DE2261095A1 - PROCESS FOR PRODUCING ORGANIC COMPOUNDS - Google Patents

Description

SANDOZ AG.

Basel Case 600-6393 / B

Process for the production of organic compounds

The invention relates to a method for producing Triasolochinazolinen of formula I,

3U9826 / 1U5

- 2 - 600-6393 / B

in which one of the symbols P or Q stands for nitrogen and the other a radical ⁼ £ ~ Κ ₂ , in which R_ stands for hydrogen or alkyl with 1-4 carbon atoms,

either a) the symbol η stands for O, 1, 2 or 3 and R is fluorine * Means chlorine, bromine, alkyl or alkoxy with 1-3 carbon atoms each, nitro or trifluoromethyl, however

1) if η is 2 or 3, the radicals R are identical or different,

2) if η stands for 2 or 3, each R has a different meaning than nitro or trifluorine thy1, and

3) if η is 3, each R is alkoxy with 1-3 carbon atoms,

or b) the symbol η stands for 2 and the radicals R on

adjacent carbon atoms and together denote methylenedioxy, and

either c) the substituent R, for a radical of the formula II,

-OR- II

stands in which R- alkyl with 1-6 carbon atoms,

Allyl, methallyl, propargyl, a radical of the formula III

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-Z-N III

^R 5

which Z meant straight-chain or branched-chainxges

Is alkylene with 1-4 carbon atoms and

R and R are identical or different and each represent alkyl with 1-3 carbon atoms,

or in which R is a radical of the formula IV

- (CH.) - CH (CH,) _ IV

2 m. . 2 ρ

means where m is 0, 1, 2 or 3 and

ρ means the number 2, 3, 4 or 5,

or d) the substituent R _{1 is} a radical of the formula V,

is where either

e) the substituent R, is hydrogen and

the substituent R "for hydrogen, alkyl with

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1-5 carbon atoms / alkoxyalkyl, in which the alkoxy and alkyl groups each contain 1-4 carbon atoms, allyl, methallyl, propargyl, cycloalkyl with 3-6 carbon atoms or a radical of the formula III already mentioned,

or f) the substituents R _c and R_ together

b /

with the nitrogen atom for dialkylamino, in which the alkyl groups are identical or different and each contain 1-3 carbon atoms, for diallylamino, di- (methallyl) amino, in which the methallyl groups are identical or different, for dipropargylamino or for a radical of the formula VI

CH ₂ (CH ₂ )

-N X VI

\ cH "(CHJ ^

stand in which X is a direct bond, methylene, oxygen or a group

= NR _O , where R _{n is} hydrogen or ο ο

Denotes alkyl with 1-3 carbon atoms, and

and y are O or 1, but X is a direct bond if χ oöer y stand for O,

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and where, if Q is nitrogen and P is = CH-, then the substituent is a radical of Formula II or a radical of the formula Va,

-N

Va

means,

where either R * is hydrogen and Rl is alkoxy

alkyl, wherein alkyl and alkoxy each contain 1-4 carbon atoms, or for Cycloalkyl with 3-6 carbon atoms,

or R 'and Rl together with the nitrogen atom ο /

a radical of the formula VI already mentioned, in which one or both symbols χ and y stand for O.

Of the compounds of the formula I, those of the formula In are new.

In

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where R and η have the above meaning and R ″, P ¹ and Q ^{1 have} the same meaning as the symbols Rw P and Q already mentioned, but if P ^{1 is} nitrogen and Q ^{1 is} a = CH group, the Substituent R 'for a radical of the formula Ha,

-OR 'Ha

is / where R 'is a radical of those already mentioned

Formula IV means, or for one

Remainder of the formula V already mentioned.

According to the invention, the compounds of the formula I are obtained by

a) for the preparation of compounds of the formula Ina,

Ina

I I

where R and η have the above meaning, and P ¹¹ , Q ¹ ', RV and Ri ^{1 have} the same meaning as P, Q, R, and R_, with the exception

O /

that, if Q ^{11 is} nitrogen and P "is a radical = CH-, the substituents Rl ¹

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-V

and R '' then have the same meaning as

R 'as well as R', ο /

a compound of the formula VIIa,

4 1

ⁿ L IL 'VIIa

(Μ e

with a compound of the formula VIII

HN VIII

^R 7

wherein R, n, P ¹¹ , Q ¹¹ / RV and R ' ^{1 have the} above meaning

O /

and Y is chlorine or bromine,

implements, or

b) for the preparation of a compound of the formula Inb,

^l 3

Inb

N-

where R and η have the above meaning and

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either 1) the substituent R '"for alkyl with 1-4

Carbon atoms and R ' ^{1 has} the same meaning as R-,

or 2) the substituent R ¹ ″ represents hydrogen

2
and R '' has the same meaning as R ',

a compound of formula VIIb

.Y

VIIb

with a compound of the formula IXa,

M-O-R ^ 'IXa

wherein Y, R '"and R' ^{1 have the} above meaning and M stands for hydrogen, alkali or alkaline earth metal.

