FI78102C - Process for the preparation of therapeutically useful pyrido / 1,4 / oxa zepine derivatives - Google Patents

Description

1 78102

Process for the preparation of therapeutically useful pyrido [1,4] oxazepine derivatives

The present invention relates to a process for the preparation of novel 2,3-dihydropyrido (C, 47) oxazepin-5 (4H) -ones and ions substituted in the 2-position by a short-chain aminoalkyl radical. These compounds have antihistamine and antiallergic activity.

3-Aryl-1,4-benzoxazepin-5 (4H) -ones substituted with the aminoalkyl radical of the oxazepine nitrogen are disclosed in CH Patent 505 × 50 <C.A. 7J5 98600s).

The conversion of flavanones to benzoxazepinones substituted in the 2-position by a phenyl radical has been reported by Le-vai A. and Bognar R. Top. Flavanoid Chem. Biochem. Proc. Hung. Bioflavonoid Symp. 4th edition 1973 (published 1975), 119-123 (C.A. £ 5.79098η). The trione derivative is obtained by treatment with phosphorus oripentasulfide.

Certain chemical intermediates, 1-substituted-3-substituted phenoxypyrrolidines, which may include: 1-methyl-3- (2-carbamoylphenoxy) pyrrolidine, 1-benzyl-3- (2-carbamoylphenoxy> pyrrolidine), and 1-methyl -3- (2-carboxyphenoxy) pyrrolidine, is disclosed in U.S. Patent 3,577,415.

It is an object of the present invention to provide certain novel 2,3-dihydropyridofl, 47-oxazepin-5 (4H) -ones and ions substituted in the 2-position by a short-chain aminoalkyl radical having antihistamine activity.

The present invention therefore relates to a process for the preparation of pyrido / 1,4-oxaepine derivatives having antihistamine activity of the formula

v— (CH) -Z

y 2 n

B ^ R

wherein the pyridine ring may be present at all four positions thereof, which pyridine ring is optionally substituted with one or two Y radicals, wherein Y is halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, B is oxygen or sulfur, R is hydrogen , lower alkyl, cycloalkyl or phenyl-lower alkyl, n is 1, 2 or 3, 12 Z is -NR R, ΙΗ-pyrazol-1-yl or 1H-imidazol-1-yl, 2 R and R are hydrogen , lower alkyl or phenyl-lower alkyl or R and R together with the adjacent nitrogen atom form a heterocyclic residue which is 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl yl, 1-pipe-. . ridinyl, 4-substituted piperidin-1-yl, 4-morpholinyl or 1,2,3,6-tetrahydropyridin-1-yl and its pharmaceutically acceptable salts, provided that when R is hydrogen, Z is never is not a primary or secondary amine, and further provided that when n = 3, z is not 1H-pyrazol-1-yl, 1H-imidazo-1-yl-1,2,5-dimethylpyrrolidin-1-yl yyl, 2-methylpyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl. In further defining the meanings of the symbols of the following formulas, and when they appear elsewhere in this specification and claims, the terms used have the following meanings.

Li 3 78102 "Lower alkyl" embraces straight and branched chain radicals having 1 to 8 carbon atoms, and examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl , isoamyl, hexyl, heptyl and octyl and the like. "Lower alkoxy" has the formula -O-lower alkyl.

"Cycloalkyl" means primary cyclic alkyl radicals having from 3 to 9 carbon atoms, and includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylecyclohexyl, cycloheptyl, and the like.

"Halo" and "halogen" mean fluorine, chlorine, bromine and iodine unless otherwise indicated.

"Pharmaceutically acceptable salts" means acid addition salts, hydrates, alcoholates and quaternary salts of the compounds of formula I which are physiologically acceptable for warm-blooded animals. Acid addition salts may be formed using either strong or weak acids. Typical weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, tartaric, cyclohexamine and the like.

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

By "sulfurizing agent" is meant any substance or mixture of substances that converts oxazepinones to oxazepine ions, such as 2,4-bis <4-methoxyphenyl--1,2,3,4-dithiadiphosphetane-2,4-disulfide and phosphorus pentasulfide and alkali metal sulfide. a mixture of phosphorus pentasulfide in pyridine.

4 78102

The compounds of the present invention have antihistamine activity in guinea pigs. The test method is a modification of the method of Tozzi et al. (Vol. 4/4 264-270, 1974) and is as follows: Guinea pigs are fasted for 18-24 h in separate cages. Water is given ad libitum. On the day of the test, groups of three guinea pigs are injected intraperitoneally. mg / kg of test compound prepared in a suitable medium 30 minutes later, histamine (1.2 mg / kg <= 2 x LDg) is injected into the marginal ear vein. Survival of guinea pigs for 24 hours is a positive indication of antihistamine activity. If the medium of the test compound is other than water, its effect is determined by testing the same amount in the control animals. The dose that protects 50X of animals (PDgg) from death can be obtained from dose-response curves.

. . Compounds of formula I are prepared according to the invention in that a) a compound of formula

(CH) -X B

wherein B and Y are as defined above, R is lower alkyl, cycloalkyl or phenyl-lower alkyl and X is chlorine or bromine is reacted with a compound of formula

ZH

wherein Z is as defined above, after which, if desired, the compound of formula I in which B is oxygen is reacted with a sulfurizing agent to give the corresponding atepine ion in which B is sulfur, or s 78102 b) to prepare a compound of formula I in which Z is amino, a reduction of a cyano compound of formula

O-λ —- (CH) -CN

(Y) 0 ^ f © TT 21-2

O

wherein Y is as defined above and R is as defined in formula II, to the primary amine of formula (V / o-r-iCH) -NH Γ \ 2 2-3 2 (Y) -hU)> 0-2 I I / Ia

O R

wherein Y and R are as defined in formula Ile, or c) to prepare a compound of formula I wherein Z is dimethylamino, a primary amine of formula> -tm (Y) o - ^ (®TH> wherein Y and R are the same as in formula II, to react with formaldehyde and formic acid to give a tertiary dimethylamine of the formula * * \ \ 21-3 32 Y o ^ TT ® 1) in which Y and R have the same meanings as in formula Ic-1, and if desired eulfurized azepinone of formula Id to give the corresponding thione, or d> to prepare a compound of formula I wherein R is hydrogen, a compound of formula 6 78102) -z "'is obtained. as above, and Z is as defined in formula IZ, taking into account the conditions set for IZ, to react with sodium and ammonia to give a compound of formula <γ) 0 —- Θ> wherein Y and Z are as defined in formula Ie, followed, if desired, by the method a, b, ct ai d The free base of the prepared compound is reacted with a pharmaceutically acceptable acid or quaternary halide or sulfate to form a pharmaceutically acceptable salt of a compound of formula I.

Compounds of formula I wherein n is 2 are most preferred due to their antihistamine activity. Process a) for the preparation of compounds having a methyl or ethyl side chain (n = 1 or 2>) constitutes a preferred process corresponding to successive steps A-F as shown below.

Compounds of formulas Ia, Ic-1, Id, Ie, If are all included in formula I.

Detailed description of the invention

The present invention comprises a process for the preparation of novel oxazepine derivatives of formula I.

li 7 78102

Schemes I and 11 illustrate the preparation of intermediates. R is never hydrogen.

Scheme III illustrates the reaction sequence for the preparation of end products where R is other than hydrogen and n is 1 or 2.

Scheme IV depicts the preparation of compounds with 2-α8emeaea ethyl and propyl radicals omega-substituted with the primary amine <-NH2>. R is never hydrogen.

Scheme V depicts methods for converting omega-NH 2 -ubstituted ethyl and propyl compounds to tertiary amines. This is an alternative method for the preparation of ethyl tertiary amines. R is never hydrogen.

Scheme VI illustrates the preparation of compounds where R

is hydrogen.

Preparation Methods 1-3 describe the synthesis of compounds of formulas IVa and IVb or the preparation of certain starting materials thereof. Intermediates 1-12 (see also Table 1) describe the preparation of compounds of formula II which are aromatic 2,3-dihydro-1,4-oxazepin-5 (4H) -ones (and their sulfur analogues) which are substituted - in the 2-position by alkylhalo or alkyl cyano radicals. Compounds of formula III are usually formed in reaction mixtures without separation. Examples 1-37 (see also Table 2) illustrate the preparation of compounds of formula I.

8 78102

Scheme I

Manufacture of intermediates (a) (b) 'iyv », ^' I * I ™ | Hydrolysis N / 1C. R rvb CT vOR * * | * 3 »H or M | Halogenate (CKa) n

(Y) 0irf®Xc ** 1ο-0 * χχ R

six

V

\ Heat and / or neutralize \ if necessary CW-iCHaln-MIe \ rv (CH,) n-

moXL / suSssiii ^ n. MJ

mp ib4 ^ 0-2 ° R 113

Possible chain

Note: for elongation a) R is never hydrogen KCi * b) n = 1 or 2 X - halogen (Cl, Br) _fCa,) «- cs W = aryl sulfonate, alkyl \ '*** n sulfonate or X / M = acid neutralizing ion, \ e ^ im. time metal 0 R 11c Q = -C-NH 2, -CN, -C-OR 3 where R is H, M or an esterifying radical * Hydrolysed when Q is other than ft «-C-OH or C-OM.

** Diagram illustrating the proposed bond formation and cleavage to effect rearrangement m or 0

/ ¾ I

u R

II

9 78102

Figure II

An alternative process for the preparation of a halide intermediate halide in a pyrido ring

° ^ -y- (CH2) 1-2_X Recovery- N 0 CHa) -X

. Jf-Ä? = .o R AJ-a g ^ dimethylformamide

NB:

X = Cl, Br. CN

E and R are defined in formula I.

a) n = 1 or 2

Figure III

Preparation of final products (n = 1 or 2; R = something other than H) -.O-CH () n-halo O (CHa) n-halo S R «b« a

2H ZH

(CHa, n.z <ΥΙο-ΤΓ® 1 / * - («o- ^ f®T)

Sulfurization / «A substance Ν /> Τ ib ia

Note: Z is defined in the same way as in formula I when n = 1 or 2.

10 781 0 2

Figure IV

Preparation of primary ethyl and propylamino compounds where R is other than hydrogen from a cyano intermediate.

L ^ m °)

o 'R ° R T

Ile Ia

Scheme V

Further preparation of tertiary aminoalkyl compounds in which R is other than H

BP · '”4 ^ 1

Figure VI

Preparation of compounds with unsubstituted azepine nitrogen (R = H) £ I nh3 V "? 0 CHa O · I t“ *

CeHe Je If

R = benzyl R = H

Note: * Z cannot be a primary or secondary amine.

