DE2424334A1 - PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS - Google Patents

Description

Process for the production of new heterocyclic compounds

The invention relates to processes for the preparation of new compounds of the formula

wherein R. is hydrogen, lower alkyl, phenyl, substituted by halogen, lower alkoxy or lower alkyl Phenyl or cycloalkyl with 3-6 carbon atoms means, R "for hydrogen, lower alkyl, chlorine, Bromine, formyl, acetyl, nitro, di (lower) alkylaminomethyl, Amino or a group A-CO-NH- in which A is hydrogen, lower alkyl or substituted by halogen lower alkyl means R-. Hydrogen, Hydroxy, lower alkyl, cycloalkyl with 3-6 carbon atoms, phenyl or one through lower alkyl, lower alkoxy or halogen substituted phenyl group, either R. for hydrogen, lower alkyl,

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lower alkenyl or lower alkynyl, the multiple bond of which is not in the α, β-position to the Nitrogen atom to which the alkenyl or alkynyl radical is attached, is a hydroxy (lower) alkyl or (lower) alkoxy (lower) alkyl group in which the oxygen atom by at least 2 carbon atoms from the nitrogen atom, what the alkyl radical is bonded to is separated, di (lower) alkylamino (lower) alkyl, its nitrogen is separated by at least 2 carbon atoms from the nitrogen atom to which this radical is attached. Cycloalkyl with 3-7 carbon atoms or cycloalkyl (lower) alkyl with 4-10 carbon atoms, 'pyridyl, pyrimidyl, Benzyl, a benzyl group substituted in the phenyl radical by lower alkoxy, lower alkyl, halogen or hydroxy, Amino, di (lower) alkylamino or an alkyleneimino group with 2-7 carbon atoms and R, hydrogen, lower alkyl,

lower alkenyl or lower alkynyl, the multiple bonds of which are not in the α, β position to the nitrogen atom, where the alkenyl or alkynyl radical is attached is a hydroxy (lower) alkyl or (lower) alkoxy (Lower) alkyl group in which the oxygen atom is replaced by at least 2 carbon atoms from the nitrogen atom on which the alkyl radical is bonded, is separated, di (lower) -alkylamino (lower) alkyl, its nitrogen by at least 2 carbon atoms from the nitrogen atom, on which this Rest is bound, is separated. Cycloalkyl with 3-7 carbon atoms or cycloalkyl (lower) alkyl with 4-10

Ra means carbon atoms or the group NC ^ _R for piperidino, pyrrolidino, morpholines, thiomorpholines

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or the N.-B-piperazino = group in which B is ( _{lower) alkyl, hydroxy (lower) alkyl, the hydroxy radical of which is separated from N 4} by at least 2 carbon atoms, phenyl or monosubstituted by lower alkyl, lower alkoxy or halogen Denotes phenyl, where, if R. and R are hydrogen, any group A denotes hydrogen, methyl or ethyl, and their acid addition salts, as well as the compounds of the formula I and their acid addition salts,

If one or more substituents R, R_, R ₃ , R ₄ or R, - represent lower alkyl, these radicals represent in particular lower alkyl groups with 1-4, preferably with 1 or 2, carbon atoms; The methyl group is then particularly preferred.

If R_ stands for di (lower) alkylaminomethyl, the are (lower) alkyl groups contained therein are preferably identical and each have in particular 1-4, preferably 1 or 2 carbon atoms.

If R ^ and / or R_ are substituted phenyl, then is the phenyl radical is in particular monosubstituted.

BL, R_ and / or B stand for one through lower alkyl or lower alkoxy-substituted phenyl groups, so contain their lower alkyl or lower alkoxy substituents in particular 1-4, preferably 1-2 carbon atoms Particularly preferred substituents in this series are tolyl and anisyl.

If R ₁ , R ₃ and / or B are a halogen-substituted phenyl group, the halogen is fluorine, chlorine or bromine, preferably fluorine or chlorine.

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If R. and / or R ₅ stand for lower alkenyl or alkynyl, then these substituents contain in particular 3-6 , preferably 3-5, carbon atoms.

R and / or Rj stand for hydroxy (lower) alkyl / contain so these substituents are preferably 2-4 carbon atoms.

If R and / or R _{5 are} (lower) alkoxyalkyl, their (lower) alkoxy radicals contain in particular 1-4, preferably 1 or 2 carbon atoms and their alkyl radicals preferably contain 2-4 carbon atoms.

Are R. and / or R ₁ . for di (lower) alkylamino (lower) alkyl, the (lower) alkyl groups are preferably identical and each contain in particular 1-4, preferably 1 or 2, carbon atoms. The alkylene group of the di (lower) alkylamino (lower) alkyl radical preferably contains 2-4 carbon atoms.

If R. stands for di (lower) alkylamino, its (lower) Alkyl groups are preferably identical and contain in particular 1-4, preferably 1 or 2, carbon atoms; The dimethylamino group is then particularly preferred.

If R. stands for substituted benzyl, the benzyl radical is in particular monosubstituted.

If R. stands for a benzyl group substituted by lower alkyl or lower alkoxy, it contains (lower) alkyl or (lower) alkoxy substituent in particular 1-4, preferably 1-2 carbon atoms. As a loading

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Particularly preferred (lower) alkyl substituent should be the Methyl, as a particularly preferred (lower) alkoxy substituent the methoxy group may be mentioned.

If R. stands for a 3-enzyme substituted by halogen

group, the halogen stands for fluorine,

Chlorine or bromine, preferably for fluorine or chlorine ..

If the radical NR.R, - stands for an N .- (lower) alkyl piperazino group, so contains its (lower) alkyl substituent in particular 1-4, preferably 1 or 2 carbon atoms. The N ^ -methyl piperazino group is then particularly preferred.

If the radical NR.R- stands for an N -hydroxy (lower) alkylpiperazino group, so this hydroxyalkyl substituent contains in particular 2-4, preferably 2 carbon atoms.

The radical A preferably denotes hydrogen, alkyl with 1-4 carbon atoms or monohalogenated alkyl with 1-4 carbon atoms. The halogen is by definition for fluorine, chlorine or bromine, preferably for chlorine. Particularly preferred radicals A are hydrogen, methyl, Ethyl, chloromethyl, tert-butyl.

According to the invention one arrives at the new compounds der-formula I and its acid addition salts by

a) for the preparation of compounds of the formula

^l 4 ^R 5

Yes,

^R 2

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wherein R ₁ , R ₄ and R _{5 have the} above meaning, R 'stands for hydrogen, lower alkyl, chlorine, bromine or nitro and R ^ hydrogen, lower alkyl, cycloalkyl with 3-6 carbon atoms, phenyl or one by lower alkyl, means lower alkoxy or halogen-substituted phenyl group, compounds of the formula

II,

wherein R ₁ , R 'and R' have the above meaning and X stands for the acid radical of a reactive ester, with compounds of the formula

HNR ₄ R ₅ III,

wherein R. and R have the above meaning, converts or

b) for the preparation of compounds of the formula

NR R
, 45

^ "N

in which R., R_, R. and R have the above meanings and R "represents hydrogen or lower alkyl _r compounds of the formula

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NO

wherein R, R ", R and R _{5 have the} above meaning with reactive derivatives of the compounds of the formula

R COQH V,

wherein R_ has the above meaning, cyclized, or

c) for the preparation of compounds of the formula

Ic,

wherein R ₁ , R-, R. and R ₁ . have the above meaning and R " ^{1 is} chlorine, bromine, formyl, acetyl, di (lower) alkylaminomethyl, nitro, amino or an A-CO-NH group in which A has the above meaning, the radical R" ^! in compounds of the formula

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^NR 4 ^R 5

wherein R ₁ , R ₃ , R, and R _{5 have the} above meanings, introduces

d) for the preparation of compounds of the formula

NO. R- ^ H -Ν

.NH ₂

wherein R ₁ - R _3r R ^ and $ _{5 have the} above meaning. Compounds of the formula

NR R

JL

AT THE

■ -

reduced, or

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- Θα -

e) for the preparation of compounds of the formula

Ic " ¹

NH-COA

in which E., R ₃ , R ₄ , R ₅ and A have the above meanings, acylated ^{compounds of the formula Ic 1}

and the compounds of the formula I thus obtained are obtained as bases or in the form of acid addition salts.