reacted, wherein if the compound of formula IXa is a free alcohol, in the presence of an inert organic Base, or under anhydrous conditions and in the presence of an inert organic base, or

c) for the preparation of a compound of the formula Ine,

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Inc

wherein R and η have the above meaning, and

either 1> the substituent R 'for alkyl rait 1-4

Carbon atoms and R * ^r 'as well

R '' ^{1 have} the same meaning as R ^

/ O

and

2) the substituent R 'represents hydrogen and Ri.' ^r and R '''have the same meaning as R' and R * _ξ

a compound of the formula X,

with a compound of the formula XI,

^ -O [O- (CH ₂ ) _Z -CH ₃

XI

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where R _f η., R ', RV ¹ and R' ^{11 have the} above meaning 2 ο /

and ζ represents O or 1, reacts under practically anhydrous conditions, or

d) for the preparation of a compound of the formula Ia,

OR, (R) _n -

Yes

wherein R, n, R-, P and Q have the above meanings, a compound of the formula VII,

VII

where R, n, Y, P and Q have the above meaning

with a compound of the formula IX,

M-O-R.

IX

where M and R- have the above meaning,

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-U-

reacted, if Q in the compound of formula VII is nitrogen, using a Compound of formula IX works in which M for Is hydrogen, and the reaction in the presence of an inert organic base, under anhydrous conditions as well as in compliance with a certain time and a certain temperature, and where one, if P in the compound of the formula VII is nitrogen, and a compound of the formula IX is used in which M denotes hydrogen, the process in the presence of an inert organic base or under anhydrous conditions and carried out in the presence of an inert organic base, or

e) for the preparation of a compound of the formula Ib,

Ib

N C - R,

where R, n, R. and R_ have the above meaning, a compound of the formula Ik,

Ik

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where R, η, R and R_ have the above meaning,

under basic conditions or by heating in the presence of an organic acid or by heating to a temperature of a rearrangement which is above the melting point for the compound of the formula Ik subject.

Process a) is expediently carried out at temperatures between ID and 20O ⁰ C. It is expedient to work in the presence of a solvent. In some cases, this solvent can also be created by the compound of the formula VIII, which is then used, for example, in excess / inert organic solvents are also possible for this purpose, for example halogenated hydrocarbons such as chloroform or methylene chloride, lower alkanols such as methanol or ethanol, aromatic hydrocarbons such as benzene or toluene, or dimethylacetamide.

The method b) is conveniently carried out at temperatures between 10 and 120 ⁰ C, preferably 15 and 60 ° C, and in the presence of a solvent. Suitable solvents are inert, non-hydroxylic solvents, and also the alcohols corresponding to the compounds of the formula IXa, for example allyl alcohol, if the compound of the formula IXa is an allyl oxide. A sodium salt is preferably used as the compound of the formula IXa.

If the compound of the formula IXa is an alcohol,

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one works expediently using an excess thereof as a solvent, the reaction take a relatively long time, for example at least about 48 hours, and at temperatures between at least 40, - 50 ° C, preferably at reflux temperature of the reaction medium is to be made. Triethylamine, for example, are suitable as inert organic bases as well as suitable inorganic bases, such as alkali or alkaline earth hydroxides, with potassium hydroxide being preferred. As can be seen, process b) results in a split and reversal of the triazole ring of the core. This is due to the presence of the strong base of formula IXa or the organic or inorganic base, if the compound of the formula IXa is a free alcohol, and the yields of the desired product are increased by running the process at relatively extreme temperature and time constraints. Nonetheless, certain amounts of non-rearranged product can be formed come (as described in procedure d)), and the desired product can, if necessary, be separated off and purified in a manner known per se.

In process c) one works expediently at temperatures {between 10 and 150 ⁰ C, preferably 15 and 50 ° C. If desired, an inert solvent can be used, but it is expedient to use an excess of the compound of the formula XI, which is preferably trimethoxymethane or an alkyl derivative

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of this represents «

Process d) is carried out in compliance with a certain reaction time and certain temperature conditions if the substituent Q in the starting product of the formula VII is nitrogen, an inert organic base being used rather than an inorganic base or a compound of the formula IX in which M means something other than hydrogen, which is strictly basic. This is intended to avoid or reduce a reversal in the triazole ring, as is the case with process b) or e). In general, in this case, the reaction is expediently carried out at temperatures between 10 and 60 ^° C., specifically over a period of time which is the reverse of the temperature. Preference is given to working at temperatures between 15 and 50 ^° C. and reaction times between 5 and 30 hours. Preferred inert organic bases are those which are also used in process b). If the substituent P in the compound of the formula VII is nitrogen, the reaction can be carried out analogously to process b) already described.

The method e) is conveniently carried out in the presence of a strong base, for example an alkali metal alkoxide such as sodium ethoxide, and at temperatures between 30 and 120 ⁰ C, preferably 50 and 100 ⁰ C. If desired, one may also employ an inert organic solvent such as a lower Alkanol, such as methanol.

