculated for C-^gH^gNC^Cl:

C 68.46 H 5.74 N 4.44

Found : C 68.47 H 5.89 N 4.32

Intermediate product 3

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

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 and the mixture was heated to reflux for 1 6 hours. The pH was adjusted to 6.8 with concentrated hydrochloric acid, the solution was filtered and concentrated. The residue was boiled with 200 ml of isopropyl alcohol and was filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in chloroform. 59g (0.50 mol) of thionyl chloride was added and the reaction mixture was heated to reflux for 4 hours. After cooling, 67 g (0.67 mol) of triethylamine were added dropwise. The mixture was washed sequentially twice with 3N hydrochloric acid, twice with water, twice with 10% sodium hydroxide, twice with water and was dried over magnesium sulfate. Evaporation of the chloroform under reduced pressure gave 44 g (58%) of a viscous dark brown oil. The material was purified by high pressure liquid chromatography (50/50 ethyl acetate/hexane) and recrystallized from isopropyl alcohol to form brown crystals, m.p. 101 - 102° C.

Analysis: Calculated for C^gH^gNC102

C 66.32 H 5.57 N 4.83

Found : C 66.19 H 5.63 N 4.77

Intermediate product 4

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

Hydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mol) of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate in 1 liter of chloroform until a pH of 6 was obtained. To the stirred mixture were added 350 g (1.34 mol) of triphenylphosphine and 350 g (2.3 mol) of carbon tetrachloride, and the resulting clear solution was stirred at reflux temperature for 1.5 hours. About 100 ml of ethanol was added and the heat was removed. The solution was stirred for 1 hour under cooling and 200 ml of isooctane was added. The solution was extracted four times with a total of 800 ml of dilute hydrochloric acid. The acid extracts were combined, basified with sodium hydroxide and extracted with chloroform. The chloroform layer was separated and dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether, and was acidified with ether

hydrogen chloride. The resulting crystals weighed 82 g

(49%) . A portion was recrystallized from isopropyl alcohol, m.p. 149 - 153° C.

Analysis: Calculated for C^H-^^C^C^ :

C 47.67 H 5.09 N 10.11

Found: C 47.57 H 5.18 N 10.oo

Intermediate 5

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) sodium hydroxide in 150 ml ml water was added 32 g (0.13 mol) 4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture was heated to reflux for 24 h. The reaction mixture was adjusted to pH 6 with concentrated hydrochloric acid and was filtered, and the filtrate was concentrated. The residue was boiled with 100 ml of isopropyl alcohol and the mixture was filtered. The filtrate was concentrated and heated at reflux with 98 g (0.83 mol) of thionyl chloride for 1 hour.

Excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 70 ml of chloroform and the solvent was evaporated under reduced pressure. The residue was dissolved in 75 ml of chloroform and 40 ml of triethylamine was gradually added. The mixture was heated to reflux for 1 hour. The solvent was evaporated under reduced pressure to give a dark brown solid. The solid 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. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of a dark brown solid. The solid was recrystallized from isopropyl alcohol to give the title compound, m.p. 85 - 87° C. Analysis: Calculated for C12Hi3NC12°2: C 52.57 H 4.78 N 5.11

Found : C 52.57 H 4.77 N 5.04

Intermediate 6

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

To a solution of 9.6 g (0.24 mol) of sodium hydroxide in 200 ml of water was added 37 g (0.12 mol) of 5-bromo-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated under reflux for 18 h. The pH of the mixture was adjusted to 6.7 with concentrated hydrochloric acid solution. The solution was concentrated under reduced pressure and the residue was boiled in 250 ml of isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in chloroform, and 28.3 g (0.24 mol) of thionyl chloride was added to the solution. The mixture was heated to reflux for 1/2 hour and was cooled to 15° C. using an ice bath. To the mixture was added dropwise 26.6 g (0.25 mol) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction mixture was stirred at room temperature for 1 hour, then was washed with 3N hydrochloric acid, 15% aqueous sodium hydroxide and water . The chloroform layer was dried over magnesium sulfate and concentrated under reduced pressure to give 23 g (60%) of a brown solid.

A portion of the solid material was recrystallized from ethyl acetate-isopropyl ether, m.p. 92 - 94° C.

Analysis: Calculated for C12H]_3NBrCl°2 :

C 45.24 H 4.11 N 4.40

Found : C 45.61 H 4.17 N 4.42

Intermediate product 7

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

Hydrogen chloride was bubbled through a solution of 113 g (0.44 mol) of 5-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide dissolved in 500 ml of glacial acetic acid for 15 minutes while the reaction mixture was cooled with an ice bath . 142 g (1.38 mol) of butyl nitrite was then added in one portion and the reaction mixture was stirred at room temperature for 16 hours and was heated to reflux for an additional 6 hours. The acetic acid was evaporated under reduced pressure, tetrachloroethane was added twice to the residue and evaporated.

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

A sample of this residue was purified on a silica gel column using ethyl acetate as eluent. Recrystallization from isopropyl alcohol gave beige crystals, m.p. 101 - 103°C.

Analysis: Calculated for C12<H>^3NC12°2<:>

C 52.57 H 4.78 N 5.11

Found: C 52.63 H 4.83 N 5.05

Intermediate 8

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

Hydrogen chloride gas was bubbled into a solution of 8 g (0.03 mol) 1-[(1-methyl-3-pyrrolidinyl)oxy]-2-naphthalenecar-. boxamide in 40 ml of acetic acid for 2 minutes. The solution was cooled with an ice bath and 6.1 g (0.06 mol) of n-butyl nitrite was slowly added below the surface of the liquid at 12-15°C (approx.

10 minutes were required). The solution was stirred at 25°C

for 18 hours and was heated on a steam bath for 3 hours. The solution was concentrated on a rotary evaporator. The residue was dissolved in 60 ml of 1,1,2,2-tetrachloroethane which was removed on the rotary evaporator at 0.5 mm/steam temperature.

The residue was dissolved in 75 ml of chloroform and was treated with 7 g (0.06 mol) of thionyl chloride and refluxed for 12 hours. The solution was extracted with water (tested acidic) followed by dilute sodium hydroxide, dried over sodium sulfate and concentrated. The residue was crystallized twice from isopropyl ether-ethyl acetate. The yield of the product was 3.2 g (37%), m.p. 109 - 111° C. Analysis: Calculated for C^gH^gNC^Cl: C 66.32 H 5.57 N 4.84

Found : C 66.15 H 5.56 N 4.76

Intermediate period 9

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

To a solution of 19.2 g (0.48 mol) of sodium hydroxide in 500 ml of water was added 60 g (0.24 mol) of 5-methoxy-2-[(1--methyl-3-pyrrolidinyl)oxy]- benzamide, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled and the pH was adjusted to 6.8 with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was boiled in isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 500 ml of chloroform, and 114 g (0.36 mol) of triethylamine was added to this solution. The mixture was heated to reflux for 48 hours and then cooled in an ice/acetone bath. 97 g was added dropwise to the mixture

(0.96 mol) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction solution was washed successively with water, 3N hydrochloric acid, water, 15% aqueous sodium hydroxide and water, and was finally dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a black solid. The solid was purified on a silica gel column using ethyl acetate as eluent to give 15 g (23%) of beige product, m.p. 98 - 100° C.

Analysis: Calculated for C-^ ^H-^NClO-j:

C 57.89 H 5.98 N 5.19

Found : C 57.53 H 6.00 N 5.16

Intermediate 10

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

A mixture of 18.5 g (0.0834 mol) phosphorus pentasulfide and 18.5 g potassium sulfide was ground together and added to a solution of 100 g (0.417 mol) 2-(2-chloroethyl)-2,3-dihydro-4 -methyl-1,4-benzoxazepin-5(4H)-one in dry toluene, and the mixture was refluxed for 24 hours and filtered. The filtrate was concentrated and partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was concentrated and

the residue was crystallized several times from ethanol. Yield-

of the product was 55 g (52%), m.p. 105 - 108° C. Analysis: Calculated for C12H14NS0C1: C 56.35 H 5.52 N 5.48 S 12.54 Found : C 56.55 H 5.4 7 N 5.4 9 S 12.55 Intermediate 11 2-( 2- Chloroethyl)- 2, 3- dihydro- 4- methylpyrido[ 3, 2- f] [ 1, 4j-oxazepin- 5( 4H)- thione To a solution of 59 g (0.25 mol) 2 -(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride in 1500 ml of chloroform was added 41.5 g (0 .19 mol) of phosphorus pentasulfide, and the mixture was heated to reflux for 18 hours. The mixture was filtered and the filtrate was extracted with dilute sodium hydroxide. The chloroform layer was concentrated and the residue was dissolved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g (44%) of a yellow solid precipitated. Part of this was recrystallized from isopropyl alcohol, m.p. 134 - 136° C. Analysis: Calculated for C-j^H-^N^lOS: C 51.46 H 5.10 N 10.81

Found : C 51.35 H 5.21 N 10.72

Intermediate 12

2-( 2- chloro thyl)- 2, 3- dihydro- 4- methylnaphtho[ 2, 3- fJ [ 1, 4] oxazepine- 5( 4H)- thione

To a solution of 16.6 g (0.06 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepine-5(4H)- on in 150 ml of dry toluene was added to a mixture of 8.6 g (0.045 mol) phosphorus pentasulphide and 8.6 g potassium sulphide which had been ground together. The reaction mixture was stirred and heated to reflux for 24 hours. The mixture was filtered hot and the filtrate was concentrated under reduced pressure. A yellow solid, 6.5 g (35%), was obtained which was recrystallized from ethanol, m.p. 166 - 168° C.

Analysis: Calculated for C-^H-^gNClOS:

C 62.84 H 5.27 N 4.58

Found : C 62.29 H 5.48 N 4.47

Intermediate 13

8- chloro- 2-( 2- chloroethyl)- 2, 3- dihydro- 4- methyl- 1, 4- benzoxazepine-5( 4H)- thione

To a solution of 43 g (0.16 mol) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 400 ml of dry toluene was added to a mixture of 23 g (0.12 mol) of phosphorus pentasulfide and 23 g of potassium sulfide which had been ground together. The reaction mixture was stirred and heated to reflux 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 on standing at room temperature. The solid was recrystallized from ethanol, m.p. 105 - 106° C.

Analysis: Calculated for C^2H]_3NC12OS :

C 49.66 H 4.52 N 4.83

Found : C 4 9.63 H 4.53 N 4.75

Intermediate 14

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

To a solution of 11.0 g (0.035 mol) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxapin-5(4H)-one in 150 ml of dry toluene was added to a mixture of 13.4 g (0.07 mol) of phosphorus pentasulfide and 13.4 g of potassium sulfide which had been ground together. The reaction mixture was heated to reflux for 5 hours under a nitrogen atmosphere. The mixture was filtered hot and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed twice with dilute aqueous sodium hydroxide, dried over magnesium sulfate and reduced under reduced pressure to give 8.5 g (72%) of a yellow solid. The solid was recrystallized from ethanol, m.p. 118 - 120° C.

Analysis: Calculated for C-^2H2.3NBrC10S:

C 43.07 H 3.92 N 4.18

Found : C 43.08 H 3.88 N 4.12

Intermediate 15

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

A mixture of 9.55 g of phosphorus pentasulfide and 9.5 g of potassium sulfate was ground together and added to a solution of 20.2 g (0.07 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth th-[2 ,1-f ] [ 1 , 4 ] oxazepin-5 (4H)-one in 200 ml of dry toluene. The mixture was stirred and heated to reflux for 7 hours. The hot reaction mixture was filtered and the product was crystallized from the cooled filtrate. Recrystallization from chloroform gave 18 g (84%) of yellow crystals, m.p. 167 - 170° C.

Analysis: Calculated for Cl6H16NClOS:

C 62.84 H 5.27 N 4.58

Found : C 62.85 H 5.20 N 4.55

Intermediate 16

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

A 49 g (0.11 mol/ sample) of 3-[(1-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile fumarate [1:2] was partitioned between chloroform and a saturated solution of potassium carbonate. The aqueous layer was extracted twice with chloroform. All chloroform extracts were combined, dried and concentrated. The residue was dissolved in 125 ml of t-butanol and added to 34 g (0.6 mol) of potassium hydroxide pellets. The mixture was stirred at room temperature for 88 hours and then diluted with 150 ml of toluene. This mixture was filtered and the filtrate was concentrated. The residue was dissolved in chloroform under cooling, and the pH was adjusted to 6.0 with hydrogen chloride gas. The resulting mixture was concentrated and 400 ml of dry toluene was added to the residue. The toluene was removed on a rotary evaporator (vapor heat/reduced pressure) to remove water. The residue was dissolved in 400 mL of chloroform and 63 g of triphenylphosphine was added followed by 70 g of carbon tetrachloride. The solution was stirred at the reflux temperature for 2 hours and additional re 30 g of triphenylphosphine was added. After a further 1 hour of reflux, a further 70 g of carbon tetrachloride and 63 g of triphenylphosphine were added and the mixture was refluxed for 4 hours. The solution was extracted with dilute sodium hydroxide and then concentrated. The residue was partitioned between toluene and dilute hydrochloric acid. The toluene layer was extracted five times with dilute hydrochloric acid. The acid extracts were combined, basified with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and concentrated. The residue was chromatographed on a 7 x 25 cm column of silica gel with acetone as the liquid phase. The free base of the title compound isolated after evaporation amounted to 5.8 g

(20%). To a portion of the free base dissolved in isopropyl alcohol, ethereal hydrogen chloride and isopropyl ether were added.