η 78102

With respect to the above methods and process steps of the invention, the following more detailed description may be applied to the preparation of compounds of formulas I, II and III.

Step 1 treats the starting compounds of formula IVb (see Scheme I) having a carboxylic acid or acid neutralizing ion, such as an alkali metal salt in the pyridine ring ortho to the ether bond, as a relatively pure product or preferably derived from the reaction mixture in the carbamoy of - or a carboxylic acid ester function, substantially without separating the carboxylic acid (or salt) from the reaction mixture with any suitable halogenating agent as described above, preferably thionyl chloride or triphenylphosphine or carbon tetrachloride. The halogenation is carried out in a suitable organic solvent, preferably a refluxing organic solvent, or the refluxing in a cooled halogenating agent, preferably thionyl chloride. Chlorination temperatures over a very wide range can be used, for example from room temperature to 100 ° C or above, but temperatures from 50 ° C to 0 ° C are most preferred, which temperatures are suitable when using refluxed chloroform or thionyl chloride. When an excess of a halogenating agent such as thionyl chloride is used as the carrier, it is preferably evaporated off. When a solvent such as chloroform is used, it can be evaporated off if desired. In any case, a solution containing the solvent and the compounds of formula III, or a residue containing the compounds of formula III, all of which can be detected by infrared analyzes, is available for the next step.

In step 2, the halogenated compounds of formula III prepared in step 1, if not already dissolved, are dissolved in an organic solvent, preferably chloroform.

12 781 02 and is usually neutralized or basified, preferably using a tertiary amine such as triethylamine, and then heated at a sufficient temperature and for a sufficient time to effect fusion of the carbonyl with basic nitrogen and cleavage of the cyclic amine and 2- (2-alkyl) of formula II. - or bromo) oxazepine compounds, for example in refluxed triethylamine. If the tendency to fuse is large enough, neutralization or basification can be omitted. The compounds of formula IIa may be separated by conventional methods, for example by partitioning between a suitable organic solvent or solvent mixture and an 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 IIa can be conveniently converted to the oxazepine ion (IIb) by heating together with a sulfurizing agent in a suitable organic solvent such as toluene. The thione (IIb) can be separated by conventional means, preferably by partitioning between an organic solvent and a dilute alkali metal base, and crystallizing from a suitable solvent such as ethanol.

In step 4, the oxazepinone (IIa) is reacted with potassium cyanide in a hot 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 ethyl acetate and isopropyl ether, or ethyl acetate alone. It can be seen that the products prepared have methyl and ethyl cyano side chains (n = 1 or 2), resulting in side chain extension to aminopropyl n = 3 or, alternatively, as a starting material for methyl chain extension to aminoethyl.

and 78102

In step 5, the oxazepinone (IIa) obtained in step 2 or the oxazepine ion (IIb) obtained in step 3 is reacted with pyrazole, imidazole or amine 1 2 of the formula HHR R, wherein R and R are as defined above in connection with formula I, to give compounds of formulas Ia and Ib. The latter reaction is preferably carried out using an excess of an amine, for example volatile methylene! ine and using. The free bases of the products of formula Ia and Ib are separated in a conventional manner by removing volatiles and partitioning between a dilute aqueous alkali metal base and a solvent such as chloroform or methylene chloride, followed by evaporation. The free base can be converted into a pharmaceutically acceptable salt using the corresponding acid, and in the case of a quaternary salt, using a lower alkyl halide or sulfate and recrystallized in a conventional manner. The free bases can be recovered from the acid addition salts, usually in a purer form, by again partitioning the salt between the aqueous base and a suitable solvent, followed by evaporation. As can be seen and shown in the diagram, the side chain of the prepared intermediate is limited to aminomethyl and amino-ethyl (<n = 2).

If desired, the compound prepared in step 5 where B is oxygen can be sulfurized in step 6, preferably by heating the reflux in dry pyridine with phosphorus pentasulfide for several hours. The resulting thione is separated by cooling the solution and partitioning between a suitable solvent such as chloroform and an aqueous base and evaporating the organic phase and separating in the usual manner.

In step 7, the cyano compound (Ile) prepared in step 4, which is oxazepinone, preferably with hydrogen, using Raney nickel as catalyst, is reduced at a temperature of about 60 ° C. The prepared primary aminoethyl or aminopropyl compound (n = 2 or 3) is preferably separated in a conventional manner. 14 781 02 as an acid addition salt which can be converted back to the free base by partitioning between a suitable solvent and an aqueous base and then drying and evaporating the organic layer.

In step 8 (see Scheme V>, the primary amine is converted to a tertiary amine by selecting the appropriate reactants. This method can prepare tertiary amino compounds of formula I where n = 3 and cannot be prepared in step 5, and further provide an alternative way to prepare tertiary amino compounds of formula I. amino compounds where n = 1 or 2. The preparation of dimethylamine derivatives by reacting a primary amine with formaldehyde and formic acid is a conventional method for preparing tertiary dimethylamines, as is the reaction of a dihalide to give a heterocyclic amine such as 1-pyrrolidino, piperidino or 4-morpholino.

In step 9, the 4-benzyloxyazepinone derivative of formula I (R = benzyl), excluding primary or secondary amines, is converted to the corresponding 4-unsubstituted (R = H> oxazepinone) by reaction with sodium and ammonia and the compound can be separated as in Example 68. Fig.

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

i5 781 02

As mentioned above, the preferred steps for preparing these preferred compounds having an ethyl side chain in the 2-position comprise steps 1-3, 5, 6 and 10 of this general method for preparing all compounds of formula I. Although compounds with a methyl side chain can be prepared using the same method, compounds with n = 1 are included within the scope of this preferred method.

These steps of this preferred method are denoted by the letters A-F, which correspond to the numbered steps of this general method, with the restriction that n = 1 or 2 and R is other than hydrogen, as follows:

Preferred treatment step Corresponding general step number in a description of the method where n = 1 or 2 A 1 B 2 C 3 D 5 E 6 F 10

Method of manufacture 1

Sodium 2-Z '(1-methyl-3-pyrrolidinyl) oxy] -3-pyridinecarboxylate

To a stirred suspension of 6.4 g <0.13 mol) of 50-X sodium hydride (in mineral oil) in 50 ml of dimethyl sulfocide was added dropwise 6.4 g (0.063 mol) of 1-methyl-3-pyrrolidinol. During the addition, the temperature rose from 25 ° C to 31 ° C. After 10 minutes, a solution of 10 g (0.063 mol) of 2-chloronicotinic acid in 50 ml of dimethyl sulfoxide was added, which caused the temperature to rise. When the temperature reached 55 ° C, it was kept at this value periodically using an ice bath until the addition of liqueur was complete. 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-methane for 1 h. The yield of the product was 5 g, decomposing at 240 ° C. NMR analysis showed that the compound contained 1/3 mole of sodium acetate as an impurity.

Analysis: Calculated for C 18 H 19 O 2 Na · 1/3 ^ 2 ^ 3 ^ 2 ^ 31: C 51.62; H 5.20; N 10.32 Found C 51.81; H 5.15; N 10.39

Preparation 2 3 - [(1-methyl-3-pyrrolidinyl) oxy] -4-pyridinecarbonitrile fumarate Γ1: 27_

A solution of 55 g (0.55 moles) of 1-methyl-3-pyrrolidinol in 55 ml of dry dimethylformamide was added dropwise to a suspension of 22 g (0.58 moles) of 60% sodium hydride. / 40% mineral oil 300 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour and 74 g (0.53 moles) of 3-chloro-4-cyanopyridine in 200 ml of dimethylformamide were added dropwise while care was taken to keep the temperature between 30-40 ° C under cooling. an equal volume of water was added. The solution was acidified with dilute hydrochloric acid and 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. Crystals obtained <51 g; 21%) was recovered. A 2 g sample was recrystallized from methyl isobutyl onis. The product yield was 1.5 g, m.p. o 172-174 C.

Analysis: Calculated for C 18 H 18 N 2 O 9: C, 52.42; H 4.86; N 9.65 Found: C 52.40; H 4.90; N 9.68 and 17 781 02

Manufacturing method 3

Sodium 2 - [(1-cyclohexyl-3-azetidinyl) oxy] -3-pyridine carboxylate

A solution of 105 g (0.68 moles) of 1-cyclohexyl-3-atetidinol and 106 g (0.68 moles) of 2-chloronicotinic acid in 400 ml of dry dimethylformamide was added rapidly dropwise to 52 g. 35 moles) of 60- * sodium hydride / mineral oil suspended in 400 ml of dry methylformamide at 60 ° C. A slight exotherm 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-methylpyrido [3,2- (7,7-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 reached. 350 g (1.34 moles) of triphenylphosphine and 350 g (2.3 moles) of carbon tetrachloride were added and the resulting cloudy solution was stirred at reflux for 1.5 h, then about 100 ml of ethanol was added and heating was stopped. 200 ml of isooctane The solution was extracted four times with a total of 800 ml of dilute hydrochloric acid, the acidic extracts were combined, basified with sodium hydroxide and extracted with chloroform, the chloroform layer was separated and dried over sodium sulfate and concentrated, the residue was dissolved in isopropyl and 500 ml. , and acidified with ethereal hydrogen chloride, the weight of the crystals obtained being 82 g <49%). recrystallized from isopropyl alcohol, m.p. 149-153 C.

ιβ 78102

Analysis: Calculated for C 18 H 18 N 2 O 2 Cl 2: C 47.67, H 5.09; N 10.11 Found C 47.57: H 5.18; N 10.00 Intermediate 2 2- <2-chloroethyl> -2,3-dihydro-4-methylpyrido [3,2-f] Cl, 47-oxazepine-5 (4H) -thione

To a solution of 59 g (0.25 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] Cl, 47-oxazepin-5 (4H) -one hydrochloride in 1500 ml chloroform, 41.5 g (0.19 moles) of phosphorous acid was added and the mixture was heated under reflux for 18 h. 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 11 H 13 N 2 ClOS: 51.46; H 5.10; N 10.81 Found: C 51.35; H 5.21; N 10.72 Intermediate 3 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-7,7 "oxazepin-5 (4H) -one hydrochloride 49 g <0.11 moles) Sample 3 - ((1-methyl-3-pyrrolidinyl) oxy] -4-pyridinecarbonitrile fumarate Cl: 27 was partitioned between chloroform and saturated potassium carbonate solution. The aqueous layer was extracted. All chloroform extracts were combined, dried and concentrated, the residue was dissolved in 125 ml of t-butanol and 34 g (0.6 mol) of potassium hydroxide powder was added, the mixture was heated at room temperature for 88 h and then diluted with 150 ml of toluene. 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 (steam heating / vacuum) to remove water. The residue was dissolved in 400 ml of chloroform, and 63 g of triphenylphosphine was added thereto, followed by 70 g of carbon tetrachloride. The solution was stirred at reflux for 2 h and an additional 30 g of triphenylphosphine was added. After refluxing for a further 1 hour, an additional 70 g of carbon tetrachloride and 63 g of additional triphenylphosphine were added and refluxing was continued for 4 h. 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 silica gel pad with acetone as the liquid phase. The free base of the title compound separated after evaporation in an amount of 5.8 g (20X). To a portion of this free base, dissolved in isopropyl alcohol, was added ethereal hydrogen chloride solution and leopropyl ether. The formed crystals were collected and dried, m.p. 188-190 C.