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Optionally, the process is expediently carried out either by heating the compound of the formula Ik in the presence of an organic acid, for example a carboxylic acid having 2-5 carbon atoms, such as acetic acid, or by heating the starting material to a temperature above its melting point, ie by melting it. If one works in the presence of an organic acid, the temperature should suitably be between 70 and 18O ° C, preferably between 100 and 160 ⁰ C, and the reaction time be, for example, at least 24 hours, preferably at least 36 hours. In this case, an inert organic solvent is expediently used, preferably a higher-boiling solvent such as xylene. When the starting material is fused, it is expedient to work with relatively short conversion times, for example at least one hour, preferably 2 to 4 hours.

The compounds of the formula I can be isolated and purified in a manner known per se.

The above description of the inventive method it can be seen that the compounds of the formula I in which Q is nitrogen, under the conditions of Process e) can suffer a rearrangement in the triazole ring. If you therefore make such connections such conditions should be partially or completely avoided. Even so, in some cases it can lead to Formation of a mixture of substances come and the obtained

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- ■ ic - ■

Products can then be isolated and purified in a manner known per se.

The free bases of compounds of the formula I in which R is a radical of the formula V in which R ^ is a radical of the formula

III means in which R _{1 is} a radical of the formula II in which R- is a radical of the formula III, or in which R ^ is a radical of the formula VI in which X is the group = NR _O , can be in usual way

convert into acid addition salts, whereby, as already mentioned above, one has to proceed carefully in some cases, to avoid relocation. The acid addition salts obtained can also be used in a known manner in their free bases are transferred.

Certain compounds of the formula VII, which are used as starting materials are used are new, namely those of the formula VIIc,

VIIc

in which R, η and Y have the above meaning and either P ^{111 stands} for a radical = C-R ″, in which R ^ ¹ denotes alkyl with 1-4 carbon atoms and Q ″ ^f denotes nitrogen, or

P ¹¹¹ denotes nitrogen and Q ¹¹¹ denotes a radical = CR ₂ , in which R has the above meaning,

and they also form the subject of the invention.

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The invention is accordingly also directed to processes for the preparation of compounds of the formula VIIc, characterized in that one

α) for the preparation of a compound of the formula Vllca,

^{(R> n} ~ t X '

^^^ N ^^ C-R'· Vllca

Il ²

N W

wherein R, n, Y and R ' ^{1 have the} above meaning, a compound of the formula XII,

XII

wherein R, η and Y have the above meaning, with a compound of the formula XIa,

^ '-C = CO- (CH ₂ ) _Z -CH ₃ 3

XIa

wherein R * 'and ζ have the above meaning, converts, or

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β) for the preparation of a compound of the formula Vll.cb,

(R)

Vllcb

ff

where R, n, Y and R_ have the above meaning, a compound of the formula XIII,

XIII

N-

where R, η and R- have the above meaning, chlorinated or brominated.

The process α) can be carried out in the presence of an acid, for example a strong acid such as p-toluenesulfonic acid, otherwise it is expedient to work under the conditions described in process c).

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■ - 19 -

Process β) is expediently carried out using phosphorus oxychloride or oxybromide as halogenating agent, an excess of which is preferably used to create a reaction medium. It is expedient to work at temperatures between 50 and 180 ^° C., preferably at the reflux temperature of the reaction medium. If desired, a small amount of a tertiary amine, such as dimethylaniline, can also be used as a catalyst.

The compounds of the formula VIIc obtained can be isolated and purified in a manner known per se.

The remaining compounds of the formula VII are known.

The compounds of the formula XII can be obtained by adding a compound of the formula XIV,

XIV

where R, Y and η have the above meaning and Y ^{1 is} chlorine or bromine,

reacts with hydrazine. '

The process is expediently carried out at temperatures between 0 and 30 ^° C., preferably 5 and 25 ^° C.,

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as well as in an inert organic solvent, for example an aromatic solvent such as benzene or toluene, a chlorinated hydrocarbon such as methylene chloride, or a dialkyl amide such as dimethylacetamide.

The compounds of the formula XII obtained can be isolated and purified in a manner known per se.

The compounds of the formula XIV are known or can be prepared in a manner known per se, for example by the method of Curd et.al., J.Chem.Soc. 1948 , 1759, and Hens et.al., J.Med.Chem. II, 130-136 (1968). According to these known methods, the 2,4-dichloro- or 2,4-Dibromchinazoline be prepared by cyclizing first anthranilic acid or an alkali cyanate with Anthranxlsäureester, preferably in acetic acid at temperatures between 80 and 120 ⁰ C to give the corresponding quinazoline 2,4-dione arrives, and this is then treated with phosphorus oxychloride or oxybromide, specifically at temperatures between 80 and 120 ° C. It has now been shown that it is better to use the methyl or ethyl ester of anthranilic acid for this reaction than the acid itself.

