FI59098B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC PYRIDO (3,2-E) -AS-TRIAZINDERIVAT - Google Patents

Description

RSS ^ l Γβΐ m, ADVERTISEMENT, -Q n Q ft JBfk lBJ (11) UTLÄGGININOSSKRIFT 3 ^ 09 8 c Patent granted 10 06 1931 • (^ 5) patent raeddelat ^ (51) Kv.lk3 /! «. Cl.3 C 07 D 471/04 FINLAND — FINLAND (21) Patent application - Patantanaekninf 75229 ^ (22) Hakemlapilvl - Anfttknlngtdig 13-08.75 ^ ^ (23) Alkupllvft - GlltigHtttdtg 13 · 08.75 (41) Become Public - Bllvlt offentll ηΜ · |. raklttwthallitu.

ratant »och ragiutaratyralaan '' Ansekan utlagd och uti.skrtften pubiicerad 27.02.61 (32) (33) (31) PjT ^ Atty privilege — Begird priority (71) E GY T Gy6gyszervegy £ szeti Gyär, 30, Kereszturi ut, Budapest X , ^ Hungary-Hungary (HU) (72) Andris Messmer, Budapest, Andras Gelleri, Budapest, Pil Benko,

Budapest, Laszlo Pallos, Budapest, Istvan Szabo, Budapest,

Lujza E. Petöcz, Budapest, Ibolya Kosoczky, Budapest, Eniko Kiszelly, Budapest, Hungary -Engem (HU) (7 ^) Oy Roister Ab (5 ^) Method for therapeutically useful pyrido (3,2-e) -as-triazine for the preparation of derivatives - For the preparation of tera-peutiskt användbara pyrido (3,2-e) -as-triazinderivat

The present invention relates to a process for the preparation of therapeutically useful pyrido (3,2-e) -as-triazine derivatives of general formula I.

I f 1 (I) R 2 wherein R is a C 1 -C 2 alkyl group, an unsubstituted phenyl group, a phenyl group substituted by a halogen atom, a hydroxy or amino group or 1 to 3 methoxy groups, or R is a phenyl-C 1 -C 4 alkyl group, and and R 2 are each hydrogen atoms or both together for an additional chemical bond, and for the preparation of pharmaceutically acceptable salts thereof.

59098

It is known from the literature that 3-alkyl or carboalkoxypyrido [3,2-e] -aziazines can be prepared by cyclization of aminopyridine compounds formed by reduction of acylhydrazinopyridine derivatives obtained by acylation with 2-hydrazino-3-carboxylate-3-nitropyridine Chem., 8, Ui (1971) and U.S. Patent No. 3,506,631). But even at high concentrations, these compounds are not effective against antibiotic-resistant bacteria.

The process according to the invention is characterized in that 2-chloro-3-nitro-pyridine is reacted with a compound of general formula II

With an acylhydrazine of the formula R - CO - NH - NH 2 (II) in which R is as defined above, or 2-hydrazino-3-nitropyridine is reacted with the general formula Ha R - CO - X (Ha)

with a carboxylic acid derivative according to the formula wherein R is the same as defined above and X is a halogen atom or a C 1-4 alkoxy group. Obtained from general formula III

| (M)

UH - NH - CO - R

a compound of formula IV wherein R is as defined above is catalytically reduced, and the compound of general formula IV thus obtained

of

^ NH - NH - CO - R

The aminoacylhydrazino compound of formula I wherein R is as defined above is cyclized in an acidic medium, and if it is desired to prepare compounds of formula I wherein R 1 and R 2 represent an additional bond, the compound of formula I wherein R 1 and R 8 are hydrogen atoms in an alkaline structure is oxidized. in a medium with potassium ferricyanide or in an alcoholic medium with hydrogen peroxide, and, if desired, the resulting compound is salified with a pharmaceutically acceptable acid.

The starting compounds, i.e. 2-Chloro-3-nitropyridine and acylhydrazines can be prepared by the method described in J. Chem. Soc., 1950 020 and Jacob Zabicky, "The Chemistry of Amides", Ch. 10, 515 (Interscience Pubi., 1970).

