FI78290B - 3- (PYRIDYLOXY) PYRROLIDINE- OCH 3- (PYRIDYLOXY) AZZEDINDERIVAT, SOM AER ANVAENDBARA SOM MELLANPRODUKTER. - Google Patents

Description

1,78290 3- (Pyridyloxy) pyrrolidine and 3- (pyridyloxy) acetidine derivatives useful as intermediates

Divided separated from application 833319

The present invention relates to novel compounds which can be used as intermediates in the preparation of 2,3-dihydropyrido [1,47 ”oxazepin-5 (4H) -ones and ions having antihistamine and antiallergic activity.

3-Aryl-1,4-benzoceazepin-5 (4H) -ones substituted with an aminoalkyl radical of the oxazepine nitrogen are disclosed in CH Patent 505,850 (C.A. 23,90000s).

The conversion of flavanones to benzoxazepinones substituted in the 2-aema with 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. S3 79098η). Trione derivatives have been obtained by treatment with phosphorus pentasulfide.

U.S. Patent 3,577,415 discloses certain chemical intermediates, 1-substituted-3-substituted phenoxypyrrolidines, for example: 1-methyl-3- (2-carbamoylphenoxy) pyrrolidine, 1-benzyl-3- (2-carbamoylphenoxy) pyrrolidine , and 1-methyl-3- (2-carboxyphenoxy) pyrrolidine. The novel compounds of this invention have the formula (Ϊ> 0-5- (O-β) 2,78290 in which the pyridine ring may be present in all four positions thereof, Y is halogen, lower alkyl , lower alkoxy, nitro or trifluoromethyl, R is lower alkyl, cycloalkyl or phenyl-lower alkyl, n is 1 or 2, and O °

II II 3 Q Q is -C-NH2, cyano or -C-OR, where R is H, an acid neutralizing ion or an esterifying group.

Compounds of formula IVa may be used as intermediates in the preparation of pyrido-doC1,41 oxazepine derivatives having antihistamine activity of formula

T— (CH) -Z

(γ) 07τί® I T

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, 1H-pyrazol-1-yl or 1H-imidazol-1-yl, and R is hydrogen aleropyl 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-di-: methylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl , 4-substituted piperidin-1-yl, 4-morpholinyl or 1,2,3,6-tetrahydropyridin-1-yl and pharmaceutically acceptable salts thereof, provided that when R is 3 78290 hydrogen * L no Ice * · oe * is not a primary or secondary amine, and further provided that when n = 3, Z is not 1H-pyrazol-1-yl-1H-im idazol-1-yl, 2,5-dimethylpyrrolidin-1-yl. 2-methoxypyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl.

In further defining the meaning of the symbols of the formulas set forth, and as they appear elsewhere in this specification and claims, the terms used have the following meanings.

Lower alkyl includes straight and branched chain radicals having 1 to 3 carbon atoms, and examples of such groups include methyl, ethyl, propyl, isopropyl »butyl, sec-butyl, tert-butyl, amyl, isoamyl. 1 H, hexyl, heptyl and octyl, etc. "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, methylcyclohexyl, cycloheptyl, and the like.

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

"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. Typical weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, cyclohexamine and the like.

4,78290

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 a mixture of alkali metal sulfide, and a mixture of phosphorus pentasulfide pyridine.

The compounds of formula I 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:

The guinea pigs are allowed to fast for 18-24 h in separate cages. Water is given ad libitum. On the day of the experiment, groups of three guinea pigs are injected intraperitoneally with 30 mg / kg of test compound prepared in a suitable medium. Thirty minutes later, histamine (1.2 mg / kg <= 2 x LDgg) 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 on the control animals. A dose that protects 50% of animals (PDgg) from death can be obtained from dose-response curves.

Compounds of formula I may be prepared by: a) a compound of formula (ϊ1ο-L0I>

./OF. ..OF

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 78290

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 azepine ion in which B is sulfur, or b) to prepare a compound of formula I in which Z is amino , reducing a cyano compound of formula (Y) o ^ t®JL /

O XR

wherein Y is as defined above and R is as defined in formula II, to the primary amine of formula

^ / 0 - ^ - (CH) -MH 0 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

YV / O — r— (CH) -MH

(ΤΓοΤΓ (®X ~ J "2

O R

wherein Y and R are as defined in formula II, to react with formaldehyde and formic acid to give a tertiary dimethylamine of formula O -r- (CH) -N (CH)

O

e 78290 wherein 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 (y) is obtained. —F (P) 1) 2 1-3 0-2 / ie O ^ CH -phenyl wherein Y is as defined above and Z is as defined in the formula for IZ, reacting with sodium and ammonia to give such a compound, of formula f- ^ Z'Y'O'y'c'Vi.r2 <Y) oTrf®l> wherein Y and Z have the same meaning as in formula Ie, followed, if desired, by the free preparation of the compound prepared by method a, b, c or d the base 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, le, If are all included in formula I.

7 78290

Detailed description of the invention

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 having 2-aemaemea ethyl and propyl radicals omega-substituted with the primary amine <-NH2>. R is never hydrogen.

Scheme V depicts methods for converting omega-N 1 -eubetylated 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 wherein R is hydrogen.

Preparation Examples 1-3 illustrate 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) substituted with 2- aemeasea with alkylhalo or alkyl cyano radicals. Compounds of formula III are usually formed in reaction mixtures without separation. Examples 1-37 (see also Table 2> describe the preparation of compounds of formula I).

8,78290

Scheme I

Preparation of intermediates (a) (b) / V °> - (CHa) n I * I TV.

} Hydrolysis - (CH *) n

(Y) o ^ T®T

Ua »H- or M.

JHalogenate -. (CKe) n (Y> o ^ {®Xc X h.10-

o "vx R

III

\ Heat and / or neutralize if necessary ^ CK-CcH *? N-h * 13

(Yi <«t®X) Srs.e / | Q

s λ Ilb ^ "^ 0-2 R 111

Possible chain

Note: to extend. xcs a) R is never hydrogen b) n * 1 or 2 X «halogen (Cl, Br) o .__ rCE3) W-aryl sulfonate, alkyl I ^ Y n * l sulfonate or X 0-2lsX [i / M * acid neutralizing ion, j—? egim. alkali metal O R 12c Q 1 -C-NH 2, -CN, -C-R 3 wherein R is H, M or an esterifying radical AHvdrolyzed when Q is other than ft ft -; -C-OH or C-OM.