The compounds of formula XIII can be prepared

¹ p

by adding a compound of the formula VIId,

3 0 9 8 2 5/1 1 k 5

N— "Ν

VIId

where R, η, Y and R_ have the above meaning, rearranged and hydrolyzed.

The process is expediently carried out either by treatment with a concentrated organic acid and subsequent hydrolysis, or by treatment with a strong inorganic base in the presence of water, whereby hydrolysis and rearrangement take place simultaneously. As ox'ganische acids are glacial acetic acid are suitable, and the treatment is herewith conveniently carried out at temperatures between 50 and 15Q ° C, preferably 100 and 130 ⁰ C. Conveniently, one works with an excess of Eactual vinegar to create a reaction medium. The subsequent hydrolysis can easily be achieved by briefly treating the reaction product obtained with water at room temperature. Treatment of the compound of the formula VIId with a strong base may be conveniently effected at temperatures between 60 and 120 ⁰ C, preferably 80 and 110 ° C, made using as are preferred bases alkali hydroxides such as potassium hydroxide. This reaction is conveniently carried out in a volatile medium, for which water is preferably used, so that after

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a preferred reaction system, for example, 10% aqueous potassium hydroxide solution is used.

The compounds of the formula XIII obtained can be isolated and purified in a manner known per se.

Those compounds of the formula Ik, which other than halfo of the scope of the formula I are known and can be prepared in a manner known per se.

The compounds of the formula I and VIIc are pharmacologically active and can therefore be used as medicaments. In particular, they have a hypotensive effect, so that they can be used as hypotensives. A suitable daily dose is for example 120-1000 mg, conveniently administered in partial amounts between 30 and 500 mg, two to four times a day, or in sustained release form.

The compounds of the formula I and VIIc also have an anti » inflaminator isch, so they prove to be anti-inflammatory Let funds be used. A suitable daily dose is between about 200 and 3000 mg, preferably administered in portions between about 50 and 1500 mg, two to four times a day, or in sustained release form.

Depending on the circumstances, the compounds of the formulas I and VIIc can be used in the form of their free bases or in the form of their pharmaceutically acceptable acid addition salts are used, the activity of the salts being that of the

820/1 145

corresponds to free bases. Acids suitable for salt formation are for example hydrochloric acid, fumaric acid, maleic acid, formic acid, acetic acid, malonic acid, or Sulfonic acids.

The compounds of the formulas I or VIIc can be mixed with customary, pharmaceutically acceptable diluents or Mixed carriers and administered, for example, in the form of capsules or tablets.

The invention is explained in more detail by means of the examples.

ά Ud 82 b / 11 Fig

Example 1: 3-methyl-5-cyclopropylamino-8,9-dimethoxy-

1,2,4-triazolo [4,3-c] quinazoline [method a)]

A mixture of 9.0 g of 2-chloro-6,7 ^ dimethoxy-4-hydrazinochinazoline, 23.0 g of triethyl orthoacetate and 200 ml of methanol is refluxed with stirring for 19 hours and then stirred for a further 24 hours at room temperature. The mixture obtained is evaporated to dryness in vacuo and the residue is dissolved in 1500 ml of methylene chloride. The solution is extracted twice with sodium carbonate solution, washed neutral with water, dried and evaporated to dryness in vacuo. The residue is crystallized twice from methylene chloride / diethyl ether to and finally from ethanol, thereby attaining the title compound, melting at 269-271 ⁰ C with decomposition.

A mixture of 10.0 g of 5-chloro-8,9-dimethoxy-2-methyl-1,2,4-triazolo [4,3-c] quinazoline, 5.0 g of cyclopropylamine and 350 ml of ethanol is refluxed for 6 hours, and then Stirred at 50 ° C. for 12 hours. The ethanol is then stripped off in vacuo, and the residue is extracted with Sodium carbonate solution and chloroform. The organic

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"Phase is evaporated dried over sodium sulfate and concentrated in vacuo. The residue was treated with diethyl ether / and thus enters into the title compound of mp. 214-215 ⁰ C.

Example 2 ; S-cyclobutylamino-S, 9-dimethoxy-l , 2,4-

triazolo [4/3-c] quinazoline [method a)]

A mixture of 13.0 g of S-chloro-S ^ -dimethoxy-l ^^ - triazolo - [4,3-c] quinazoline 8.0 g of cyclobutylamine and 500 ml of ethanol is refluxed for 4 1/2 hours . The solvent is then removed in vacuo and the residue is treated with 1 liter of chloroform and 200 ml of 2N sodium carbonate solution. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue is taken up in 150 ml of methanol, and after treatment with diethyl ether leads to the title compound, melting at 235-237 ⁰ C.