The resulting crystals were collected and dried, m.p.

188 - 190° C.

Analysis: Calculated for C^^H^^N202Cl2:

C 47.67 H 5.09 N 10.11

Found : C 48.33 H 5.22 N 9.73

Intermediate 17

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

In the procedure described under Intermediate 4, equal molar amounts of sodium 4-[(l-methyl-3-pyrrolidinyl)-oxy]-3-pyridinecarboxylate were used instead of 2-[(l-methyl-3-pyrrolidinyl)oxy]- 4-pyridinecarboxylic acid to form the title compound.

Intermediate 18

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

In the procedure described under Intermediate 16, 3-[(l-methyl-3-pyrrolidinyl)oxy]-2-pyridinecarbonitrile fumarate was used instead of 3-[(l-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile fumarate to form the title compound . Intermediate 19

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

To a solution of 20 g (0.07 mol) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 200 ml of toluene was added to a mixture of 9.55 g (0.05 mol) of phosphorus pentasulphide and 9.5 g of potassium sulphide which had been ground together. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow solid. Recrystallization from absolute ethanol gave 12.5 g (68%) of the product, m.p. 102 - 104° C.

Analysis: Calculated for C12H13NCI2OS:

C 49.66 H 4.52 N 4.83

Found : C 4 9.62 H 4.55 N 4.76

Intermediate 2 0

2-( 2- chloroethyl)- 7, 9- diiodo- 2, 3- dihydro- 4- methyl- 1, 4- benzoxa-pin- 5 ( 4H)- one

When in the procedure indicated during the preparation of Intermediate 1, 3,5-diiodo-2-[(1-methyl-3-pyrrolidinyl)-oxy]-benzamide was used instead of 2-[(1-methyl-3-pyrrolidinyl)oxy ]benzamide, the title compound was prepared. Intermediate product 21

2- chloromethyl- 2, 3- dihydro- 4- methylpyrido[ 3, 2- f][ 1, 4] oxazepine-5 ( 4H)- hydrochloride

When, in the procedure described during the preparation of Intermediate 4, an equal molar amount of sodium 2-[(l-methyl-3-azetidinyl)oxy]-3-pyridine carboxylate sodium acetate was used instead of sodium 2-[(l -methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate, the title compound was prepared. Intermediate 2 2

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

A solution of 5 g (0.021 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepin-5(4H)-one and 5, 1 g (0.0126 mol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiodiphosphetane-2,4-disulfide in 100 ml of dry toluene was stirred under reflux for 2.5 hour. The solution was cooled and extracted three times with sodium bicarbonate solution. The toluene layer was dried over sodium sulfate and concentrated. The residue was chromatographed (high pressure liquid chromatography) using a silica column and ethyl acetate liquid phase. The fraction containing the product was concentrated by evaporation and the residue was crystallized from ethyl alcohol to give 0.6 g (11%) of the title compound.

Intermediate 2 3

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

To a solution of 10.3 g (0.04 mol) 2-(2-chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-one in 200 ml of chloroform was added to a mixture of 5.7 g (0.03 mol) of phosphorus pentasulphide and 5.7 g of potassium sulphide which had been ground together. The reaction mixture was stirred and heated to reflux under a nitrogen atmosphere for 5 hours. The mixture was filtered hot and the filtrate was concentrated under reduced pressure. The residue, an orange solid, was recrystallized from ethanol to give 7.4 g (65%)

of the product, m.p. 98 - 100° C.

Analysis: Calculated for C-^H^gNClC^S:

C 54.64 H 5.65 N 4.90

Found : C 54.57 H 5.6 7 N 4.58

Intermediate 24

When, in the procedure described during the preparation of Intermediate 2, equal molar amounts of the following compounds were used instead of 2-(l-benzyl-3-pyrrolidinyloxy)benzoic acid: 2-[(l-cyclohexyl-3-pyrrolidinyl)oxy]benzoic acid, 2 -[(l-ethyl-3-pyrrolidinyl)oxy]benzoic acid, 2-[(l-isopropyl-3-pyrrolidinyl)oxyJbenzoic acid, 2-[[(1-(4-chlorobenzyl)-3-pyrrolidinyl]oxy]benzoic acid, 2-[[1-(4-methylbenzyl)-3-pyrrolidinyl]oxy]benzoic acid, 2-[[1-(3,5-dimethoxybenzyl)-3-pyrrolidinyl]oxy]benzoic acid 2-[[1-(trifluoromethylbenzyl) -3-pyrrolidinyl]oxy]benzoic acid and 2-[[1-(4-nitrobenzyl)-3-pyrrolidinyl]oxy]benzoic acid, it was obtained: a) 2-(2-chloroethyl)-4-cyclohexyl-2,3 -dihydro-1,4-benzoxazepin-5-(4H)-one, b) 2-(2-chloroethyl)-2,3-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-one, c) 2-(2-chloroethyl)-2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5(4H)-one, d) 2-(2-chloroethyl)-4-(4-chlorobenzyl) -2,3-dihydro-1,4-benzoxazepin-5(4H)-one, e) 2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)-1, 4- ) benzoxazepin-5(4H)-one, f) 2-(2-chloroethyl)-2,3-dihydro-4-(3,5-dimethoxybenzyl)-1,4-benzoxazepin-5(4H)-one, g ) 2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)-1,4-benzoxazepin-5 (4H)-one h) 2-(2-chloroethyl)-2,3-dihydro -4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)-one.

Intermediate 25

When, in the procedure described during the preparation of Intermediate 4, equal molar amounts of the following compounds were used instead of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate: 2- [ (l -cyclohexyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate, 2-[(1-ethyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate, 2-[1-isopropyl-3-pyrrolidinyl)oxy] -3-pyridine carboxylate, 2-[[1-(4-chlorobenzyl)-3-pyrrolidinyl]oxy]-3-pyridine carboxylate, 2-[[1-(4-methylbenzyl)-3-pyrrolidinyl]oxy] -3-pyridine carboxylate, 2- [ [1-(4-methoxybenzyl)-3-pyrrolidinyl]oxy]-3-pyridinecarboxylate, 2-[[1-(3-trifluoromethylbenzyl)-3-pyrrolidinyl]oxy]-3 -pyridinecarboxylate, and 2-[[1-(4-nitrobenzyl)-3-pyrrolidinyl]oxy]-3-pyridinecarboxylate, it was obtained: a) 2-(2-chloroethyl)-4-cyclohexy1-2,3-dihydro- pyrido[3,2-f]-[1,4]oxazepin-5(4H)-one hydrochloride, b) 2-(2-chloroethyl)-2,3-dihydro-4-ethylpyrido[3,2-f ][1,4]-oxazepin-5(4H)-one hydrochloride, c) 2-(2-chloroethyl)-2,3-dihydro-4-isopropylpyrido[3,2-f][1,4]- oxazepin-5(4H)-one hydrochloride d, d) 2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydropyrido-[3,2-d][1,4]-oxazepin-5(4H)-one hydrochloride, e) 2-(2-chloroethyl)-2,3-dihydro-4 (4-methylbenzyl)-pyrido-[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride, f ) 2-(2-chloroethyl)-2,3-dihydro-4-(4-methoxybenzyl)pyrido-[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride, g) 2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)-pyrido[3,2-f][1,4]-5(4H)-one hydrochloride, and h) 2- (2-Chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)pyrido)-[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride.

Intermediate 26

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

A mixture of 80.75 g (0.34 mol) of 2-[(1-methyl-3-pyrrolidinyl)thio]-3-pyridinecarboxylic acid, 500 ml of chloroform, 200 g of carbon tetrachloride and 178 g (0.68 mol) of triphenylphosphine was stirred at the reflux temperature for 2.5 hours. The resulting solution was extracted with one 500 mL and three 125 mL portions of 1N hydrochloric acid. The acid extracts were combined and extracted with isopropyl ether. The aqueous layer was basified with sodium hydroxide and extracted three times with chloroform. The combined chloroform extract was dried over sodium sulfate and concentrated. A portion of the residue was chromatographed on the high pressure liquid chromatograph using a silica column and ethyl acetate. The compound obtained was crystallized from isopropyl ether-isopropyl alcohol, m.p. 97 - 100° C.

Analysis: Calculated for C-^H-^^OSCl:

C 51.46 H 5.10 N 10.91

Found : C 51.63 H 5.12 N 10.85

Intermediate 2 7

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

A mixture of 4.3 g (0.017 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepin-5(4H)-one,

100 ml of toluene and 4.8 g (0.012 mol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphethane-2,4-disulfide were refluxed for 3 hours and then > ^extracted twice with dilute sodium hydroxide. The organic layer was concentrated and the residue was chromatographed on high pressure liquid chromatography using a silica column and 50% ethyl acetate-50% hexane. The yield of the title compound was 2 g, m.p. 160 - 162° C.

Analysis: Calculated for C^H12N2S2C-'-:

C 48.43 H 4.80 N 10.27

Found : C 4 8.46 H 4.81 N 10.51

Intermediate 2 8

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

A solution of 78 g (0.5 mol) 4-chloronicotinic acid and 52 g (0.52 mol) 1-methylpyrrolidinol in 150 ml dimethylformamide was added to a suspension of 44 g (1.1 mol) 60% sodium hydride/mineral oil in 800 ml of dimethylformamide at such a rate that the temperature was maintained at 55 - 70°C (preheated to 55°C). The resulting mixture was heated to 60°C for 4 hours and filtered hot. The filtrate was concentrated on a rotary evaporator (5 mm/water vapor temperature). The residue was dissolved in 600 ml of water and was extracted with isopropyl ether. The pH of the aqueous layer was adjusted to 6 with hydrochloric acid and the solution was concentrated on the rotary evaporator (5 mm/steam bath). The residue was suspended in 800 ml of chloroform and 188 g (1.1 mol) of triphenylphosphine was added followed by 250 ml of carbon tetrachloride. The mixture was gently heated to 60°C whereupon the reaction became exothermic and an ice bath was used to maintain the temperature at 60-65°C for 20 minutes. The ice bath was removed and the mixture was heated to reflux for 3.5 hours and cooled. The solution was extracted with 600 ml water followed by two 200 ml<1>s portions of 1N hydrochloric acid. The hydrochloric acid layer was basified with sodium hydroxide and extracted three times with chloroform. The chloroform was concentrated and the residue was chromatographed by high pressure liquid chromatography using silica gel and ethyl acetate as eluent. The yield of the product was 30 g (25%). The mass spectrum and NMR are consistent with the structure of the title compound.

Intermediate 2 9 2-( 2- chloroethyl)- 2, 3- dihydro- 4- methylpyrido[ 3, 4- f][ 1, 4] oxazepine- 5 ( 4H)- thione- monohydrochloride

15 g (0.06 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one was dissolved in 200 ml dry toluene and 15 g (0.037 mol) [2,4-bis-(4-methoxyphenyl)-1.3.2.4-dithiaphosphethane-2,4-disulfide were added. The mixture was refluxed for 2.5 hours and the toluene solution was decanted. The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried and concentrated. The residue was chromatographed on a high pressure liquid chromatograph (Waters 500) using a silica column and using ethyl acetate as eluent. The fraction containing material with molecular weight 2 57 was concentrated. The residue in isopropyl alcohol was treated with hydrogen chloride, and the resulting crystals were collected. Yield of the hydrochloride salt was 0.1 g (0.6 %),

sm.p. 168 - 171° C.

Analysis: Calculated for C-^H-^^OSC^ :

C 45.06 H 4.81 N 9.55

Found : C 45.15 H 4.98 N 9.26

Intermediate 30

2. 3. 4. 5- tetrahydro- 4- methyl- 5- oxopyrido[ 3, 2- f] [ 1, 4] oxazepine-2- propanenitrile

100 g (0.415 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride was distributed between 200 ml dilute aqueous sodium hydroxide and 200 ml of chloroform. The organic layer was separated and the aqueous layer was extracted with 3 x 50 ml chloroform. The organic layers were combined, dried over sodium sulfate and concentrated on a rotary evaporator (70° C., water aspirator). The residue, the free base of the hydrochloride starting material, 89 g (0.37 mol) was dissolved in 150 ml of toluene and to the solution was added 9 g (0.027 mol) of tetrabutylammonium bromide. 100 ml of saturated aqueous potassium cyanide was then added and the mixture was stirred mechanically at the reflux temperature. After 2 hours an additional 3 g (0.009 mol) of tetrabutylammonium cyanide was added and 20 ml of saturated aqueous sodium cyanide was added and the mixture was stirred for 3/4 hour at the reflux temperature. The contents of the reaction vessel were extracted with 3 x 50 ml of ethyl acetate. (Note that chloroform can be used instead). The organic layer was dried over sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator) to 1/3 of the original volume. When cooling started

the crystallization. The crystals were filtered and washed with several portions of ethyl acetate and isopropyl ether. 30 g (35%) off-white crystals were collected, m.p. 104 — 105° C. A sample was recrystallized from ethyl acetate, m.p. 104 - 105° C.