In the first step of the process of the invention, 3-nitropyridine derivatives can be prepared either from 2-chloro-3-nitropyridine by reacting it with an excess of carboxylic acid hydrazides or using equimolar amounts of triethylamine, especially dimethylformamide or tert-butanol. . In a preferred embodiment, 2-hydrazino-3-nitropyridine is acylated with carboxylic acid halides. In the latter case, mainly 3-aryl- and 3-aralkyl-substituted hydrazinonitropyridines are also obtained in fairly good yields. In part, this reaction is surprising because another reaction procedure for 2-hydrazino-3-nitropyridine is known from the literature (J. Heterocycl. Chem., J, 1019 (1970)).

In the next reaction step, the nitro compounds are catalytically hydrogenated to the corresponding 3-amino derivatives. The latter are converted in an acidic medium into aqueous or non-aqueous ethanol or even dioxane containing hydrochloric acid or by reaction with polyphosphoric acid or its ester 3-alkyl, aryl or aralkyl-1,2-dihydropyrido (3,2-e) -as -triazine hydrochlorides. The dihydro compounds can be used either as active pharmaceutical ingredients in stabilized salts with pharmaceutically acceptable acids, preferably mineral acids, e.g. hydrochloric acid, or by oxidation with e.g. potassium ferricyanide (III) in basic medium or hydrogen peroxide in ethanol. a-triazine derivatives having an aromatic ring system.

As a preferred method, especially for 3-aryl substituents, mention should be made of the abbreviated synthesis in which aromatic 3-aryl-substituted pyrido (3,2-e) -as-triazines are obtained from 3-amino-k-acylhydrazinopyridines in the same apparatus, e.g. by oxidation with polyphosphoric acid. .

The compounds according to the invention have a remarkable anti-inflammatory effect, which occurs when doses corresponding to one tenth of the LDj-q value are administered. The degree of potency is greater than that of the "lower alkyl" derivatives described in U.S. Patent No. 3,9 · '9,631. In addition, the novel compounds of the invention have excellent antibacterial activity and, to some extent, fungicidal activity. In particular, their highly advantageous antibacterial activity - the effect is manifested by inhibiting the growth of bacteria which are resistant to antibiotics or INH at very low concentrations (0.1 pg / ml) In these specific areas of action, the "lower alkyl" derivatives described in the aforementioned U.S. patent have proved ineffective. The oral toxicity of the compounds of the invention to mice is 800-3000 mg / kg.

The different activity of the compounds according to the invention depending on the meaning of the substituent R is shown in the following table: 59098

Table

Impact ---; - - - - - —.— - ..._

Hexyl Octyl Benzyl Phenyl p-anisyl | p-hydroxy-Methyl _______. Phenyl _

Inflammatory- <5 - 5-10 5 ~ 10 - 5-IO

against j

Analgesic 5 ~ 10 5-10 i 20-50 <5 <5 - ^ 5

Fever- ~ - - <5 <5 way! j

Gastrointestinal st o- <5 | <5 | 20-50 20-50 10-20 10-20 peristals iikan '; against j -1-1 ---------- R1 and Rg = hydrogen atoms.

The following examples illustrate the invention.

Example 1 3- (3 ', * +', 5'-Trimethoxyphenyl) -1,2-dihydropyrido [3 ', 2'-n-triazine hydrochloride

Dissolving 3.6 g (0.012 mol) of 3-amino-2- (3 ', 1 + *, 5'-trimethoxybenzhydrazino) pyridine in a mixture of 1 + 0 ml of ethanol and 0 ml of anhydrous ethanolic hydrochloric acid solution gives an orange-red solution. where a precipitate begins to form. Boiling the suspension for 10 minutes, cooling and filtering gives 3.2 g of orange-red crystals. Yield 75 m.p. 225 ° -228 ° C (decomposes, ethanol). Example 2 3 - (* + '- Hydroxyphenyl) -1,2-dihydropyrido [3,2-e] -triazine dihydrochloride By operating as described in Example 1 but using as starting material 3-Amino-2- (k'-hydroxybenzhydrazino) pyridine gives a yellow crystalline product, yield 67%, m.p. 28 ° C (methanol-ether).