Example 3 ; [Method a)]

Analogously to Example 1 or 2 and using suitable ones The following compounds are obtained from starting products in appropriate quantities:

a) S-cyclohexylamino-S, 9-dimethoxy-l, 2,4-triazolo [4,3-c] quinazoline, mp, 210-212 ⁰ C _1,

b) 5-CyclQpentylamino-8 , 9-dimethoxy-l, 2,4-triazolo [4,3-c] quinazoline with a melting point of 213-214 ° C,

c) 5-Cyclopropylamino-8,9-dimethoxy-1,2,4-triazolo [4,3-c] quinazoline from »Smp. 25O-251 ° C,

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d) 5-arziridino-8,9-dimethoxy-l _# 2,4-triazolo [4,3-cJ quinazoline with a melting point of 160 ° C (decomposition)

Example 4: S-cyclopropylmethyloxy-S, 9-dimethoxy-l, 2 _f 4-triazolo [l, 5-clchinazolin [Process b) 1

A mixture of 1.38 g of sodium hydride dispersion (57 % iron mineral oil), 150 ml of anhydrous dimethylformamide and 2.0 g of cyclopropylcarbinol is stirred at room temperature for 2 hours. The mixture obtained is then mixed with 5/4 g of 5-chloro-8,9-dimethoxy-1,2,4-triazolo [4,3-c] quinazoline and then stirred at room temperature for 1 hour. The mixture obtained in this way is then poured into 1 liter of ice / water, the precipitate is filtered off, washed with a further liter of water, with 100 ml of cold methanol and with 500 ml of diethyl ether, and the title compound has a melting point of 220-224 ° C.

Example 5; [Method b)]

Analogous to Example 4 and using suitable starting materials in appropriate quantities one arrives at the following compound:

5-cyclopentyloxy-8,9-dimethoxy-1,2,4-triazolo [1,5-c} -quinazoline of m.p. 189-19O ° C.

Example 6 ; S-Cyclop rop ylam i no-e, 9-dimethoxy-l, 2 , 4-

triazolo [4,3-quinazoline [method c)]

A mixture of 20 g of 2-chloro-4-hydrazino-6,7-diiuethoxy-

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BATH ORIGINAL

quinazoline, 28 g of cyclopropylamine and 50,000 ml of ethanol Heated to reflux for 17 hours. The reaction mixture is then concentrated in vacuo and the residue is taken in 1 liter of chloroform. The chloroform layer is washed with 2N sodium carbonate solution and then with water, dried over sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue arrives one to the title compound.

A mixture of 10 g of 2 ~ cyclopropylamino ~ 4-hydrazino ~ 8,9-dimethoxy-quinazoline and 200 ml of trimethoxymethane is refluxed for 1 hour. The mixture is in vacuo evaporated to dryness, and the residue is taken up in chloroform, chromatographed on silica gel, and the Fractions eluted with 95% chloroform + 5% methanol are collected and evaporated in vacuo. The residue is recrystallized from chloroform / diethyl ether, and the title compound is obtained in this way with a melting point of 250-251.degree.

Example 7; [Method c)]

Analogous to Example 6 and using suitable starting materials The compounds of Examples 1, 2 and 3a), 3b) and 3d) are obtained in corresponding amounts.

Example 8: 5- (4-Methylpip Eraz ino) -8,9-dimeth oxy -l, 2,4 - __ triazo lo [1, 57c] china Zolin [Process a)]

_BA D 3 0 8 8 2 5/1 U b

500 mg of S-chloro-e ^ -dimethoxy-1,2,4-triazolo [4,3-c] quinazoline are refluxed for 1 hour together with 50 ml of glacial acetic acid. The mixture is then evaporated to dryness in vacuo. The residue is treated with water / methylene chloride / diethyl ether, and the title compound obtained in this way is filtered off with. Water and dimethyl ether washed and dried, it melts at 320-325 ° C.

[Compound VIleb)]

300 mg of 8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazolin-5-one are refluxed for 18 hours with 5 ml of phosphorus oxychloride and a catalytic amount of N, N-dimethylamine. The mixture is then evaporated to dryness in vacuo, the residue is taken up in methylene chloride and extracted the methylene chloride layer several times with cold sodium bicarbonate solution and with water, dries and evaporates in the Vacuum to dryness. The residue is recrystallized from methylene chloride / diethyl ether, and the title compound is obtained in this way, which melts at 258-260 ° C.

lL'-2 _i 4-triazolo

Analogous to example Ib), but using appropriate Amounts of 5-chloro-3,9-dimethoxy-l, 2,4-triazolo [1,5-c] quinazoline and 4-methylpiperazine instead of triazolo

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[4,3-c] quinazoline and cyclopropylamine are obtained from Title compound melting at 194-195 ° C.