The free bases can be used in a known manner Prepare acid addition salts and vice versa.

The inventive implementation according to method a is a nucleophilic substitution reaction in the 4-position of the pyrazolo [l, 5-a] -s-triazine skeleton can be carried out analogously to known methods.

In the meaning given for X, “esters” are by definition both alcohol derivatives (including thiol-r derivatives) as well as Acid Abkömralinge, in which the characteristic hydrogen atom is replaced by an alkyl radical (in the broadest sense) (see Klage's "textbook of organic chemistry, 1959, volume 1, page 230).

Suitable compounds of the formula II are, for example, compounds of the formula

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0-S0_R

I ²

^ Ti N

Ha,

where R., R 'and R' have the above meanings and R is lower alkyl, in particular methyl or optionally substituted phenyl, in particular p.Tolyl.

Preferred compounds of the formula II are compounds of the formula

T N

L L

Jk

3 ^ ^ r R ₁

_R.

where R,, R * and R 'have the above meaning and Hai Chlorine or bromine, preferably chlorine, and compounds of the formula

SR
N ^ NN

L L

wherein R,, R 'and R'_ have the above meaning and R_ for

JL Z J D.

lower alkyl, cycloalkyl with 3-6 carbon atoms, benzyl or one in the phenyl radical by lower alkoxy, lower alkyl, halogen or hydroxy substituted benzy! group stands.

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Of the compounds of the formula lic are particularly suitable the compounds in which Rg is lower alkyl, is preferably methyl, for the inventive reaction with the compounds of the formula III.

In practice, for example, one proceeds in such a way that a solution of a compound of the formula Hb, for example the 4-

Chlorine derivative ■ in one

organic solvent which is inert under the reaction conditions, for example a chlorinated aliphatic Hydrocarbon such as chloroform, a compound of formula III adds. The implementation takes place in this Preferably trap at room temperature and is after Finished 10 minutes to a few hours.

The compounds of formula Hb in which Hai stands for chlorine are found to be unstable and are therefore preferably made in situ from the compounds of the formula

OH

l | vi,

TJl

wherein R-, R 'and R' have the above meaning, for example by treatment with phosphorus oxychloride.

The implementation of a compound of the formula Hc with a The compound of the formula III is also expediently made in an organic compound which is inert under the reaction conditions Solvent, for example a lower alkali

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-IV

nol like methanol, but can also be carried out without a solvent. The reaction temperature can from room temperature to 200 ° - or higher if no solvent is used - vary. The reaction time depends on the reaction temperature.

The cyclization according to the invention according to process b can be carried out analogously to methods known for the preparation of triazines.

Suitable reactive derivatives of the compounds of the formula V are, for example, the orthoesters of these compounds the formula

R ₃ -C (OR ₇ V ₃ VII ₇

where R_ has the above meaning and R _{7 is} lower alkyl, the mixed anhydride of acetic acid and formic acid or the compounds of the formula

R ₃ -CO-N I VIII,

in which R _{3 has the} above meaning, or, for the preparation of compounds of the formula Ib in which R is hydroxy, phosgene or phosgene derivatives such as chloroformic acid ester, N, N'-carbonyldiimidazole, etc.

The cyclization of the compounds of the formula IV with the compounds of the formula VII is generally practical with heating in an organic solvent which is inert under the reaction conditions, for example in a cyclic or open-chain ether such as dioxane,

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carried out. Preference is given to refluxing the reaction mixture at the boiling point.

In the cyclization with the mixed anhydride of acetic acid and formic acid, compounds of the Formula Ib, in which R, stands for hydrogen.

If the cyclization is carried out with an excess of the mixed anhydride of acetic acid and formic acid, if R ₄ and R ₅ in the compounds of the formula IV are hydrogen, 4-pyrazolo [l, 5-a] which are unsubstituted in the 2-position are obtained. -s-triazines, the 4-position amino group of which is formylated.

The condensation of the compounds of the formula IV with the compounds of the formula VIII or with Ν, Ν'-carbonyldiimidazole is also preferably carried out with heating in an organic solvent which is inert under the reaction conditions, for example in a cyclic or open-chain ether such as dioxane. The compounds of the formula VIII are conveniently prepared in situ by reacting N, N ¹ -carbonyldiimidazole with an acid of the formula V.

Compounds of the formula Ib in which R ^ is hydroxy is obtained, for example, by reacting a 1-pyrazole carboxamidine of the formula IV with a chloroformic acid ester and cyclization of the condensation product formed.

Chloroformic acid esters particularly suitable for the reaction are chloroformic acid (lower) alkyl esters, in particular the methyl or ethyl ester. The reaction is preferably carried out with heating and in an inert

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organic solvents * for example; a cyclic or open-chain ethers such as tetrahydrofuran.

It is expedient in the presence of a basic condensing agent worked like triethylamine.

The cyclization of the condensation product is carried out at an elevated temperature. The ones to use Solvents therefore expediently have a high boiling point: tetralin, for example, is the solvent very suitable.

Process b is particularly suitable for the preparation of compounds of the formula

• Ν

Ie,

R ₃ "

ρ "
^R 2

wherein R ,, R "and R _{3 have the} above meanings, R 'signify hydrogen, lower alkyl or benzyl and R' signify hydrogen or lower alkyl.

The introduction of a chlorine, bromine, nitro, formyl, acetyl, di (lower) alkylaminomethyl, amino or A-co-a Substituents in the compounds of the formula Id can be carried out analogously to known methods.

A chlorine or bromine atom can be generated through halogenation, a nitro group through nitration, and a ViIsmeier reaction the formyl or acetyl group, or a di (lower) alkylamino group by aminomethylation

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to be introduced. For the purpose of introducing an amino or ty-CO-NH group one proceeds appropriately from the corresponding one Nitro compound.

In practice, halogenation is carried out, for example, in such a way that the compounds of the formula Id are in a suitable, organic solvent inert under the reaction conditions with the desired halogenating agent treated.

Suitable halogenating agents are, for example, sulfuryl chloride, N-chlorosuccinimide, bromine or sulfuryl bromide, etc. The Choice of solvent depends on the solubility of the compounds of formula Id in this solvent and the type of halogenating agent used: At. Chlorination with sulfuryl chloride turns out to be a Mixture of glacial acetic acid and carbon tetrachloride, in the case of bromination with bromine, glacial acetic acid is suitable.

The chlorination with sulfuryl chloride is preferably carried out at elevated temperature, preferably at the boiling point of the reaction mixture.

The bromination with bromine is advantageously carried out at room temperature. The reaction time depends on the reaction temperature addicted

The nitration of the compounds of the formula Id can be carried out in a solvent such as glacial acetic acid by adding fuming Nitric acid, or by dissolving the compounds of the formula Id in excess nitric acid

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acid. It is preferable to work at room temperature.

The introduction of the formyl or acetyl group according to ViIsmeier takes place, for example, by reacting the compounds of the formula Id with a formamide, for example a di- (lower) alkylformamide such as dimethylformamide, or acetamide, for example a di (lower) alkylacetamide such as Dimethylacetamide, in the presence of phosphorus oxychloride.

The reaction is then conveniently carried out using excess dimethylformamide or dimethylacetamide carried out as a solvent. One works at elevated temperature, for example between 60 and 90 °. the Reaction takes 1 to a few hours.

The aminomethylation of the compounds of the formula Id is expediently carried out under the conditions of a Mannich reaction. It is carried out, for example, by mixing a compound of the formula Id with formaldehyde or a formaldehyde-releasing compound such as paraformaldehyde, and the desired di (lower) alkylamine in a solvent which is inert under the reaction conditions, for example in an alkanol such as ethanol or isopropanol, or in an ether such as dioxane in the presence of an acid, e.g. of one equivalent Hydrochloric acid, heated. One works appropriately with stirring and / or at reflux temperature. That used Di (lower) alkylamine is expediently used as an acid addition salt, for example as the hydrochloride, in the reaction brought.