Analysis: Calculated for Cj: C 47.67, H 5.09; N 10.11 Found: C 48.33, H 5.22; N 9.73 Intermediate 4 2- <chloroethyl> -2,3-dihydro-4-methylpyrido [4,3-f] 7,7-oceatepine-5 (4H) -thione

A solution of 5 g (0.021 mol) of 2- (2-chloroethyl--2,3-dihydro-4-methylpyrido), 3- [7H, 4,7] oxazepin-5 (4H) -one and 5.1 g of g (0.0126 mol) of 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithio-diphosphetane-2,4-disulfide in 100 ml of dry toluene, it was stirred at reflux. The solution was cooled and extracted three times with sodium bicarbonate solution, the toluene layer was dried over sodium sulfate and concentrated. 0.6 g (11%) of the title compound.

Intermediate 5 2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [4,7] oxazepin-5 (4H) -one_

A solution of 78 g (0.5 mol) of 4-chloronicotinic acid and 52 g (0.52 mol) of 1-methylpyrrolidinol in 150 ml of dimethylformamide was added to a suspension of 44 g <1.1 mol) of 60- % sodium hydride / mineral oil in 800 ml of dimethylformamide at such a rate that the temperature is between 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 / steam bath). The residue was dissolved in 600 ml of water and extracted with isopropyl ether. The pH of the aqueous layer was adjusted to 6 with hydrochloric acid and the solution was concentrated on a rotary evaporator (5 mm / steam bath). 188 g (1.1 moles) of phenylphosphine were added followed by 250 ml of carbon tetrachloride, the mixture was gently heated to 60 ° C, after which the reaction became exothermic and cooled o using an ice bath to maintain the desired temperature of 60-65 ° C for about 20 minutes. the mixture was removed and heated to reflux for 3.5 h and then cooled, the solution was extracted with 600 ml of water and then with two 200 ml portions of 1N hydrochloric acid, the acid layer was basified with sodium hydroxide and extracted three times with chloroform, concentrated by chromatography on chloroform and concentrated. -nestekro - 2i 78102 by chromatography using silica gel and eluting with ethyl acetate. The product yield was 30 g <25 X). The mass spectrum and NMR value corresponded to the structure of the title compound.

Intermediate 6 2- (2-Chloroethyl) -2H-dihydro-4-methylpyrido [3,4-f] (47,7-oxazepine-5 (4H) -t ion monohydrochloride (2- (2-chloroethyl) -2) 3-dihydro-4-methylpyrido [3,4- (71,47-oxazepin-5 (4H) -one, 15 g <0.06 mol) was dissolved in 200 ml of dry toluene and 15 g <0.037 mol was added). 2,4-Bis (4-methoxyphenyl) -1,3,2,4-dithiaphosphetane-2,4-disulfide. The mixture was heated at reflux for 2.5 h 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 by high pressure liquid chromatography ("Waters 500") using a silica column and ethyl acetate as eluent. The fraction containing 257 molecular weight material was concentrated. The residue was treated with hydrogen chloride in isopropyl alcohol, and the resulting crystals were collected. The yield of the hydrochloride disalt was 0.1 g <0.6 X), βρ. 168-171 C.

Analysis: Calculated for H 14 N 2 OSCl 2: C, 45.06; H 4.81; N 9.55 Found: C 45.15; H 4.98; N 9.26 Intermediate 7 2,3,4,5-Tetrahydro-4-methyl-5-oxypyrido [3,2- [77,4] oxazepine-2-propanenitrile (100 g <0.415 mol) 2- <2 -chloroethyl) -2,3-dihydro-4-methyl-pyrido [2,2-b] oxazepin-5 (4H) -one hydrochloride was partitioned between dilute aqueous sodium hydroxide solution (200 ml) and chloroform (200 ml). The organic layer was collected and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined, dried over sodium euphate and concentrated on a rotary evaporator <70 ° C; vesiaspiraatto-ether). The residue, free base of the starting hydrochloride (89 g <0.37 mol), was dissolved in 150 ml of toluene, and to this solution was added 9 g (0.027 mol) of tetrabutylammonium bromide. Saturated aqueous potassium cyanide solution (100 ml) was then added and the mixture was stirred mechanically under reflux. After 2 hours, an additional 3 g (<0.009 mol) of tetrabutylammonium bromide and 20 ml of aqueous potassium cyanide were added and the mixture was stirred at reflux for 0.75 h. The contents of the reaction vessel were extracted with ethyl acetate (3 x 50 mL). <Note. chloroform should have been used instead). The organic layer was dried over sodium sulfate and concentrated on a rotary evaporator <70 ° C; water aspirator) 1/3 of the original volume. After cooling, crystallization began. The crystals were filtered and washed with several portions of ethyl acetate and isopropyl ether. 30 g <35%) of light crystals were collected, m.p. 104-105 C. The sample was recrystallized from ethyl acetate, m.p. 104-105 C.

Analysis: Calculated for q 62.33; H 5.67; N 18.17 Found: C 62.06; H 5.65; N 17.97 Intermediate 8 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [2,3-f] 2,7,7-oxazepine-5 <4H ) -one hydrokloridi_

To a mixed sodium oil suspension of sodium hydride <81.45 g of a 60% dispersion; 2.036 moles) in dimethyl sulfoxide (<500 ml) heated to 50 ° C was added dropwise a solution of 2-chloronicotinic acid <142 g; 0.905 moles) and N-ethyl-2-pyrrolidinol <99 g; 0.86 moles) in dimethyl sulfoxide (500 ml), at such a rate that the temperature remained in the range of 55-60 ° C (cooling from time to time was necessary). When the addition was complete, the mixture was stirred at 50-60 ° C for 1.5 h and allowed to cool to 23,781 ° 2. The precipitated solid was filtered, washed with ethyl acetate and dried.

Dry sodium salt <172.53 g; 0.62 mol) was suspended in chloroform (1 liter). Hydrogen chloride gas was bubbled through the suspension until the pH was 5.76. Triphenylphosphine <365.5 g was then added; 1.395 moles) and CCl 4 (365.5 g) and the mixture was stirred at reflux. Within 45 minutes, an IR assay indicated that the 95-X reaction had occurred. Additional triphenylphosphine <100 g was then added; 0.38 mol) and CCl 4 (100 g) and the solution was stirred at reflux for a further 45 minutes. The IR assay indicated that the reaction was greater than 99-X. After cooling, the solution was extracted several times with dilute hydrochloric acid (a total of 1.5 liters). The aqueous layer was then basified with concentrated sodium hydroxide solution and extracted into chloroform (3 x 250 mL). The organic layer was dried over sodium sulfate and concentrated on a rotary evaporator (<70 ° C, water aspirator). The residual oil was dissolved in isopropyl alcohol (500 mL) and acidified with hydrogen chloride gas. After cooling, an oil was obtained and the volume was reduced to 1/3 of the original volume. After cooling, 70 g <0.241 mol were recovered; 28 X) light brown crystals, m.p. 153-155 C.

Analysis: Calculated for O 2 · 2 ^ 16 ^ 2 ^ 2 ^ 2: C 49.50; H 5.53; N 9.62 Found: C 49.64; H 5.62; N 9.32 Intermediate 9 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [3,2-f] [47,4-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 partitioned between dilute aqueous sodium hydroxide solution (50 ml) and chloroform < 50 ml). The organic layer was collected and the aqueous layer was extracted with methylene chloride (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator (70 ° C, water aspirator) to give 39 g (0.153 mol) of the free base. The free base thus obtained was dissolved in chloroform (1.2 L) and phosphorus pentasulfide (33.9 g) was added thereto; 0.153 moles) while stirring. The resulting mixture was heated to reflux for 16 hours. After cooling, the reaction mixture was filtered, washed with dilute aqueous sodium hydroxide solution (3 x 300 mL), dried over sodium sulfate o and concentrated on a rotary evaporator (70 ° C, water aspirator) to give a yellow aqueous oil.

This oil was dissolved in isopropyl alcohol (about 200 mL) and acidified with hydrogen chloride gas. After cooling o, 20 g <43 X) of crystals were recovered, m.p. 133-135 ° C. Analysis: Calculated for compound: c 46.91; H 5.25; N 9.12 Found: C 47.33; H 5.38; N, 9,10,197-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2- f] [7,4] oxazepin-5 (4H) -one_ 2- (2) (chloroethyl) -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] oxazepin-5 (4H) -one hydrochloride <10 g; 136 moles) was dissolved in methylformamide (150 mL) and heated to reflux. Sulfuryl chloride <20 g was then added; 0.148 moles) dropwise over 40-50 minutes. The reaction mixture was stirred at reflux for 30 minutes and then SO 2 Cl 2 was added. After cooling, the contents of the flask were partitioned between water (150 ml) and benzene (150 ml). The benzene layer was retained and the aqueous layer was further extracted with benzene (2 x 50 mL). The benzene extracts were combined and washed with dilute aqueous potassium hydroxide (2 x 50 mL) followed by dilute aqueous hydrochloric acid (2 x 50 mL). The benzene layer was dried over sodium sulfate and concentrated on a rotary evaporator (ca. 70 ° C, water aspirator) to give 2.61 g of crude material. This crude material was recrystallized from isopropyl ether to give 1.25 g (12.6%) of white crystals, m.p. 78-o 79 C.