** Diagram illustrating the proposed formation and cleavage of bonds to effect rearrangement - (CH2ll or 0 m «r®A Χ, ίΧβ

0 R

9,78290

Figure II

An alternative method for the preparation of a halogenated intermediate in a pyrido ring

/ N> sx0 '^ r- (CHa) -X recovery- w. 0 - (CHa) -X

<%. , Jf-ÄJ „O r $ £ 1Je 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 = other than H) / v-S-tCH2-halo O_ (c: ^) n-halo ;;; "" "€ Q„ S R ZIb £ k Ha

ZH ZH

+ s, <? 'T (CH “' n'Z 0 ~ T- C CH,) n-2 (Υ) 0-ΤΙ" ® 1 / * - (Υ) 0 ^ 2Κν) |)

Sulfurization- L Jv /

Ji | substance \ - N

S R o j,

Ib Ia

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

10 78290

Figure IV

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

/ V ^ O-T-TCHa ^ a-CN ^ 0 (cHsJj.j-SK,

Reduction J

· Rt "" I

O R 0 R T

Ile Ia

Scheme V

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

/ V / i-3-NH2 ίσί2} 1 “3N (CIV 2 ®μΓ © Ι) H00CH (Υ) 0-π®Τ)

Ic-1 ° ° Ic-2

Figure VI

Preparation of compounds having an unsubstituted azepine nitrogen (R = H) ° (V) (CH2 ^ 1-3 ”2 * O '-T-Cl2).

CaHs xe Jf

R = benzyl R = H

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

11,78290

With respect to the above methods and process steps, 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 pyridine ring ortho to the ether moiety, as a relatively pure product or, preferably, derived from the reaction mixture of the hydrolyzate 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 and carbon tetrachloride. The halogenation is carried out in a suitable organic solvent, preferably a refluxing organic solvent or a refluxing halogenating agent, preferably thionyl chloride. Chlorination temperatures in a very wide range can be used, for example from room temperature to 100 ° C or above, but temperatures of 50-80 ° 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, 12,78290 and usually neutralized or basified, preferably using a tertiary amine such as triethylamine, and then heated to a sufficient temperature and for a time sufficient to effect fusion of the carbonyl with basic nitrogen and cleavage of the cyclic amine and formation of 2- (2-alkylchloro- or bromo-oxazepine compounds of formula II) in, for example, 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 crystallization 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 tetrabutylaromonium 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 = i or 2), which results in side chain extension to aminopropyl n = 3 or alternatively as a starting material for methyl chain extension to aminoethyl.

13 78290

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 NHR R, wherein R and R are as defined above in connection with formula I, so that to give compounds of formulas Ia and Ib, respectively. The latter reaction is preferably carried out using an excess of amine, for example using volatile methylamines. 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 aminoethyl (n = 2).

If desired, the compound prepared in Step 5, wherein B is oxygen, can be sulfurized in Step 6, preferably by refluxing 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 a 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. 78290 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 the tertiary amine by selecting the appropriate reactants. This method can produce tertiary amino compounds of formula I where n = 3 and which cannot be prepared in step 5, and further provides an alternative way to prepare tertiary amino compounds of formula I where n = 1 or 2. Preparation of dimethylamine derivatives by reacting a primary amine with formaldehyde and with formic acid is a conventional method for the preparation of 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-benzyloxyacepone 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.

15 78290

The following invention is further described by way of examples. Prepared Examples 1-3 illustrate the preparation of compounds IVa of the invention. Intermediate Examples 1-12 and Examples 1-37 describe the preparation of intermediates and final products.

Preparation Example 1

Sodium 2-C (1-methyl-3-pyrrolidinyl) oxy 3-3-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 sulfoxide 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 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-methanol. The yield of the product was 5 g, decomposed at 240 ° C. NMR analysis showed that the compound contained 1/3 mole of sodium acetate as an impurity.

Analysis: Calculated for C 11 H 18 N 2 O 3 Na 2. 1/3 C 2 H 3 O 2 Na: C, 51.62; H 5.20; N 10.32 Found C 51.81; H 5.15; N 10.39

Preparation Example 2 3-C (1-Methyl-3-pyrrolidinyl) oxy 3-4-pyridinitrile fumarate C1: 2 3______

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-X sodium hydride. / 40 X mineral oil in 300 ml dimethylformamide. The mixture was stirred at room temperature for 1 hour and 16,78290 was added dropwise (74 g <0.53 moles) of 3-chloro-4-cyanopyridine in 200 ml of dimethylformamide while care was taken under cooling to keep the temperature between 30-40 ° C: The solution was stirred for 3 hours and an equal volume of water was not 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 X) was recovered. A 2 g sample was recrystallized from methyl isobutyl ketone. The product yield was 1.5 g, m.p. 172-174 C.

Analysis: Calculated for C 18 H 21 N 3 O 9: C, 52.42; H 4.86; N 9.65 Found: C 52.40; H 4.90; N 9.68

Preparedness example 3

Sodium 2-C (1-cyclohexyl-3-acetidinyl) oxy] -3-pyridinecarboxylate _____

A solution of 105 g <0.68 mol) of 1-cyclohexyl-3-acetidinol and 106 g <0.68 mol) of 2-chloronicotinic acid in 400 ml of dry dimethylformamide was added rapidly dropwise to 52 g <1, 35 moles) of 60-X sodium hydride / mineral oil suspended in 400 ml of dry methylformamide at 60 ° C. A slight exotherm could be 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 X) of crude title compound.

78290 Intermediate 1 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrr {10 [3,2-fHl, 4] -pK-α-?-Pin-5 (4H) -one hydrochloride __________

Hydrogen chloride gas was bubbled into euepenio with 150 g (0.61 mol) of sodium 2-C (1-methyl-3-pyrrolidinyl) oxy-3-pyridinecarboxylate in 1 liter of chloroform until pH 6 was reached. 350 g (1.34 moles) of triphenylphoefin and 350 g <2.3 moles) of carbon tetrachloride were added to the mixture, 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. The solution was stirred for 1 hour while cooling, and 200 ml of isooctane was added. The solution was extracted four times with a total of Θ00 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 a mixture of 500 ml of both isopropyl alcohol and isopropyl ether and oxidized with ethereal hydrogen chloride solution. The weight of the obtained crystals was Θ2 g <49 X). Some of them were recrystallized from isopropyl alcohol, m.p. 149-153 C.