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II-

Zn the 8 ~ amino-pyrazolotriazinen of formula Tt leads, for example by reducing the corresponding 8-nitro-compounds ". This reduction can be analogous to the reduction of aromatic nitro compounds known methods, for example by means of hydrogen, with a metal and Acid * or

be done with an alkali metal or ammonium sulfide.

As a catalyst for the catalytic hydrogenation of the nitro compounds, e.g. palladium / Raney nickel, Suitable for platinum etc. When using palladium as a catalyst, it is expedient to work at normal pressure and room temperature. The reduction is carried out in a solvent which is inert under the reaction conditions, for example carried out in a lower alkanol such as methanol or ethanol.

The reduction with a metal and acid

also takes place according to known methods? iron, zinc or tin are suitable as metal and hydrochloric acid

or acetic acid as an acid.

In the case of reduction by this process, it is preferred to work at an elevated temperature. Do you work in In the presence of formic acid, propionic acid or in concentrated acetic acid, the corresponding ones are obtained directly 8-formamido, 8-propionylamino or 8-acetylamino compounds of formula I.

Suitable solvents for the reduction with. or ammonium sulfide are, for example, lower alcohols or water. This process is used for reduction one also expediently at elevated temperature, for example at the reflux temperature of the reaction mixture

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sches. · · - (.

"If R ^ and / or R ₅ stand for alkenyl or alkynyl, the reduction of the nitro group, insofar as it is carried out by catalytic hydrogenation, is to be carried out under mild conditions. If R ^ and / or Rc stand for alkenyl, Lindlar- Catalysts are used: the double bond of an alkenyl group is then not impaired.Any alkenyl or alkynyl groups do not react when the nitro group is reduced with a metal and acid or with an alkali metal or ammonium sulfide.

Unless both radicals R * and R _{c are} hydrogen, the 8-A-CO-NH-pyrazolotriazines of the formula I can also be prepared by acylation of the corresponding 8-alaino compounds by known methods.

The acylating agents used in the preparation of the 8-formamido compounds of formula I e.g. formic acid or its mixed anhydride with acetic acid and for the production of the remaining 8-A-CO-NK compounds of the Formula I the corresponding carboxylic acid halides, in particular carboxylic acid chlorides and bromides, or carboxylic acid anhydrides suitable.

For the formylation of an 8-amino compound of the formula I. this is treated with the mixed anhydride of acetic acid and formic acid, preferably at room temperature. The reaction can take place in excess anhydride or else in one under the reaction conditions inert solvents are carried out.

For the production of the remaining "8-A-CO-NH-.

derivatives of the formula I by acylation of the corresponding 8-amino compounds can in an inert organic

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Solvent, for example, a cyclic or open-chain ethers such as dioxane. the The reaction temperature can vary between room temperature and the boiling point of the reaction mixture. the Reaction takes about 2-15 hours.

The work-up and isolation of the compounds of the formula I obtained by the process described can be take place according to methods known per se.

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The compounds of the formula lic and their acid addition salts, The present invention also relates to the preparation of these compounds.

If Rg stands for lower alkyl, this radical represents in particular represents a lower alkyl group with 1-4, preferably with 1 or 2 carbon atoms.

If Rg stands for substituted benzyl, the benzyl radical is especially monosubstituted.

Rg stands for one in the phenyl radical through lower alkyl
or lower alkoxy-substituted benzyl group, its lower alkyl or lower alkoxy substituent contains in particular 1-4, preferably 1 or 2, carbon atoms.

If R- stands for a benzyl group substituted by halogen in the phenyl radical, the halogen stands for
Fluorine, chlorine or bromine, preferably for fluorine or chlorine.

The compounds of the formula lic and their acid addition salts is obtained according to the invention by compounds the formula

SH

_N A _N _

^R 2

in which R., R 'and R' are as defined above, alkylated and the compounds of the formula lic obtained in this way as

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Bases or as acid addition salts wins.

Acid addition salts can be prepared from the free bases in a known manner and vice versa.

The alkylation of the compounds of the formula IX can be carried out by known methods.

For example, one proceeds in such a way that one makes the connections of formula IX in a suitable solvent, for example a lower alkanol such as methanol, and in the presence of an acid-binding agent such as sodium methylate with an alkylating agent, for example a (lower) alkyl halide such as (lower) alkyl iodide or a (lower) alkyl sulfate. the Depending on the alkylating agent, alkylation takes place at room temperature to boiling temperature.

If RL in the compounds of the formula IX is hydrogen, the pyrazolotriazine skeleton can then also be substituted in the 8-position by chlorine or bromine. The introduction of the chlorine or bromine substituent can be carried out as described for the chlorination or bromination of the compounds of the formula Id.

The compounds of the formula lic obtained in this way can be worked up and cleaned by known methods.

The compounds of the formula IX are new. You can after known methods., e.g. by treating a solution of the compounds of the formula VI in a suitable organic

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niche solvents such as pyridine, dioxane or xylene with a sulfurizing agent such as phosphorus pentasulfide. The implementation is expedient with him carried out at a higher temperature.

The compounds of the formula VI are likewise new and the subject matter of the invention.

According to the invention, the new compounds of the formula VI are obtained by adding compounds of the formula

NHR ₈

^R 3

^R 2

where R ,, R 'and R' have the above meaning and R ₀ what-

X Z j ο

hydrogen and, if R 'is hydrogen, can also be formyl, hydrolyzed, and if desired in 8-position of the compound of the formula VI thus obtained, in which R 'is hydrogen, a chlorine, bromine or Introduces nitro substituents.

The hydrolysis of the compounds of the formula X can be carried out by known methods, for example by Warming with aqueous bases, e.g. with sodium hydroxide in aqueous-methanolic solution, or with acids, e.g. with dilute sulfuric or formic acid.

If R 'in the compounds of the formula X is hydrogen, acids are preferably used, since the corresponding pyrazolo [1,5-a] -s-triazines by alkali treatment to be partially split.

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-AV

The occasional introduction of a chlorine, bromine or nitro substituent in the 8-position of the compounds of the formula VI, in which R 'is hydrogen, can be carried out as described for processes

The compounds of the formula X in which R _{β is} hydrogen are encompassed by the formula I. The preparation of the compounds of the formula X in which R _{p is} formyl and R 'is hydrogen or lower alkyl has already been mentioned earlier in the text. Any 8-chloro, 8-bromine or 8-nitro substituents can be introduced as described for process c.

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The starting compounds of the formula IV can be prepared by reacting a di-salt of an aminoguanidine, e.g. di-hydrochloride, with an alkali metal salt, e.g. sodium alz, a compound of the formula

CN-CH-COR ₁

^R 2 '

where R, and R * 'have the above meaning, in water or a lower alkane1.

Insofar as the production of the starting compounds is not described, these are known or can v / ground according to known methods or prepared analogously to those described herein or in analogy to processes known per se.

The compounds of the formulas I, lic and VI, as well as theirs Pharmacologically acceptable salts have interesting pharmacodynamic properties with low toxicity Properties and therefore can be used as a remedy.

In particular, they have bronchospasmolytic effects, as has been shown in animal experiments. For example, they inhibit on guinea pigs (Konzett-Rössler method) with doses of approx. 1 to approx. 10 mg / kg electrical irritation of the vagi caused bronchoconstriction.

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Due to their bronqhospasmolytic effects, the substances can be used to treat obstructive airways diseases such as bronchospasm, e.g. bronchial asthma / used v / earth. The cans to use naturally vary depending on the type of substance, the administration and the condition to be treated. in the in general, however, satisfactory results are obtained with a dose of 0.1 to 10 mg / kg body weight p.o. administered j this dose can be used if necessary in 2 to 4 parts or as a sustained release form can be administered. For larger mammals, the daily dose is at about 10 to 100 mg. For oral applications, the partial doses contain about 2.5 to 50 mg of that according to the invention Compounds in addition to solid or liquid carriers.