Analysis: Calculated for ^ 48.02, H 4.40; N 10.18 Found: C 48.07, H 4.53; N 10.10 Intermediate 11 7-Chloro-2- (2-chloroethyl> -2,3-dihydro-4-methylpyrido [3,2-d] Cloxa] oxazepine-5 (4H) -thione 6.0 g <0.022 mol ) 7-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-b] 1,47-oxazepin-5 (4H) -one was suspended in 200 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. Since the reaction was not complete, an additional 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 under reflux for 2 h and then allowed to stand for 56 h at room temperature. The toluene layer was decanted and washed with 50 ml of dilute aqueous sodium hydroxide solution and 50 ml of dilute hydrochloric acid. The toluene was removed on a rotary evaporator (about 80 ° C; water aspirator). The crude oil was recrystallized from isopropyl alcohol to give 3.5 g (54%) of pale yellow crystals, m.p. 125-127 C.

Analysis: Calculated for ^ * 5 »37; H 4.15; N 9.62 Found: C 45.40; H 4.20 N 9.71 Intermediate 12

2- <chloromethyl) -4-cyclohexyl-2,3-dihydro-3,2-£ t J

fl. 47 octazepin-5 (4H) -one (15 g <0.05 moles) sample of sodium 2-26 7 8 1 02 β 1 -cyclohexyl-β-3-acetidinyl) obtained from method 23 Jee i-7-3 The pyridine carboxylate was suspended in 100 ml of chloroform and hydrogen chloride was introduced until the pH remained at 5.8. To this stirred mixture was added 18 g of thionyl chloride. The resulting solution was stirred at room temperature for 3 h. The IR spectrum showed a peak at 1770 cm, which is characteristic of the acid chloride. 40 ml of triethylamine were then added dropwise while cooling to about 25 ° C with an ice bath. The chloroform solution was stirred for another half hour and 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 the first to be removed from the statue. The ethanol solution was concentrated and the residue was crystallized once from ethyl acetate-isopropyl ether and once from isopropyl alcohol. The yield of the title compound was 1 g <7 X), m.p.

o 120-122 C.

Analysis: Calculated for C 15 H 18 N 2 O 2 · 2 · · · · C 61.12; H 6.50; M 9.50 Found: C 61.11; H 6.62; N 9.32

Example 1 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [7,4] oxataepin-5 (4H) -one fumarate Z ~ 2 : To 37-90 g of CO (8 moles) of 40-X aqueous diethylamine was added in a steel bomb 25 g (0.09 moles) of 2-C2-chloroethyl) -2,3-dihydro-4-methylpyrido3,2-f7Cl , 4-oceazepin-5 (4H) -one hydrochloride. The mixture was heated at 100 ° C for 15 h with gentle stirring. The mixture was partitioned between dilute sodium hydroxide and two chloroform extractions. The chloroform layers were combined and concentrated. The residue, consisting essentially of the free base of the title compound, was dissolved in 200 ml of isopropyl alcohol, and 9 g of oxalic acid was added thereto. The oxalate salt was recrystallized from 95-X ethanol to give 18 g of product.

27 7 8 1 02

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 reacted with fumaric acid to give 13 g of a white solid (34 ° C), m.p. 146-148 C.

Analysis: Calculated for C 18 H 18 N 2 O 9: C, 53.90; H 5.90; N 9.92 Found: C 53.76; H 6.02; N 9.96

Example 2 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido, 2- [4,4] oxazepine-5 (4H) -thion fumarate C1: 17, ethanol C2: 17_

To a solution of 32.8 g (0.29 moles) of 40-X aqueous dimethylamine and 100 mL of ethanol in a steel bomb was added 15 g (0.058 moles) of 2- (2-chloroethyl) -2,3-dihydro- 4-methylpyrido [3,2-t] (1,4,7-oxazepine-5 (4H) -thione. The mixture was heated at 100 ° C for 18 h 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 consisted essentially of the free base of the title compound and 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, m.p. 105-129 C. A 14 g sample of this salt was recrystallized from ethanol to give 10.5 g of a yellow solid, m.p. 103-118 ° C. The NMR spectrum showed that the crystals contained 1/2 mole of ethanol.

Analysis: Calculated for E 36 → 52 ^ 50} 1S 2: C 53.45, H 6.48; N 10.39 Found C 53.07, H 6.53; N 10.23 28 781 02

Example 3 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] β. 47-oceazepine-5 (4H) -thione fumarate :1: 17_

To a solution of 113 mL (1.0 mole) of a 40% aqueous solution of dimethylamine and 326 mL of ethanol in a steel bomb was added 48.4 g (0.189 moles) of 2- (2-chloroethyl) -2,3-dihydro- 4-methyl-pyrido [2,3-b] oceazepin-5 (4H) -thione. The mixture was heated at 100 ° C for 14 h. The ethanol was removed on a rotary evaporator leaving some water in the residue. This residue was dissolved in 200 ml of methylene chloride and washed three times with 100 ml portions of 20% aqueous potassium carbonate solution. The combined aqueous layers were extracted three times with 150 mL portions of methylene chloride. The methylene chloride solutions were combined and treated with charcoal. The carbon was filtered off and the filtrate was evaporated to give an oil. This oil was dissolved in 215 ml of isopropyl alcohol and the solution was heated to boiling slowly. To the isopropyl alcohol solution was then added a solution of 21.9 g (0.19 mol) of fumaric acid in 150 ml of boiling methanol. A crystalline solid weighing 63.4 g (88 X) was obtained. This solid was recrystallized from 95% ethyl alcohol. The crystals were filtered off and triturated with isopropyl ether at room temperature and filtered off again. After drying in vacuo overnight at 85 ° C, 72.45 g (79X) of crystals were obtained, m.p. 130-133 C.

Analysis: Calculated for C 23 H 23 058: C 53.53; H 6.08; N 11.02 Found: C 53.23; H 6.11 N 10.64

Example 4 2- (2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido-η 3 - [7,7,4] oxazepine-5 (4H) -thione hydrochloride ok * 2: 3.7 To a solution of 0, 5 g (0.002 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,7,7] oxazepine-5 (4H) -29 7 8 1 0 2 thione 20 ml of ethyl alcohol, 2 ml of an aqueous solution of 40-X dimethylamine were added, the mixture was heated in a steel bomb at 100 DEG C. for 14 h, 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 crystals of the hydrochloride salt were recrystallized by dissolving in ethyl alcohol and boiling while replacing the ethyl alcohol with isopropyl alcohol to give a product yield of 0.3 g (47X), ep (decomposes) above 200 ° C.

Analysis: Calculated for C 29 H 40 N 2 O 2 S 2 Cl 2: C 48.78, H 6.46; N 13.13 Found: C 49.34, H 6.47; N 13.03

Example 5 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] Ci. 47-oxazepine-5 (4H) -thion-methiodide-2-C2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] Cl, 47-oceazepine-5 (4H) -thione fumarate E1: U in ethanol C2: 17, 3.8 g (0.01 mol), 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-X ethanol to 50-X methyl isobutyl ketone gave 2.5 g (78 X) of product, m.p. 221-225 C.

Analysis: Calculated for C 14 H 22 N 3 OSI: C, 41.28; H 5.44; N 10.31 Found: C 41.29; H 5.51; N 10.30

Example 6 2-Z'2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido-β, 4- [f, 4,7] oxazepin-5 (4H) -one oxalate (1: 2) hemihydrate _________ _ 30 7 81 0 2

A solution of 5 g (0.02 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrrolidin-3,4-oxathepine-5 <4H ) in 25 ml of dimethylamine, passed into a sealed vessel and stirred for 72 h. The vessel was opened and the excess dimethylamine was allowed to evaporate. 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 was treated with 3 g (0.033 mol) of oxalic acid in 50 ml of isopropyl alcohol and using enough water to dissolve the salt in the boiling solution. The obtained crystals were recrystallized from the same solvent. The product yield was 5.3 g <60 X), m.p. 179-181 ° C. Analysis: Calculated for C 9 H 18 N 2 O 2 N 2 O 2: C, 46.48; H 5.52; N 9.58 Found: C 46.58; H 5.70; N 9.61

Example 7 2 - ((2-Dimethylamino) ethyl) 17,3,3-dihydro-4-methylpyrido-D. 4- [1- [1,47-oxat8epine-5 (4H) -thione octalate <1: 2) A sample of 4 g (0.009 moles) of 2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl 1 ipyr idor3,4-7,7 ', 1,7 oceateepin-5 <4H> -one ocealate <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 concentrated again in vacuo to effect drying. The residue was dissolved in dry pyridine (10 ml) and treated with 2.8 g (0.01 mol) of phosphorus pentasulfide. The mixture was stirred at reflux for 20 h. 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-X water. The obtained crystals were collected by filtration. The yield of the oxalate salt was 0.37 g, m.p. 111-114 C.

Analysis: Calculated for C 18 H 18 N 2 O 2: C, 45.84; H 5.20; N 9.43 Found: C 45.46; H 5.38; N 9.28

Example 8 2- (2-Aminopropyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [4,7] oxazepin-5 (4H) -one oxalate f1: 17__ 5 g <0, 22 moles) of 2,3-dihydro-4-methyl-5 (4H) -oxopyrido [3,2- [7,4] oxazepine-2-propanenitrile in 150 ml of ethanol was treated with 1.5 g of Raney nickel The mixture was hydrogenated in a Parro 2 apparatus at a temperature of 60 ° C and a pressure of about 2.8 kp / cm.

The mixture was cooled and filtered and the filtrate was 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 C 28 H 40 N 6 O 7: C 50.30; H 6.03; N 12.57 Found: C 50.46; H 5.71; N 12.21

Example 9 2,3-Dihydro-4-methyl-2- (2- (4-morpholinyl) ethyl] pyrido [3,2-f] [7] oxazepin-5 (4H) - is i-mal obtained O: 17__ 16 g <0 .58 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride was dissolved in morpholine. <30 ml) and stirred overnight at room temperature. To this solution was added dilute sodium hydroxide solution (50 ml) and the resulting mixture was extracted with chloroform (3 x 30 ml). Chloroform was removed on a rotary evaporator using an aspirator. Residual morphine was removed

O

under vacuum at 50 ° C <rotary evaporator). To the free base obtained as residue 32 7 81 0 2 <15.5 g; 0.053 mol) was added isopropyl alcohol (1 liter) and maleic acid (9.24 g); 0.080 moles). The mixture was heated to boiling point and the clear solution was cooled to 20 ° C and allowed to stand at this temperature for several hours. The formed crystals (16 g <68.1%) were recrystallized from isopropyl alcohol, m.p. o 163-165 C.