Analysis: Calculated for C 21 H 21 N 2 O 2 Cl 2: C 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- (3Cl, 4] -oxathaepine-5 (4H) -thione ___ -. To a solution of 59 g (0.25 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido (3,2-f] Cl, 4] oxazepin-5 (4H) -one hydrochloride in 1500 ml in chloroform, 41.5 g (0.19 mol) of phosphorus pentasulfide 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 x) of a yellow solid precipitated. Part of this was recrystallized from ieopropyl alcohol, m.p. 134-136 C.

Analysis: Calculated for C 18 H 18 N 2 ClOS: C, 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-f] Cl, 4-oxazepin-5 (4H) -one hydrochloride 49 g (0.11 mol) sample 3 C (1-methyl-3-pyrrolidinyl) oxy] -4-pyridinecarbonitrile fumarate C1: 2 was partitioned between chloroform and saturated potassium carbonate solution. The aqueous layer was extracted twice with chloroform. All chloroform extracts were combined, dried and concentrated. The residue was dissolved in 125 ml of tbutanol and 34 g (0.6 mol) of potassium hydroxide solution was added. The mixture was heated at room temperature for 88 h 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 (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 789,78290 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 column with acetone as the liquid phase. The free base of the title compound was isolated after evaporation in an amount of 5.8 g (20%). To a portion of this free base, dissolved in isopropyl alcohol, was added ethereal hydrogen chloride solution and isopropyl ether. The formed crystals were collected and dried, m.p. 188-190 C.

Analysis: Calculated for 4N 2 O 2 Cl 2: 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] Cl, 4-oxathepine-5 (4H) -thione]

A solution of 5 g (0.021 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoC4,3-f] [1,4] oxazepin-5 (4H) -one and 5.1 g ( 0.0126 mol) of 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithio-diphosphetane-2,4-disulfide in 100 ml of dry toluene, stirred at reflux for 2.5 h. 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 an 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 5 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [3,4-oxazepin-5 (4H) -one _________

A solution of 78 g (0.5 moles) of 4-chloronicotinic acid and 52 g (0.52 moles) of 1-methylpyrrolidinol in 150 ml of dimethylformamide was added to a suspension of 44 g (1.1 20 7 8 2 90 moles) of 60% sodium hydride / mineral oil in 800 ml of dimethylformamide at a rate such that the temperature remains between 55-70 ° C (preheated to 55 ° C) The resulting o βθοβ 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). The residue was suspended in 800 ml of chloroform, and 188 g (<1.1 moles) of phenylphosphine was added, followed by 250 ml of carbon tetrachloride. The mixture was gently heated to 60 ° C, after which the reaction became exothermic and an ice bath was used for cooling to maintain the desired temperature at 60-65 ° C for about 20 minutes. The ice bath was removed and the mixture was 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. The chloroform was concentrated and the residue was chromatographed by high pressure liquid 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 (2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido (3,4 - [3,4] 4] oxazepine - 5 (4H) -thione monohydrochloride (2- (2-chloroethyl) -2, 3-Dihydro-4-methylpyrido [3,4-f] C1,4] oxazazin-5 (4H) -one (15 g <0.06 mol) was dissolved in 200 ml of dry toluene and added 15 ml of dry toluene. g <0.037 mol) of 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 column of silica and ethyl acetate as eluent. The fraction containing the material with a molecular weight of 257 was concentrated. , 1 g (0.6%), mp 168-171 ° C.

Analysis: Calculated for C 19 H 18 N 2 O 2 O 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-f] Cl, 4-oxathepine-2-propanenitrile --- 100 g (0.415 moles) 2- (2 -chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] Cl, 4-oceazepin-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 sulfate and concentrated on a rotary evaporator (70 ° C; water aspirator). The residue, the 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 calcium 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) to 1/3 of the original volume. After cooling, crystallization began. The crystals were filtered and washed with several portions of 22,782,290 ethyl acetate and ieopropyl ether. 30 g <35 X) 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 c 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 [3,2-f] Cl, 43-oxazepin-5 (4H) -one hydrochloride

To a stirred suspension of sodium hydride mineral oil (81.45 g of a 60% dispersion; 2.036 moles) in dimethyl sulfoxide o <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 sulfokide <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. 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 more than 99% complete. 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 (chloroform (3 x 250 mL)). The organic layer was dried over sodium sulfate and concentrated on a rotary evaporator (<70 ° C, calf spirator). 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 0 ^ 2 ^ ^ 6 ^ 2 ^ 2 ^^ - 21 ^ 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] [1,4] oxathepin-5 (4H) -t ion hydrochloride

About 50 g of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido (3,2 - [(1,4)] oxazepin-5 (4H) -one hydrochloride was partitioned between dilute aqueous sodium hydroxide solution (50 ml) and chloroform (50 ml). ) in progress. 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 viscous oil.

This oil was dissolved in isopropyl alcohol (ca. 200 mL) and acidified with hydrogen chloride. After cooling, 20 g <43 X) of crystals were collected, m.p. 133-135 C.

24 7 8 2 9 0

Analysis: Calculated for C 12 H 16 N 2 OSCl 2: C, 46.91; H 5.25; N 9.12 Found: C 47.33; H 5.38; N 9.10 Intermediate 10 7-Chloro-2- (2-chloroethyl> -2,3-dihydro-4-methylpyrido C 3,2- [3C] oxyepepin-5 (4H) -one-2- (2-chloroethyl) > -2,3-Dihydro-4-methylpyrido [3,2-f] Cl, 4-oxazepin-5 (4H) -one hydrochloride (10 g; 136 moles) was dissolved in methylformamide (150 mL) and heated to reflux. Sulfuryl chloride (20 g; 0.148 mol) was then added 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 preserved 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 C 11 H 48.42, 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 C 3,2- [311.4] oxazepine-5 (4H) -thione 6.0 g (0.022 moles) 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoC,2,2-f] [1,43-oxazepin-5 (4H) -one was suspended in 7 7 2 2 9 0 To 200 ml of toluene. To this suspension was added 2,4-bis (4-methoxyphenyl) -1,3-di-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 at reflux for 2 h and allowed to stand. 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 C: C 45.37; H 4.15; N 9.62 Found: C 45.40; H 4.20 N 9.71 Intermediate 12 2- (chloromethyl) -4-cyclohexyl-2,3-dihydropyridoC3,2-f]

Cl. 4 3-oxathepin-5 (4H) -one_.