Of the compounds according to the invention, the compounds of the formula show in particular

Il

R ₁

^R 2

wherein R, R_ and R have the above meaning and R _{Q is} lower alkyl, cycloalkyl or cycloalkyl (lower) alkyl, of the formula

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-H

IOG-4004

where R, and R "have the above meaning and R" is hydrogen, Means methyl or ethyl, and compounds of the formula

SCH- ³

CH

. & x

^R 2

lld,

where R, and Ri have the same meaning as above, an interesting effect.

Particularly preferred are ^
pyrazolo [1,5-a] -s-triazine, 2-ethyl-4-aminopyrazolo- [1,5-a] -s-triazine, 4-amino-2-methylpyrazolo [1,5-a] -s-triazine , 2,7-dimethyl-4-methylthiopyrazolo [1,5-a] -striazine and compounds of the formula

NHCH

wherein R "has the above meaning, R is hydrogen, methyl, ethyl or cyclohexyl and R is hydrogen, chlorine, bromine or represent methyl; of the latter compounds include 2, T-dimethyl ^ -methylaminopyrazolo-

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ti, 5-a] -s-triazine, 2, 8-dimethyl 1-4-methylaitiinopyrazolo-Ll _/ 5-a] -s-triazine, 7-ethyl-2-methyl-4-methylaminopyrazoloti, 5-a] - s-triazine and in particular 8-chloro-2-ynethyl-4-methylaminopyrazoloti, 5-a] -s-triazine have a pronounced effect.

The compounds of the formulas I, lic and VI or their Physiologically compatible salts can be used in pharmacy in a manner known per se, together with suitable salts common auxiliaries, too common, too solid or liquid pharmaceutical preparations suitable for oral, rectal or parenteral administration such as tablets, capsules, coated tablets, drop solutions, syrups, suppositories or sterile solutions v / earth. The active ingredient can be mixed with the auxiliaries in the usual way and in the desired dosage form to be brought. A preferred embodiment is provided in solid form suitable for oral administration Preparations, such as tablets, capsules, coated tablets, etc.

The solid preparations can contain the abovementioned amount of active ingredient per single dose.

The preparations can also contain suitable preservatives, Contain stabilizers or wetting agents, solubilizers, sweeteners, colorings, aromas, etc. A The invention therefore also relates to the production of these preparations in a manner known per se, and also the use of the compounds in the above-mentioned indications in the form of the said preparations.

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Example 1: 2 _χ 7-Dirneth ^ l-4-meth ^; laininogYrazolo | l _x 5 ~ a3_- s-triazine (method a)

A mixture of 35 g of 4-hydroxy-2,7-dimethylpyrazolo- [1,5-a] -s-triazine, 550 ml of phosphorus oxychloride and 8.6 ml of pyridine are refluxed for 1 1/2 hours. then is evaporated in vacuo / the residue is dissolved in chloroform •, the solution once with ice water and once with ice-cold saturated sodium hydrogen carbonate solution shaken out, dried with magnesium sulfate and im Concentrated in vacuo to a volume of approx. 750 ml. The solution of 4-chloro-2, 7-dimethylpyrazolo [1,5-a] s-triazine thus obtained is cooled in a dry ice bath, treated with 33 g of methylamine and 3 hours at room temperature ditched. The chloroform solution is then extracted with ice-cold 2N sodium hydroxide solution, with Magnesium sulfate dried and evaporated in vacuo. The product is crystallized from benzene. 178 °. Hydrochloric: m.p. 280 ° (decomposition) (from alcohol).

The 4-hydroxy-2,7-dimethylpyrazolo required as the starting product For example, [1,5-a] -s-triazine can be prepared by

4-Amino-2 _/ 7-dimethylpyrazolo [1,5-a] -s-triazine (see Example 9) hydrolyzed with sodium hydroxide in aqueous-methanolic solution at the boiling point. (M.p. 260 °)

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At game 2 : 2 _i 7-DimethYl-4 -_ (2-gYridYlaraino) _pYrazolo-

4.8 g of 2,7-dimethyl-4-methylthiopyrazolo [1,5-a] -s-triazine (see Example 27) are heated to 200 ° with 3 g of 2-aminopyridine for 1 1/2 hours. Then the mixture is at 500 g Chromatographed silica gel, the product with chloroform-ethanol (49: 1) is eluted. After crystallization from ether-petroleum ether, it melts at 128 °.

By the following examples 3, 4, 5 and 6 illu states that the process conditions can vary greatly:

Example. 3; i

s ^ triazine

7.4 g of 2,7-dimethyl-4-methylthiopyrazolo [1,5-a] -s-triazine are refluxed in 40 g of diallylamine for 20 hours (bath temperature: 125 °). The hydrochloride the title compound melts at 151 °.

Example 4; ^

h ^ drazin

7.6 g of 2-methyl-4-methylthiopyrazolo [l, 5-a] -s-triazine (see Example 28) are dissolved in 76 ml of methanol, the 4.2 ml of hydrazine hydrate are added to the solution and at room temperature left to stand »After 3 hours, the precipitated product is suction filtered and recrystallized from methanol. (M.p. 210 °) (decomposition)

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Example 5; 2 _Z 7-Diiuethylg ^ razolo [l _y 5-a2-s-triazine-4-

From 2, 7-dimethyl-4-methylthiopyrazolo [1,5-a] -s-triazine (see Example 27) by reacting with hydrazine hydrate in methanol at room temperature for 2 hours. The product is recrystallized from methylene chloride. (M.p. 161 °)

Example 6; 4-Amino-2-methylpyrazolo [1,5-a] -s-triazine

2-Methyl-4-methylthiopyrazolo [l, 5-a] -s-triazine is with an excess of a saturated methanolic ammonia solution in the autoclave heated to 120 ° for 7 hours. Then the solution is evaporated in vacuo and the pro. product crystallized from methanol, - mp. 216 °

Example 7:

Analogously to Example 1 or 2, starting from 4-Hydroxy-2,7-dimethyIpyrazolo [1,5-a] -s-triazine and using the corresponding amines of formula III:

- 2,7-Dimethyl-4- (4-methyl-1-piperazinyl) pyrazolo [1,5-a] s-triazine (M.p. 114 °)

- 4- (2,7-Dimethylpyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazine ethanol (M.p. 134 °)

- 1- [4- (2,7-Dimethylpyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazinyl] -2-propanol (M.p. 127 °)

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- 4-Amino ~ 2 _f 7-dimethylpyrazolo [l, 5-a] -s-triasine (m.p. 172 °)

* ■ 4-Dimethylamino-2,7-dimethylpyrazolo [1,5-a] -s-triazine (M.p. 136 °)

4-Benzylamino-2,7-dimethylpyrazolo [1,5-a] -s-triazine (M.p. of the hydrochloride 192 °, decomposition)

Example 8:

Analogously to Example 1 or 2, raan, using the corresponding amines of the formula III and starting from

a) 4-Hydroxy-7-methylpyrazole [I ₁ 5-a] -s-triazine:

- 7-methyl-4- (4-methyl-l-piperazinyl) pyrazolo [I ₁ 5-a] -s-triazine (Srnp. 87 °)

- 4- (2-hydroxyethylamino) -7-methyl-pyrazolo [I ₁ 5-a] -s ~ triazine (mp 167 °.).