Analysis: Calculated for C^H-^N^C^ :

C 62.33 H 5.67 N 18.17

Found : C 62.06 H 5.65 N 17.97

Intermediate 31

2-( 2- chloroethyl)- 4- ethyl- 2, 3- dihydropyrido[ 3, 2- f][ 1, 4] oxazepin- 5 ( 4H)- one- hydrochloride

To a stirred suspension of sodium hydride mineral oil (81.45 g of 60% dispersion, 2.036 mol) in 500 ml of dimethyl sulfoxide heated to 50° C. was added dropwise a solution of 142 g (0.905 mol) of 2-chloronicotinic acid and 99 g (0.86 mol) of N-ethyl-2-pyrrolidinol in 500 ml of dimethylsulfoxyd

o

at a rate sufficient to maintain 55-60 C (occasionally cooling was required). After the addition was complete, the mixture was stirred at 50-60°C for 1.5 hours and then allowed to cool. The solid material that precipitates was filtered, washed with ethyl acetate and dried.

172.53 g (0.62 mol) of the dry sodium salt was suspended in 1 liter of chloroform. Hydrogen chloride gas was bubbled through the suspension until the pH read 5.76. 365.5 g (1.395 mol) of triphenylphosphine and 365.5 g of CCl 4 were added and the mixture was stirred at the reflux temperature. After 45 minutes, IR showed 95% turnover. Additional 100 g

(0.38 mol) of triphenylphosphine and 100 g of CCl 4 were added and the solution was stirred at the reflux temperature for an additional 45 minutes. IR showed more than 99% turnover. After cooling, the solution was extracted several times with dilute hydrochloric acid (1.5 liters in total). The aqueous layer was then basified with concentrated sodium hydroxide solution and extracted 3 x 250 ml chloroform. The organic layer was dried over sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The residual oil was dissolved in 500 ml isopropyl alcohol and acidified with hydrogen chloride gas. On cooling, an oil was observed and the vol

was reduced to 1/3 of the original volume. On cooling, 70 g (0.241 mol, 28%) of light brown crystals were collected, m.p. 153 - 155° C.

Analysis: Calculated for C-^H^g^C^C^ :

C 49.50 H 5.53 N 9.62

Found : C 49.64 H 5.62 N 9.32

Intermediate 32

2-( 2- chloroethyl)- 4- ethyl- 2, 3- dihydropyrido[ 3, 2- f][ 1, 4] oxazepine- 5( 4H)- thione- hydrochloride

About. 50 g of 2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido-[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride was distributed between 50 ml of dilute aqueous sodium hydroxide and 50 ml of chloroform. The organic layer was saved and the aqueous layer was extracted with an additional 2 x 50 mL of methylene chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated by rotary evaporation (70°C, water aspirator) to give 39 g (0.153 mol) of the free base. The free base thus obtained was dissolved in 1.2 liters of chloroform and 33.9 g (0.153 mol) of phosphorus pentasulphide was added with stirring. The resulting mixture was heated to reflux for 16 hours. After cooling, the reaction mixture was filtered, washed with dilute aqueous sodium hydroxide (3 x 300 mL), dried over sodium sulfate, and concentrated by rotary evaporation (70° C., water aspirator) to give a yellow viscous oil. The oil was taken up in isopropyl alcohol (ca. 200 ml) and acidified with hydrogen chloride gas. After cooling, 20 g (43%) of crystals were collected, m.p. 133 - 135° C.

Analysis: Calculated for C-L2H1gN20scl2:

C 46.91 H 5.25 N 9.12

Found : C 47.33 H 5.38 N 9.10

Intermediate 33

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

A sample of 10 g (136 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5-(4H)-one hydrochloride was dissolved in 150 ml of dimethylformamide and heated to reflux. 20 g (0.148 mol) of sulfuryl chloride was then added dropwise over 40-50 minutes. The reaction mixture was stirred at the reflux temperature for 30 minutes followed by the addition of SC₂CT₂. After cooling, the contents of the flask were distributed between 150 ml of water and 150 ml of benzene. The benzene layer was saved and the aqueous layer was extracted with an additional 2 x 50 mL of benzene. The benzene extracts were combined and washed with 2 x 50 ml dilute aqueous potassium hydroxide followed by 2 x 50 ml dilute aqueous hydrochloric acid. The benzene layer was dried over sodium sulfate and concentrated by rotary evaporation (approx. 70° C., water aspirator) to give 2.61 g of impure material.

The crude material was recrystallized from isopropyl ether to give 1.25 g (12.6%) of off-white crystals, m.p. 78 - 79° C.

Analysis: Calculated for C^H^2N2°2C-'-2 :

C 48.02 H 4.40 N 10.18

Found : C 48.07 H 4.53 N 10.10

Intermediate 3 4

7- chloro- 2-( 2- chloroethyl)- 2, 3- dihydro- 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]oxazepin-5(4H)-one was suspended in 200 ml of toluene. To this suspension was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. The mixture was heated to reflux with vigorous stirring for 2 hours. Because the reaction was not complete, a further 3.0 g of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and the mixture was stirred at the reflux temperature for 2 hours, and allowed to stand for 56 hours at room temperature. The toluene layer was decanted and washed with 50 ml of dilute aqueous sodium hydroxide and 50 ml of dilute hydrochloric acid. The toluene was removed by rotary evaporation (approx. 80° C, water aspirator). The crude oil was recrystallized from isopropyl alcohol to give 3.5 g

(54%) of light yellow crystals, m.p. 125 - 127° C.

Analysis: Calculated for C11H^2N2OSC12:

C 45.37 H 4.15 N 9.62

Found : C 45.40 H 4.20 N 9.71

Intermediate 35

2-(chloromethyl)- 4- cyclohexyl- 2, 3- dihydropyrido[ 3, 2-f][ 1, 4]-oxazepin- 5( 4H)- one

A 15 g (0.05 mol) sample of sodium 2-[(1-cyclohexyl-3-azetidinyl)oxy]-3-pyridine carboxylate obtained in Preparation 23 was suspended in 100 ml of chloroform and hydrogen chloride was bubbled through the solution until a pH of 5.8 remained stable. 18 g of thionyl chloride were added to the stirred mixture. The resulting solution was stirred at room temperature for 3 hours. An IR spectrum showed a peak at 1770 cm^ which is characteristic of acid chloride. 40 ml of triethylamine was added dropwise while cooling to 25° C. with an ice bath. The chloroform solution was stirred for an additional 1/2 hour and was extracted with water, dried over sodium sulfate and concentrated. The residue was chromatographed on a 7 x 20 cm silica column using ethanol as eluent. The desired material was first removed from the column. The ethanolic solution was concentrated and the residue crystallized once from ethyl acetate-isopropyl ether and once from isopropyl alcohol. The yield of the title compound was lg (7%), m.p. 120 - 122°C. Analysis: Calculated for C^H^g^C^Cl: C 61.12 H 6.50 N 9.50

Found: C 61.11 H 6.62 N 9.32

Intermediate 36

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

The title compound was prepared in impure form i

first part of Example 67.

Example 1

2 -[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methyl- 1, 4^ benzoxazepine- 5( 4H)- one- hydrochloride

A solution of 9 g (0.2 mol) of dimethylamine in 250 ml of ethanol was added to 24 g (0.1 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine -5(4H)-one in a steel bomb. The mixture was heated at 100°C for 18 hours. The solution

was concentrated in vacuo and the residue partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate layer

was concentrated and the residue consisting mainly of the free base of the title compound was dissolved in methyl isobutyl ketone-isopropanol mixture. The solution was acidified with hydrogen chloride gas to form the title compound, m.p. 188 - 197° C.

Example 2

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

All of the hydrochloride salt obtained in Example 1 was partitioned between chloroform and dilute sodium hydroxide and the chloroform layer was concentrated. The residue was crystallized several times from isopropyl ether to give 6 g (21%) of the free base, m.p. 56 - 76° C.

Analysis: Calculated for ci4<H>2<0N>2°2<:>

C 67.72 H 8.12 N 11.28

Found : C 67.35 H 8.16 N 11.09

Example 3

2, 3- dihydro- 4- methyl- 2-[ 2-( 4- morpholino) ethyl]- 1, 4- benzoxazepine- 5( 4H)- one- fumarate [ 1:1]

To 50 ml of morpholine was added 20 g (0.084 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one. The solution was refluxed for 5 hours and then concentrated in vacuo. The residue was dissolved in chloroform and the solution was washed with dilute sodium hydroxide, dried over sodium sulfate and concentrated in vacuo. The residue consisting mainly of the free base of the title compound was reacted with 10.5 g (0.09 mol) of fumaric acid in isopropanol-water. The resulting solid was recrystallized from isopropanol-water to give 21.5 g (64%), m.p. 199 - 201° C.

Analysis: Calculated for C2oH26<N>2°7<:>

C 59.10 H 6.45 N 6.89

Found : C 58.95 H 6.52 N 6.88

Example 4

4- benzyl- 2, 3- dihydro- 2-[ 2 -( 4- morpholino) 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 and chloroform. The chloroform layer was dried over sodium sulfate and concentrated in vacuo. The solid obtained was recrystallized from isopropyl ether-ethyl acetate three times, yielding 15.2 g of solid (43%), m.p. 97 - 99° C.

Analysis: Calculated for C22H26N2°3:

C 72.10 H 7.15 N 7.64

Found : C 72.25 H 7.22 N 7.64

Example 5

4- benzyl- 2, 3- dihydro- 2-[ 2-( methylamino)- 3- ethyl]- 1, 4- benzoxazepine- 5( 4H)- one- fumarate [ 1:1]

A solution of 7.95 g (0.19 mol) of monomethylamine in 200 ml of ethanol was added to 30 g (0.095 mol) of 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4 -benzoxazepin-5 (4H)-one in a steel bomb. The mixture was heated to 100°C for 16 hours. The solution was concentrated in vacuo and the residue partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was concentrated and the residue, consisting mainly of the free base of the title compound, was dissolved in isopropanol and reacted with fumaric acid to form the fumarate. The salt was dried under vacuum at 100°C until entrapped isopropyl alcohol was removed, m.p. 178 - 181° C.

Analysis: Calculated for C2 3H26N2°6:

C 64.77 H 6.15 N 6.57

Found : C 64.87 H 6.20 N 6.62

Example 6

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methyl- 1, 4- benzoxazepine- 5( 4H)- thione- hydrochloride [ 1:1]

To a solution of 7.2 g (0.16 mol) dimethylamine in 350 ml absolute ethanol was added 20.4 g (0.08 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methyl- 1,4-benzoxazepine-5(4H)-thione. The solution was heated in a steel bomb for 18 hours at 100°C and then concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated. The solid material consisting mainly of the free base of the title compound was reacted with hydrogen chloride gas in ethanol to form the hydrochloride salt. The salt was recrystallized from ethanol and dimethylformamide followed by three recrystallizations from ethanol, yielding 7.5 g

(28%), m.p. 233 - 236° C.

Analysis: Calculated for Cl4H21<N>2<S>OCl:

C 55.90 H 7.04 N 9.32

Found : C 55, 72 H 7.26 N 8.94

Example 7

4- benzyl- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 1, 4- benzoxazepine- 5( 4H)- one- monohydrate

Following the procedure described in Example 1, 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)-one and dimethylamine were reacted, and the free base of the title compound was obtained in the concentrated residue. Recrystallization from ethanol-water gave the product, m.p. 75 - 77° C. Analysis: Calculated for c2o<H>26<N>2°3: C 70.13 H 7.65 N 8.21

Found : C 70.02 H 7.53 N 8.25

Example 8

2, 3- dihydro- 4- methyl- 2-[ 2-( 4- morpholino) ethyl]- 1, 4- benzoxazepine- 5( 4H)- thione- hydrochloride [ 1:1]

A solution of 20.4 g (0.08 mol) of 2,3-dihydro-4-methyl-2-(2-chloroethyl)-1,4-benzoxazepin-5(4H)-thione in 60 ml of morpholine was boiled under refluxed for 5 hours and was then concentrated. The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried over sodium sulfate and concentrated to give a residue consisting mainly of the free base of the title compound. The hydrochloride salt was prepared in methyl isobutyl ketone-dimethylformamide solution with hydrogen chloride gas. The salt was recrystallized from ethanol-dimethylformamide to give 14 g of solid material (51%), m.p. 253 - 256° C. Analysis: Calculated for C^gH23N2S02Cl: C 56.04 H 6.76 N 8.17

Found : C 55.73 H 6.63 N 7.97

Example 9

2-[ 2-( dimethylamino) ethyl3- 2, 3- dihydro- 4- methylnaphtho[ 2, 3- f]-[ 1, 4]- oxazepin- 5( 4H)- one- oxalate [ 1:1]

A steel bomb was charged with 5.0 g (0.017 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphtho[2,3-f][1,4]oxazepin-5(4H)-one , 50 ml absolute ethanol and 3.78 g (0.034 mol) dimethylamine as a 40% aqueous solution. The bomb was heated to 100°C for 16 hours. Volatiles were removed under reduced pressure and the residue partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer was washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure to give 2.7 g (54%) of a viscous yellow 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 ethanol-water, m.p. 192 - 194° C.