A sample of 15 g (0.05 mol) of sodium 2-C (1-cyclohexyl-3-azetidinyl) oxy 3-3-pyridinecarboxylate obtained from method 23 was suspended in 100 ml of chloroform and hydrogen chloride was introduced thereto. 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 -1 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 q (7%), mp 120-122 ° C.

Analysis: Calculated for C 15 H 19 N 2 O 2 Cl: C, 61.12; H 6.50; N 9.50 found: c 61.11; H 6.62; N 9.32

Example 1 2-C2- (Dimethylamino) ethyl 3-2,3-dihydro-4-methylpyrido [3,2-f] C 1-3 oxazepin-5 (4H) -one fumarate [2: 33-90 g to <0.8 moles) of a 40-X aqueous solution of diethylamine was added in a steel bomb (25 g <0.09 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] C1,4] oxazepin-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 extracts. 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. 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 28 N 2 O 8: C, 53.90; H 5.90; N 9.92 Found: C 53.76; H 6.02; N 9.96 27 78290

EeimgrKlU 2 2-C 2- (dimethylamino) ethyl 1-2,3-dihydro-4-methylpyrido-C3,2-f3Cl, 4-oxazepine-5 (4H) -thion fumarate C1: 11,9a.n9li._2: 13_

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-methylpyridoC3,2-f3Cl, 4-oxateepine-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 (86X) 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 o solid, m.p. 103-118 ° C. The NMR spectrum showed that the crystals contained 1/2 mole of ethanol.

Analysis: Calculated for C 35 H 52 N 6 O 11 S 2 · · 53.45, H 6.48; N 10.39 Found: C 53.07, H 6.53; H 10.23

Example 3 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido-C3-2- [C13.43] oxateepine-5 (4H) -thion fumarate C1.13 To a solution of 113 ml (1 .0 moles) of 40-X aqueous dimethylamine and 326 ml of ethanol in a steel bomb, 48.4 g (0.189 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoC3,2- f3Cl, 43oksatsepiini-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-X 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-X ethyl alcohol. The crystals were filtered off and triturated with isopropyl ether at room temperature and again filtered off. After drying under vacuum at 85 ° C overnight, 72.45 g (79X) of crystals were obtained, m.p. 130-133 C.

Analysis: Calculated for C 17 H 23 N 3 O 5 S: 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 1-2,3-dihydro-4-methylpyrido-C4-3- [C1-4] oxazepine-5 (4H) -thione hydrochloride C2: 33

To a solution of 0.5 g (0.002 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoC4,3- [3Cl, 4-oxazepine-5 (4H) -thione in 20 mL of ethyl alcohol was added 2 ml of 40-X aqueous dimethylamine solution. The mixture was heated in a steel bomb at 100 ° 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. The product yield was 0.3 g o <47 X), m.p. (decomposes) above 200 C.

29 7 8 2 9 0

Analysis: Calculated for C 29 H 41 N 2 O 2 S 2 Cl 3: 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-b] 1,4-oxazepine-5 (4H) -thionimidodide 2- [2- (dimethylamino) ethyl 1-2 , 3-dihydro-4-methylpyrido [3,2-f] C 1-4] oxazepine-5 (4H) -thion fumarate Cl in ethanol C 2 (13, 3.8 g <0.01 mol), 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-X ethanol to 50-X methyl isobutyl ketone gave 2.5 g (78%) of product, m.p. 221-225 C.

Analysis: Calculated for C 22 H 22 N 2 O 3: C, 41.28; H 5.44; N 10.31 Found: C 41.29; H 5.51; N 10.30

Example 6 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyridol 3,4- [3,4-c] oceate-5 (4H) -one oxalate [1: 2] hemi - hvdraatti_

A solution of 5 g (0.02 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] Cl, 4-oxazepin-5 (4H) -one in 25 ml of dimethylamine, was 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 30 7 8 2 9 0 moles) 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. 179-161 ° C. Analysis: Calculated for C 34 H 48 N 6 O 21: C, 46.48; H 5.52; N 9.58 found: c 46.58; H 5.70; N 9.61

Example 7 2-C (2-Dimethylamino) ethyl 12,3-dihydro-4-methylpyrido-L3,4,4,11R, 1,4,3-oxathepine-6 (4H) -thione oxalate <1.2) 4 g (0.009) moles) sample 2-C2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyridoC3,4-f] C1,4] oxazepin-5 (4H) -one oxalate (1: 2) hemihydrate was partitioned between dilute sodium hydroxide and chloroform. in progress. 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 iso-propyl alcohol / 10-X water. The obtained crystals were collected by filtration. The yield of the oxalate salt was 0.37 g, ap. 111-114 C.

Analysis: Calculated for C 17 H 23 N 3 SO 8: C, 45.84; H 5.20; N 9.43 Found: C 45.46; H 5.38; N 9.28 78290

Example 8 2- (2-Aminopropyl) -2,3-dihydro-4-methyl-pyridoC3,2- (3Cl), 43-oxathepin-5 (4H) -one oxalate Cl; 13__ 5 g (0.22 mol) of 2,3-dihydro-4-methyl-5 (4H) -oxopyrido [3,2-f] C 1,43-oxazepine-2-propanenitrile in 150 ml of ethanol were treated with 1.5 g : 11a Raney nickel. The mixture was hydrogenated on a Parr 0 O 2 equipment temperature at 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 X), m.p. 126-134 C.