Analysis: Calculated for C 19 H 25 N 3 O 7 · · C 56.01; H 6.18; N 10.31 Found: C 55.71; H 6.21; N 10.18

Example 10 2,3-Dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1]. 47-oxazepin-5 (4H) -one fumarate Cl: L7_ Sample of 16 g <0.058 moles) 2- (2-chloroethyl> -2,3-dihydro-4-methylpyrido / 3,2- (47,4oxazepin-5 (4H) -one hydrochloride was dissolved in 65 ml of pyrrolidine. The stirred solution was heated to 80 ° C and allowed to stand at this temperature for 3 h. The solution was cooled to room temperature and dilute sodium hydroxide solution (50 ml) was added. The resulting solution was extracted with chloroform (3 x 30 mL) and concentrated in vacuo. The residue was dissolved in boiling isopropyl alcohol (500 ml) and fumaric acid (9.2 g) was added; 0.079 moles). The solution was filtered hot and the filtrate was cooled to 20 ° C and allowed to stand at this temperature for several hours. The obtained crystals (14 g <47.8%) were collected and recrystallized from isopropyl alcohol, m.p. 147-149 ° C. Analysis: Calculated for ¢ 230 ^: C 54.43; H 5.76; N 8.28 Found: C 54.38; H 5.83; N 8.27

Example 11 2- (2- (Dibutylamino) ethyl] -2,3-dihydro-4-methylpyrido-Z 5,2- [7,7,4] oxazepin-5 (4H) -one maleate / 1: 17: 33 7810 2 16 g (0.058 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2- [3,4-oxazepin-5 (4H) -one hydrochloride were dissolved in dimethylformamide <30 ml ) and di-n-butylamine (30 .mu.l. The solution was stirred at 90 DEG C. for 3 h in J. limp at 100 DEG C. for 2.5 h. The solution was cooled and 50 ml of dilute sodium hydroxide solution was added. The resulting mixture was extracted with chloroform (3 x 50 The chloroform was removed on a rotary evaporator using a water aspirator at 50 ° C.

The residual dimethylformamide and di-n-butylamine o were removed under low vacuum at 50 ° C (rotary evaporator). To 13.8 g (0.041 mol) of the free base obtained as a residue were added isopropyl alcohol (900 ml) and oxalic acid (5.6 g <0.062 mol) and the solution was heated to boiling point. The clear solution was cooled to room temperature overnight

Patient at 20 ° C and filtered to give 13.6 g (56.5%> of crystals which were recrystallized from isopropyl alcohol, mp 195-196 ° C).

Analysis: Calculated for H 33 N 3 O 6: C, 59.59; H 7.85; N 9.72 Found: C 59.37: H 7.91; N 9.86

Example 12 2- [2- (Diethylamino) ethyl] -2,3-dihydro-4-methylpyrido [2,3-f]

Ci. 4-Oxazepin-5 (4H) -one ocealate (1: 17-16 g (0.058 moles) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido (3,2- (7) 1,47 branches) sepin-5 (4H) -one hydrochloride was suspended in diethylamine (30 mL). This suspension was stirred for 72 h at room temperature. The mass spectrum indicated that the reaction was 33-X at this point. The mixture was heated at reflux for 6 h. The diethylamine was removed on a rotary evaporator (70 ° C, water aspirator). The residue was dissolved in chloroform (100 mL) and washed with dilute aqueous sodium hydroxide (2 x 30 mL). The organic layer was concentrated on a rotary evaporator (70 ° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and the fence was treated with oceanic acid. After cooling, 18.6 g (87.7 X) of light brown crystals were collected, m.p. 150-155 ° C). Their sample was recrystallized three more times from isopropyl alcohol, m.p. 156-157 C.

Analysis: Calculated for C 55.57; H 6.86; N 11.43 Found: C 55.28; H 6.85; N 11.27

Example 13 2,3-Dihydro-4-methyl-2 - ((2- (1-piperidinyl) ethyl) pyrido [3,2-f] 7,4-1,47-oxazepin-5 (4H) -one oxalate ΖΓ1: 17-4 g <0.015 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [2,3-b] 1,4] oxathepin-5 (4H) -one hydrochloride

was added to piperidine (30 mL) and heated to 80 ° C

while stirring for 20 minutes. The piperidine was removed on a rotary evaporator (85 ° C, vacuum pump) and the residue was dissolved in chloroform (50 mL). The organic layer was washed with dilute aqueous sodium hydroxide solution (2 x 20 mL) and concentrated on a rotary evaporator (80 ° C, water aspirator). The resulting oil was dissolved in hot isopropyl alcohol and treated with oxalic acid. After cooling, the oxalate salt crystals were collected and recrystallized from isopropyl alcohol to give 3.4 g (62X) of light brown crystals, m.p. 133-136 C.

Analysis: Calculated for C 18 H 18 N 2 O 9: C, 56.98; H 6.64; N 11.07 Found: C 56.95; H 6.87; N 10.79

Example 14 2,3-Dihydro-4-methyl-2- (2-methyl (phenylmethyl) amino] ethyl] -7-pyrido [3,2-f] oxazepin-5- (4H) -one maleate rt: 17 4 g (0.015 moles) 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] 7,4-oxazepin-5 (4H) -one hydrochloride was dissolved in methylbenzylamine (30 ml). ) and heated to 80 ° C with stirring. Excess amine was removed after 3 hours on a rotary evaporator (90 ° C, vacuum pump). The residual oil was dissolved in chloroform (40 mL) and washed with dilute aqueous sodium hydroxide (30 mL).

o

The chloroform layer was concentrated on a rotary evaporator (<90 ° C, water aspirator). The residual oil was dissolved in hot isopropyl alcohol and treated with maleic acid. After cooling, 4.23 g (<66 X) of light brown crystals were obtained, m.p. 167-169 C.

Analysis: Calculated for C 23 H 27 N 3 O 6: C, 62.57; H 6.16; N 9.52 Found: C 62.26; H 6.16; N 9.24

Example 15 2,3-Dihydro-4-methyl-2 - [(2- (methylphenylamino) ethyl] pyrido [3 · 2 - [(4,7] oxazepin-5 (4H) -one) (4.00 g <0.015 moles) 2- <2 -chloroethyl) -2,3-dihydro-4-methylpyrido [3,2- (f] [1,4] oxazepin-5 (4H) -one hydrochloride was dissolved in N-methylaniline (30 ml) and heated at 95 ° C with stirring. Excess N-methylaniline was removed by rotary evaporation (<95 ° C; vacuum pump). The residue was dissolved in chloroform (80 mL) and washed with dilute aqueous sodium hydroxide solution (30 mL). The remaining residue was dissolved in ethyl acetate (50 ml) and purified by high pressure liquid chromatography using a column of silica gel and ethyl acetate as eluent, after which crystals were formed from ethyl acetate, which were recrystallized from ethyl acetate to give n gave 1.40 g <31 X) of light brown crystals.

Analysis: Calculated for 01-21Ν3Ο2: C, 69.43; H 6.79; N 13.49 found. c 69.31; H 6.77; N 13.54 7 810 2

Example 16 2- [2- (2,5-Dimethyl-1-pyrrolidinyl) ethyl] -2,3-dihydro-4-methylpyrido [1,2-f] oxazepin-5 (4H) -one fumarate: 17 5.0 g (0.021 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] Cl, 47-oxazepin-5 (4H) -one were dissolved in 25 ml of absolute ethanol. and to this was added 3 g (0.03 mol) of 2,5-dimethylpyrrolidine. The solution was heated at 75 ° C for 48 h with stirring. Since the reaction was incomplete, an additional 2,5-dimethylpyrrolidine <1.00 g was added at this time; 0.01 mol) and the reaction was continued. After 5 days, the reaction was still incomplete and additional 2,5-dimethylpyrrolidine <1.00 g was added; 0.01 mol). The reaction appeared to be complete after 2 days.

o

The solvent was removed on a rotary evaporator (80 ° C, water aspirator). Excess 2,5-dimethylpyrrolidine was removed on a rotary evaporator <80 ° C; vacuum pump). The residue was dissolved in chloroform (200 mL) and washed with dilute aqueous sodium hydroxide (<2 x 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated on a rotary evaporator (<70 ° C, water aspirator). The resulting oil was dissolved in hot isopropyl alcohol and treated with fumaric acid. After cooling, 2.38 g (27.4%) of light brown crystals, m.p. 161-162 ° C. Analysis: Calculated for ^ 21 ^ 29 ^ 3 ^ 61 C 60.13; H 6.96; N 10.02 Found: C 59.79; H 6.93; N 9.76

Example 17 2,3-Dihydro-4-methyl-2- [2- (2-methyl-1-pyrrolidinyl) ethyl] pyrrolidol-3,2-tJ CL. 47oksateepin ~ 5 <4H> -oni_

To a solution of 3.5 g (0.0145 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-Γ 7 Cl], 47-oxazepin-5 (4H) -one in ethanol < 15 ml), 2-methylpyrrolidine 37,781 O 2 (5.0 g; 0.063 mol) was added. The solution was heated to reflux for 3 hours with stirring. The ethanol was removed on a rotary evaporator (water aspirator, Θ0 ° C). The residual oil was partitioned between dilute aqueous sodium hydroxide solution (50 ml) and chloroform <50 ml). The organic layer was preserved and the aqueous layer was extracted with chloroform (2 x 30 mL). All chloroform layers were combined, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (water aspirator, 70 ° C). The residual oil was then distilled at 200 ° C under high vacuum <vacuum pump> to give 1.5 g (35.7 X) of a clear oil.

Analysis: Calculated for C 16 ** 23 ** 3® 2: C, 66.41; H 8.01; N 14.52 Found: C 65.83; H 8.06; N 14.39

Example 18 2,3-Dihydro-4-methyl-2- (2- (1H-pyrazol-1-yl) ethyl] pyrido [3,2-b] ethyl. 47oxazepin-5 (4H) -one_

To a suspension of sodium hydride <1.2 g active; 0.05 mol) in dimethylformamide (15 ml), a solution of pyrazole <3.10 g was added dropwise; 0.045 mol) in dimethylformamide (15 ml). The resulting solution was then added to a solution of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [4,7] oxazepin-5 (4H) -one (9.12 g; 0.038 mol). In 30 ml of dimethylformamide. The flask was sealed and stirred overnight. Since the reaction was not complete at this stage, pyrazole <3.12 g was added; 0.045 mol) to the reaction solution and stirred overnight. The reaction was not yet complete, so another <0.5 g of active sodium hydride was added; 0.021 moles) and pyrazole <1.5 g; 0.022 mol) suspension in dimethylformamide (10 ml) and the reaction mixture was stirred overnight. The reaction then appeared to be complete. Dimethyl lyformamide was removed on a rotary evaporator (80 ° C, vacuum pump) and the residue was dissolved in chloroform (100 mL), 3β 7 810 2 which was washed with dilute aqueous sodium hydroxide (1 x 50 mL), dried over anhydrous sodium sulfate and concentrated in a rotary evaporator. 70 ° C, water aspirator).