Analysis: Calculated for ^<qI>^4^<0>(5<:>

C 61.84 H 6.23 N 7.21

Found : C 61.41 H 6.27 N 7.09

Example 10

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

To 90 g (0.8 mol) 40% aqueous dimethylamine i

to a steel bomb was added 25 g (0.09 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one -hydrochloride. The mixture was heated to 100°C for 15 hours with gentle stirring. The mixture was partitioned using dilute sodium hydroxide and two chloroform extractions. The chloroform layers were combined and concentrated. The residue consisting mainly of the free base of the title compound was dissolved in 200 ml of isopropyl alcohol and 9 g of oxalic acid was added. The oxalate salt was recrystallized from 95% ethanol to give 18 g. The oxalate salt was then converted to the free base by partitioning between chloroform and dilute sodium hydroxide, and evaporating the chloroform layer. The residue, the free base of the title compound, was dissolved in isopropyl alcohol and treated with fumaric acid to give 13 g of a white solid (34%), m.p. 146 - 148° C.

Analysis: Calculated for C^<gH>^<N>^Og:

C 53.90 H 5.90 N 9.92

Found : C 53.76 H 6.02 N 9.96

Example 11

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido[ 3, 2-f]-[ 1, 4]- oxazepine- 5( 4H)- thione- fumarate [ 1:1], ethanol [2:1]

15 g (0.058 mol) of 2-(2-chloroethyl)-2,3-dihydro- 4-Methylpyrido-[3,2-f][1,4]-oxazepine-5(4H)-thione. The mixture was heated to 100°C for 18 hours with gentle stirring. The solution was cooled and partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated. The residue consisting mainly of the free base of the title compound was 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%) of product, mp 105 - 129° C. A 14 g sample of the salt was recrystallized from ethanol to give 10.5 g of yellow solid with m.p. 103 - 118° C. The NMR spectrum indicated that the crystals contained 1/2 mol of ethanol.

Analysis: Calculated for C36H52<N>6°11<S>2<:>

C 53.45 H 6.48 N 10.39

Found : C 53.07 H 6.53 N 10.23

Example 12

2- [ 2- ( dimethylamino) ethyl ]- 2 , 3- dihydro- 4- methylpyrido [ 3, 2- f ].-[ 1, 4]- oxazepine- 5( 4H)- thione- fumarate [ 1:1]

48.4 g (0.189 mol) 2-(2-chloroethyl)-2,3-dihydro- 4-Methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione. The mixture was heated to 100°C for 14 hours. The ethanol was removed in a rotary evaporator leaving some water in the residue. The residue was dissolved in 200 ml of methylene chloride and was washed with three 100 ml portions of 20% aqueous potassium carbonate solution. The combined aqueous layers were extracted with three 150 ml<1>s portions of methylene chloride. The methylene chloride solutions were combined and treated with bone charcoal. The bone char was filtered off and the filtrate was evaporated to form an oil. The oil was dissolved in 215 ml of isopropyl alcohol and the solution was heated to slow boiling. A solution of 21.9 g (0.19 mol) of fumaric acid in 150 ml of boiling methanol was added to the isopropyl alcohol solution. Crystalline solid material was obtained weighing 63.4 g (88%).

The solid was recrystallized from hot ethyl alcohol. The crystals were filtered off and triturated in isopropyl ether at room temperature and were again separated by filtration. After drying in a 1-vacuum oven overnight at 85° C, crystals were obtained in an amount of 72.45 g (79 m.p. 130 - 133° C.

Analysis: Calculated for C^H^N^O^S :

C 53.53 H 6.08 N 11.02

Found : C 53.23 H 6.11 N 10.64

Example 13

4- benzyl- 2, 3- dihydro- 2-[ 2-( 4- morpholino) ethyl]- 1, 4- benzoxazepine- 5( 4H)- thione

To a suspension of a finely ground mixture of 2.9 g (0.013 mol) of phosphorus pentasulfide and 2.9 g of potassium sulfide in 75 ml of dry toluene was added 12 g (0.033 mol) of 4-benzyl-2,3-dihydro-2-[2 -(4-morpholino)ethyl]-1,4-benzoxazepin-5(4H)-one. The mixture was stirred at the reflux temperature for 10 hours and was filtered. The filtrate was concentrated and the residue crystallized from isopropyl ether-toluene to give 2.54 g

(20%), m.p. 236 - 238° C.

Analysis: Calculated for C22H26N2(")2S:

C 69.08 H 6.85 N 7.32

Found : C 69.60 H 6.96 N 7.15

Example 14

2, 3- dihydro- 4- methyl- 2-[ 2-( methylamino) ethyl]- 1, 4- benzoxazepine- 5( 4H)- one- fumarate [ 1:1]

By following the procedure described in Example 5, 50 g (0.21 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one and 13, 0 g (0.42 mol) monomethylamine

(in 400 ml of ethanol) reacted to form the free base of the title compound which was reacted with fumaric acid, which after isolation and recrystallization from ethyl alcohol gave 17 g

(23%) of the title compound, m.p. 154 - 156° C.

Analysis: Calculated for C^^H22<N>2^6:

C 58.27 H 6.33 N 8.00

Found : C 58.34 H 6.52 N 7.82

Example 15

2, 3- dihydro- 4- methyl- 2-[ 2-( methylamino) ethyl]- 1, 4- benzoxa- z epin- 5 ( 4H)- one

2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]-1,4-benzoxazepin-5(4H)-one fumarate was converted back to the free base by partitioning into dilute sodium hydroxide and chloroform. Evaporation of the chloroform layer and distillation, bp 182°/0.2 mm, gave 4.3 g of the product.

Analysis: Calculated for C-^H-^<g>^<C>^<:>

C 66.64 H 7.74 N 11.96

Found : C 66.4 8 H 7.6 9 N 11.88

Example 16

2, 3- dihydro- 2-[ 2-( 4- hydroxy- 4- phenyl)- piperidinylethyl]- 4-methyl- 1, 4- benzoxazepine- 5( 4H)- thione (and hydrochloride salt)

A suspension of 10.7 g (0.078 mol) potassium carbonate, 13.7 g (0.078 mol) 4-hydroxy-4-phenylpiperidine and 19.8 g (0.078 mol) 2-(2-chloroethyl)-2,3-dihydro -4-methyl-1,4-benzoxazepine-5(4H)-thione in 200 ml of n-butanol was refluxed overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned in ethanol-ligroin and reacted with hydrogen chloride gas to form the hydrochloride salt, which was recrystallized from ethanol-dimethylformamide. The hydrochloride salt was converted back to the free base by partitioning into chloroform and dilute sodium hydroxide and evaporating the chloroform. Recrystallization twice from isopropyl alcohol gave 9.27 g (30%) of the free base product, m.p. 142 - 148° C.

Analysis: Calculated for C^^g^C^S:

C 69.66 H 7.12 N 7.07

Found : C 6 9.78 H 7.18 N 7.00

Example 17

2, 3- dihydro- 4- methyl- 2-[ 2-[ 1-( 4- phenyl- 1, 2, 3, 6- tetrahydro)-pyridinyl] ethyl]- 1, 4- benzoxazepine- 5 ( 4H) thione

A suspension of 24.3 g (0.176 mol) potassium carbonate, 11.5 g (0.059 mol) 4-phenyl-3,4-tetrahydropyridine and 15 g (0.059 mol) 2-(2-chloroethyl)-2,3-dihydro -4-methyl-1,4-benzoxazepin-5(4H)-thione and sufficient n-butanol to form a slurry was refluxed for 72 hours. The reaction mixture was filtered hot and the filtrate was cooled to room temperature and filtered again. The last filtrate was concentrated and the residue dissolved in ethyl acetate. The crystals obtained on cooling were recrystallized from ethyl acetate to form 7 g of product (31%), m.p. 153 - 155° C.

Analysis: Calculated for C23H2gN2OS:

C 72.98 H 6.92 N 7.40

Found : C 73.36 H 7.01 N 7.47

Example 18

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

A solution of 9.8 g (0.04 mol) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml absolute ethanol and 10 ml of a 40% aqueous solution of dimethylamine were mixed and heated in a steel bomb at 100° C. for 16 hours. The ethanol was evaporated under reduced pressure and the residue was dissolved in chloroform and partitioned with 10% sodium hydroxide solution. The chloroform layer was evaporated under reduced pressure to give an amorphous solid. The solid material was dissolved in 6N hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was basified with 50% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was evaporated under reduced pressure to give a viscous oil consisting mainly of the free base of the title compound which was dissolved in absolute ethanol and reacted with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol to give 30 g (25%) of product, m.p. 196 - 199° C.

Analysis: Calculated for C-^H-jqN2C12OS :

C 50.15 H 6.01 N 8.35 Found : C 50.15 H 6.18 N 8.07 Example 19 8- chloro- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4 - methyl-1,4-benzoxazepine-5(4H)-one-oxalate [1:1] A solution of 10 g (0.037 mol) 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4 -methyl-1,4-benzoxazepin-5(4H)-one in 50 ml absolute ethanol and 10 ml 40% aqueous solution of dimethylamine were mixed and heated in a steel bomb at 100° C. for 16 hours. The solution was concentrated under reduced pressure and the residue was dissolved in chloroform and partitioned with 15% sodium hydroxide (2 washes). The chloroform layer was dried over magnesium sulfate and evaporated under reduced pressure to give an oil consisting mainly of the free base of the title compound.

The oil was dissolved in absolute ethanol and reacted with oxalic acid. The oxalate salt was recrystallized from ethanol in an amount of 4 g (38%), m.p. 198 - 201°C.

Analysis: Calculated for C^gH2^N2C10g:

C 51.55 H 5.68 N 7.51

Found : C 51.07 H 5.69 N 7.43

Example 2 0

7- bromo- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methyl- 1, 4- benzoxazepine- 5( 4H)- one- oxalate [ 1:1]

To a solution of 3.0 g (0.01 mol) 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 50 ml of absolute ethanol was added to 2.2 ml of a 40% aqueous solution of dimethylamine. The reaction mixture was heated in a stainless steel bomb to 100°C for 16 hours, and was 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 acid layer was basified with 50% aqueous sodium hydroxide and extracted with chloroform. The chloroform was evaporated under reduced pressure to give 2.4 g (73%) of a viscous brown oil, 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 isopropyl alcohol/water to give the title salt, m.p. 192 - 194° C.

Analysis: Calculated for C-^H^O<g>Br^:

C 46.06 H 5.07 N 6.71

Found : C 46.00 H 5.10 N 6.68

Example 21

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylnaphtho[ 2, 1, f]-[ 1, 4] oxazepine- 5( 4H)- one- oxalate [ 1:1]

A solution of 8 g (0.028 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1f][1,4]oxazepin-5(4H)-one and 6,2 g of 40% dimethylamine (0.055 mol) in 100 ml of ethanol was heated in a steel bomb to 100° C. for 18 hours. The resulting solution was partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride layer was dried over sodium sulfate and concentrated. The residue consisting mainly of the free base of the title compound was dissolved in isopropyl alcohol and reacted with 2.6 g of oxalic acid. The oxalate salt obtained was recrystallized from isopropyl alcohol in water, m.p. 206 - 209° C.

Analysis: Calculated for C2oH24N2°6:

C 61.85 H 6.23 N 7.21

Found : C 61.61 H 6.26 N 7.13

Example 22

When, in the procedure described in Example 10, equal molar amounts of the following compounds are used instead of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-[1,4]- oxazepin-5(4H)-one hydrochloride: 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]- oxazepin-5(4H)-one hydrochloride, 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]- oxazepin-5(4H)-one hydrochloride and 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[2,3-f][1,4]- oxazepin-5-(4H)-one hydrochloride is obtained: 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido- [4,3-f][1,4]-oxazepin-5(4H)-one fumarate, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido- ]3,4-f][1,4]oxazepin-5(4H)-one fumarate and 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[2,3- f][1,4]-oxazepine-5(4H)-one fumarate.