Example 3 3- (1+'-Hydroxyphenyl) -1,2-dihydropyrido [3,2-e] -az-triazine The product is liberated from its hydrochloride by treatment with saturated sodium hydrogen carbonate solution. Green-yellow crystals are obtained, m.p. 330 ° -331 ° C (dioxane).

Example k 3-Benzyl-1,2-dihydropyridoyl,2,2-ε-α-triazine dihydrochloride Cyclization of 3-amino-2-phenylacetylhydrazinopyridine as described in Example 1 gives the product, yield 85%, m.p. 155 ° C (methanol ether), thin yellow crystals.

5 59098

Example 5 3-Phenylpyrido [3,2-b] as-triazine 11.1 g (0.07 mol) of 2-chloro-3-nitropyridine and 19.0 g (0.1 * mol) of benzoic acid hydrazide are heated to 70 ° C. in 80 ml of dimethylformamide for 7 hours, then the mixture is poured into 150 ml of ice water. Recrystallization of the crude product from 70- $ ethanol gives 11.3 g (63.5%) of yellow crystals of 3-nitro-2-benzhydrate s inopyridine.

7.72 g (0.03 mol) of 3-nitro-2-benzhydrazinopyridine are shaken under a mixture of ethanol (350 ml) in glacial acetic acid (100 ml) and Pd / C catalyst (Ig) under a hydrogen atmosphere until the theoretical amount of hydrogen is bound, whereupon the compound is The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo at a temperature below 30 ° C. Recrystallization of the residue from isopropanol gives 2.1 g (71%) of white crystalline 3-amino-2-benzhydrazinopyridine, m.p. 186 ° C, U .5 g (0.02 mol) of 3-amino-2-benzhydrazinopyridine are boiled for 10 min in 15 ml of a chloroform solution of polyphosphoric acid ester, and the mixture is then evaporated to dryness in vacuo. the red oil is extracted with chloroform, the solvent is distilled off to give 1.8 g (UU%) of 3-phenyl-pyrido / 3,2-eJ-as-triazine as bronze thin crystals, mp 221 + ° C (isopropanol).

Example 6 3- (3 ', U', 5'-Trimethoxyphenyl) -pyrido [3,2-e] -az-triazine

Reaction of 3,5-trimethoxybenzoic acid hydrazide with 2-chloro-3-nitropyridine as described in Example 5 gives golden-needle-like crystals of 3- {11-O-2- (31,5,5-trimethoxybenzhydrazino) pyridine at 57.7%. in yield, m.p. 16U ° C (ethanol).

The obtained compound is hydrogenated as described in Example 5 to give 3% amino-2- (3 '', 5'-trimethoxybenzhydrazino) pyridine in 7% yield as white crystals, m.p. 199 ° C (isopropanol).

The obtained compound is cyclized by the method described in Example 1 to give 3 - (3 ',?', 5'-trimethoxyphenyl-1H-dihydropyrido / S, N'-as-triazine hydrochloride, mp 225-228 ° C in 75 # yield). (dec).

3.3 g (0.01 mol) of 3- (3 ', 5'-trimethoxyphenyl) -1,2-dihydropyrido [3,2-e] -az-triazine hydrochloride are dissolved in 100 ml of hot water and the solution is made early to pH 10 by the addition of potassium carbonate. 30 ml of 30 # potassium ferricyanide solution are then added and the resulting pale yellow suspension is stirred at 50 [deg.] C. for 0.5 hour. The dark yellow crystals are filtered and crystallized from isopropanol to give 2.2 g (75%) of the title compound, m.p. 208-209 ° C.

Example 7 3- (2'-Hydroxyphenyl) -pyrido-3,2-e7-as-triazine

Reaction of salicylic acid hydrazide with 2-chloro-3-nitropyridine 659098 as described in Example 5 gives 3-nitro-2- (2'-hydroxybenzhydrazino) pyridine as red zero crystals in 56% yield, m.p. 216 ° C (aqueous acetic acid).