The material was purified by high pressure liquid chromatography using ethanol-methanol in a volume ratio of 95: 5 on a silica gel column. Fractions containing the desired product were concentrated on a rotary evaporator (<70 ° C, water aspirator). Crystallization occurred upon cooling. The crystals were collected and recrystallized from ethanol. Yield o was 1.5 g <14.5%), m.p. 132-134 C.

Analysis: Calculated for C 11 H 14 N 2 O 7.75; H 5.92; N 20.58 Found C 61.35; H 5.89; N 20.67

Example 19 2,3-Dihydro-2- [2- (1H-imidazol-1-yl) ethyl] -4-4-methylpyrido-Z3,2-L7-oxoxepepin-5 (4H) -one

To a solution of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] (1,4-oxazepin-5 (4H) -one, 9.12 g <0.038 mol) in dimethylformamide <30 ml), 5.66 g (0.083 mol) of imidazole were added. The solution was heated at 30 ° C for 18 h.

Dimethylformamide was removed on a rotary evaporator (<80 ° C, water pump) and the residue was dissolved in chloroform (100 ml). The chloroform was washed with dilute aqueous sodium hydroxide solution (30 ml), dried over sodium sulfate and concentrated on a rotary evaporator (70 ° C, water aspirator) to an oil. Crystallization was achieved with ethanol. 1.5 g (14.5%) of white crystals were collected, m.p. 150-152 C. Analysis: Calculated for C 14 H 18 N 4 O 2: C, 61.75; H 5.92; N 20.58 Found: C 61.36; H 5.92; N 20.60 39 781 02

Example 20 2- (1- (Dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido-Z3,2-t] Cl, 47 oxazepin-5 (4H) -one oxalate: 17-30 ml of dimethylamine recovered at room temperature. At 0 ° C, 6 g (0.021 mol) of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [1,2-f] E, 47 oceateepin-5 (4H) -one hydrochloride were added. sealed and stirred for 70 h at room temperature, the solution was then cooled to 0 ° C and the flask cap was removed, the dimethylamine was allowed to evaporate, the residue was dissolved in chloroform (1 x 150 ml) and washed with dilute aqueous sodium hydroxide solution (1 x 50 ml). the layer was dried over sodium sulfate, filtered and concentrated on a rotary evaporator o (70 ° C, water aspirator) The residue was dissolved in hot io-propyl alcohol and treated with oxalic acid, after cooling 4.5 g (61.5%> product, m.p. 208) were collected. C.

Analysis: Calculated for C 54.38; H 6.56; N 11.89 Found: C 54.26; H 6.61; N 11.81

Example 21 2,3-Dihydro-4-ethyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [1-12CX] 47 octate-5 (4H-one oceaeate L): 17-3 g (0 .01 moles) 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [2,3-f] [1,47] oceateepin-5 (4H) -one hydrochloride 1 was relied upon for pyrrolidine (30 After cooling, the contents of the reaction flask were diluted with dilute aqueous sodium hydroxide solution (40 mL) and extracted with chloroform (2 x 30 mL) .The chloroform layer was dried over sodium sulfate, filtered and concentrated to a viscous oil. The oil was dissolved in hot isopropyl alcohol and treated with oxalic acid, and after cooling, the resulting 40 7 8 10 O solid was recrystallized from isopropyl alcohol to give light brown crystals of 1.80 g <45.4 X ), sp. 185-188 ° C. Analysis: Calculated for C 18 H 18 N 2 O 9: C 56.98; H 6.64; N 11.07 Found: C 56.90; H 6.67; N 10.90

Example 22 2,3-Dihydro-4-methyl-2-72- (4-morpholinyl) ethyl] pyrido-Z5.2-f-7β. 4-oxazepine-5 (4H) -thione (4.5 g (0.018 mol)) (2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido) -3,2-7,7'-oceateepine-5 <4H> -thion 1 was relied upon in morpholine (30 ml) .This solution was heated with stirring at 50-60 ° C for 6 h. The morpholine was then removed o by rotary evaporation <90 ° C, vacuum pump>. The residue was dissolved in chloroform (100 ml). and washed with dilute aqueous sodium hydroxide solution (2 x 30 ml) .The organic layer was concentrated on a rotary evaporator (<60 ° C, water aspirator). The residue was recrystallized from ethanol to give 3.26 g (<60 ° C) of pale yellow crystals. mp 152- o 153 C.

Analysis: Calculated for ε ^ ςΗ2ΐΝ3θ25: C, 58.61; H 6.89; N 13.66 Found: C 58.48; H 6.92; N 13.62

Example 23 2- (2- (Dibutylamino) ethyl] -2,3-dihydro-4-methylpyrido [2,2-c] (4'-oxazepine-5 (4H) -thione oceaeate rt: 17-4 g <0.016 mol) 2- <2 -Chloroethyl-2,3-dihydro-4-methyl-pyrido [3,2- (1,7,7-oxazepine-5 (4H) -thione] was suspended in di-n-butylamine (30 ml). Dimethylformamide (about 10 ml) was then added to the stirred mixture until dissolution occurred. The solution was heated at 140 ° C for 3.5 h with stirring. Di-n-butylamine and dimethylformamide were removed on a rotary evaporator (80 ° C, 11 78102 vacuum pump). The residue was then diluted with dilute aqueous sodium hydroxide solution (50 ml) and extracted with chloroform (3 x 40 ml) Chloroform was removed by rotary evaporation (70 ° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. After cooling, the resulting oxalate salt was filtered off and recrystallized from isopropyl alcohol to give 3.2 g of <47 X) yellow crystals, βρ. 20 ° C. Analysis: Calculated for C 21 H 33 N 3 O 5 S: C, 57.30; H 7.57; N 9.56 Found: C 57.04; H 7.63; N 9.31

Example 24 2 - [(2- (Diethylamino) ethyl] -2,3-dihydro-4-methylpyrido-Z5,2- [1,7] oxathepepine-5 (4H) -thione oxalate Cl: 17 4 g <0.016 mol ) 2- (2-chloroethyl) -2,3-dihydro-4-methyl-β, 2- (7H, 4-oxazepine-5 (4H) -thione) was suspended in diethylamine (30 ml). Dimethylformamide was added to the stirred suspension until dissolution (<10 ml).

o

The stirred solution was heated at 65 ° C for 8 h. The dioethylamine was removed by rotary evaporation (70 ° C, water aspirator) and the remaining dimethylformamide was removed under reduced pressure (vacuum pump) at 90 ° C. The residue was then dissolved in chloroform (100 ml) and washed with dilute solution. with aqueous sodium hydroxide solution <2 x 30 ml).

o

The organic layer was concentrated on a rotary evaporator (70 ° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. After cooling, 1.7 g (<28.5 X) of the oxalate salt were obtained, m.p.

o 142-144 C.

Analysis: Calculated for C 17 H 25 N 3 O 5 S: C, 53.25; H 6.57; N 10.95 Found: C 53.14; H 6.60; N 10.72 42 7 8 1 02

Example 25 2,3-Dihydro-4-methyl-2-72- (1-pyrrolidinyl) ethyl] pyrido [5,2-f]. 47eaceateepine-5 (4H) -thioneacetate Cl: 17-5 g (0.02 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido73,2-t7 Cl, 4 [rivereaepine-5 < The 4H) -thione was dissolved in 30 ml of pyrrolidine. The solution was heated at 60-80 ° C for 35 minutes with stirring. After cooling to room temperature, the reaction mixture was diluted with dilute aqueous sodium hydroxide solution (50 mL) and extracted with chloroform (2 x 50 mL). The organic layer was concentrated on a rotary evaporator (70 ° C, water aspirator). The residual pyrrolidine was removed at 90 ° C by means of a vacuum pump. The residue was dissolved in hot ethanol and treated with oxalic acid. After cooling, the oxalate salt was collected and recrystallized twice from ethanol to give 3.35 g (45X) of product, m.p. 141 C. Analysis: Calculated for O ^ 1123 ^ 055: C 53.53; H 6.08; M 11.02 Found: C 53.39; H 6.11; N 10.91

Example 26 2,3-Dihydro-2-72- (1H-imidazol-1-yl) ethyl] -4-methylpyrido-73.2-7,7. 47 oxazepine-5 (4H) - ti is an i-ok salad £ 2: 37_

To a solution of 4.5 g (0.018 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione in dimethylformamide ( 35 ml), imidazole (2.20 g; 0.038 mol) was added. The resulting solution was heated at 130 ° C for 15 h. The dimethylformamide was removed by rotary evaporation (80 ° C, vacuum pump) and the residue was diluted with dilute aqueous sodium hydroxide solution (50 ml). The aqueous solution was extracted with chloroform (1 x 50 mL), dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (water aspirator, 70 ° C).

The resulting oil was treated with oxalic acid in ethanol. 4 g (54 X) of pale yellow crystals were collected and recrystallized again with ethanol, m.p. 163-167 C.

43 7 8 1 02

Anal. Calcd. For C 21 H 19 N 2 O 2 N 2 S: C, 46.22; H 4.52; N 13.23 Found: C 46.04; H 4.62; N 13.16

Example 27 2- [2- (Dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido-13,2- [1,42] branches of cepine-5 (4H) -t ion (5.00 g <0.016 moles) 2- <2 (chloroethyl) -4-ethyl-2,3-dihydropyrid-2,3,2-7,7,4-oceateepine-5 (4H) -thion hydrochloride was added to 20 ml of anhydrous dimethylamine. The reaction vessel was sealed and its contents were stirred at room temperature for 6 days. After cooling to 0 ° C, the flask was opened and the dimethylamine was allowed to evaporate at room temperature. The residue was dissolved in chloroform (100 mL) and washed with dilute aqueous sodium hydroxide solution (1 x 30 mL). The chloroform layer was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. The residual oil was dissolved in hot cyclohexane.

After cooling, 1.76 g (<39.4 X) of light yellow crystals were collected, m.p. 73 C.