Example 2 3

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

To a solution of 0.5 g (0.002 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepine-5(4H)-thione 2 ml of a 40% aqueous dimethylamine was added to 20 ml of ethyl alcohol. The mixture was heated in a steel bomb to 100° C. for 14 hours. The resulting solution was filtered and concentrated. The residue was dissolved in isopropyl alcohol and a few drops of ethereal hydrogen chloride were added. The hydrochloride salt crystals were recrystallized by dissolving in ethyl alcohol and boiling while replacing the ethyl alcohol with isopropyl alcohol. The yield of the product was 0.3 g (47%), m.p.: decomposition above 200°C.

Analysis: Calculated for C26H4 -jNgC^S^l-j:

C 48.78 H 6.46 N 13.13

Found : C 49.34 H 6.47 N 13.03

Example 24

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]-oxazepin-5(4H)-thione and diethylamine in ethanol were heated together to form the title compound .

Example 25

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylnaphtho[ 2, 3- f]-[ 1, 4]- oxazepine- 5 ( 4H)- thione- oxalate [ 1:1] hemihydrate

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

Analysis: Calculated for C4oH50<N>4°ll<S>2:

C 58.09 H 6.09 N 6.77

Found : C 58.42 H 5.85 N 6.70

Example 2 6

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 7, 9- diiodo- 4- methyl-1, 4- benzoxazepin- 5( 4H)- one

Using the procedures described in Examples 1 and 2 and using 2-(2-chloroethyl)-7,9-diiodo-4-methyl-2,3-dihydro-4-methyl-1,4-benzoxazepine -5 (4H)-one instead of 2-(chloroethyl)-4-methyl-2,3-dihydro-1,4-benzoxazepin-5(4H)-one, the title compound was obtained.

Example 2 7

7- chloro- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methyl- 1, 4- benzoxazepine- 5( 4H)- one- oxalate [ 1:1]

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

Analysis: Calculated for C^<gH>^^<Og>Cl:

C 51.55 H 5.68 N 7.51

Found : C 51.52 H 5.72 N 7.44

Example 2 8

2-(dimethylamino) methyl- 2, 3- dihydro- 4- methylpyrido[ 3, 2-f]—

[ 1, 4]-oxazepin-5(4H)-one

When, in the procedure described in Example 10, 2-chloromethyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one is used instead of 2-(2- chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one, the title compound is obtained which, if desired, can be isolated as a pharmaceutically acceptable salt.

Example 2 9

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

3.8 g (0.01 mol) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)- thione fumarate [1:1], ethanol [2:1], was partitioned between chloroform and dilute sodium hydroxide. The chloroform extract was dried over sodium sulfate and concentrated. The residue was dissolved in 15 ml of methyl isobutyl ketone and added to a solution of 1.4 g (0.01 mol) of methyl iodide in 15 ml of isobutyl ketone. Recrystallization from 50% ethanol - 50% methylisobutyl ketone gave 2.5 g (78%) of the product, m.p. 221 - 225° C.

Analysis: Calculated for C-^H^N^OSI:

C 41.28 H 5.44 N 10.31

Found : C 41.29 H 5.51 N 10.30

Example 30

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

To a solution of 8.0 g (0.027 mol) 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-thione in 50 ml of absolute ethanol was added to 6 ml (0.054 mol) of a 40% aqueous solution of dimethylamine. The solution was heated in a steel bomb to 90° C. for 14 hours. The ethanol was removed under reduced pressure and the residue partitioned between chloroform and aqueous sodium hydroxide. The chloroform layer was concentrated to give a viscous yellow oil. The oil was dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt precipitated immediately. The mixture was heated and a small amount of water was added to dissolve the salt. A white, crystalline powder was obtained, m.p. 150 - 151° C. Analysis: Calculated for C^^^^^^H^ : C 48.30 H 5.57 N 7.04

Found : C 48.74 H 5.34 N 6.95

Example 31

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylnaphtho[ 2, 1- f]-[ 1, 4]- oxazepine- 5( 4H)- thione- hydrochloride [ 1:1]

To a solution of 15.0 g (0.05 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]-oxazepine-5(4H) -thione in 50 ml of absolute ethanol was added to 10 g of a 40% aqueous solution of dimethylamine. The resulting solution was heated in a steel bomb to 100°C for 40 hours and concentrated under reduced pressure. The residue was distributed between 15% aqueous sodium hydroxide and chloroform. The chloroform layer was evaporated and the residue partitioned between 3N hydrochloric acid and chloroform. The aqueous layer was made alkaline with 50% sodium hydroxide and extracted with chloroform. The chloroform extract was concentrated and the residue was dissolved in isopropyl alcohol. Etheric hydrogen chloride was added. Recrystallization of the precipitate from isopropyl alcohol/water gave 3.0 g

(20%) of the product, m.p. 238 - 240° C.

Analysis: Calculated for C^g^ -^^ClOS :

C 61.61 H 6.61 N 7.98

Found : C 51.80 H 6.61 N 7.91

Example 32

When, in the procedure described in Example 11, equal molar amounts of the following compounds are used instead of 2-(2-chloroethyl)-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)-thione and

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

obtained:

a) 2-([2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,4,f][1,4]-oxazepine-5(4H)-thione-fumarate and b) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[2,3-f][1,4]-oxazepine-5(4H)-thione fumarate.

Example 33

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

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

176 - 178° C.

Analysis: Calculated for C^<H>^<qN>^<O->^:

C 54.10 H 7.78 N 7.54

Found : C 54.29 H 6.59 N 7.53

Example 34

7- bromo- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methyl- 1, 4- benzoxazepine- 5 ( 4H)- thione- oxalate [ 1:1] monohydrate

To a solution of 13 g (0.04 mol) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol was added to 8 ml of a 45% aqueous solution of dimethylamine. The solution was heated to 100° C. in a steel bomb for 16 hours. The ethanol was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and 3N aqueous hydrochloric acid. The aqueous extract was basified with 50% aqueous sodium hydroxide and extracted with chloroform. The chloroform was concentrated under reduced pressure. The residue, the free base of the title compound, was dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt was recrystallized from 95% ethanol to form the title salt, m.p. 155 - 157° C.

Analysis: Calculated for C-^^g^B^O-^E^ :

C 42.58 H 5.14 N 6.12

Found : C 42.93 H 4.79 N 6.19

Example 35a to h

When, in the procedure described in Example 27, equal molar amounts of the following compounds are used instead of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H )-one: 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-1,4-benzoxazepine- 5(4H)-one,

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

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

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

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

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

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

obtained:

a) 4-cyclohexyl-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazepin-5(4H)-one-oxalate, b) 2-[2-(dimethylamino)ethyl] -2,3-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-one-oxalate, c) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-isopropyl-1 ,4-benzoxazepine-5(4H)-one-oxalate, d) 4-(4-chlorobenzyl)-2-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazepine-5(4H )-one-oxalate, e) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-methylbenzyl)-1,4-benzoxazepin-5(4H)-one-oxalate, f) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(3,5-dimethoxy-benzyl)-1,4-benzoxazwpin-5(4H)-one-oxalate, g) 2-[2 -(dimethylamino)ethyl]-2,3-dihydro-4-[(3-(trifluoro-methyl)benzyl]-1,4-benzoxazepin-5(4H)-one-oxalate, and h) 2-[ 2 -(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)-one oxalate.

Example 36a - h

When, in the procedure described in Example 10, equal molar amounts of the following compounds are used instead of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-[1,4]- oxazepin-5(4H)-one hydrochloride: 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]- oxazepin-5(4H)-one hydrochloride,

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

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

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

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

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

2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethylbenzyl)pyrido-[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride, and 2- (2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)-pyrido[3,2-f]-[1,4]-oxazepin-5(4H)-one hydrochloride,

obtained:

a) 4-cyclohexyl-2-[2-(dimethylamino)ethyl]-2,3-dihydropyrido-[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, b) 2 -[2-(dimethylamino)ethyl]-2,3-dihydro-4-ethylpyrido-[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, c) 2-[2 -(dimethylamino)ethyl]-2,3-dihydro-4-isopropylpyrido-[3,2-f][1,4]-oxazepin-5(4H)-one-fumarate, d) 4-(4-chlorobenzyl) -2-[2-(dimethylamino)ethyl]-2,3-dihydropyrido [3,2-f][1,4]oxazepin-5(4H)-one fumarate, e) 2-[2-(dimethylamino )ethyl]-2,3-dihydro-4-(4-methylbenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, f) 2-[2- (dimethylamino)ethyl]-2,3-dihydro-4-(4-methoxybenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one-fumarate, g) 2-[ 2-(dimethylamino)ethyl]-2,3-dihydro-4-(3-trifluoromethyl-benzyl)-pyrido[3,2-f][1,4]oxazepin-5(4H)-one fumarate, and h) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitrobenzyl)-pyrido [3,2-f] [1,4]-oxazepin-5(4H)-one- fumarate.

Example 37a - d

When, in the procedure described in Example 3, equal molar amounts of the following compounds are used instead of morpholine:

pyrrolidine,

piperidine,

piperazine and

4-methyl-piperazine,

obtained:

a) 2,3-dihydro-4-methyl-2-[2-(1-pyrrolidino)ethyl]-1,4-benzoxazepin-5(4H)-one fumarate, b) 2,3-dihydro-4- methyl-2-[2-(1-piperidino)ethyl]-1,4-benzoxazepin-5(4H)-one fumarate, c) 2,3-dihydro-4-methyl-2-[2-(1- piperazino)ethyl]-1,4-benzoxazepin-5(4H)-one fumarate, and d) 2,3-dihydro-4-methyl-2-[2-(4-methylpiperazin-1-ylXethyl]-1, 4-Benzoxazepin-5(4H)-one fumarate.

Example 38

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

A solution of 1.5 g (0.0058 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepine-5(4H)- on in 20 ml of dimethylamine was stirred at 25°C in a sealed container for 72 hours. Excess dimethylamine was allowed to evaporate and the residue was evaporated between chloroform and dilute sodium hydroxide. The chloroform layer was concentrated and the residue, the free base of the title compound, was dissolved in isopropyl alcohol and reacted with hydrogen chloride. The resulting hydrochloride salt weighed 1.5 g (77%), m.p. greater than 250° C. Analysis: Calculated for C-^^H^N-jOSC^ : C 46.16 H 6.27 N 12.42

Found : C 45.68 H 6.18 N 12.35

Example 3 9

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

A solution of 1.5 g (0.005 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepine-5(4H)-thione in 40 ml of dimethylamine was stirred at 25°C in a sealed container for 96 hours. The dimethylamine was allowed to evaporate and the residue was partitioned between methylene chloride and diluted with sodium hydroxide. The chloroform layer was concentrated and the residue, the free base of the title compound, was reacted with 0.4 g of hydrochloric acid in a solution of 30 ml of 90-100 isopropyl alcohol-water. The resulting crystals were recrystallized from the same solvent to give 1 g of product,

sm.p. 191 - 193° C.

Analysis: Calculated for ^i5H21<N>3^2^4<:>

C 48.50 H 5.70 N 11.33

Found : C 48.49 H 5.84 N 10.99

Example 40

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

A solution of 5 g (0.02 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one in 25 ml of dimethylamine was placed in a closed vessel and stirred for 72 hours. The vessel was opened and excess dimethylamine was evaporated. The residue was dissolved in chloroform and the solvent was evaporated

in vacuo to remove excess dimethylamine. The residue was partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and the residue treated with 3 g (0.033 mol) of oxalic acid in 50 ml of isopropyl alcohol and sufficient water to dissolve the salt under boiling. The resulting crystals were recrystallized from the same solvent. The yield of the product was 5.3 g (60%), m.p. 179 - 181° C.

Analysis: Calculated for C34H4gN6°21:

C 46.48 H 5.52 N 9.58

Found : C 46.58 H 5.70 N 9.61

Example 41

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

A 4 g (0.009 mol) sample of 2-[2-(dimethylamino)-ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepine-5(4H)- on-oxalate (1:2) hemihydrate was partitioned between dilute sodium hydroxide and chloroform. The aqueous layer was extracted three times and the combined chloroform extracts were dried over sodium sulfate and concentrated. The residue was dissolved in 200 ml of dry toluene and again concentrated in vacuo to effect drying. The residue was dissolved in 10 ml of dry pyridine and treated with 2.8 g (0.01 mol) of phosphorus pentasulfide. The mixture was stirred at the reflux temperature for 20

hours. The cooled mixture was partitioned between dilute sodium hydroxide and chloroform. The aqueous layer was extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated. 1 g of the residue was treated with 0.6 g of oxalic acid in isopropyl alcohol/10% water. The resulting crystals were collected by filtration. The yield of the oxalate salt was 0.37 g, m.p. 111 - 114° C.

Analysis: Calculated for 0-^^ 22^ 25Q9 :

C 45.84 H 5.20 N 9.43 Found : C 45.46 H 5.38 N 9.28 Example 42 2-(2-aminopropyl)-2,3-dihydro-4-methyl-pyrido[3, 2- f][ 1, 4]-oxazepine- 5( 4H)-one- oxalate [ 1:1] 5 g (0.22 mol) 2,3-dihydro-4-methyl-5(4H)-oxopyrido- [3,2-f][1,4]-oxazepih-2-propanenitrile in 150 ml of ethanol was treated with approx. 1.5 g wet Raney nickel. The mixture was hydrogenated in a Parr apparatus at 60°C and 2.8 kg/cm 2 . The mixture was cooled and filtered and the filtrate concentrated. The residue was treated with 3.9 g of oxalic acid 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 oxalate hemihydrate was 3 g (43%), m.p. 126 - 134° C.

