CS249541B2 - Method of 1,2,4-oxadiazine's new derivatives production - Google Patents

Abstract

the 1,2,4-oxadiazine compounds of formula I, where they mean R 11 is phenyl optionally monosubstituted chlorine atom or methyl group, R2 * phenyl, R 4 is hydrogen or methyl; R 5 is cyclohexyl or R 4 and R 5 taken together the group of formula V, wherein R6 is hydrogen or alkoxy s With 1 to 4 carbon atoms and n and m are 0 or 1. These compounds are prepared by reacting the compound of formula II wherein R 1, R 2, m and n are the same as above and Z is a halogen atom or a sulfonyloxy group; the compound of formula (III) wherein the meaning is R4 and R5 are the same as above. New compounds exhibit anti-inflammatory properties diuretic and antiarrhythmic effect.

Description

The invention relates to a process for the preparation of novel 1,2,4-oxadiazine derivatives of the general formula I / NH _V

CHj 'Χθχ Λ (I) where they mean

.....--------. · R ·, - ......

R ^{1 is} phenyl, optionally monosubstituted with a chlorine atom or a methyl group,

R ² phenyl,

R ⁴ is hydrogen or methyl,

R ⁵ cyclohexyl or

R ⁴ and R ⁵ together represent a group of formula V

(Iv) where

R ⁶ is hydrogen or C 1 -C 4 alkoxy and m and n are 0 or 1.

The compounds of the formula I as well as the pharmacologically acceptable acid addition salts of the quaternary acid salts and quaternary salts are prepared according to the invention by reacting the compound of the formula II. NH.

R '- (C 1-4) _m - (CH) _n -c' ^{c H} 2 ', ii l

R ² S Sh 1 -CH ² -Z '0 cm meaning R ¹ , R ² , man is the same as above and

Z is a halogen atom or a sulfonyloxy group, with a compound of formula III

R ⁴ /

HN (ΙΠ)

^B-1 and it fil wherein the meaning of R ⁴ and R ⁵ is the same as above.

The reaction is carried out in the melt or solvent by heating, preferably to temperatures between 80 and 180 ° C. The amine of general formula (III) used in excess may also serve as solvent. Suitable organic solvents are aromatic hydrocarbons such as benzene, toluene, xylene or their chlorinated derivatives. The reaction is preferably carried out in the presence of an acid binding agent.

Preferred acid-binding agents are alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, as well as the amine used in excess.

The starting compounds of formula II can be prepared by known methods [Chem. Ber. 108, 1911 (1975)], from the corresponding 6-hydroxymethyl-1,2,4-oxadiazines derivatives by halogenation or acylation with sulfonic acid halides.

The compounds of the formula I obtained according to the above process can be isolated in a manner known per se, for example by extraction or crystallization from the reaction mixture.

The compounds of formula I may be converted by reaction with inorganic or organic acids into the corresponding acid addition salts or may be liberated from their salts. By reaction with alkyl halides or alkyl sulfates, the compounds of formula I can be converted into the corresponding quaternary salts.

The compounds of formula I exhibit a potent and long-lasting effect causing peripheral blood vessel widening and lowering blood pressure. They increase the patency of coronary arteries and, in addition to their anti-inflammatory and diuretic effect, their antiarrhythmic effect is also significant.

To date, only 1,2,4-oxadiazine derivatives having an imino group at the 5-position have been known from the literature [J. Heterocycl. Chem. 9, 435 (1972)], or substituted by a nitrophenyl group [C. A. 75, 20 450 (1971)] The known compounds have an antibacterial effect.

The compounds of formula (I) may be used in pharmacy in the form of the active ingredient, as well as preparations containing inert solid or liquid, inorganic or organic carriers. The preparations are prepared in a manner customary for the manufacture of medicaments.

The preparations may be formulated in the form of tablets, dragees, solutions, emulsions, etc.

The active compound content of the preparations can vary within wide limits and ranges from 0.005 to 90%.

The daily dosage of the active ingredient can vary within wide limits depending on the age, weight and condition of the patient, the type of formulation and the activity of the active ingredient. The daily dose is generally 1 to 500 milligrams / kg. These figures are indicative; Depending on the requirements of the individual case and the doctor's prescription, the deviation may move up or down.

Further details of the invention can be seen from the following examples, which are not limiting.

Example 1

To 5.0 g of 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine (Chem. Ber. 108, 1911 (1975)) was added 37 ml of cyclohexylamine, followed by reaction mixture. The excess cyclohexylamine was evaporated in vacuo, 100 ml of ethyl acetate was added to the residue, then the mixture was heated to boiling point and the insoluble material was filtered off. acidification by introducing hydrogen chloride gas to give 4.0 g of 3-phenyl-6-cyclohexylaminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine hydrochloride.

Mp: 240-244 ° C (dec.) From isopropanol.

Analysis for C16H25N3OCl2 calculated:

C 55.49, H 7.28, N 12.14,

20.48% Cl;

found:

H, 7.40; N, 12.04.

20.25% Cl.