The compound obtained (U, 88 g, 0.0178 mol) is hydrogenated in a 2: 1 mixture of ethanol / dioxane (1 * 00 ml) using 0.8 g of Pd / C catalyst as catalyst until the theoretical amount of hydrogen is bound. The catalyst is filtered off, the solution is evaporated in vacuo and the residue is crystallized from isopropanol to give 3.95 g (89%) of 3-amino-2- (2'-hydroxybenzhydrazino) pyridine as yellowish-white crystals, m.p. 196 ° C.

12.2 g (0.05 mol) of this compound are boiled for 1 hour in a chloroform solution of polyphosphoric acid ester (50 ml), then the homogeneous red solution is evaporated in vacuo. Ice water is added to the residue, and the solution is neutralized with sodium hydrogencarbonate, followed by 150 ml of a 36 - # potassium ferricyanide solution. The solution is allowed to stand at 1 * 5 ~ 50 ° C for 0.5 hours to give 6 g (53%) of the title compound as brownish-red crystals, m.p. 21 DEG-6 DEG C. (butanol).

Example 8 3- (1''-Hydroxyphenyl) -pyrido [3,2-e], - as-triazine

In analogy to the procedure described in Example 5, yellow crystalline 3 'nitro-2- (h'-hydroxybenzhydrazino) pyridine is prepared. Yield 78%. Sp. 216 ° C (butanol).

kt6 g (0.0168 mol) of the compound obtained above and 10 ml of glacial acetic acid in 250 ml of a 1: 1 mixture of dioxane and ethanol are hydrogenated in the presence of a Pd / C catalyst (0.8 g) until the theoretical amount of hydrogen is bound. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo at a temperature below i + 0 ° C. The residue is crystallized from ethanol to give 3.1 g (78%) of 3-amino-2- (h'-hydroxybenzhydrazino) pyridine as white crystals, m.p. L86 ° C.

This compound is cyclized as described in Example 1 and oxidized as described in Example 6. The title compound is obtained in 78% yield, m.p. 303 ° C (2-methoxyethanol).

Example 9 3-Benzylpyrido / 3,2-n-as-triazine 2.72 g (0.01 mol) of 3-nitro-2-phenylacetylhydrazinopyridine are hydrogenated in 150 ml of methanol in the presence of a Pd / C catalyst (0.6 g). , until the theoretical amount of hydrogen is bound (20 min). The catalyst is filtered off and the filtrate is evaporated to dryness. Isopropanol is added to the residue to give 2.1 g (87%) of 3-amino-2-phenylacetylhydrazino-pyridine as white needle-like crystals, m.p. 113 ° C. Recrystallized from dichloroethanol, m.p. is 118 ° C.

The obtained compound is reduced and cyclized as described in Example 1. Yield: 80% of 3-benzyl-1,2-dihydropyrido [3,2-b] α-triazine di-59098 hydrochloride, m.p. 212-213 ° C.

Oxidation of the compound thus obtained as described in Example 6 gives the title compound in 95% yield, m.p. 125 ° C (60% ethanol).

Example 10 3- (¾'-Aminophenyl) -1,2-dihydropyrido [3,2-b] az-triazine trihydrochloride 3-Nitro (¾'-nitrobenzhydrazino) pyridine is reduced in the same manner as in Example 9 to give 90%: in the yield of 3-amino-2- (4'-aminobenzhydrazino) pyridine. 1.5 g (1.85 mmol) of the compound obtained are dissolved in 50 ml of anhydrous ethanol saturated with HCl gas and the solution is allowed to stand for a further 10 minutes at the same temperature, whereupon the white precipitate turns rust-brown.

The mixture is allowed to stand overnight and the resulting precipitate (3.6 g, 57%) is filtered. The product is purified by crystallization from methanol / ether to give 2.9 g (w / w%) of a reddish brown crystalline title compound, m.p. 275-277 ° C (decomposes).