Analysis: Calculated for C28H40<N>6°7:

C 50.30 H 6.03 N 12.57 Found : C 50.46 H 5.71 N 12.21 Example 4 3 2, 3- dihydro- 4- methyl- 2-[ 2-( 4- morpholinyl) ethyl ] pyrido[ 3, 2- f ]-[ 1, 4]- oxazepine- 5( 4H)- on- maleate [ 1:1] 16 g (0.58 mol) 2-(2-chloroethyl)-2,3 -dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of morpholine and stirred overnight at room temperature. To the solution was added 50 ml of dilute sodium hydroxide solution, and the resulting mixture was extracted with 3 x 30 ml of chloroform. The chloroform was evaporated on the rotary evaporator with suction. The morpholine residue was removed in vacuum at 50° C (rotary evaporator). To 15.5 g (0.053

mol) of the free residual base was added to 1 liter of isopropyl alcohol and 9.24 g (0.080 mol) of maleic acid. The mixture was heated to boiling and the clear solution was cooled to 20°C over several hours. The resulting crystals, 16 g

(68.1%), was recrystallized from isopropyl alcohol, m.p.

163 - 165° C.

Analysis: Calculated for ci9H25N3°7:

C 56.01 H 6.18 N 10.31 Found : C 55.71 H 6.21 N 10.18 Example 44 2, 3- dihydro- 4- methyl- 2-[ 2-( 1- pyrrolidinyl) ethyl] - pyrido[3,2-f]-[l,4]-oxazepine-5(4H)-one-fumarate [1:1] A sample of 16 g (0.058 mol) 2-(2-chloroethyl)-2, 3-Dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 65 ml of pyrrolidine. The stirred solution was heated to 80° C. for 3 hours. The solution was cooled at room temperature and 50 ml of dilute sodium hydroxide solution was added. The resulting solution was extracted with 3 x 30 mL chloroform and concentrated in vacuo. The residue was taken up in 500 ml of boiling isopropyl alcohol and 9.2 g (0.079 mol) of fumaric acid was added. The solution was filtered hot and the filtrate was cooled to 20° C. over several hours. The resulting crystals, 14 g (47.8%) were collected and recrystallized from isopropyl alcohol, m.p. 14 7 - 14 9° C. Analysis: Calculated for C23°io<N>3H29: C 54.43 H 5.76 N 8.28 Found: C 54.38 H 5.83 N 8.27 Example 4 5 2 -[ 2-( dibutylamino) ethyl]- 2, 3- dihydro- 4- methyl- pyrido[ 3, 2- f]-[ 1, 4]- oxazepin- 5( 4H)- on- maleate [ 1:1] 16 g (0.058 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of dimethylformamide and 30 ml of di-n-butylamine.

The solution was stirred at 90° C. for 3 hours and at 100° C. i

2.5 hours. The solution was cooled and to this was added 50 ml of dilute sodium hydroxide solution. The resulting mixture was extracted with 3.: x 50 ml chloroform. The chloroform was removed on the rotary evaporator with water suction at 50° C. Residues of dimethylformamide and di-n-butylamine were removed at low vacuum and 50° C (rotary evaporator). 13.8 g (0.041 mol) of the residual free base was added to 900 ml of isopropyl alcohol and 5.6 g (0.062 mol) of oxalic acid and the solution was heated to boiling. The clear solution was cooled overnight to 20°C and was filtered to give 13.6 g (56.5

%) of crystals recrystallized from isopropyl alcohol, m.p. 195 - 196° C.

Analysis: Calculated for C2i<H>33<N>3<0g:>

C 59.59 H 7.85 N 9.72 Found : C 59.37 H 7.91 N 9.86 Example 4 6 2-[ 2-( diethylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido[ 3, 2- f]-[ 1, 4]- oxazepine- 5( 4H)-one- oxalate [ 1:1] 16 g (0.058 mol) 2-(2-chloroethyl)-2,3-dihydro-4- methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride was suspended in 30 ml of diethylamine. The suspension was stirred for 72 hours at room temperature. The mass spectrum indicated that the reaction had proceeded to 33% at this point. The mixture was then heated to reflux for 6 hours. Diethylamine was removed by rotary evaporation (70° C, water aspirator). The residue was taken up in 100 ml of chloroform and was washed with 2 x 30 ml of dilute aqueous sodium hydroxide.

The organic layer was concentrated by rotary evaporation

(70° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. On cooling, 18.6 g (87.7%) of light brown crystals with a melting point of 150 - 155° C. were collected. A sample was recrystallized a further three times from isopropyl alcohol, m.p. 156 - 157°C. Analysis: Calculated for C^7<H>25N3°6: C 55.57 H 6.86 N 11.43

Found : C 55.28 H 6.85 N 11.27

Example 4 7

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

2 g (0.015 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of piperidine and was heated to 80° C. with stirring for 20 minutes. The piperidine was removed by rotary evaporation (85° C., vacuum pump) and the residue was taken up in 50 ml of chloroform. The organic layer was washed with 2 x 20 ml of dilute sodium hydroxide and was concentrated by rotary evaporation (80°C, water aspirator). The resulting oil was taken up in hot isopropyl alcohol and treated with oxalic acid. On cooling, crystals of the oxalate salt were collected and recrystallized from isopropyl alcohol to give 3.4 g (62%) of pale yellow crystals, m.p. 133 - 136°C. Analysis: Calculated for C-^gH^N-^Og: C 56.98 H 6.64 N 11.07 Found : C 56.95 H 6.87 N 10.79 Example 4 8 2, 3- dihydro- 4 - methyl- 2-[ 2-[ methyl( phenylmethyl) amino] ethyl]-pyrido[ 3, 2- f][ 1, 4]- oxazepin- 5( 4H)- on- maleate [ 1:1] 4 g ( 0.015 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of benzylamine and was heated to 80° C. with stirring. After 3 hours, excess amine was removed by rotary evaporation (90° C., vacuum pump). The residual oil was taken up in 40 ml of chloroform and was washed with 30 ml of dilute aqueous sodium hydroxide. The chloroform layer was concentrated by rotary evaporation (90° C, water aspirator). The residual oil was dissolved in hot isopropyl alcohol and treated with maleic acid. On cooling, 4.23 g (66%) of light brown crystals were collected, m.p. 16 7 - 16 9° C.

Analysis: Calculated for C23H2 7N30g:

C 62.57 H 6.16 N 9.52

Found : C 62.28 H 6.16 N 9.24

Example 4 9

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

4.00 g (0.015 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of N-methylaniline and was heated to 95°C

and stirring for 2 days. Excess N-methylaniline was removed by rotary evaporation (95° C, vacuum pump). The residue was taken up in 80 ml of chloroform and was washed with 30 ml of dilute aqueous sodium hydroxide. The chloroform layer was decolorized with activated carbon and was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The remaining residue was dissolved in 50 ml of ethyl acetate and purified by high-pressure liquid chromatography using a silica gel column and ethyl acetate as eluent. After purification, crystals were formed from ethyl acetate. These crystals were recrystallized from ethyl acetate to give 1.40 g (31%) light brown crystals.

Analysis: Calculated for ^i8H21N3^2:

C 69.43 H 6.79 N 13.49

Found : C 69.31 H 6.77 N 13.54

Example 50

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

5.0 g (0.021" mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one was dissolved in 25

ml of absolute ethanol and 3 g (0.03 mol) of 2,5-dimethylpyrrolidine were added. The solution was heated to 75° C. for 48 hours with stirring. Because the reaction was incomplete at this time, an amount of 1.00 g (0.01 mol) of 2,5-dimethylpyrrblidine was added and the reaction was continued. After 5 days the reaction was still incomplete and an additional 1.00 g (0.01 mol) of 2,5-dimethylpyrrolidine was added. The reaction appeared to be complete 2 days later. The solvent was removed by rotary evaporation (80° C, water aspirator). Excess 2,5-dimethylpyrrolidine was removed by rotary evaporation (80° C, vacuum pump). The residue was taken up in 200 ml of chloroform and was washed with 2 x 75 ml of dilute aq.

sodium hydroxide. The organic layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation (70°C, water aspirator). The resulting oil was dissolved in hot isopropyl alcohol and treated with fumaric acid.

During cooling, 2.38 g (27.4%) of light brown crystals were collected, m.p. 161 - 162° C.

Analysis: Calculated for C2iH2 9N3°6:

C 60.13 H 6.96 N 10.02

Found : C 59.79 H 6.93 N 9.76

Example 51

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

To a solution of 3.5 g (0.0145 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f] [1,4]-oxazepine-5 (4H) -one in 15 ml of ethanol was added 5.0 g (0.063 mol) of 2-methylpyrrolidine. The solution was heated to reflux for 3 hours

while stirring. The ethanol was removed by rotary evaporation (water aspirator, 80° C.). The residue was partitioned between 50 ml of dilute aqueous sodium hydroxide and 50 ml of chloroform.

The organic layer was saved and the aqueous layer was extracted with 2 x 30 ml of chloroform. All chloroform layers were combined, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (water aspirator, 70°C). The residual oil was then distilled at 200°C and low vacuum (vacuum pump) to give 1.5 g (35.7%) of a clear oil. Analysis: Calculated for C^5H23<N>3°<3:>C 66.41 H 8, Oi:, N 14.5 2

Found : C 65.83 H 8.06 N 14.39

Example 52

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

To a suspension of 1.2 g active (0.05 mol) sodium hydride in 15 ml dimethylformamide was added dropwise to a solution of 3.10 g (0.045 mol) pyrazole in 15 ml dimethylformamide. The resulting solution was then added to a solution of 9.12 g (0.038 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine- 5(4H)-one in 30 ml of dimethylformamide. The flask was sealed and stirred overnight.

Because the reaction was not yet complete, 3.12 g (0.045 mol) of pyrazole was added to the reaction solution and stirred overnight. The reaction was still not complete and a further suspension of 0.5 g of active sodium hydride (0.021 mol) and 1.5 g (0.022 mol) of pyrazole in 10 ml of dimethylformamide was added and the reaction mixture was stirred overnight. The reaction appeared to be complete. Dimethylformamide was removed by rotary evaporation (80° C, vacuum pump) and the residue was taken up in 100 ml of chloroform and was washed with 1x50 ml of dilute aqueous sodium hydroxide and was dried over anhydrous sodium sulfate and concentrated by rotary evaporation (70° C, water aspirator). The material was purified by high pressure liquid chromatography, 95:5 ethanol:methanol on a silica gel column. The fractions containing the desired product were concentrated by rotary evaporation (70° C, water aspirator). Crystallization started on cooling. The crystals were collected and recrystallized from ethanol. The yield was 1.5 g (14.5 %), m.p. 132 - 134° C.

Analysis: Calculated for ci4Hi6<N>4°2<:>

C 61.75 H 5.92 N 20.58

Found : C 61.35 H 5.89 N 20.6 7

Example 53

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

To a solution of 9.12 g (0.038 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one 5.66 g (0.083 mol) of imidazole was added to 30 ml of dimethylformamide. The solution was heated to 130° C. for 18 hours. The dimethylformamide was removed by rotary evaporation

(80° C., vacuum pump) and the residue was taken up in 100 ml of chloroform. The chloroform was washed with 30 mL of dilute aqueous sodium hydroxide, dried over sodium sulfate, and concentrated by rotary evaporation (70° C., water aspirator) to an oil. Crystallization was induced with ethanol. 1.5 g (14.5%) of white crystals were collected, m.p. 150 - 152° C.

Analysis: Calculated for C14H16N402:

C 61.75 H 5.92 N 20.58

Found : C 61.36 H 5.92 N 20.60

Example 54

2- [ 2-( dimethylaminoXethyl]- 4- ethyl- 2, 3- dihydropyrido[ 3, 2- f]-[ 1, 4]- oxazepin- 5( 4H)- one- oxalate [ 1:1]

To 30 ml of dimethylamine collected at 0° C was added 6 g (0.021 mol) of 2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido [3,2-f] [1,4]-oxazepine- 5(4H)-one hydrochloride. The flask was tightly sealed and stirred for 70 hours at room temperature. The solution was then cooled to 0°C and the stopper of the flask was removed. Dimethylamine was allowed to evaporate. The residue was taken up in 1 x 150 ml chloroform and was washed with 1 x 50 ml dilute aqueous sodium hydroxide. The organic layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation (70° C., water aspirator). The residue was dissolved in hot isopropyl alcohol and treated with oxalic acid. During cooling, 4.5 g (61.5%) were collected, m.p. 208° C. Analysis: Calculated for cigH2 3N3°6: C 54.38 H 6.56 N 11.89

Found : C 54.26 H 6.61 N 11.81

Example 55

2, 3- dihydro- 4- ethyl- 2-[ 2-( 1- pyrrolidinyl) ethyl] pyrido[ 3, 2- J -

[ 1, 4]- oxazepine- 5( 4H)- one- oxalate [ 1:1]

3 g (0.01 mol) of 2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido [3,2-f][1,4]-oxazepin-5(4H)-one hydrochloride was dissolved in 30 ml of pyrrolidine and was heated to 70°C for 30 minutes with stirring. After cooling, the contents of the reaction flask were diluted with 40 ml of dilute aqueous sodium hydroxide and were extracted with 2 x 30 ml of chloroform. The chloroform layer was dried over sodium sulfate, filtered and concentrated to a viscous brown oil by rotary evaporation (70°C, water aspirator). The oil was taken up in hot isopropyl alcohol and treated with oxalic acid. On cooling, the resulting solid was recrystallized from isopropyl alcohol to give 1.80 g (4 5.4%) light brown crystals, m.p. 185 - 188° C.