Example 9 ; [Method a)]

Analogously to Example 8 and using suitable starting materials in appropriate amounts, the following results are obtained Links:

1) 1 * 2,4-triazolo [l, 5-c] quinazolin-5-one, m.p. 310-314 ° C / as well

2) S-chlorine-l ^^ - triazoloCl ^ -clquinazoline [compound Vllcb]

a) S-cyclopropylamino-S, 9-dimethoxy-l, 2,4-triazolo [1,5-cJ quinazoline, mp. 209 ⁰ C,

b) 5- (4-methylpiperazino) -1,2,4-triazolo [l, 5 ~ c] quinazoline, mp. 131-133 ⁰ C ₇

c> S-Cyclopentylamino-S, 9-dimethoxy ~ l, 2,4-triazolo [] .., 5 ~ c] quinazoline, m.p. 153-154 ° C,

d) S-cyclobutylamino-Ö , 9 ~ dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, m.p. 166-168 ° C _#

e) 5-Cyclopropylamino-2-methyl-8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, m.p. 188-189 ° C,

f) S-cyclohexylamino-e, 9-dimethoxy-l, 2,4-triazolo [1,5-c] quinazoline, mp. 184-185 ⁰ C.

g) 5 ™ aziridino-8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, melting point 186-19O ⁰ C,

h) 5- (2-methoxyethyl) amino-8,9-dimethoxy-1,2,4-triazolo- [1,5-c] quinazoline, M.p. 143-144 ° C,

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i) 3-Cyclopropylamino-1,2,4-triazolo [1,5 -c] quinazoline, m.p. 135-137 ° C.

Example 10 ; 5,8, 9-trimethoxy-1,2,4-triazolo [4, 3-c] quinazoline [process d) J

A mixture of 500 mg of 5-chloro-8,9-dimethoxy ~ l, 2 _r 4 ~ triazolo [4,3-c] quinazoline and 25 ml Triäthylarain in 25 ml of methanol is stirred for 24 hours at 40 ° C. The solution is then evaporated to dryness in vacuo, treated with water and the aqueous layer extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in the smallest possible amount of chloroform and chromatographed on silica gel, eluting first with chloroform and then with chloroform containing constantly increasing amounts of methanol. The desired fractions are collected and evaporated to dryness in vacuo. After recrystallization of the residue from methylene chloride / diethyl ether, Z '.; T title compound, which melts at 245-25O ° C., is obtained.

Example 1.1 : [method e)]

Analogous to Example 10 and using suitable starting materials the following compounds are obtained in appropriate quantities:

a) 5-methoxy-1,2,4-triazolo [4,3-c] quinazoline, m.p. 172-175 ° C,

b) 5-allyloxy-0,9-dimethoxy-1,2,4-triazolo [4,3-c] quinazoline, M.p. 171-173 ° C.

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Example 12 ; 5- (4-Methylpiperazino) -8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline [method e)]

10.1 g of 5- (4-methylpiperazino) -8,9-dimethoxy-1,2,4-triazolo [4,3-c] quinazoline are refluxed with 2 g of sodium methoxide in 600 ml of methanol for 90 minutes. That The mixture is evaporated to dryness in vacuo, treated with water and extracted several times with methylene chloride. the organic extracts are combined, washed with water, dried and evaporated in vacuo. Dissolves the residue one in as little chloroform as possible, after which it is chromatographed over silica gel and worked up as in Example 10. the title compound obtained here melts at 194-196 ° C,

Example 13: [method e)]

Analogous to Example 12 and using suitable starting materials The compounds of Examples 9a) to 9i) and the compounds of Examples.4 are obtained in corresponding amounts as well as 5, and the compounds mentioned below:

a) 5 ~ Methoxy-l, 2,4-triazolo [1,5-c] quinazoline, mp. 163-164 ⁰ C.

b) 5,8,9-trimethoxy-1,2,4-triazolo [1,5-c] quinazoline, M.p. 228-230 ° C,.

c) 5-allyloxy-8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, M.p. 189-191 ° C,

d) 5-ethoxy-8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, M.p. 212 ° C,

e) 5- [2- (diethylaminoethoxy) -8,9-dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, Srap. 159-166 ⁰ C,

30 9825/1 1U

f) 5- [3- (diethylaminopropoxy)] - 8,9-dimethoxy-1,2,4-triazolotl, 5-cJquinazoline, M.p. 128-130 ° C,

g) S-methoxy-e ^ -dimethoxy-1,2,4-triazolo [1,5-c] quinazoline, M.p. 228-230 ° C.

Example 14; 5,8,9-trimethoxy-1,2,4-triazolo [1,5-c] quinazoline [method d)]

a) 2/64 g S-chloro-e ^ -dimethoxy-1,2,4-triazolo [1,5-c] quinazoline are added to a solution of 5.94 g of sodium methoxide in 30 ml of methanol. The reaction mixture turns 90 Heated to reflux for minutes, after which the solvent is removed in vacuo. The residue is treated with water and extracted three times with methylene chloride. The combined methylene chloride extracts are saturated with water and with Washed sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After recrystallization the residue from methylene chloride / diethyl ether leads to the title compound, which at 228-230 °? melts.

b) Analogous to method a) above, but using 5 ml of triethylamine instead of sodium methoxide, and by heating the reaction mixture for 48 hours instead 90 minutes leads to the same product.

Example 15: [method d)]

Analogously to Example 14 and using suitable starting materials in corresponding quantities one arrives at the

309826/1146

Compounds of Examples 4, 5 and 9a) and 9c) to 9g).