- 4-Amino-7-methylpyrazolo [l _f 5-a] -s-triazine (m.p. 188 °)

- 4-Diallylamino-7-methylpyrazolo [1 , 5-a] -s-triazine (m.p. of the hydrochloride: 148 °)

f ^ methyl-methylaminopyrazolo / T, 5-a7-s-triazine (m.p. .188 °)

b) 4-Hydroxy-2-methylpyrazolo [1,5-a] -s-triazine:

- 4- (2 ~ methylpyrazolo [l _/ 5-a] -s-triazin-4-yl) -l-pipe ~ razine ethanol (m.p. 146 °)

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2 ~ methyl-4- (4-methyl-1-piperazinyl) pyrazole [1,5-a] -s-triazine (M.p. 81 °)

2-methyl-4-methylaminopyrazolo [1,5-a3-s-triazine (M.p. 173 °)

4-Ethylairino-2-methylpyrazolo [1,5-a] -s-triazine (M.p. 9 8 °)

4 - Isopropylam.tno "2-methylpyrazolo [1,5 ~ a] -s-triazine (M.p. 61 °)

4-Diruethylaniino-2-methylpyrazolo [1,5 ~ a] ~ s-triazine (M.p. 91 °)

2-methyl-4-piperidinoaminopyrazolo [l _/ 5-a] -s-triazine (m.p. of the hydrochloride 2 30 °)

4- (2-dimethylaminoathylami.no) -2-methylpyrazolo- [1,5-a] -s-triazine (oily)

4-Butylamino-2-methylpyrazolo [I ₇ 5-a] -s-triazine (m.p. 59 °) (Hydrochloric! M.p. 205 °)

2-methyl-4-propylaminopyrazolo [1/5-a] -s-triazine (M.p. 91 °)

4-Amino-2-methylpyrazolo [l, 5-a] -s-triazine (m.p. 216 °)

4-diallylamino-2-methylpyrazolo [1,5-a] -s-triazine (M.p. of the hydrochloride 152 °)

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c) 4-Hydroxypyrazolo [I ₇ 5-a] -s-triazine:

- 4-methylaniinopyrazolo [1,5 ^; a] -s-triazine (m.p. 14 6 °)

- 4- (4-Methyl-1-piperazinyl) pyrazolo [1,5-a] -s-triazine (M.p. 69 °)

- 4- (Pyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazine ethanol (M.p. of the hydrochloride 2 34 °)

- 4-aminopyrazolo [1,5-a] ~ s ~ triazine (m.p. 211 °)

d) 4-Hydroxy-2, 8 ~ dimethylpyrazolo [1,5-a] -s-triazinr

- 2,8-Dimethyl-4-methylaminopyrazolo [1,5-a] -s-triazine (M.p. 179 °)

4-Butylamino-2,8-dimethylpyrazolo [l, 5-a] -s ~ triaciii (M.p. 71 °)

2.8 Dimethyl-4- (4-methyl-1-piperazinyl) pyrazolo- [1,5-a3-s-triazine (M.p. 124 °)

- 4-Amino-2 , 8-dimethylpyrazolo [1,5-a] --s-triazine (m.p. 193 °)

e) 2-Ethyl-4-hydroxy-7-methylpyrazolo [l, 5-a] -s-triazine:

- 2-Ethyl-7-methyl-4- (4-methyl-1-piperazinyl) pyrazolo [l, 5-a] -s-triazine (m.p. 95 °)

- 2-Ethyl-7-methyl-4- (2-pyridylamino) pyrazolo [1 _/ 5-a3- - s-triazine (m.p. 106 °).

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2-ethyl-4-ethylamino-7-π ^ ethylpyrazolo [1,5 ~ a] ~ striazine (M.p. 81 °)

2-ethyl ~ 7-methyl 1-4-piperidinopyrcizolo [1,5-a] -triazine (M.p. of the hydrochloride 165 °)

2-Ethyl-4-amino-7-raethylpyrazolo [l, 5-a] -s-triazine (M.p. 140 °)

f) 7-Ethyl-4-hydroxy-2-methylpyrazolo [l, 5-a] -s-triazine:

- 7-Ethyl-2-methyl-4-methylaminopyraz <Jlo [1/5-a] -triazine (M.p. 92 °)

- 7-Ethyl-4-amino-2-methylpyrazolo [l _f 5-a] -s-triazine (melting point 138 °)

g) 4-Hydroxy ~ 7,8-dimethylpyrazolo [1,5-a] -s-triazine:

- 7 _/ 8-Dimethyl-4-methylaminopyrazolotl _f 5-a] -s-triazine (melting point 150 °)

- 4-Amino-7,8-dimethylpyrazolo [1,5-a] -s-triazine (M.p. 255 °)

h) 4-Hydroxy-7-methyl-2-phenylpyrazolo [l _# 5-a] -s-triazine:

- 4-Amino-7-methyl-2-phenylpyrazolo [1 , 5-a] -s-triazine (m.p. 221 °)

i) 2-Ethyl-4-hydroxypyrazolo [1,5-a] -s-triazine:

- 2-Ethyl-4-ainopyrazoloIl, 5-a] -s-triazine (melting point 194 °)

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- 2-Ethyl-4-methylaininopyrazolo [1,5-a] -s-triazine (M.p. 78 °)

j) 4-Hydroxy-2,7,8-trimethylpyrazolo [1,5-a] -s-triazine:

4-Amino-2,7,8-trimethylpyrazolo [1,5-a] -s-triazine (M.p. 216 °)

k) 7-Cyclohexyl-4-hydroxy-2-methylpyrazolotl, 5-a] -striazine:

- 4-Amino-7-cyclohexyl-2-methylpyrazolo [1,5-a] -triazine (M.p. 192 °)

1) 2-Cyclohexyl-4-hydroxy-7-methylpyrazolo [l _/ 5-a] -s ~ triazine:

- 4-Amino-2-cyclohexyl-7-iTiethylpyrazolo [1,5-a] -triazine (M.p. 19 3 °)

m) 8-Erom-4-hydroxy-2-raethylpyrazolo ti, 5-a] -s-triazine:

- 8-Bromo-4-butylamino-2-methylpyrazoloti, 5-a] -striazine (M.p. 70 °)

- e-bromo ^ -raethyl ^ -propylaminopyrazolo tl, 5-a] -s ~ triazine (m.p. 92 °)

- 8-Bromo-2-methyl-4- (2-dimethylaminoethylamino) pyrazolotl, 5-a] -s-triazine (M.p. of the hydrochloride 225 °)

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η) 8-Bromo-4-hydroxy ~ 2,7-dimethylpyrazolo [1,5-a] -s-triazine:

- 8-Bromo-2,7-dintethyl-4-methylaminopyrazolo [1,5-a] -triazine (M.p. 177 °)

o) 4-Hydroxy-2-methyl-8-nitropyrazolo [l, 5-a] -s-triazine:

4-Butylamino-2-methyl-8-nitropyrazolo [1,5-a] -triazine (M.p. 126 °)

- 2-Methyl-8-nitro-4-propylaminopyrazolo ti, 5-a] -s ~ triazine (m.p. 118 °)

- 2-Methyl-4-methylamino-8-nitropyrazolo [1,5-a] -triazine (M.p. 272 °)

p) 8-chloro-4-hydroxy ~ 7-iriethylpyrazolo [1,5-a] ^ s-triazine:

- 8-chloro-4- (2-hydroxyethylaraino) -7-methylpyrazolotl, 5-a] -s-triazine (M.p. 165 °)

- 8-Chloro-7-methyl-4-methylaminopyrazolo [1,5-a] -s-triazine

q) 8-chloro-4-hydroxy-2-methylpyrazolo [1,5-a] -s-triazine:

- 8-chloro-2-methylIM-methylaminopyrazolo [1,5-a] -triazine (M.p. 170 °)

- 8-chloro-2-methyl-4- (4-methyl-1-piperazinyl) pyrazolo [1,5-a] -s-triazine (m.p. of the hydrochloride 320 °)

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4-ethylamino-8-chloro-2-methylpyrazolo [l _/ 5-a] -s-triazine (melting point 102 °)

8-chloro-4-isopropylamino-2-raethylpyrazo.lo [1,5-a] triazine (M.p. 66 °)

S-chloro ^ -dimethylamino ^ -methylpyrazolo [1,5-a] -s ~ triazine (m.p. 132 °)