Analysis: Calculated for C 28 H 40 N 6 O 7; C 50.30; H 6.03; H 12.57 Found: C 50.46; H 5.71; N 12.21

Example 9 2,3-Dihydro-4-methyl-2-C2- (4-morpholinyl) ethyl 3-pyrido [C3.2-MC14] oxataepin-5 (4H) -one maleate C1: 1 3___ 16 g <0.58 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2- [3,4-oxathepin-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 morpholine was removed in vacuo at 50 ° C (rotary evaporator). To the free base obtained as a residue <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 leopropyl alcohol, m.p. o 163-165 C.

78290

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- (C2- (1-pyrrolidinyl) ethyl) pyrido [13,2- f] Cl. 4 3-oxazine-ft (4H) -one fumarate Cl: 13_ A sample of 16 g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] C 1-3 oxazepin-5 (4H) -one hydrochloride were 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 X) were collected and refilled with isopropyl alcohol, m.p. 147-149 c. Analysis: Calculated for C23 ° N3H29: 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-13,2-f] C 1-4 octanene-5 (4H) -one maleate [1: 1] ____ 16 g <0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoC3,2-f] C1,4] oxazepin-5 (4H) -one hydrochloride was dissolved dimethylformamide (30 ml) and di-n-butylamine o (30 ml). The solution was stirred at 90 ° C for 3 h and at 100 ° 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 mL) 33 7 8 2 9 0. Chloroform was removed on a rotary evaporator using a water epirator at 50 ° C.

The residual dimethylformamide and di-n-butylamine were removed under low vacuum at 50 ° C (rotary evaporator). To 13.6 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

At 20 ° C and filtered to give 13.6 g (56.5 X) of crystals which were recrystallized from isopropyl alcohols, m.p. 195-196 C.

Analysis: Calculated for C 21 H 23 N 2 O 3 • 61 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 D-2,3-dihydro-4-methylpyrido [3,2- [1,4] oxazepin-5 (4H) -one oxalate C1: 13-16 g (0.058 mol) ) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2- [3C] oxazepin-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 to reflux for 6 h. Diethylism was removed by rotary evaporation (70 ° C, water epirator). 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 (70 ° C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. After cooling, 18.6 g (87.7 X) of light brown crystals o (m.p. 150-155 ° C) were collected. Their sample was recrystallized three more times from isopropyl alcohol, m.p. 156-157 C.

34 7 8 2 9 0

Analysis: Calculated for C 17 H 25 N 3 O 8: 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-C2- (1-piperidinyl) ethyl;] pyrido-C3.2-al-1.43.9a (U-SPin-5 (4H) -one) was prepared by C1: 1 and 4 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2- (3Cl, 4] oxazepin-5 (4H) -one hydrochloride were dissolved in piperidine (30 ml) and heated at 80 ° C with stirring for 20 minutes. 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 oil crystals were collected and recrystallized from isopropyl alcohol to give 3.4 g (<62 X) of light brown crystals, m.p. 133-136 ° C.

Analysis: Calculated for C 18 H 25 H 3 O 6: C, 56.98; H 6.64; H 11.07 Found: C 56.95; H 6.87; N 10.79

Example 14 2,3-Dihydro-4-methyl-2- [2- [methyl (phenylmethyl) aminoethyl] -pYCidPC? 2-f 3 Cl.4] oxazoin-s- (4H) -one 4 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] C1,4] 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 aqueous sodium hydroxide (30 mL).

35 78290

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%) of light brown crystals were obtained, m.p. 167-169 C.

Analysis: Calculated for ^ 23-27Ν3 ° 6: c 62.57; H 6.16; N 9.52 Found: C 62.28; H 6.16; N 9.24

Example 15 2,3-Dihydro-4-methyl-2- (2- (methylphenylamino) ethyl] pyrido [L3.2- [C3-4] 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 to room temperature. at 95 C with stirring for 2 days. Excess N-methylaniline was removed by rotary evaporation

O

<95 C; vacuum pump). The residue was dissolved in chloroform (80 ml) and kept with dilute aqueous sodium hydroxide solution (30 ml). The chloroform layer was decolorized with activated carbon and dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The remaining residue was dissolved in ethyl acetate (50 mL) and purified by high performance liquid chromatography using silica gel pad and ethyl acetate as eluent. After purification, crystals of ethyl acetate formed. These crystals were recrystallized from ethyl acetate to give 1 <40 g of οι X) light brown crystals.

Alarm: calculated for c 18 H 21 O 3 • 2: C, 69.43; H 6.79; N 13.49 Found: C 69.31; H 6.77; N 13.54 36 78290

Example 16 2- [2- (2,5-Dimethyl-1-pyrrolidinyl) ethyl] -2,3-dihydro-4-methyldridido [2,3-b] aze-indin-5 (4H) -one fumarate 1: 17 5.0 g (0.021 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-L7 Cl, 47] oxazepin-5 (4H) -one were dissolved in 25 ml: absolute ethanol and 3 g (0.03 mol) of 2,5-dimethylpyrrolidine were added, the solution was heated at 75 DEG C. for 48 h with stirring, and since the reaction was incomplete, a further 2,5-dimethylpyrrolidine was added at this time ( 1.00 g; 0.01 mol) and the reaction was continued, after 5 days the reaction was still incomplete and more 2,5-dimethylpyrrolidine (1.00 g; 0.01 mol) was added and 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 solution (2 x 75 ml). The organic layer was dried over sodium sulfate, filtered and concentrated on a rotary evaporator (70 ° C, water epirator). 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 were collected, m.p. 161-162 ° C. Analysis: Calculated for C 21 H 29 N 3 O 6: 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] pyrrolidin-2-yl] oxazepin-5 (4H) To a solution of 3.5 g (0.0145 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2 - {1,4] oxazepine-5 (4H > -one in ethanol (15 ml), 2-methylpyrrolidine (37,78290 (5.0 g, 0.063 mol)) was added and the solution was heated to reflux for 3 hours with stirring. The ethanol was removed on a rotary evaporator (water aspirator, 80 DEG 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%) of a clear oil.