Example 16 t 5- (4-Methylpiperazino) -Sr.g-di

triazolo [1, 5-c jchinazoli n [method e)]

A mixture of 500 mg of 5- (4-methylpiperazino) -8,9-dimethoxy-1,2,4-triazolo [4,3-c] quinazoline, 10 ml of xylene and 5 ml of acetic acid is refluxed for 48 hours. The mixture it is evaporated to dryness in vacuo, the residue is taken up in methylene chloride, the methylene chloride solution it is washed three times with 2N sodium hydroxide solution and then with water, dry it over sodium sulfate and evaporate to dryness in vacuo. After recrystallization the residue from methylene chloride / diethyl ether leads to the title compound with a melting point of 194-195.5 ° C.

Example 17 ; [Method e)]

Analogously to Example 16 and using suitable starting materials The compounds of Example 13 are obtained in corresponding amounts.

3 0 9 8 2 S / 114 6

Claims (7)

Claims: Process for the preparation of triazoloquinazolines of the formula I (R) NQ in which one of the symbols P or Q is nitrogen and the other is a radical = (^ ~ R2, in which R2 is hydrogen or alkyl with 1-4 carbon atoms , either a) the symbol η stands for 0, 1, 2 or 3 and R denotes fluorine, chlorine, bromine, alkyl or alkoxy with 1-3 carbon atoms each, nitro or trifluoromethyl, but v / obei 1) if η is 2 or 3, the radicals R are identical or different, 2) if η stands for 2 or 3, each R has a different meaning than nitro or trifluoromethyl, and 3) if η is 3, each R is alkoxy with 1-3 Carbon atoms means or b) the symbol η stands for 2 and the radicals R on neighboring carbon atoms lieyin and together Methylene! Ioxy mean, and 309825/1146 ^BAD ORIGINAL either c) the substituent R, for a radical of the formula II, II where R _{3 is} alkyl with 1-6 carbon atoms, Allyl, methallyl, propargyl, a radical of the formula III -ZN III which Z meant straight-chain or branched-chain Is alkylene with 1-4 carbon atoms and R and R ^ are identical or different and each represent alkyl with 1-3 carbon atoms, or in which R- is a radical of the formula IV, (CH ₂ ) _p IV means where m is 0, 1, 2 or 3 and ρ means the number 2, 3, 4 or 5, 30982E / 1U5 or d) the substituent R _{1 is} a radical of the formula V, is where either e) the substituent R _{g is} hydrogen and the substituent R _{7 is} hydrogen, alkyl with 1-5 carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl groups each contain 1-4 carbon atoms, allyl, methallyl, propargyl, cycloalkyl with 3-6 carbon atoms or a radical of the formula III already mentioned, or f) the substituents R- and R "together ο / with the nitrogen atom for dialkylamino, wherein the alkyl groups are the same or different and each have 1-3 carbon atoms contain, for diallylarnlno, di- (methallyl) amino, in which the methallyl groups are identical or different, for dipropargylamino or for a radical of the formula VI -N X VI 3 0 9 8 2 5/1 U 5 are, in which X stands for a direct bond, methylene, oxygen or a group = NR ", in which R _{rt is} hydrogen or ο ο Äikyl with 1-3 carbon atoms means and
ν κ and y stand for O or 1, however K means a direct bond, if χ or y stand for 0, and where, if Q is nitrogen and P is sCM-, the substituent R is then a radical of Formula II or a radical of the formula Va,. . especially means, . where either IU is hydrogen and RA is alkoxy alkyl, v / orin alkyl and alkoxy, respectively Contain 1-4 carbon atoms, odei? for cycloalkyl with 3-6 carbon atoms stands, or R 'and R4 together with the nitrogen atom 6 7 mean a radical of the formula VI already mentioned, in which one or both symbols χ and y stand for O, 309825/1146 characterized in that one a) for the preparation of compounds of the formula Ina, Ina where R and η have the above meaning / and P ¹¹ , Q ¹¹ , R · 'and Ri' have the same meaning as P, Q, R. and R ^ , with the exception that if Q ¹ 'stands for nitrogen and P '' means a radical ^ ^{CH-, the Substituofiteü Rg 1} and R ' ¹ then have the same meaning as R' and Rl, O / a compound of the formula VIIa,
(R) -, - '"' VIIa with a compound of the formula VIII, HN VIII 7 BATH 3 U 9 8 2 5/1 U B - 39 - 600-6393 / B wherein R, η, P ' ¹ , Q ¹¹ , R' ¹ and R ' ^{1 have the} above meaning own and
Y represents chlorine or bromine. implements, or