LD50 = 51 mg / kg b.w. in mice. In anesthetized cats, the compound reduces blood pressure by 20% at a dose of 2.5 mg / kg i. V. 10 minutes after administration. In dogs, the compound reduces peripheral resistance by 15% at a dose of 10 mg / kg i.v. At a dose of 5.1 mg / kg, the compound provides a 15% protective effect in the dextran edematous test in rats.

Example 2

Following the procedure described in Example 1, 3-phenyl-6- (N-methyl-N-cyclohexyl-6-amino) was prepared by reacting 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine with methylcyclohexylamine. methyl 5,6-dihydro-4H-1,2,4-oxadiazine hydrochloride.

Mp: 243-246 ° C (from abs. Alcohol). Analysis for C17H27N3OCl2 calculated:

% C, 56.66;% H, 7.55;% N, 11.66.

19.68% Cl;

found:

H, 7.91; N, 11.35.

20.09% Cl.

Example 3

To 2.0 g of 3-phenyl-6-tosyloxymethyl-1,5,6-dihydro-4H-1,2,4-oxadiazine was added 30 ml of chlorobenzene and 3 ml of methylcyclohexylamine. The reaction mixture was refluxed for 8 hours. After cooling, the precipitated product is filtered off, dissolved in ethyl acetate and the solution is acidified with an alcohol acidified with hydrochloric acid. 1.1 g of 3-phenyl-6- (N-methyl-N-cyclohexylamino) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride are obtained. The product is identical to the product of Example 2.

Example 4

To 10.5 g of 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine was added 6.7 g of 1,2,3,4-tetrahydroisoquinoline, 6.9 g of anhydrous carbonate. potassium chloride and 8 ml of chlorobenzene. The reaction mixture was refluxed for 6 hours, then the solution was filtered hot and cooled. 6.5 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine are obtained in crystalline form.

Mp: 187-189 ° C.

Example 5

To 3.46 g of 3-phenyl-6-tosyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine was added 1.33 g of 1,2,3,4-tetrahydroisoquinoline, 1.38 g of anhydrous carbonate potassium chloride and 30 ml of chlorobenzene. The reaction mixture was refluxed for 2 hours, then decolorised warm and filtered. After cooling, 1.95 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine is obtained in crystalline form. form. The product melts at 187-189 ° C

Example 6

The procedure was as in Example 5, except that the reaction was carried out in 60 ml of butanol instead of in chloroform. There was obtained 1.88 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinoline-49541-nolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine.

Mp: 187-189 ° C.

Example 7

As described in Example 5, 1.86 g of 3-phenyl-6-mesyloxymethyl-5,6-dihydro-1H-1,2,4-oxadiazine are reacted with 1,2,3,4-tetrahydroisoquinoline (2.7 g) -phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine. The product is identical to that of Example 4.

Mp: 187-189 ° C.

Example 8

Following the procedure described in Example 4, 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was prepared using 3- phenyl-6- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine.

Mp: 162-163 ° C (from abs. Alcohol). Analysis for C21H55N3O3 calculated:

% C, 68.64;% H, 6.86;% N, 11.44; found *

H, 7.20; N, 11.85.

The hydrogen maleate salt of the product is prepared in an alcoholic solution with maleic acid.

Mp: 177 ° C.

Analysis for C25H29N3O7 calculated:

H, 6.05; N, 8.69.

Πί) 1Ρ7ΡΓ) ’’

% H, 5.97;% N, 8.62.

LD50 = 148 mg / kg i.v. in mice. At 10 mg / kg i.v., the compound decreases blood pressure permanently in anesthetized cats.

Example 1 9

Following the procedure described in Example 4, the reaction of 3- (2-chlorophenyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine with 1,2,3,4-tetrahydroisoquinoline produced 3- (2 chloro-phenyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine.

Mp: 147-150 ° C (from ethyl acetate). Molecular Weight: 341,83

Analysis for C 19 H 20 N 3 OCl calculated:

% C, 66.76;% H, 5.90;% N, 12.29.

10.37 0/0 Cl;

found:

% C, 66.38;% H, 5.83;% N, 12.00;

10.69% Cl.

The product dihydrochloride salt is prepared in an isopropanol solution by introducing hydrogen chloride gas.

Mp: 227-230 ° C.

Analysis for C19H22N3OCl3 calculated:

25.65% Cl;

found:

25.42% Cl.

Example 10

Using the procedure described in Example 4, 3- (4-chlorophenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine) with 1,2,3,4-tetrahydroisoquinoline produces 3- (4- chlorophenyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine hemihydrate.

Mp: 190-192 ° C (96% alcohol). Analysis for C19H20N3OCl. 0.5 H2O calculated:

H, 6.03; N, 11.98.

10.11% Cl;

found:

% C, 65.48;% H, 6.20;% N, 11.84.

10.50% Cl.

The product dihydrochloride salt is prepared in isopropanol by introducing hydrogen chloride gas.

Mp: 249-252 ° C.

Analysis for C19H22N3OCl3 calculated:

25.56% Cl;

found:

25.32% Cl.