Analysis: Calculated for C]_8H25N3°6 :

C 56.98 H 6.64 N 11.07

Found : C 56.90 H 6.67 N 10.90

Example 56

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

4.5 g (0.018 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione was dissolved in 3 0 ml of morpholine. The solution was heated with stirring until

50 - 60° C for 6 hours. The morpholine was then removed by rotary evaporation (90° C, vacuum pump). The residue was taken up in 100 ml of chloroform and was washed with 2 x 30 ml of dilute aqueous sodium hydroxide. The organic layer was concentrated by rotary evaporation (60° C, water aspirator). The residue was recrystallized from ethanol to give 3.26 g (60%) of pale yellow crystals, m.p. 152 - 153° C. Analysis: Calculated for C^ .-H^N^C^S: C 58.61 H 6.89 N 13.66 Found : C 58.48 H 6.92 N 13.62 Example 57 2-[ 2-( dibutylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido[ 3, 2- f]-[ 1, 4]- oxazepine- 5( 4H)- thione- oxalate [ 1:1] 4 g (0.016 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione was suspended in 30 ml of di- n-butylamine. About. 10 mL of dimethylformamide was added to the stirred mixture until dissolution occurred. The solution was heated to 140° C. for 3.5 hours with stirring. Di-n-butylamine and dimethylformamide were removed by rotary evaporation (80° C., vacuum pump). The residue was then diluted with 50 ml of dilute aqueous sodium hydroxide and was extracted with 3 x 40 ml of chloroform. The chloroform was removed by rotary evaporation (70° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. On cooling, the resulting oxalate salt was filtered and recrystallized from isopropyl alcohol to give 3.2 g (47%) of yellow crystals, m.p. 208° C. Analysis: Calculated for C2-L<H>33<N>3<O>5<S:>C 57.38 H 7.57 N 9.56

Found : C 57.04 H 7.63 N 9.31

Example 58

2-[ 2-( diethylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido[ 3, 2- f]-[ 1, 4]- oxazepine- 5( 4H)- thione- oxalate [ 1:1] 4 g (0.016 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl[3,2-f][1,4]-oxazepine-5(4H)-thione was suspended in 30 ml of diethylamine. Dimethylformamide was added to the stirred suspension until dissolution occurred (10 mL).

The stirred solution was heated to 65°C for 8 hours. Diethylamine was removed by rotary evaporation (70° C, water aspirator), and the remaining dimethylformamide was removed at low pressure (vacuum pump) and 90° C. The residue was taken up in 100 ml of chloroform and was washed with 2 x 30 ml of dilute aqueous sodium hydroxide. The organic layer was concentrated by rotary evaporation (70° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. During cooling, 1.7 g (28.5%) of the oxalate salt was obtained, m.p. 142 - 144° C.

Analysis: Calculated for ^H^^N-jOi-S :

C 53.25 H 6.57 N 10.95 Found : C 53.14 H 6.60 N 10.72 Example 5 9 2,3-dihydro-4-methyl-2-[2-(1-pyrrolidinyl)ethyl ] pyrido[ 3, 2- f ]-[ 1, 4]- oxazepine- 5( 4H)- thione- oxalate [ 1:1] 5 g (0.02 mol) 2-(2-chloroethyl)-2,3 -dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-thione was dissolved in

30 ml pyrrolidine. The solution was heated to 60 - 80° C i

35 minutes while stirring. After cooling to room temperature, the reaction mixture was diluted with 50 ml of dilute aqueous sodium hydroxide and was extracted with 2 x 50 ml of chloroform. The organic layer was concentrated by rotary evaporation (70° C, water aspirator). The residual pyrrolidine was removed at 90° C and with a vacuum pump. The residue was dissolved in hot ethanol and treated with oxalic acid. On cooling, the oxalate salt was collected and recrystallized twice from ethanol to give 3.35 g (45%) of product, m.p. 141°C. Analysis: Calculated for C-^H^^^Oi-S : C 53.53 H 6.08 N 11.02

Found : C 53.39 H 6.11 N 10.91

Example 6 0

2, 3- dlhydro- 2-[ 2-( 1H- imidazol- 1-yl) ethyl]- 4- methyl- pyrido-[ 3, 2- f][ 1, 4]- oxazepine- 5( 4H)- thione - oxalate [ 2:3]

To a solution of 4.5 g (0.018 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione 1 35 ml of dimethylformamide was added to 2.20 g (0.038 mol) of imidazole. The resulting solution was heated to 130°C for 15 hours. Dimethylformamide was removed by rotary evaporation (80°C, vacuum pump), and the residue was diluted with 50 mL of dilute aqueous sodium hydroxide. The aqueous solution was extracted with 1 x 50 ml chloroform, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (water aspirator, 70°C). The remaining oil was treated with oxalic acid in ethanol. 4 g (54%) of pale yellow crystals were collected and recrystallized in ethanol, m.p. 163 - 167° C.

Analysis: Calculated for C-^yH^gOyN^S:

C 48.22 H 4.52 N 13.23

Found : C 48.04 H 4.62 N 13.18

Example 61

2 -[ 2-( dimethylamino) ethyl]- 4- ethyl- 2, 3- dihydropyrido[ 3, 2- f]-[ 1, 4]- oxazepine- 5( 4H)- thione

5.00 g (0.016 mol) of 2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]-oxazepine-5(4H)-thione hydrochloride was added to 20 ml of anhydrous dimethylamine. The reaction flask was tightly sealed and stirred at room temperature for 6 days. The flask was opened after cooling to 0° C, and the dimethylamine was allowed to evaporate at room temperature. The residue was taken up in 100 ml of chloroform and was washed with 1 x 30 ml of dilute aqueous sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was dissolved in hot cyclohexane. On cooling, 1.76 g (39.4%) of pale yellow crystals were collected, m.p. 73° C.

Analysis: Calculated for C-j^H^N^OS:

C 60.18 H 7.58 N 15.03

Found : C 60.32 H 7.70 N 15.13

Example 62

2, 3- dihydro- 4- methyl- 2-[ 2-[ methyl( phenylmethyl) amino] ethyl]-pyrido[ 3, 2- f][ 1, 4]- oxazepine- 5( 4H)- thione- oxalate [ 1:1]

For a single solution of 4 g (0.0155 mol) 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione in 70 ml of chloroform was added to 10.0 g (0.086 mol) of benzylmethylamine. The solution was stirred under reflux for 24 hours. The reaction solution was washed with 2 x 50 ml of water and was concentrated by rotary evaporation (approx. 70° C, water aspirator). The residue was distilled on a molecular distillation apparatus at 165° C./0.1 mm. The residue was treated with oxalic acid in hot isopropyl alcohol. During cooling, two masses of crystals were collected. The purity of each mass was checked. The two masses were combined and recrystallized together in hot isopropyl alcohol. On cooling, 3.69 g (55%) of light yellow crystals were collected, m.p. 163 - 166° C,

Analysis: Calculated for C2iH25N3°5S:

C 58.45 H 5.84 N 9.74

Found : C 58.24 H 5.92 N 9.61

Example 6 3

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

4.0 g (0.16 mol) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione was suspended in a 30% solution of methylamine in 70 ml of ethanol, and was stirred for 56 hours at room temperature. Due to incomplete reaction, the reaction solution was slowly heated over a 2 hour period to 55°C and stirred at this temperature for 24 hours. Methylamine was removed by water suction<g>for 1.5 hours. The resulting solution was concentrated by rotary evaporation (70°C, water aspirator). The residual oil was taken up in 150 ml of chloroform and washed with 2 x 50 ml of 2M aqueous sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator). The residue was dissolved in hot ethanol and treated with oxalic acid. On cooling, 2.0 g (37.5%) of yellow crystals were collected, m.p. 137 - 138° C.

Analysis: Calculated for C-^H^<qN->jO^S:

C 46.63 H 5.22 N 10.67

Found : C 46.47 H 5.35 N 10.85

Example 64

7- chloro- 2, 3- dihydro- 4- methyl- 2-[ 2-[ 1- pyrrolidino) ethyl]-pyrido[ 3, 2- f][ 1, 4]- oxazepin- 5( 4H)- one- fumarate [ 1:2, 5]

2j. 5 g (0.00 9 mol) 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f] [1,4]-oxazepine-5 (4H)- on was dissolved in 50 ml of pyrrolidine and the solution was heated to 80° C. for 1 hour. The pyrrolidine was removed by rotary evaporation (80° C, water aspirator) and the residue was dissolved in 100 ml of chloroform. The organic layer was washed with 2 x 50

ml of water, was dried over sodium sulfate and concentrated by rotary evaporation (approx. 80° C, water aspirator). The residue was treated with fumaric acid and allowed to stand overnight. The resulting crystals were collected and 1.25 g (23.2%) was obtained, m.p. 164 - 166° C.

Analysis: Calculated for Cn<rH>,„N,On0C1:

2o 30 3 12

C 50.05 H 5.04 N 7.00

Found : C 50.22 H 5.14 N 7.02

Example 65

7- chloro- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido-[ 3, 2- f][ 1, 4]- oxazepine- 5( 4H)- one- oxalate [ 1 :1]

A 2.8 g (0.01 mol) sample of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5 (4H)-one was added to 25 mL of dimethylamine and stirred for 96 hours in a sealed flask. Excess amine was allowed to evaporate and the residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over sodium sulfate and concentrated. The residue was treated with 0.7 g of oxalic acid in isopropyl alcohol. The resulting crystals were recrystallized from the same solvent. The yield was 1.5 g of oxalate salt (40%), m.p. 150 - 156° C.

Analysis: Calculated for ^H^N^Ogd :

C 48.20 H 5.39 N 11.24

Found : C 48.09 H 5.47 N 11.12

Example 6 6

4- cyclohexyl- 2- [ (dimethylamino) methyl]- 2, 3- dihydropyrido-[ 3, 2- f][ 1, 4]- oxazepin- 5( 4H)- one- oxalate

Using the procedure described

in Example 10, 2-(chloromethyl)-4-cyclohexyl-2,3-dihydropyrido [3,2-f][1,4]-oxazepin-5(4H)-one (intermediate 35) was reacted with 40% aqueous dimethylamine and was reacted with oxalic acid in isopropyl alcohol.

Example 6 7

2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- phenylmethyl- pyrido-[ 3, 2- f][ 1, 4]- oxazepin- 5( 4H)- one- oxalate [ 1:1 , 5] hemihydrate

A solution containing 94.2 g (0.6 mol) of 2-chloronicotinic acid and 100 g (0.54 mol) of 1-benzyl-3-pyrrolidinol in 800 ml of dry tetrahydrofuran was added dropwise rapidly to a stirred suspension of 52 g ( 1.3 mol) 60% sodium hydride/mineral oil in 500 ml dry tetrahydrofuran at the reflux temperature (addition time was about 1 hour. The mixture was heated to the reflux temperature for another 1.5 hours and was then cooled to room temperature. Approx.