b) for the preparation of a compound of the formula Inb, (R) _n Inb where R and η have the above meaning and either 1) the substituent R ^ "for alkyl with 1-4 Carbon atoms stands u has meaning like R-, Carbon atoms and R ″ the same or 2) the substituent R ¹ ″ represents hydrogen 2 and Rl ^{1 has} the same meaning as R ', 3 -3 a compound of formula VIIb .Y VIIb BAD .'iü9825 / 1145 ra.it a compound of the formula IXa, M-O-R ^ 'IXa where Y, R '"and R' ^{1 have the} above meaning and M stands for hydrogen, alkali or alkaline earth, reacted, if the compound of formula IXa is a free alcohol, in the presence of an inert organ pool Gases, or under anhydrous conditions and in the presence: an inert organic base works, or c) for the preparation of a compound of the formula Ine, mc v / orin R and η have the above meaning, and either 1) the substituent R 'for alkyl with 1-4 Carbon atoms and R ^'11 as well R ' ¹ ' have the same meaning as R- and R ", or 2) the substituent R 'is hydrogen and RV ¹ and R ^{'11 have} the same meaning have like R 'sov; ie R', ο / 309826 / 1U6 ORIGINAL BATHROOM a compound of the formula X, NHNH, with a compound of the formula XI, RJJ-O [O- XI wherein R, n, R ', R' ¹¹ and R ' ¹ ' have the above meaning and ζ stands for 0 or 1, reacts under practically anhydrous conditions, or d) for the preparation of a compound of the formula Ia, OR. Yes where R, n, R_, P and Q have the above meaning, BATH 309826 / T146 a compound of the formula VII, VII where R, n, Y, P and Q have the above meaning with a compound of the formula IX, M-O-R. IX wherein M and R _{3 have the} above meaning, reacted, if Q in the compound of formula VII is nitrogen, using a Compound d ^ r Formula IX works, in which M for Is hydrogen, and the reaction in the presence of an inert organic base, under anhydrous conditions as well as in compliance with a certain time and a certain temperature, and where one, if In the compound of the formula VII, P stands for nitrogen, and a compound of the formula IX is used in v / elcher M denotes hydrogen, the process in the presence of an inert organic base or under anhydrous conditions and carried out in the presence of an inert organic base, or BATH ORIGINAL 309825/1 U6 e) for the preparation of a compound of the formula Ib, .R ₁ Ib N C - R, wherein R, n, R and R _{0 have the} above meaning, a compound of the formula Ik, Ik where R, n, R. and R have the above meaning, under basic conditions or by heating in the presence of an organic acid or by heating to a temperature of a rearrangement which is above the melting point for the compound of the formula Ik subject. .UJ 9 8 2 5/1 U 5 2. Process for the preparation of compounds VIIc, VIIc N Q t »I wherein R, η and Y have the meaning given in claim 1 and either P ¹ "for a radical = CR ^ ', in which R ^' denotes alkyl with 1-4 carbon atoms * ^ and Q ¹¹¹ denotes nitrogen, or P ¹ ' ¹ denotes nitrogen and Q ¹¹¹ denotes a radical = CR ₂ , in which R has the meaning given in claim 1, characterized in that one α) for the preparation of a compound of the formula Vllca, _VIIca N N where R, n, Y and R ' ^{1 have the} above meaning, BAD ORIGINAL 3Ü9825 / 1145 a compound of the formula XII, XII NHNH, where R / η and Y have the above meaning, with a compound of the formula XIa, J'-OCO-. XIa where R '' and ζ have the above meaning, implements, or ß) for the preparation of a compound of the formula Vllcb, Vllcb where R, n, Y and R ^ have the above meaning, 309826/1148 a compound of the formula XIII, XIII where R, η and R. have the above meaning, chlorinated or brominated. 303826/1146 3. Triazoloquinazolines of the formula In _f In wherein R and η have the meaning given in claim 1 and R ', P ¹ and Q ^{1 have} the same meaning as the symbols R ₁ , P and Q already mentioned in claim 1, but if P' stands for nitrogen and Q ¹ denotes a = CH group, the substituent R 'denotes a radical of the formula Ha, -OR 'Ha stands, wherein R ^ is a radical of the claim 1 already Formula IV mentioned, or for a radical of the in claim 1 Formula V already mentioned is available. 4. Triazoloquinazolines according to Claim 3, characterized in that that R. denotes a radical of the formula V mentioned in claim 1, in which R_ represents a radical of the im Claim 1 mentioned formula III stands, or that R denotes a radical of the formula II mentioned in claim 1, in which R_ is a radical of the formula III mentioned in claim 1, or that R .. is a radical of the in claim 1 3Ü982S / 1U5 - 48 - 600-6393 / B Formula VI mentioned denotes, in which X stands for = MR _O , wherein M and R. have the meaning given in claim 1 to have. 5. Triazoloquinazolines of the formula VIIc, VIIc wherein the substituents R, n, Y, p ¹¹¹ and Q ^{111 have} the meaning given in claim 2. 6. Pharmaceutical preparation, characterized by a content of compounds of those mentioned in claim 4 Formula In as an active ingredient. 7. Pharmaceutical preparation, characterized by a content of compounds mentioned in claim Li Formula VIIc as an active ingredient. 3U982S / 1U5