IOr-2-methyIpyrazolo [1,5-a] -s-triazine (M.p. 230 °)

8-chloro-4-cyclopropylamino-2-methyIpyrazolo [1,5-a] -triazine

S-chloro ^ -cyclopropylmethylamino ^ -methylpyrazolo - [1,5-a] ~ s-triazine

8-chloro-4-cyclohexylamino-2-methyIpyrazolo ti, 5-a] -triazine

8-chloro-4-cyclohexylmethylamino-2-methyIpyrazolo [1,5-a] s-triazine

4-tert-Butylamino-8-chloro-2-methylpyrazolo [1,5-a] -triazine

4-Allylamino-8-chloro-2-methylpyrazolo [1,5-a] -s-triazine

- 8-chloro-2-methyl-4-propargylaminopyrazolo [1,5-a] -triazine

- 8-chloro-4- (2-methoxyethylamino) -2-methylpyrazolo-

azin ^ smy>. ^ f ( ⁰ J

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- 8-Chloro-2-methyl-4- (2-pyrylidylamino) pyrazolo [1,5-aj s-triazine "

- 8-Chior-4 ~ (3, 4-dimethoxyben2ylami.no) -2-iaethylpyrazolotl / 5-a] -s-triazine

- .8-chloro-4-p-chlorobenzylino-2-methylpyrazolo [l _/ 5-a] -

s-triazine

- 8 ~ chloro-2-methyl ~ 4-propylair.inopyrazolo [1,5-a] -s-triazine

r) 4-Hydroxy-2-methyl-7-phenylpyrazolo tl, 5-a3-s-triazine:

- 4-Amino-2-methyl-7-phenylpyrazolo [l _/ 5-a] -s-triasin (m.p. 258 °)

s) 8-chloro-4-hydroxy-2,7-dimethylpyrazolo [1,5-a] -s-triazine:

- 8-chloro-2,7-dimethyl-4-methylaminopyrazolo [1 , 5-a} -triazine (melting point 204 °)

t) 2-Ethyl-8-chloro-4-hydroxypyrazolo [l, 5-a] -s-triazine:

- 2-Ethyl-8-chloro-4-methylaminopyrazolo [l, 5-a] -s-triazine (M.p. 106 °)

u) 8-Ethyl-4-hydroxy-2-methylpyrazolo [l, 5-a] -s-triazine!

- 8-Ethyl-4-arftino-2-methylpyrazolo [1,5-a] -s-triazine (M.p. 139 °)

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- 8-Ethyl-2-raethyl-4-methylaminopyrazolo [1,5-a] -triazine (M.p. 130 °)

v) 7-Ethyl-8-chloro-4-hydroxy-2-methylpyrazolo ti, 5-a] -striazine:

- 7-Ethyl ~ 8-chloro-2-methyl-4-methylaminopyrazolo [1,5-aj ■ s-triazine

v /) 8-chloro ~ 4-hydroxy-2-propylpyrazolo [l, 5-a] -s-triazine:

- 8-Chloro-4-methylaInino-2-propylpyrazolo ti, 5-a] -s-triazine

x) 8-chloro-7-cyclohexyl-4-hydroxy ~ 2-methylpyrazolo f1 , 5-a] s-triazine:

- 8-chloro-7-cyclohexyl-2-methγl-4-Inethylaminopyrazolo- [1, 5-a] -s-triazine

y) 8-chloro-4-hydroxypyrazolo [l, 5-a] -s-triazine:

- 8-Chloro-4-methylaminopyrazolo [1,5-a] -s-triazine

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Example 9: ^ Ι ^ 1ΒΪ22ΐΐ2χ7-αΐΐη6 ^ ίιγ1ργΓ§ζο1ο_ [1 _χ 5-§3-s-ϊίί ^ ζΐη (method b)

For dissolving 150 g of 5-amino ~ 3-methyl-1-pyrazolecarboxamidine 350 g of triethyl orthoacetate are placed in 750 ml of dioxane and heated to reflux for 4 hours. It is then evaporated in vacuo and the product crystallized from methylene chloride. 172 °

The 5-amino-3-methyl-lpyrazolecarboxamidine required as the starting product is obtained e.g. as follows:

5-methylisoxazole is mixed with the equivalent amount of sodium methylate opened in methanol by brief boiling to the sodium salt of Cyana'cetons and the obtained Solution with aminoguanidine dihydrochloride in boiling methanol or with an aqueous solution of aminoguanidine dihydrochloride reacted at room temperature, with S-amino-S-uiethyl-l-pyrazolecarboxamidine being formed (m.p. 125 °; Hydrochloride. M.p. 164 °).

Example 10: i

(Method b)

A mixture of 11 g of S-amino-S-methyl-1-pyrazolecarboxainidine, 100 ml of dioxane and 46 g of triethyl orthoformate is refluxed for 2 hours and then evaporated in vacuo. The product is recrystallized from alcohol-methylene chloride-ether. 188 °

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Example 11: i

(Method b)

The solution of 3I ₇ 5 g of Ν, Ν'-carbonyldiirnidazole in 240 ml of dioxane is cooled in an ice bath and a solution of 8 ml of formic acid in 160 ml of dioxane is rapidly added dropwise with stirring. After 20 minutes, 20 g of 5-amino- l-pyra-zolcarboxamidine was added and the mixture was gradually heated to 110 ° bath temperature with stirring. After stirring for 1 hour at this temperature, the mixture is evaporated in vacuo and the product is crystallized from alcohol. (M.p. 211 °)

Example 12; ■ '

Analogously to Examples 9 and 10, reaction of the corresponding orthoester (formula VII) with

a) S-Amino-S-methyl-l-pyrazolecarboxamidine:

- '2-Ethyl-4-amino-7-methylpyrazolo [l _/ 5-a] -s-triazine

{M.p. 140 °)

- 4-Amino-7-methyl-2-phenylpyrazolo [l _/ 5-a] -s-triazine (m.p. 221 °).

b) 5-Amino-l-pyrazole carboxamidine (from isoxazole):

- 2-Ethyl-4-aminopyrazolo ti ₁ 5-a] -s-triazine (melting point 194 °)

- 4-Amino-2-methylpyrazolo [l _/ 5-a] -s-triazine (m.p. 216 °).

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c) S-ethyl-S-amino-l-pyrazolecarboxamidine:

- 7-Ethyl-4-amino-2-methylpyrazoio [1,5-a] -s-triazine (M.p. 138 °)

The 3 ~ ethyl-5-amino-1-pyrazolecarboxamidine required as the starting product is obtained by reacting 3-oxovaleronitrile with aminoguanidine hydrochloride in aqueous-methanolic solution at room temperature.

d) 5-Amino-3,4-dimethyl-1-pyrazolecarboxamidine:

- 4-amino-2,7, 8-trimethylpyrazolo [1,5-a] -s ~ triazine (mp 216 °).