~ Example 11 3- (p-Chlorophenyl) -pyrido / 3,2-ey7-as-triazine 1¾ g (0.091 mol) of 2'-chloro-3'-nitropyridine and 31.5 g (0.183 mol) of p- chlorobenzhydrazine in 150 ml of anhydrous dimethylformamide is allowed to stand at 90 ° C for 12 hours to give a dark brown solution. It is poured into 800 ml of water, the precipitated crude product is filtered off, washed thoroughly with water and recrystallized from 600 ml of isopropanol to give 10.1 g (51%) of yellow crystalline 3-nitro-2- (p-chlorobenzhydrazino) pyridine, m.p. . 176-177 ° C.

2.1 g (7.2 mmol) of 3-nitro-2- (p-chlorobenzhydrazino-pyridine and 1 g of stannous chloride) are refluxed in 18 ml of concentrated hydrochloric acid for 20 minutes. After cooling, the crystals are filtered, washed with 30 ml of dioxane, dissolved in 15 ml of dimethylformamide, and the solution is treated with 20 ml of concentrated ammonia to turn green, 15 ml of water are added to the solution and then 10 ml are added to the resulting suspension. 36% potassium ferricyanide solution to give a thick crystalline precipitate over 0.5 hours (35 DEG C.) The product is extracted with 80 ml of chloroform, the extract is washed with 2 x 100 ml of water, dried and evaporated to give 0 .95 g (5%) of the title compound as yellow needle-like crystals, mp 211-212 ° C (butanol).

Example 12 3-Benzylpyrido / 3,2-ey-as-triazine

As described in Example 5, 3-nitro-2-phenylacetylhydrazinopyridine is prepared as yellow plate-like crystals, m.p. 122-123 ° C (benzene / cyclohexane). Yield 55% · This compound is converted to 3-amino-2-phenylacetylhydrazinopyridine as described in Example 9. Yield 87%. Sp. 113 ° C. By recrystallization from dichloroethane m.p. is 11 ° C.

8 59098

The product obtained is treated as described in Example 5 to give the title compound in a yield of 95 / S. Sp. 125 ° C (60- $ ethanol).

Example 13 3- (3,1,1 '', 5'-Trimethoxyphenyl) -pyrido [5,2-e] -az-triazine 15. U g (0.1 mol) of 2-hydrazino-3-nitropyridine and 23, 0 g (0.1 mol) of 3,1 *, 5-trimethoxybenzoic acid are reacted with 600 ral of benzene in the presence of triethylamine (10.1 g, 0.1 mol) at the boiling point of the solvent.

The hot solution is filtered and, after cooling, is chromatographed on a 30 cm alumina column. The resulting solution is evaporated to give 17.1 g (50%) of 3-nitro-2- (3 ', 1' ', 5'-trimethoxybenzhydrazino) pyridine, m.p. 163-161 ° C.

The resulting compound is then treated as described in Example 6 to give the title compound in 75 # yield, m.p. 208-209 ° C.

The starting 2-hydrazino-3-nitropyridine is prepared as follows: 18 g (0.11 mol) of 2-chloro-3-nitropyridine are dissolved in 113 ml of boiling water, 6 ml of hydrazine hydrate are added and the mixture is boiled for 30 minutes.

5.8 g of (87 #) 2-hydrazino-3-nitropyridine are obtained, m.p. 210-211 ° C.

Example lU

3-heksyylipyrido / 3,2-ec ~ as-triazine

A solution of 36.0 g (0.23 mol) of 2-chloro-3-nitropyridine, 33.1 g (0.23 mol) of heptanoylhydrazine and U0 ml of triethylamine in 250 ml of dry dimethylformamide is heated at 85 ° C for 2 hours. :in. The mixture is then evaporated in vacuo to give 5-6.6 g (89%) of 3-nitro-2-heptanoylhydrazinopyridine as needle crystals, m.p. 82-81 + ° C (methanol).

The obtained compound (3.9 g, 0.13 mol) is hydrogenated in a mixture of ethanol (500 ml) and glacial acetic acid (20 ml) in the presence of a R 1 / C catalyst (1.2 g). The mixture is filtered and 250 ml of HCl-saturated ethanol are added to the filtrate. After boiling for a few minutes, the solution is evaporated and the residue is crystallized from absolute ethanol. 23.6 g (72%) of 3-hexyl-1,2-dihydropyrido [3,2-e] -az-triazine hydrochloride are obtained as needle-like crystals, m.p. 11 + 9-150 ° C (decomposes).