Analysis: Calculated for C 18 H 23 N 2 O 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-C2- (1H-pyrazol-1-yl) ethyl] pyrido [3.2- f] oxazepin-5 (4H) -one

To a suspension of sodium hydride (1.2 g active; 0.05 mol) in dimethylformamide (15 ml) was added dropwise a solution of pyrazole (3.10 g; 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] [4,4] oxathepin-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 78290 which was washed with dilute aqueous sodium hydroxide solution (1 x 50 ml), dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. , water aspirator).

The material was purified by high pressure liquid chromatography using ethanol: methanol 95: 5 by volume 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 14 H 16 N 4 O 2: C, 61.75; 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] -7-4-methylpyrido-Z3-2-7,7-oxoxepepin-5 (4H) -one_

To a solution of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,47] oceazepin-5 (4H) -one, 9.12 g < 0.038 mol) in dimethylformamide (30 ml), 5.66 g (0.083 mol) of imidazole were added and 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 by rotary evaporation (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 18 H 18 N 2 O 2: C, 61.75; H 5.92; N 20.58 I found: C 61.36; H 5.92; N 20.60 39 78290

Example 20 2- [1- (Dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido [2- (1'-oceacepin-5 (4H) -one oxalate) in 17-30 ml of dimethylamine which was recovered at 0 DEG C., 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 sealed and stirred for 70 h at room temperature. The solution was then cooled to 0 ° C and the bottle 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 organic layer was dried over sodium sulfate, filtered and concentrated on a rotary evaporator (<70 ° C, water aspirator). The residue was dissolved in hot isopropyl alcohol and treated with oxalic acid. After cooling, 4.5 g (61.5%) of product were recovered, m.p. 208 C.

Analysis: Calculated for C 18 H 18 N 2 O 2 · 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 [1,2-f] n. 47 branches sepin-5 (4H) -one - oxa 11a Z (1: 17_ 3 g <0.01 mol) 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [2 3- [1,7,4'-oxazepin-5 (4H) -one hydrochloride was dissolved in pyrrolidine (30 ml) and heated at 70 ° C for 30 minutes with stirring. 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 brown oil using a rotary evaporator (70 ° C, water aspirator). The oil was dissolved in hot isopropyl alcohol and treated with oxalic acid. After cooling, the obtained 40,78290 solid was recrystallized from isopropyl alcohol to give light brown crystals of 1.80 g <45.4%>, m.p. 185-188 ° C. Analysis: Calculated for ^ 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- (2- (4-morpholinyl) ethyl) pyrido [2,3-b] oxa] epine-5 (4H) -thione (4.5 g <0.018 mol) 2 (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2- (f] [1,4] oxazepine-5 (4H) -thione) was dissolved in morpholine (30 ml). This solution was heated with stirring at 50-60 ° C for 6 h. The morpholine was then removed using a rotary evaporator (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%) of pale yellow crystals, m.p. 152 o o 153 C.

Analysis: Calculated for C 15 H 21 N 2 O 2 S: C, 58.61; H 6.89; N 13.66 Found: C 58.48; H 6.92; N 13.62

Example 23 2-C2- (Dibutylamino) ethyl L7-2,3-dihydro-4-methylpyrido-Z3. 2-f7 ΖΊ. (4-oxazoline-5 (4H) -thione oxalate Z -1: 17-4 g (0.016 mol) 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1-pyrido [3,2-f] [1], The 47-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 dime; o Stylformamide was removed by rotary evaporation <80 ° C, 4i 78290 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 using a rotary evaporator o (70 ° C, water aspirator). The residue was dissolved in boiling water and treated with oxalic acid. After cooling, the resulting oxalate salt was filtered off and recrystallized from isopropyl alcohol to give 3.2 g (47%) of yellow crystals, m.p. 208 ° C. Calculated for C 21 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 24 2- [2- (Diethylamino) ethyl] -2,3-dihydro-4-methylpyrrolo [3,2- [7,7] oxazepine-5 (4H) -thione oxalate Z - 1: 17_ 4 g (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-, 2- (7,4-oxazepine-5 (4H) -thione) were suspended in diethylamine (30 ml). - type formamide until dissolution occurred <10 ml).

o

The stirred solution was heated at 65 ° C for 8 h. The di-ethylamine 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 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. Cooling. . then 1.7 g <28.5%) of the oxalate salt were obtained, ep.

o 142-144 C.

Analysis: Calculated for C 17 H 25 N 3 O 5 S: C, 53.25; H 6.57; M 10.95 Found: C 53.14; H 6.60; N 10.72 42 78290

Example 25 2,3-Dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [2-UCl] 47 oxazepine-5 (4H) -thione octalate Li: 17-5 g (0.02 mol) 2 - (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-t] Cl, 47 ° xazepine-5 (4H) -thione was dissolved in 30 ml of pyrrolidine, and the solution was heated at 60-80 ° C. 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 of <45%> product, m.p. 141 C. Analysis: Calculated for C 21 H 19 N 2 O 3 S: C, 53.53; H 6.08; N 11.02 Found: C 53.39; H 6.11; ; N 10.91

Example 26 2,3-Dihydro-2 - [(2- (1H-imidazol-1-yl) ethyl] -4-methylpyrido-η 2 -2,7-oxazepine-5 (4H) -thione oxalate E 2: 37_

To a solution of 4.5 g (0.018 moles) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-d] Cl, 4-ioxazepine-5 (4H> -thione in dimethylformamide (35 mL)) was added. imidazole <2.20 g; 0.038 mol). 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 78290

Analysis: Calculated for C 18 H 18 N 2 O 2 N 2 N 2 S: C, 48.22; H 4.52; N 13.23 Found: C 48.04; H 4.62; N 13.18

Example 27 2- (2- (Dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido-Z,2- [7,4] oxazepine-5 (4H) -thione] 5.00 g (0.016 mol) of 2- (2- chloroethyl) -4-ethyl-2,3-dihydropyrid-2,3,2-7,7-oxathepine-5 (4H) -1 ion 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 (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%) of pale yellow crystals were collected, m.p. 73 C.