Analysis: Calculated for C 14 H 21 N 3 OS: C, 60.18; H 7.58; N 15.03 Found: C 60.32; H 7.70; N 15.13

Example 26 2,3-Dihydro-4-methyl-2- (2- (methyl-phenyl) -amino] -ethyl} -pyrido [3,2- (1,7,7-oxateepine-5 (4H) -thione oceacetate]: 17_

To a solution of 4 g (0.0155 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione in 70 ml chloroform, 10.0 g <0.066 mol) of benzylmethylamine was added. The solution was heated to reflux for 24 h. The reaction solution was washed with water (2 x 50 mL) and concentrated by rotary evaporation (ca. 70 ° C, water 44 7 8 1 0 2 aspirator). The residue was distilled using molecular distillation.

O

device at a temperature of 165 C / 0.1 mm. The residue was treated with oxalic acid in hot isopropyl alcohol. After cooling, two batches of crystals were collected. The purity of both batches was examined. The batches were combined and recrystallized together in hot isopropyl alcohol. After cooling, 3.69 g (55%) of pale yellow crystals were obtained, m.p. 163-166 C.

Analysis: Calculated for C 21 H 25 N 3 O 5 S: C, 58.45; H 5.84; N 9.74 Found: C 58.24; H 5.92; N 9.61

Example 29 2,3-Dihydro-2- (2- (methylamino) ethyl) -4-methylpyrido [3,2-e] -Δ. 4R-oxazepine-5 (4H) -thione oxalate Γ1: 1.57__ 4.0 g (0.016 mol) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido The 7 ', 1,42-oxazepine-5 (4H) -thione was suspended in a 30- * solution of methylamine in 70 ml of ethanol and stirred for 56 h at room temperature. Due to the incomplete reaction, the reaction solution was slowly heated to 55 ° C over 2 hours and stirred at this temperature for 24 hours. The methylamine was removed with a water aspirator over 1.5 hours. The resulting solution was concentrated on a rotary evaporator <70 ° C, water aspirator>. The residual oil was then dissolved in chloroform (150 mL) and washed with 2M aqueous potassium hydroxide (2 x 50 mL). The chloroform layer was dried over sodium sulfate and concentrated on a rotary evaporator (<70 ° C, water aspirator). The residue was dissolved in hot ethanol and treated with oxalic acid. After cooling, 2.0 g (37.5%) of yellow crystals were obtained, m.p.

137-138 C.

Analysis: Calculated for C 15 H 20 N 3 O 7 S: C, 46.63; H 5.22; N 10.67 found: c 46.47; H 5.35; N 10.85 «78102

Example 30 7-Chloro-2,3-dihydro-4-methyl-2- [2- (1-pyrrolidino) ethyl] -7-. 2.-C7a-L-4ZoKgftUJ> Pi, nR (4H) -one formate 1: 2 57 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido-Z3,2 -f7n, 47-oxateepin-5 (4H) -one <2.5 g; 0.009 mol) was dissolved in 50 ml of pyrrolidine and the solution was heated to reflux

At 80 DEG C. for 1 h. The pyrrolidine was removed by rotary evaporation (<80 DEG C., water aspirator) and the residue was dissolved in 100 ml of chloroform. The organic layer was washed with water (2 x 50 mL), dried over sodium sulfate and concentrated on a rotary evaporator (ca. 80 ° C, water aspirator). The residue was treated with fumaric acid and allowed to stand overnight. The obtained crystals were collected, 1.25 g o <23.2 X), m.p. 164-166 C.

Analysis: Calculated for C 25 H 30 N 3 O 2 Cl 2: C 50 → 05; H 5.04; N 7.00 Found: C 50.22; H 5.14; N 7.02

Example 31 7-Chloro-2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [2- (2- [trans] ocaacin-5 (4H) -one oxalate Z - 1: 13 2 , 8 g (<0.01 mol) of a sample of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] (4,7-oxazepin-5 (4H) -one) was added. to 1 ml of dimethylamine and stirred for 96 h in a sealed flask. The excess amine was allowed to evaporate and the residue 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 obtained crystals were recrystallized from the same solvent. Yield 1.5 g of oxalic salt <40 X), m.p. o 150-156 C.

Analysis: Calculated for C 18 H 18 N 2 O 2 Cl: C, 48.20; H 5.39; N 11.24 46 781 02 found: C 48.09; H 5.47; N 11.12

Example 32 4-Cyclohexyl-2-dimethyl-isomethyl-3-2,3-dihydropyrido [3- (2-phenyl) -4- (4H) - β-ox salad____ Using the procedure of Example 10, 2- (chloromethyl> -4-cyclohexyl-2,3-dihydropyrido [3,2-f], 4'-oxazepin-5 (4H) -one (interm. 12) was reacted With a 40% aqueous solution of dimethylamine and oxalic acid in isopropyl alcohol.

Example 33 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-phenylmethylpyrido 3,2- [1,7] oxazepin-5 (4H) -one oxalate 0: 1.57 hemi-hydrate__

A solution of 94.2 g (0.6 moles) of 2-chloronicotinic acid and 100 g (0.54 moles) of 1-benzyl-3-pyrrolidinol in 800 ml of dry tetrahydrofuran was added rapidly dropwise to a stirred suspension of 52 g (1.3 moles) of 60% sodium hydride / mineral oil in 500 ml of dry tetrahydrofuran at reflux temperature (addition time was about 1 h). The mixture was heated to reflux for an additional 1.5 h and then cooled to room temperature. About 1 liter of ethyl acetate was added and the subsequent filtration attempt failed. The mixture was allowed to stand overnight at room temperature and then concentrated on a 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. To the stirred solution were added 383 g (1.0 mole) of triphenylphosphine and 383 g (2.48 moles) of carbon tetrachloride. The mixture was heated under reflux for 1 h 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. The mass spectrum showed the presence of 2- (2-chloroethyl> -2,3-dihydro-4- (phenylmethyl) pyrido [3,2-t] CX, 47-oxazepin-5 <4H> -one (value 316), triphenylphospho- fin (value 262) and triphenylphosphine oxide (value 276).

1/3 of the residue was chromatographed by high pressure liquid chromatography, but purification of the compound failed. The remaining 2/3 of the residue was dissolved in 30 ml of chloroform and added to a solution of 30 g of dimethylamine in ethanol. This solution was heated to reflux for 4 h and concentrated on a 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 obtained crystals 9 g (5 X) o were recrystallized from the same solvent mixture, βρ. 95-96 C. Analysis: Calculated for C 44 H 54 N 9 O 7: C, 56.28; H 5.79; N 8.95 Found: C 56.61; H 5.76; N 8.77

Example 34 2- [2- (Dimethylamino) ethyl] -2,3-dihydropyrido [3,2-c] C, M-oxazidin-5 (4H) -one

A solution of 3.0 g (0.006 moles) of 2- [2- (dimethylamino) -ethyl] -2,3-dihydro-4-phenylmethylpyrido [3,2-e] Z, 47-oxazepin-5 (4H ) -one oxalate (1: 1,57-hemihydrate in about 50 ml of water, basified with dilute aqueous sodium hydroxide solution and then extracted three times with 50 ml portions of benzene. The residue was further azeotroped twice with about 50 ml of dry benzene and evaporated to dryness each time, the final residue was dissolved in 40 ml of liquid ammonia and small spheres of sodium were added to the solution 48 7 8 1 0 2 with stirring until the blue color remained. 20 minutes (addition time was about 1 h), then 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 was chromatographed. was prepared using preparative high pressure liquid chromatography and a silica gel column, and eluted with 75-X ethyl acetate / 25-X dimethylformamide. The product yield was 0.1 g <7 X). The ionization mass spectrophotometer of the chemicals gave a peak at 236, corresponding to a molecular weight of 235. The 1 H-NMR spectrum of the title compound was obtained in CDCl 3 containing 1 X tetramethylsilane (TMS) and corresponded to the putative structure, with minor impurities in the presence of dimethylformamide. <DMF) and mineral oil. Chemical shifts, stripe quality, and their significance are shown below: «ID-— CH2CH2N (CH3 * 2; C?’

6 O 1 H

Chemical shifts (line quality) Meanings 8.45 (multiline) H (8) and H (6) 8.00 (line) C-H (DMF>

7.85 (broad line) N-H

7.20 (two double lines) H (7) 4.65 (5-line) H <2) 4.05 (wide line) unknown impurity 3.50 (triple line) H2 <3) 2.95 (line) CH3 ( DMF) 2.90 (line) CH3 (DMF> 2.60 (triple line) ϋ2 ~ amino nitrogen 2.25 (line) N (CH3> 2 2.05 (multiline) H2 ~ amino nitrogen 0.7-1.7 (multiline) mineral oil i 49 7 8 1 02

Example 35 2- [3- (Dimethylamino) propyl] -2,3-dihydro-4-methylpyrido-Z3,2- [1,4] oxazepin-5- (4H-one fumarate): 1.57 hemihydrate To 5.0 g (0.021 moles) of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [5,2,2-C 7,4] oxathepin-5 (4H) -one was added while cooling with a water bath 20 g ( 0.38 mol) of a ΘΘ% aqueous solution of formic acid. To the resulting solution was added a solution of 37 X aqueous formaldehyde (treated with 13-X methanol), 10.7 g (0.13 mol). The resulting solution was heated on a steam bath for 5.5 h. 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 solution and extracted with four 50 ml portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was reacted with fumaric acid in hot isopropyl alcohol. The recovered product, 3.0 g (31.8 X), was recrystallized twice from isopropyl alcohol, m.p. 108-110 ° C. Analysis: Calculated for C 53.81; H 6.32; H 9.41 Found: C 53.69; H 6.33; N 9,41 36 2- [3- (Dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [5,2-f] £ 1,4,4-oxazepine 5 <4 H) -thione oxalate Z ~ 1; 27_

To a solution of 11.0 g (0.042 moles) of 2- [3- (dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,47] oxathepin-5 (4H) - in 125 ml of pyridine, 9.25 g (0.042 mol) of phosphorus pentasulfide were added. The mixture was heated to reflux for 3.5 h 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 i.e. 78102 potassium hydroxide, dried over sodium sulfate, filtered and concentrated on a rotary evaporator (water aspirator, 70 ° C). The residual oil was placed under reduced pressure with a vacuum pump o for 2 hours at 90 ° C, then cooled and reacted with oxalic acid in isopropyl alcohol. Two portions of product, 4.5 and 3.1 g, were collected, combined and recrystallized from isopropyl alcohol to give 6.5 g (34%) of yellow crystals, m.p. 136-138 C.