The 5-amino-3,4-dimethyl-1-pyrazolecarboxamidine required as the starting product obtained by reacting 2-methyl-3-oxobutyronitrile with aminoguanidine hydrochloride (analogous to example 12c)

e) S-Ami.no-S-cyclohexyl-1-pyrazolecarboxamidini

- 4-Amino-7-cyclohexyl-2-methylpyrazolo [1,5-a] -triazine (M.p. 192 °)

For S-amino-S-cyclohexyl-l-pyrazolecarboxamidine can to arrive as follows:

Cyclohexanecarboxylic acid methyl ester is dissolved in liquid ammonia in the presence of sodium amide with acetonitrile condensed and the resulting aqueous solution of the sodium salt of 3 "cyclohexyl-3-oxopropiponitrile

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reacted with aminoguanidine in weak hydrochloric acid aqueous solution at room temperature, with 5-amino-3-cyclohexy1-1-pyrazolecarboxamidine arises. (M.p. 125 °)

f) 5-Amino-4-methyl'-l ~ pyrazolecarboxamidine:

- "4-Amino-2, 8-dimethylpy'razolo [1 , 5-a] -s-triazine (melting point 193 °)

For S-amino - ^ - methyl-l-pyrazolecarboxamidine one can get as follows:

The condensation of propionitrile in liquid ammonia in the presence of sodium amide with ethyl formate The sodium salt of 2-cyanopropionaldehyde obtained is made more acidic in aqueous, weakly hydrochloric acid Solution reacted with aminoguanidine at room temperature, with 5-amino-4-methyl-1-pyrazolecarboxamidine arises. (Raw further processed)

Example 13:

Analogously to Example 11, by reacting the desired compounds of the formula VIII (prepared in situ) with

a) 5-Amino-3,4-dimethyl-l-pyrazolecarboxamidine:

- 4-Amino-7,8-dimethylpyrazolo [1,5-a] -s-triazine (M.p. 255 °)

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b) S-amino-S-methyl-l-pyrazolecarboxamidine:

- 4-Amino-2-cyclohexyl-7-methylpyrazolo [l _/ 5-a] -striazine (melting point 193 °)

Example 14:

Analogously to example 9, 10 or 11 is obtained using of the corresponding pyrazole:

- 2, 7-Dimethyl-4-methylaminopyrazolo [1,5-a] -s-triazine . (M.p. 178 °)

- 2 _/ 7-Dimethyl-4- (4-methyl-l-piperazinyl) pyrazolo [1,5-ci] s-triazine (m.p. 114 °)

- 4- (2,7-Dimethylpyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazine ethanol (m.p. 134 °).

- 1- [4- (2, 7-Dimethylpyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazinyl] ~ 2-propanol (m.p. 127 °)

- 4-Benzylamino-2,7-dimethylpyrazolo ti, 5-a] -s-triazine (M.p. of the hydrochloride 192 °)

- 4-Dimethylainino-2 , 7-dimethylpyrazolo [1 , 5-a] -s-triazine (melting point 136 °)

7-methyl-4- (4-methyl-1-piperazinyl) pyrazolo [1,5-a] -s-triazine (M.p. 87 °)

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- · 4- (2-Hydroxyäthylamino) -7-methylpyrazolo [1 , 5-a] -s-

triazine (m.p. 167 °).

- 4 ~ Diallylamino-7-methylpyrazolo [1,5-a] -s-triazine (Srap. Of the hydrochloride: 148 °).

7-methyl-4-methylaminopyrazolo / T, 5-a7-s-triazine (m.p. 188 °)

- 4- (2-Methylpyrazolo [1,5-a] -s-triazin-4-yl) -1-pi.perazine ethanol (M.p. 146 °)

~ 2-methyl ~ 4- (4-iuethyl-1-piperazinyl) pyrazolo [1,5-a] ~ s-triazine (m.p. 81 °).

- 2-Methyl-4-methylaminopyrazolo [1,5 ~ a] -s-triazine (Snip. 173 °)

- 2 ~ methyl-4-piperidinoaminopyrazolo [l _/ 5-a] -s-triazine (m.p. of the hydrochloride 230 °)

- 4- (2-Diiaethylaitiinoäthylamino) -2-methylpyrazolo- [1,5-a] -s-triazine (oily)

- 4-butylamino-2-raethylpyrazolo [I ₁ 5-a] -s-triazine
(Snip. 59 °) (hydrochloride m.p. 205 °)

- 2-methyl-4-propylamine pyrazolo [1,5-a] -s-triazine (Snip. 91 °).

4-Diallylamino-2-methylpyrazolo [l _# 5-a] -s-triazine (m.p. of the hydrochloride 152 °).

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- 4-methylaminopyrazolo [l, 5-a] -s-triazine (m.p. 14 6 °)

- 4- (4-Methyl-1-piperazinyl) pyrazolo [1 _f 5-a] -s-triasine (m.p. 69 °>

- 4- (Pyrazolo [1,5-a] -s-triazin-4-yl) -1-piperazine ethanol (M.p. of the hydrochloride 234 °)

- 2 _/ 8-Dimethyl-4-methylaminopyrazolotl _/ 5-a] -s-triazine (m.p. 179 °)

- 4-Butylamino-2,8-dimethylpyrazolo [I ₁ 5-a] -s-triazine (melting point 71 °)

2,8-Dimethyl 1-4- (4-methyl-1-piperaziny1) pyrazolo- [1,5 ~ a] -s-triazine (M.p. 124 °).

- 2-Ethyl-7-methyl-4- (4-methyl-1-piperazinyl) pyrazolo [1, 5-a] -s-triazine (m.p. 95 °)

- 2-Ethyl-7-methyl-4- (2-pyridylamino) pyrazolo [l _# 5-a3 s-triazine (m.p. 106 °).

- 2-Aethyl-4-ethylamino-7-methylpyrazolo [1,5-a] -triazine (M.p. 81 °)

- 2-Ethyl-7-methyl-4-piparidinopyrazolo [1,5-a3-striazine (M.p. of the hydrochloride 165 °)

- 7-Ethyl-2-methyl-4-methylaminopyrazolo [1,5-a] -triazine (M.p. 92 °)

- 7 _r 8-Dimethy1-4-methylaminopyrazolo [1,5-a] -s-triazine (melting point 150 °)

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4-ethylamino ~ 2-methylpyrazolo [l, 5-a] -s-triazine (melting point 98 °)

4-Isopropylamino ~ 2-methylpyrazolo [1,5-a] - s-triazine (M.p. 61 °)

2-Ethyl-4-methylaminopyrazolo [1,5-a] -s-triazine "(M.p. 78 °)

4-dimethylamino-2-methylpyrazolo [1,5-a] -s-triazine (M.p. 91 °)

2,7-Dimethyl ~ 4- (2-pyridylamino) pyrazolo [1.5 "a3-striazine (M.p. 128 °)

4-niallylamino-2,7-dimethylpyrazolo ti , 5 ~ a] -s-triazine (m.p. of the hydrochloride 151 °)

2-methylpyrazolo [1,5-a] -s-triazin-4-yl-hy'drazine (M.p. 210 °)

2,7-Dimethylpyrazolo [1,5-a] -s-triazin-4-ylhydrazine (M.p. 161 °)

Example 15; ^

s-triazine (method b)

S-Amino-S-methyl-1-pyrazolecarboxamidine is in tetrahydrofuran in the presence of 1 mole of triethylamine with 1 mole of ethyl chloroformate at 60 ° to give N-ethoxycarbonyl-S-amino-S-methyl-1-pyrazolecarboxamidine (M.p. 126 °) implemented. This compound is dissolved in tetralin and the The solution was heated to a bath temperature of 220 ° for 1 hour while the alcohol formed was distilled off. The title compound crystallizes out and has a melting point of 310 °

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Λ *

According to a variant of this process, 10 g of B-amino-S-methyl-l-pyrazolecarboxamidine with 14 g of Ν, Ν ¹ -carbonyldiimidazole in 240 ml of dioxane are heated to boiling for 2 hours, whereupon the title compound (melting point 310 °) crystallizes out.

Example 16 '; 4-Amino-2-hydroxypyrazolo [1,5-a] -s-triazine

The procedure is analogous to Example 15 and starting from this one obtains of 5-amino-1-pyrazolecarboxamidine the title compound of m.p. 334 °.

Bei p iel 17; S.

s-triazine

That by condensation of butyronitrile with ethyl formate sodium salt of 2-cyanobutyraldehyde obtained in liquid ammonia in the presence of sodium amide is reacted in an aqueous, weakly hydrochloric acid solution at room temperature with aminoguanidine, with 4-ethyl-5-amino-1-pyrazolecarboxamidine is obtained (m.p. c 69 °). This compound is boiling in dioxane cyclized with triethyl orthoacetate, with 8-ethyl-4-amino-2-methylpyrazolo [1,5-a] -s-triazine arises. The product is crystallized from methanol.