25.0 g (0.98 mol) of the compound obtained above and 18.5 g of potassium hydroxide dissolved in 100 ml of water are stirred and oxidized at 60 [deg.] C. with 350 ml of an aqueous 20-8 potassium ferricyanide solution. The solution is continuously extracted with chloroform, and the extract is evaporated to dryness to give 12.6 g (60%) of the title compound as bronze crystals, m.p. 79-80 ° C (petroleum ether).

Example 15 3-Tridecylpyrido / 3,2-e7-az-triazine From 2-chloro-3-nitropyridine and myristic acid hydrazide is obtained by the method described in Example 1U in 78% yield 3-nitro-2-myristoyl-hydrazino-pyridine, m.p. 98-100 ° C.

The obtained compound is hydrogenated as described in Example 5 to give 9,59098% yield of white crystalline 3-aminomyristoylhydrazinopyridine, m.p. 106-10 ° C (ethanol).

This compound is cyclized by the method described in Example 1. Yield 8%. Sp. 160-162 ° C (nitromethane), and the obtained compound is obtained by oxidizing the title compound according to Example 1k in a yield of 81%. Sp. 85-86 ° C (ethanol).

Claims (1)

59098 Patents: Process for the preparation of therapeutically useful pyrido / 3,2-e_7-as-triazine derivatives or of general formula I CX r IR 'E2 wherein R is a C 1-20 alkyl group, an unsubstituted phenyl group, a phenyl group having a halogen atom, a hydroxy or amino group, or a 1 -. (2) -to-toxic group as a substituent, or R is a phenyl-C 1-4 alkyl group, and and R 2 are each a hydrogen atom or both together an additional chemical bond, and for the preparation of their pharmaceutically acceptable salts, characterized in that 2-chloro-3-nitropyridine is reacted with an acylhydrazine of the general formula II R - CO - NH - NH 2 (II) in which R is as defined above, or 2 -hydrazino-3-nitropyridine is reacted with a carboxylic acid derivative of the general formula Ha R - CO - X (IIa) in which R is as defined above and X is a halogen atom or a C 1-4 alkoxy group. The obtained compound of the general formula III / N 2 NO 2 I II (III) NH - NH - CO - R in which R is the same as above is catalytically reduced, and the compound of the general formula IV CX (IV) N 2 NH - The aminoacylhydrazino compound of the formula NH-CO-R, in which R is as defined above, is cyclized in an acidic medium and, if desired, compounds of formula I are prepared, in which R 1 and R 8 represent an additional bond, the compound of formula I obtained above is oxidized. , wherein and R 1 are hydrogen atoms, in an alkaline medium with potassium ferricyanide or in an alcoholic medium with hydrogen peroxide, and, if desired, the compound obtained is salified with a pharmaceutically acceptable acid. 12 59098 Pat entkrav; For the preparation of a therapeutically active pyrido (3,2-e) -as-triazine derivative with all the compounds of formula I Oc'x * I * 'R2 color R is en C 1-4 alkyl group, and o is a substituent of phenyl group, en a phenyl group which is substituted by a halogen atom, a hydroxy- or an amino group or a 1-3 methoxy group, or a R-en phenyl-C 1-6 -alkyl group, and a R-och R 1-4 alkyl moiety or a bridgehead or chemical group extraction, with the addition of pharmaceuticals, of the same form, with respect to 2-chloro-3-nitropyridine in the form of acylhydrazine in the form of formula II R - CO - NH - NH2 (II) color R 3-Nitropyridine is provided with carboxylic radicals in the form of the formula When R - CO - X (IIa) color R is present in some form, and X is a halogen atom or a C 1-4 alkoxy group. The compounds of formula III (Ύ ”NH - NH - CO - R color R have the following characteristics, catalytic reducers and the amino-acylhydrazine compounds of formula IV NH0 ex N ^ NH - NH - CO - R the color R is the same as in the case of the medium, and if the medium is the same as that of the form I,