Analysis: Calculated for C 16 H 18 N 2 O 3 S: C, 47.05; H 5.42; N 9.16 Found: C 46.76; H 5.75; N 9.04

Example 37

7-Chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oceateepine-5 (4H) -t ion - fumarate] Tl: U

hemihydrate hemi-isopropyl alcoholate To 55 ml of a methanol solution containing 57 volumes of * dimethylamine was added 2.50 g (0.009 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido. The reaction vessel was sealed and allowed to stand for 16 h. Thin layer chromatography indicated that the reaction had proceeded to about 60 ° C. The solution was gradually heated to 45 ° C. C <heating time about 5 h) The methanol and unreacted dimethylamine were removed on a rotary evaporator o (water epirator, 60 ° C), the residue was dissolved 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. The residue was reacted with fumaric acid in isopropyl alcohol, and the resulting crystals (1.43 g <36.5 °) were recrystallized from isopropyl alcohol, dried thoroughly with a drying gun, mp 98-104 ° C.

5t 78102

Analysis: Calculated for C 48.84, H 5.98; N 9.23 Found: C 48.82, H 5.80; N 9.37 52 781 02

Table 1/0-γ (εΗ2'η-χ mQ ^ 2 '' 'V- ·

B R

Väii product

Well. A (Y) 0-2 BRX n Salt 1 pyrido ^ 3,2-tJ O -CH3 Cl 2 HCl 2 pyrido [3,2-f] S -CH3 Cl 2 3 pyrido [4,3-f] O -CH3 Cl2 HCl 4 pyrido / "4,3-f7 S -CH3 Cl2 5 pyrido /" 3,4-f7 O -CH3 Cl2 6 pyrido / 73,4-f7 S -CH3 Cl2 HCl7 pyridoZ "3,2-f7 O -CH 3 -CN 2 8 pyrido £ 3, 2- £ 7 O -C 2 H 5 Cl 2 HCl 9 pyrido £ 3.2- £ 7 S -C 2 H 5 Cl 2 HCl 10 7-Cl-pyrido O -CH 3 Cl 2 £ 3, 2- £ 7 11 7-Cl-pyrido S -CH3 Cl 2 a, 2-a 12 pyrido £ 3,2-fJ O “CgHj ^ Cl 11.

Table 2 53 781 02

v 0 * ~ r- (CHJ -Z

/ "'n / \ 2n; A / (V) Ύ'

u, 0-2 B R

Es im.

Well. A <Y) 0-2 BRZ n Salt 1 pyrido £ 3,2-f_7 0 -CH3 -N (CH3> 2 2 1.5 fumarate 2 pyrido / 3,2-f7 S -CH3 -N <CH3) 2 2 fumarate 3 pyrido £ 3,2-f_7 S -CHo -N (CH3), 2 0.5 ethanol JJ z fumarate 4 pyndo £ 4,3-fJ S -CH3 -N <CH3> 2 2 0.5 HCl 5 pyrido £ 3.2- £ 7 S -CH3 -N <CH3> 2 2 methiodide 6 pyrido £ 3,4-f_7 0 -CH3 -N <CH3> 2 2 J HoO.2 oxa- 7 pyrido £ 3, 4-fJ7 S -CH3 -N (CH3) 2 2 2 oxalate 8 pyrido £ 3.2-f7 O -CH3 -NH23 H2O oxalate 9 pyrido £ 3.2- £ 7 -CH3 -rf 2 maleate 10 pyrido £ 3, 2- £ 7 O -CH3 1-pyrrolidine-2 2 fumarate ny 11 i pyrido £ 3,2-f_7 O -CH3 N- (n-butyl) 2 2 maleate 12 pyrido ido £ 3,2-tJ O -CH3 -N (C2H5> 2 2 oxalate 13 pyrido £ 3, 2- [_7 O -CH3 1 -piperidinyl 2 oxalate 14 pyrido? 3,2-tJ O -CH3 -N < CH3> <Bent cause 1 i) 2 maleate 15 pyrido £ 3.2-Γ7 O -CHg -N <CH3) -CgH5 2 - 16 pyrido £ 3,2-fJ O -CH3 CH3 2 fumarate

V

17 py r ido £ 3.2 - f7 O -CH3 CHo 2 -

-G

ch3 18 pyrido £ 3,2-f7 O -CH3 y-> 2 - Λ f

OF

19 pyrido β 3,2-f_7 O -CHo -N N 2 - N / 54 7810 2

Table 2 (continued)

Es im.

Well. A (Y) 0-2 BRZ n Salt 20 pyridoZ "3,2-iJ 0 ~ C2 ^ 5 -NtCHg ^ 2 oxalate 21 pyrido £ 3.2-iJ O -CoHe 1-pyrrolidinyl oxyate 22 pyridoZB, 2-f7 S -CH3 -N_ O 2 - 23 pyrido £ 3.2- f7 S -CH3 -N (n-butyl i 2 2 oxalate 24 pyrido £ 3.2 ~ f.7 S -CH3 -N (C2H5) 2 2 oxalate 25 pyrido £ 3,2-f S -CHo 1-pyrrolidinyl oxalate P = 1 26 pyrido E 3,2-f_7 S -CH3 -N ^ N 2 1/5 oxalate 27 pyrido <f3,2-f7 S -C2H5 -N <CH3> 2 2 - 28 pyrido £ 3,2-f7 S -CH8 -N <CH3> <benzyl> 2 oxalate 29 pyrido £ 3,2-f_7 ”S -CH3 -NHCH3 2 1.5 oxalate 7 7-Cl-pyrido-O -CH3 -1-pyrrolidinyl 2 2.5 fumarate £ 3.2 - f7 31 7-Cl -pyrido-O -CH 3 -N (CH 3) 2 2 oxalate E 3,2-f7 32 pyrido E 3,2-fJ O -CgH 2 -N (CH 3) 2 1 oxalate 33 pyrido Z3,2-fJ O -CH 2 C 8 H 5 -N (CH 3) 2 2, 5 oxalate 34 pyrido 3,2- {JOH -N (CH 3) 2 2 - Η 2 ° 35 pyrido ^ 3,2-f_ 7 O -CH 3 -N <CH 2> 2 3 1/5 fumarate

0.5 HoO

36 pyrido £ 3,2-f7 S -CH3 -N (CH3) 2 3 2 oxalate 37 7-Cl-pyrido-S -CH3 -N <CH3> 2 2 J H2O

£ 3,2-μM (GH3) 2HOH

Claims (7)

78102 A process for the preparation of therapeutically useful pyrido ^ T, 47 oxazepine derivatives of the formula O-r— (CH) -Z, / Χν \ 2 n (Y ^^ - fOT) B ^ R in which the pyridine ring may be present in all its four positions which pyridine ring is optionally substituted by one or two Y radicals, wherein Y is halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, B is oxygen or sulfur, R is hydrogen, lower alkyl, cycloalkyl or phenyl-alpine alkyl, n is 1, 2 or 3, • 12 Z is -NP R, 1H-pyrazol-1-yl or 1H-imidazol-1-yl, 12 R and R are hydrogen, lower alkyl or phenyl-previous alkyl, 12 or R and P. together with the adjacent nitrogen atom form a heterocyclic residue which is i-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl, 4-substituted piperidin-1-yl yl, 4-morpholin-yl or 1,2,3,6-tetrahydronyridin-1-yl and its pharmaceutically acceptable salts, provided that when R is hydrogen, Z is never a primary or secondary amine, and further provided that when n = 3, Z is not 1H-pyrazol-1-yl, 1H-imidazol-1-yl, 2, 5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl, characterized in that a) a compound of formula 40 * 78102 .0- Γ— ( CH) -X wherein Β and Υ are as defined above, R is lower alkyl, cycloalkyl or phenyl-lower alkyl and X is chlorine or bromine is reacted with a compound of formula ZH wherein 7. is as defined above, followed by , if desired, the resulting compound of formula I wherein B is oxygen is reacted with a sulfurizing agent to give the corresponding azepine ion in which B is sulfur, or b) a cyano compound of formula CH is prepared to prepare a compound of formula I wherein Z is amino ) -CN 1 Ic where Y is as defined above and R is as defined in formula II, prim to a terminal amine of formula * O-r- (CH) -NH! "1 0 R wherein Y and R are as defined for formula Ile, or 57 781 02 c) for the preparation of such a compound of formula I. wherein Z is dimethylamino, reacting a primary amine of formula ΥΎ / O-r- (CH) -MHVVY \ 2 1-3 2 (Y) o-Tix) l) wherein Y and R are as defined in formula II with formaldehyde and formic acid to give a tertiary dimethylamine of formula ΥΎ ^ .0-r- (CH) -N (CH) Λ-NY \ 2 1-3 3 2 <Y, o: rf® ^ ry Id where Y and R are as defined in formula Ic-1, and, if desired, the resulting azepinone of formula Id is sulfurized to give the corresponding thione, or d) to prepare a compound of formula I wherein R is hydrogen, a compound of formula γ-' c— (CH) -z (y) —npjT / 2 13 Ie ° -2 (VL / I / '' S * CH 2 -phenyl wherein Y is as defined above and Z is as defined for IZ in the formula reacting with sodium and ammonia to give a compound of formula 58 7 8 1 02 —c - * (CH) -Ζ »V-rföO 1 σ h wherein Y and Z are as defined in formula Ie, followed, if desired, by m the free base of the compound prepared by method a, b, c or d is reacted with a pharmaceutically acceptable acid or a quaternary halide or sulfate to form a pharmaceutically acceptable salt of the compound of formula I. Process according to Claim 1, characterized in that 2- [5- (dimethylamino) ethyl] -2,3,3-dihydro-4-methylpyrido [3,2-f] (1,4-oxazepine-5 (4H) -thione) is prepared or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that 2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3.2-1] (1,4-oxazepin-5 (4H) -) is prepared. oni or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that 2- [2- (dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido [3,2-f] [1,47] oxazepine-5 (4H) -ion or its a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that 2,3-dihydro-2- [2- (methylamino) ethyl] -4-dimethylpyrido] -2,2- [1,7,4] oxazepine-5 (4H) -thione or a pharmaceutically acceptable suitable salt. Process according to Claim 1, characterized in that 7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-] 7β * oxazepine 5 (4H) -one or a pharmaceutically acceptable salt thereof. 781 02 Process according to Claim 1, characterized in that 7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-b] oxazepine 5 (4H) -thione or a pharmaceutically acceptable salt thereof.