Analysis: Calculated for C 18 H 18 N 2 OS: C, 60.18; H 7.58; N 15.03 Found: C 60.32; H 7.70; N 15.13

Example 28 2,3-Dihydro-4-methyl-ΐ-Σ-Ζ'Σ-β-methyl (phenyl) -imethyl) amino] -ethyl] PyridoZ3,2-f7 <T1, 47oxateepine-5 <4H> -thion-oceanate £ Ί: 17_! To a solution of 4 g (0.0155 moles) of 2- (2-chloroethyl) -V, 2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 <4H > - thione in 70 ml of chloroform, 10.0 g (0.086 mol) of benzylmethylamine were added. The solution was heated to reflux for 24 h. The reaction solution was washed with water (2 x 50 mL) and concentrated to dryness on a rotary evaporator (ca. 70 ° C, water 44 7 8 2 9 0 epirator). The residue was distilled using a molecular distillation apparatus at 165 ° C / 0.1 mm. The residue was treated with oxalic acid in hot ieopropyl 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 ieopropyl 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-methylpyrrole-3,7,4-oxazepine-5 (4H) -t ion oxalate Z - 1; 1.57 - 4.0 g (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-b] Cl, 47-oxazepine-5 (4H) -t the ion 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 an aqueous aspirator over 1.5 hours. The resulting solution was concentrated on a rotary evaporator (<70 ° C, water aerator). 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.

o 137-138 C.

Analysis: Calculated for C 18 H 28 N 2 O 2 S: C, 46.63; H 5.22; N 10.67 found C 46.47; H 5.35; N 10.85 7 8290

Example 30 7-Chloro-2,3-dihydro-4-methyl-2- (2- (1-pyrrolidino) ethyl] -7-pyrido [3,2-L] Cl. 47-oxazepin-5 (4H) -one fumarate: 2,57 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [5,2-f] Cl, 4-oxazepin-5 4H) -one <2.5 g; 0.009 mol) was dissolved in 50 ml of pyrrolidine and the solution was heated to reflux

At Θ0 ° C for 1 h. The pyrrolidine was removed on a rotary evaporator (<80 ° 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 <-25 ^ 30 ^ 3 ^ 12 ^ *: ^ 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 [3,2- [1,4] oxataepin-5 (4H) -one oxalate f1; 11-2.8 g <0.01 mol) sample 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [4,7] oxazepine-5 (4H)] -one was added to 25 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 (40X), m.p.

::: o 150-156 C.

Analysis: Calculated for C 18 H 28 N 2 O 9 Cl: C, 48.20; H 5.39; N 11.24 46 78290 Found C 48.09; H 5.47; N 11.12

Example 32 4-Cyclohexyl-2-Z "(dimethylaminomethyl 1L7-2,3-dihydropyrido-Z3.2- [1,47] oxazepin-5 (4H) -one oxalate_ Using the procedure of Example 10, 2- ( Chloro-dimethyl-1--4-cyclohexyl-2,3-dihydropyrido [3,2- [7] * 1,47-oxazazin-5 <4H> -one (intermediate 12>) to react with 40% dimethylamine with aqueous solution and oxalic acid isopropyl alcohol.

Example 33 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-phenylmethylpyrido-3.2- [7,7] oxa-sepin-5 (4H-one-oxa) , 57 hemi- hvdraat t i_

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] Cl, 4 / oxazepin-5 (4H) -one (value 316), triphenylphosphine (value 262) and triphenylphosphine oxide (value 278).

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 any 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 1M 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, m.p. 95-98 C. Analysis: Calculated for 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-f] [1,4] oxataepin-5 (4H) -one__

A solution of 3.0 g (0.006 moles) of 2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-phenylimethylpyrido [3,2-f] 2,7,4-oxate sepin-5 (4H) -one oxalate ε1: 1.57 hemihydrate in about 50 ml of water, basified with dilute aqueous sodium hydroxide solution and then extracted three times with 50 ml of separate benzene. The combined benzene extracts were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (steam bath / 50 mm). 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 no liquid ammonia and small spheres of sodium were added to the solution 48 7 8 2 9 0 with stirring until the blue color remained for 20 minutes. (Addition time was about 1 h). 3 g of ammonium chloride were then 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 using preparative high pressure liquid chromatography and silica gel column, and eluted with 75% ethyl acetate / 25% dimethylformamide. The product yield was 0.1 g <7%). The chemical ionization mass spectrophotometer 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% tetramethylsilane (TMS) and corresponded to the putative structure with dimethylformamides as minor impurities. (DMF) and mineral oil. Chemical shifts, stripe quality and their significance are presented below:

DO

B

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 (stripe) CH3 (DMF) 2.60 (triple stripe) H2-amino nitrogen 2.25 (stripe) N (CH3) 2 2.05 (multiline) H2-ti amino nitrogen 0.7-1.7 (multiline) mineral oil 49 78290

Example 35 3- [3- (Dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3- (4,7-oxazepin-5 (4H) -one fumarate]: 1.57 hemi-hydrate ____ To 5.0 g (0.021 mol) of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [C3.2-17] 1,47-oxazepin-5 (4H> -one) was added while cooling in a water bath. g <0.38 moles) of 88 X 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 40 H 59 N 9 O 17: C, 53.81; H 6.32; N 9.41 Found: C 53.69; H 6.33; N '9.41

Example 2 2- [3- (Dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2-f] 7,4,7-oxazepine-5 <4 H) -thione oxalate £ 1: 2

To a solution of 11.0 g (0.042 moles) of 2- (3- (dimethylamino) propyl] -7-2,3-dihydro-4-methylpyrido [3,2-f] [1,47] oxat-. . epin-5 (4H) -one in 125 mL of pyridine, 9.25 g <0.042 moles) of phosphorus pentasulfide was 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 50,78290 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 (34X) of yellow crystals, o βρ. 136-138 C.

Analysis: Calculated for C 47.05; H 5.42; K 9.16 Found: C 46.76; H 5.75; N 9.04

Example 37 7-Chloro-2- (2- (dimethylamino) ethyl) -2,3-dihydro-4-methyl-

pyrido * f3,2-f_ZZ "1,4,4-oxazepine-5 (4H) -t ion - fumarate 1: 1J

hemihvdraatti. hemi-isopropyl alcohol-55 any methanol solution containing 57 volumes of X-dimethylamine was added 2.50 g (0.009 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3], 2- [7,7,4] oxazepine-5 (4H> -thion. The reaction vessel was sealed and allowed to stand for 16 h. Thin layer chromatography indicated that the reaction was about 60-X. The solution was gradually heated to o-45 ° C. (heating time about 5 h) The methanol and unreacted dimethylamine were removed on a rotary evaporator (water aspirator, 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 (36.5X), were recrystallized from isopropyl alcohol, dried thoroughly with a drying gun, mp 98-104 ° C.