1 liter of ethyl acetate was added and the filtration proceeded unsatisfactorily. The mixture was allowed to stand overnight at room temperature and was then concentrated on the rotary evaporator at 100° C. and 50 mm pressure. The residue was dissolved in 1 liter of chloroform and the pH of the solution was adjusted to 6.15 with hydrogen chloride gas. 383 g (1.0 mol) triphenylphosphine and 383 g (2.48 mol) carbon tetrachloride were added to the solution with stirring. The mixture was boiled under reflux for 1 hour and 50 ml of ethanol was added. The solution was cooled to room temperature and extracted three times with 400 ml portions of dilute hydrochloric acid. The chloroform layer was extracted with dilute sodium hydroxide, dried over sodium sulfate and concentrated. Mass spectra indicated the presence of 2-(2-chloroethyl)-2,3-dihydro-4-(phenylmethyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one (mass 316) , triphenylphosphine (mass 262) and triphenylphosphine oxide (mass 278). One third of the residue was chromatographed on the high pressure liquid chromatograph in an unsuccessful attempt to purify the compound. The other 2/3 of the residue was dissolved in 30 ml of chloroform and added to a

solution of 30 g of dimethylamine in ethanol. The solution was heated to reflux for 4 hours and concentrated on the rotary evaporator. The residue was partitioned between chloroform and 1N hydrochloric acid. The acid layer was basified with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and concentrated. The residue (10 g) was treated with an equivalent amount of oxalic acid in a mixture of isopropyl alcohol ethanol-isopropyl ether. The resulting crystals in an amount of 9 g (5%) were recrystallized from the same solvent mixture, m.p. 95 - 98°C. Analysis: Calculated for C^H^NgO-^: C 56.28 H 5.79 N 8.95

Found : C 56.61 H 5.76 N 8.77

Example 68

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

A solution of 3.0 g (0.006 mol) of 2-[2-(dimethyl-aminoethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f] [1,4]-oxazepine-5(4H) -one-oxalate [1:1.5] hemihydrate in about 50 mL of water was basified with dilute aqueous sodium hydroxide solution, and then extracted with 5 3 mL portions of benzene.

The combined benzene extract was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was further dried by 2 times azeotropic distillation with approx. 50 ml of dry benzene and where evaporation to dryness was carried out each time. The final residue was dissolved in 40 ml of liquid ammonia and small beads of sodium were added with stirring to the solution until a blue color lasted for 20 minutes. (The addition took about 1 hour). 3 g of ammonium chloride was slowly added and the ammonia was allowed to evaporate. The residue was suspended in chloroform and the mixture was filtered. The filtrate was concentrated and the residue chromatographed on a preparative high pressure liquid chromatograph using a silica gel column eluting with 75% ethyl acetate/25% dimethylformamide. The yield of the product was 0.1 g (7%). The chemical ionization mass spectrophotometer gave a peak at 236 corresponding to a molecular weight of 2 35. The H NMR spectrum of the compound was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is consistent with the proposed structure and with dimethylformamide (DMF) and mineral oil as minor pollutants. The chemical shifts and attributions are listed below:

Example 6 9

2-[ 3-(dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f]-[1,4]-oxazepine-5(4H)-one-fumarate [1:1. 5] hemihydrate

To 5.0 g (0.021 mol) of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one was added under cooling in a water bath, an 88% aqueous solution of formic acid, 20 g (0.38 mol). To the resulting solution was added 10.7 g (0.13 mol) of a solution of 37% aqueous formaldehyde (inhibited with 13% methanol). The resulting solution was heated on a steam bath for 5.5 hours. The mixture was cooled and 100 ml of dilute aqueous hydrochloric acid was added. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The solution was neutralized with dilute aqueous potassium hydroxide and extracted with four 50 mL portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated by rotary evaporation. The residue was reacted with fumaric acid in hot isopropyl alcohol. The collected product, 3.0 g (31.8%)

was recrystallized twice from isopropyl alcohol, m.p.

108 - 110° C.

Analysis: Calculated for C4oH56N6°17:

C 53.81 H 6.32 N 9.41

Found : C 53.69 H 6.33 N 9.41

Example 70

2-[ 3-( dimethylamino) propyl]- 2, 3- dihydro- 4- methylpyrido[ 3, 2-f]-[ 1, 4]- oxazepine- 5( 4H)- thione- oxalate [ 1:2]

To a solution of 11.0 g (0.042 mol) 2-[3-(dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5 (4H )-one in 125 ml of pyridine was added 9.25 g (0.042 mol) of phosphorus pentasulfide. The mixture was heated to reflux for 3.5 hours with stirring. After cooling to room temperature, the reaction solution was added to an equal volume of 2 molar potassium hydroxide. The mixture was extracted with 800 ml of methylene chloride in several portions. The organic phase was washed with three 100 ml portions of dilute potassium hydroxide, was dried over sodium sulfate, filtered and concentrated by rotary evaporation (water aspirator, 70° C.). The residual oil was subjected to reduced pressure from the vacuum pump for 2 hours at 90° C., and was then cooled and reacted with oxalic acid in isopropyl alcohol. Two masses of 4.5 and 3.1 g were collected, combined and recrystallized from isopropanol to give 6.5 g (34%) of yellow crystals, m.p. 136 -

138°C.

Analysis: Calculated for C-^gP^i^N^OgS:

C 47.05 H 5.42 N 9.16

Found : C 46.76 H 5.75 N 9.04

Example 71

7- chloro- 2-[ 2-( dimethylamino) ethyl]- 2, 3- dihydro- 4- methylpyrido-[ 3, 2- f][ 1, 4]- oxazepine- 5( 4H)- thione- fumarate [ 1 :1] hemihydrate, hemiisopropyl alcoholate

To 55 ml of a methanolic solution containing

57 vol% of dimethylamine was added to 2.50 g (0.009 mol) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine- 5(4H)-thione. The reaction vessel was sealed and allowed to stand for 16 hours. Thin-layer chromatography indicated that the turnover was approx. 60%. The solution was gradually heated to 45°C (heated for approx. 5 hours). Methanol and unreacted dimethylamine were removed by rotary evaporation (water aspirator, 60° C). The residue was taken up in 100 ml of chloroform and the solution was washed with two 40 ml portions of water. The organic layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was reacted with fumaric acid in isopropyl alcohol. The resulting crystals, 1.43 g (36.5

%) was recrystallized from isopropyl alcohol and dried thoroughly in a drying gun, m.p. 98 - 104° C.

Analysis: Calculated for C-^Ht-^NgO-^C^^ :

C 48.84 H 5.98 N 9.23

Found : C 48.82 H 5.80 N 9.37

Pharmaceutical preparations

The invention also relates to pharmaceutical preparations for administration to a patient comprising as active ingredients at least one of the compounds of formula I in connection with a pharmaceutical carrier or excipient. The compounds are thus presented in a therapeutic preparation suitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, intravenous or intranasal administration. Thus, for example, preparations for oral administration can be in the form of elixirs, capsules, tablets or coated tablets containing carriers which are usually used in the pharmaceutical field. Suitable tableting excipients include lactose, potato and corn starch, talc, gelatin and stearic and silicic acids, magnesium stearate and polyvinylpyrrolidone.

For parenteral administration, the carrier or excipient may comprise a sterile parenterally acceptable liquid, e.g. water or arachis oil contained in ampoules.

In preparations for rectal administration, the carrier can be composed of a suppository base, e.g. cocoa butter or a glyceride.

Application to the nose, throat and bronchial area can be made in the form of a gargle or an aerosol spray containing small particles of the compound of formula I in a spray or in dry powder form.

Preferably, the preparations are formulated as unit doses, where each unit is adapted to provide a specific dose of active ingredient. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms. It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose will be in accordance with the dosage form used. The exact individual doses as well as the daily doses will of course be determined according to standard medical practice under the direction of a doctor or veterinarian. In general, pharmacological tests in guinea pigs compared to certain other antihistamine drugs have suggested that an effective dose for an adult patient would be in the range of 2 to 8 mg for the more active compounds.

Based on animal data, unit doses containing an amount of the compound equivalent to 0.03 to 0.10 mg of active compound per kg body weight. Daily doses of 0.2 to 0.6 mg/kg body weight are contemplated for humans and of course several small unit dosage forms can be administered. Examples of dosage preparations are as follows:

Capsules:

Procedure for tablets:

1. Mix 1, 2, 3, 4 in large quantities.

2. Add sufficient water in portions to mix the mixture from step 1, stirring gently after each addition. Such additions of water and stirring are continued until the mass is of such a consistency that a transformation into wet granules is possible. 3. The wet pulp is converted into granules by passing it through an oscillating granulator using an 8 mesh sieve.

4. The wet granules are then dried in an oven at 60°C.

5. The dry granules are lubricated with magnesium stearate.

6. The lubricated granules are pressed on a suitable tablet press.

Procedure:

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step 1.

3. The sterile solution is now aseptically filled into sterile ampoules.

4. The ampoules are sealed under aseptic conditions.

Procedure:

1. Melt the 2 and 3 dam and stir until a smooth mixture is achieved. 2. Dissolve No. 1 in the melted mass from step 1 and stir until a smooth mass is obtained. 3. Pour the melted mass from step 2 into suppository molds and cool. 4. Remove the suppositories from the molds and wrap them up.

Therapeutic preparations for combating histamine in unit dosage form, comprising a pharmaceutical carrier and an effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, are therefore an embodiment of the invention.

Claims (3)

1. Aromatic or heterocyclic oxazepines and thiazepines, characterized in that they have the general formula I wherein A represents an aromatic or heterocyclic ring system having two of its carbon atoms in common with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene and pyridine in any of its four positions, and wherein any of the ring systems is optionally substituted with one or two Y radicals selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, B and E are selected from oxygen or sulphur, and may be the same or different, R is selected from the group consisting of lower alkyl, cycloalkyl or phenyl-lower alkyl in which phenyl is optionally substituted with one or two radicals selected from halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, n is 1 or 2, X is halogen selected from chlorine, bromine or cyano, and acid addition salts thereof. 2. Connection according to claim 1, characterized in that it is 2-(2-chloroethyl)-2,3-dihydro-4-methyl-benzoxazepin-5(4H)-one, or 4-benzyl-2-(2-chloroethyl)-2,3-dihydro -1,4-benzoxazepin-5(4H)-one, or 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth-^2,3-f][1,4]-oxazepin-5(4H)-one, or 2-(-2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one, or 8-chloro-2-(2- chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one, or 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1 ,4-benzoxazepin-5(4H)-one, or 7- chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one, or 2-(2-chloroethyl)-2,3-dihydro- 4-methylnaphtho[2,1-f] [1,4]-oxazepin-5(4H)-one, or 2-(2-chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1, 4-benzoxazepin-5(4H)-one, or 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-thione, or 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f] [1,4]-oxazepine-5(4H)-thione, or 2-(2-chloroethyl)-2, 3-dihydro-4-methylnaphtho[2,3-f][1,4]-oxazepine-5(4H)-thione, or 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H)-thione, or 7-bromo-2-(2-chloroethyl)-2, 3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione, or 2-(2-chloroethyl)-2,'3-dihydro-4-methylnaphth[2,1-f] [1, 4]-oxazepin-5(4H)-one, or 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-thione, or 2 -(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepine-5(4H)-thione, or 2-(2-chloroethyl)-2,3 -dihydro-7-methoxy-4-methyl-1,4-benzoxazepine-5(4H)-thione, or 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][ 1,4]-thiazepin-5(4H)-one, or 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepin-5(4H )-thione, or 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one, or 2-(2-chloroethyl)-2, 3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepine-5(4H)-thione, or 2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,4]-oxa zepine-2-propanenitrile, or 2-(2-chloroethyl)-4-ethyl- 2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-(4H)-one, or 2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2 -f] [ 1,4]-oxazepine-5(4H)-thione, or 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1, ]-oxazepin-5(4H)-one, or 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrxdo[3,2-f][1, J oxazepin-5(4H) -thione, or 2-(chloromethyl)-4-cylohexyl-2,3-dihydropyrido[3,2-f][1, ]-oxazepin-5(4H)-one or an acid addition salt thereof. 3. Process for the production of an aromatic or heterocyclic oxazepine or thiazepine with the gene real formula I wherein A is selected from an aromatic or heterocyclic ring system having two of its carbon atoms in common with the oxazepine or thiazepine moiety, selected from benzene, naphthylene and pyridine at any of its four positions, wherein any of the ring systems is optionally substituted with one or two Y radicals selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, B and E are selected from oxygen or sulfur and may be the same or different, R is selected from the group consisting of lower alkyl, cycloalkyl or phenyl-lower alkyl in which phenyl is optionally substituted with one or two radicals selected from halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, n is 1 or 2, X is halogen selected from chlorine, bromine or cyano, and acid addition salts thereof, characterized in that Step 1) a compound of formula wherein A, E, R, n and Y are as defined above, with the exception that the two carbon atoms in A are not bonded at the oxazepine or thiazepine rings and R 3 is hydrogen or an acid salt neutralizing ion, forming an acid halide of formula or its free base wherein X is chlorine or bromine and A, E, n, R and Y are as defined above, Step 2) condensation of the compound prepared in Step 1 to form an oxazepinone or thiazepinone of formula wherein A, E, X, n and Y are as defined in Step 1 and A has 2 of its carbon atoms in common with the oxazepine or thiazepine moiety, Step 3) if necessary reaction of the compound prepared in Step 2 with a sulfurizing agent during formation of an oxazepinthion or thiazepinthion of formula in which A, E, R, X, Y and n are as defined above, Step 4) if necessary, reacting a compound prepared in Step 2 with an alkali metal cyanide to form a compound of formula where A, E, Y and R are as defined in Step 2, Step 5) possible halogenation of a compound prepared in Step 2 or 4 of formula wherein E and R are as defined above and X is chlorine, bromine or cyano, with sulfuryl chloride in a suitable solvent to form a compound of formula in which E and R are as defined above and X is chlorine, bromine or cyano.