Example 11

To 5.94 g of 3- (4-tolyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine was added 5.32 g

1.2.3.4-tetrahydroisoquinoline, 5.52 g of anhydrous potassium carbonate and 40 ml of absolute xylene. The reaction mixture is refluxed for 8 hours, then the insoluble portion is filtered off. After cooling the filtrate, the precipitated product is filtered off, dried and converted into the dihydrochloride salt in isopropanol solution by introducing hydrogen chloride gas. 4.1 g of 3- (4-tolyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride are obtained.

Mp: 250 ° C.

Analysis for C20H25N3OCl2 calculated:

17.98% Cl;

found:

18.44% Cl.

LD50 = 69 mg / kg i.v. The compound reduces the blood pressure of narcotized cats.

Example 12

Using the procedure described in Example 1, 3- (2,2-diphenylethyl) -6-methyl-6,6-dihydro-4H-1,2,4-oxadiazine was reacted with cyclohexylamine by reaction of 3- (2,2-diphenylethyl) -6-chloromethyl -cyclohexylaminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine hydrochloride.

Mp: 252-255 ° C.

Analysis for C24H33N3OCl2 calculated:

% C, 63.99;% H, 7.38;% N, 9.33.

15.74% Cl;

found:

H, 7.49; N, 9.28.

15.66% Cl.

LD50 = 160 mg / kg i.v. in mice.

Example 13

Using the method described in Example 1, 3- (2,2-diphenylethyl) -6-methyl-cyclohexylamine was prepared by reacting 3- (2,2-diphenylethyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine. - (N-methylcyclohexylamino) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride.

Mp: 227-230 ° C.

Analysis for C25H33N3OCl2 calculated:

% C, 64.64;% H, 7.60;% N / 9.05;

15.27% Cl;

found:

H, 7.75; N, 9.14.

14.94% Cl.

LD50 = 160.0 mg / kg i.v. in mice. 5 minutes after administration, the compound at a dose of 1 mg / kg in the anesthetized dogs increases the femoral artery flow by 70%. At a dose of 1 mg / kg i.v., it reduces the blood pressure of narcotized cats by 20%. At a dose of 16 mg / kg, the compound provides a 55% protective effect in the dextranedematous test in rats. The compound increases the amount of urine excreted in rats at a dose of 16 mg / kg to 160% (100% control). Example 14

To 1.2 g of 3- (2,2-diphenylethyl) -6-mesyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine was added 1.0 ml of 1,2,3,4-tetrahydroisoquinoline and 15 ml of chlorobenzene. The reaction mixture was refluxed for 10 hours, then the solvent was evaporated and ethyl acetate was added to the residue. 0.6 g of 3- (2,2-diphenylethyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4- is obtained. oxadiazine.

Mp: 163 ° C.

Example 15

The procedure is as in Example 14 except that 2.0 g of 3- (2,2-diphenylethyl) -6-tosyloxymethyl-5,6-dihydro-4H-1,2,4 are used as the starting product. There was obtained 1.0 g of 3- (2,2-diphenylethyl) -6- (1,2,3,4-tetrahydr o-2-isoquinolyl) methyl-5,6-dihydro-4H-1-oxadiazine. 2,4-oxadiazine.

Mp: 163 ° C.

The product is identical to the product of Example 14.

Example 16

Tablets of the following composition are produced:

Active substance

3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-4H-5,6-dihydro-1,2,4-oxadiazinedihydrochloride 25 mg starch 80 mg silica gel 22 mg magnesium stearate 3 mg

Example 17

Capsules of the following composition are prepared: Active ingredient

3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-4H-5,6-dihydro-1,2,4-oxadiazinedihydrochloride 25 mg lactose 40 mg filler 5 mg

Claims (4)

PREDM2T I will invent A process for the preparation of novel 1,2,4-oxadiazine derivatives of the general formula I Cli-Cfj _Q N. where they mean ch, P (!) Where R ^{1 is} phenyl, optionally monosubstituted with a chlorine atom or a methyl group, R ² phenyl, R ⁴ is hydrogen or methyl, R ⁵ cyclohexyl or R ⁴ and R ⁵ together represent a group of formula V R ⁶ represents hydrogen or C 1-4 alkyl Aman have a value of 0 or 1, and the pharmacologically acceptable acid addition salts and quaternary salts, characterized by reacting a compound of formula II FT-ICH) _m - ( CHp _n -CCH, K = Νχθ / CH-CH 3 -Z (II) the meaning of R ⁴ and R ⁵ is the same as above, and Z is a halogen atom or a sulfonyloxy group, with a compound of formula III R ⁴ OF HN (III) wherein the meaning of R ¹ , R ² , and m is the same as above 2. A process according to claim 1, wherein the reaction is carried out in a melt or in an organic solvent at the boiling point of the solvent used. 3. The process of claim 1 wherein the reaction is carried out in the presence of an acid binding agent. 4. The process of claim 3, wherein the acid binding agent is an excess of an amine of formula III or an alkali metal hydroxide or alkali metal carbonate.