51 78290

Analysis: Calculated for C 9 H 8 N 2 O 3 gCl 2 Sg; C 48.84, H 5.98; N 9.23 Found: C 48.82, H 5.80; N 9.37

Table 1 52 78290

, -, / O-V- <CH2> n-X

> i} Intermediate

Well. A <Y) 0-2 BRX n Salt 1 pyrrole-3,2-f7 O -CH3 Cl2 HCl 2 pyrido [3.2-f7 S -CH3 Cl2 - 3 pyrido / f4,3-f3 O -CH3 Cl 2 HCl 4 pyrido / -4,3-f7 S -CH3 Cl2-5 pyridoAB4-4-CH3 Cl2-6 pyrido / 3, A-iJ S -CH3 Cl2 HCl7 pyridoZ "3.2- £ 7 O -CH 3 -CN 2 8 pyrido73,2-C 7 O -C 2 H 5 Cl 2 HCl 9 pyrido £ 3,2-C 7 S -C 2 H 5 Cl 2 HCl 10 7-Cl-pyrido O -CH 3 Cl 2

£ 3,2-f

11 7-Cl-pyrido S -CH 3 Cl 2 - r n, 2-a 12 pyrido E 3,2-f7 O -CgH 2 Cl 1 -

Table 2 53 78290

CO -T- (CEU -Z

T

w ·

'*' 0-2 B R

Es im.

Well. A <Y) 0-2 BRZ n Salt 1 pyrido £ 3,2-f70 O -CH3 -N (CH3) 2 2 1,5 fumarate 2 pyrido [3.2-f7 S -CH3 -N <CH3> 2 2 fumarate 3 pyrido ε 3,2-tJ S -CH 0 -N (CH 2 O, 2 0.5 ethanol J 0 * fumarate 4 pyridoZT4,3-f7 S -CH 3 -N (CH 3) 2 2 0.5 HCl 5 pyrido ε 3,2-C7 S -CH3 -N (CH3> 2 2 methiodide 6 pyrido [3,4-f] O -CH3 -N (CH3) 2 2 | HgO4 oxa-7 pyrido [3,4-f7 S - CH3 -N <CH3> 2 2 2 oxalate 8 pyrido £ 3,2-tj O -CH3 -NH2-3 i H2O oxalate 9 pyrido do 3,2-tJ O -CH3 -1 $ O 2 maleate 10 pyrido £ 3,2-f-70-CH3 1-pyrrolidine-2 2 fumarate yl 11 pyrido £ 3,2-f-70-CH3 N- (n-butyl) 2 2 maleate 12 pyrido £ 3,2-f CH3 -N <C2H5> 2 2 oxalate 13 pyrido / "3.2- £ 7 -CH3 1-piperidinyl 2 oxalate 14 pyrido £ 3.2-f7 O -CH2 -N <CH3> <benzyl> 2 maleate 15 pyrido £ 3,2-fJ O -CHg -N <CH3> -C6H5 2 "16 pyrrole to £ 3,2-f_7 O -CH3 CH3 2 fumarate - y

-OF

17 pyrido ε 3,2-f7 O -CH3 CH3 2 -? : ch3 *. *. 18 pyrido £ 3,2-f7 O -CH3 / == T \ ^ “J Λ /

OF

r = ^ 19 pyrido £ 3,2-f7 O -CH, -N N 2 - • ··· d X / · 54

Table 2 (continued) 78290

Es im.

Well. A <Y) 0-2 BRZ n Salt 20 pyrido ^ 3.2-17 O -C2H5 -N (CH3> 2 2 oxalate 21 pyridoZ3.2-17 O-c2 ^ 5 1-pyrrolidinyl 2 oxalate 22 pyridoZS, 2 -f7 S -CH3 -li_ O 2 - 23 pyridoZ3,2-f7 S -CH3 -N (n-butyl) 2 2 oxalate 24 pyrido £ 3,2-f7 S -CH3 -N <C2H5> 2 2 oxalate 25 pyridoZ3,2-f7 S -CHo1-pyrrolidinyl oxalate Γ = Η 26 pyrido £ 3,2-fJ S -CH3 2 1.5 oxalate 27 pyridoZ3,2-iJ S -C2H5 -N (CH3 > 2 2 - 28 pyridoZ3,2-fJ S -CH3 -N (CH3) (Bent cause 1 i) 2 oxalate 29 pyrido £ 3.2-iJ S -CH3 -NHCH3 2 1.5 oxalate 30 7-Cl-pyrido - O-CH3 -1-pyrrolidinyl 2 fumarate Z3,2-f7 31 7-Cl-pyrido-O-CH3 -N (CH3> 2 2 oxalate Z3,2-f7 32 pyrido £ 3 , 2-f_7 0 -CgH 2 -N <CH 3) 2 1 oxalate 33 pyridoZB, 2-t10 O -CH 2 C 6 H 5 -N (CH 3> 2 2 5 oxalate 34 pyridoZ3,2-f7 OH -N (CH3) 2 2 - 2 35 pyrido <f3,2-f7 O -CHo -N (CH3) o 3 1.5 fumarate 0.5 H2O 36 pyrido £ 3.2 f7 S CH3 -N <CH3> 2 3 2 oxalate 37 7-Cl- pyrido- S -CH3 -N <CH3> 2 2 $ h20 a, 2-zj i (ch3) 2hoh

Claims (2)

78290 55 A compound of the formula - (CH) (y, o - ^ - @ Cq i in which the pyridine ring may be present in all four positions thereof, Y is halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl, R is lower alkyl , cycloalkyl or phenyl-lower alkyl, n is 1 or 2, and: V: OO II II 3 Q Q is -C-NH, cyano or -C-OR, where R is H, an acid neutralizing ion or an esterifying group. Compound according to Claim 1, characterized in that it is sodium 2 - [(1-methyl-3-pyrrolidinyl) oxy] -3-pyridinecarboxylate or its free base.