(M.p. 139 °)

Analogous to example 17 one obtains:

- 8-Ethyl-2-methyl-4-methylaminopyrazolo [1,5-a] -s-triazine (M.p. 130 °)

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Example IS: SziS ^ Z ^ l ^ yyl

(Method c)

For the solution of 1.38 g of 4-butylamino-2-methylpyrazolo- [l, 5-a] ~ s - tria:? In A solution of 1.1 g of bromine in 5 ml of glacial acetic acid is added dropwise to 15 ml of glacial acetic acid and the mixture is then stirred completed dropping for 20 minutes at room temperature. Then the solution is evaporated in vacuo / the The residue is extracted with chloroform and ice-cold 2 N sodium hydroxide solution, the chloroform solution with sodium sulfate dried and evaporated in vacuo. The product is crystallized from petroleum ether (melting point 70 °) M.p. of the hydrochloride (alcohol-ether) 155 ° ..

Analogously to Example 18, the bromination gives the corresponding compounds of the formula Id:

- 8-Bromo-2-methyl-4-propylaminopyrazolo [l / 5-a] -s-triazine (M.p. 92 °).

- 8-Bromo - 2/7-dimethyl-4-methylaminopyrazolo [1/5-a] -triazine (M.p. 177 °) (from ether).

Example 19;

(Method c)

The bromination is analogous to Example 18. in glacial acetic acid carried out. After evaporating the glacial acetic acid solution in vacuo, the resulting crystalline hydrobromide is recrystallized from methanol-ether. (M.p. 225 °).

409 85 1 / 1U5

- 4-6 - '100-4004

Example 20; i ~ ^ But ^ lam ^ no ~ 2-methYl-8-nitroDyrazolo-

(Method c)

1 g of 4 butylamino-2-methylpyrazolo [1,5-a] -s-triazine

is dissolved in 15 ml 9 8% nitric acid and the solution Left to stand at room temperature for 2 hours. This is followed by three times the volume with ice water diluted, the solution made alkaline by adding dropwise concentrated sodium hydroxide solution with cooling at approx. 0 ° and extracted with chloroform. After drying over sodium sulfate, the chloroform solution is evaporated in vacuo and the product is crystallized from ether. (M.p. 126 °)

Analogously to Example 20, the nitration gives the corresponding compounds of the formula Id:

- 2-methyl-8-nitro-4-propylaminopyrazolo [1,5-a] -triazine (M.p. 118 °)

- 2-methyl-4-methylamino-8-nitropyrazolo [1,5-a] -striazine (M.p. 272 °; from chloroform-alcohol)

Example 2.1: eiiililliY ^

l (method c)

For the solution of 5 g of 4- (2-hydroxyethylamino) -7-methylpyrazolotl, 5 ~ a] -s-triazine 3 ml of glacial acetic acid and 6.9 g of N-chlorosuccinimide are added to 100 ml of chloroform and the mixture is stirred Mixture for 16 hours at room temperature. After that, the

4 0 9 8 5 1/114 5

100-4004

Chlorine form solution washed with ice-cold 2 N sodium hydroxide solution, dried with magnesium sulfate and evaporated in vacuo. The product becomes crystal out of alcohol! - sated. (M.p. 165 °) ■

Chlorination as in Example 21 gives

- 8 "chloro-2-methyl-4-methylaminopyrazolo ti, 5-a] -s-triazine (M.p. 170 °) (from ether-petroleum ether)

triazine (m.p. 204 °)

8-chloro-2-methyl ~ 4- (4-methyl-1-piperazinyl) pyrazclotl, 5-a] -s-triazine (M.p. of the hydrochloride 320 °)

4-ethylamino-8-chloro-2-methylpyrazolotl, 5-a] -s-triazine (M.p. 102 °) (reaction temperature 70 °, solvent: dioxane-water mixture, which contains 10% water)

8-chloro-4- isopropylamino-2-methylpyrazolo ti / 5-a] -triazine (M.p. 66 °) (reaction temperature 70 °, solvent: Dioxane-water mixture, which contains 10% water)

2-Ethyl-8-chloro-4-methylaminopyrazoloti, 5-a] -s-triazine (M.p. 106 °) (reaction temperature 70 °, solvent: dioxane-water mixture, which contains 10% water)

409851 / 1U5

- -fro - 100-4004

8-chloro-4-dimethylamino-2-methylpyrazolo [1,5-a] -triazine (M.p. 132 °)

4-Ainino-8-chloro-2-methylpyrazolo [1,5-a] -s-triazine (M.p. 230 °)

- · 7-Ethyl-8-chloro-2-methyl-4-methylaminopyrazolo [1,5-a] -

s-triaziri

- e-chloro ^ -cyclopropylamino ^ -methylpyrazolo [1,5 ~ a] -triazine

- e-chloro ^ -cyclopropylmethylamino ^ -inethylpyrazolo [1,5-a] -s-triazine

8-chloro-4-cyclohexyiamino-2-methylpyrazolo [1,5-a3-striazine

- 8-chloro-4-cyclohexylmethylaInino-2-methylpyrazolo [1,5-a] s-triazine

- 4-tert.Buty! Amino-8-chloro-2-methylpyrazole [1,5-a] -s-triazine (J * p. <\ L °)

4-Allylamino-8-chloro-2-methylpyrazolo [1,5-a] -s-triazine

S-chloro ^ -methyl ^ -propargylaininopyrazolo [1,5-a] -triazine

8-chloro-4- (2-methoxyethylamino) -2-methylpyrazoJ.o [1,5-a] s-triazine

8-chloro-2-methyl-4- (2-pyrimidylamino) pyrazolo [1,5-a] -s triazine 409851/1 HS

100-4004

8 - Chlox - 4- (3,4-dimethoxybenzylamino) -2-methylpyrazoio [1,5-a] ~ s-triazine

8 ~ chloro-4-p-chlorobenzylamino-2-methylpyrazolo [1,5-a] s-triazine

8 - chloro-2-methyl-4-propylaminopyrazolo [1,5-a] -triazine

8-chloro-4-methylamino-2-propylpyrazolo [1,5-a] -triazine

8-chloro-7-cyclohexyl - 2-methyl-4-methylaminopyrazolo [1,5-a] ~ s-triazine

8-chloro-4-methylaminopyrazolo

8- ⁱ chloro-7-methyl-4-methylaminopyrazolo [1,5-a] -s triazine

Example 22 ' ^ IlAmino-4-butjrlaiti ± ng ~ 2-methvlgyr-azolo-

(Procedure eh

g of 4-butylainino-2-methyl-8-nitropyrazolo [l _/ 5-a3 "S-triazine v / earth dissolved in 100 ml of ethanol and after addition of 6 g of 10% palladium catalyst (palladium on carbon) at normal pressure and Hydrogenated at room temperature, after the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated in vacuo. The product is crystallized from ether. (Snip. 92 °)

A 0 9 8 5 1/1 U 5

100-4004

Example 23: B 2 ^ ^CG

l (procedure

5 g of iron powder are added in portions at 95 ° to the solution of 5 g of 4-butylamino-2-methyl-8-nitropyrazolo [1,5-a] -s-triazine in 85 ml of glacial acetic acid and 15 ml of water and the mixture is stirred Mixture for 1 hour at the same temperature. Then it is cooled, 100 ml of ice water and 200 itu. Chloroform was added, the excess iron powder was filtered off, the filtrate was shaken out, the chloroform phase was washed once with ice-cold 2 M sodium hydroxide solution, dried with magnesium sulfate and evaporated in vacuo. The product is recrystallized from ether. (M.p. 153 °)

Example 2 4: i

(Method c)

A mixture of 2 g of 4-Dimethylamine-2,7-dimethylpyrazo-Io [1,5-a] -s-triazine, 1.1 g of dimethylamine hydrochloride, l _r 57 g of paraformaldehyde and 20 ml ethanol 16 hours at reflux cooked. It is then evaporated in vacuo, the residue is shaken out with ice-cold 2N sodium hydroxide solution and chloroform, the chloroform solution is dried over magnesium sulfate and evaporated in vacuo. The product is converted into the dihydrochloride with an ethanolic hydrogen chloride solution and this is crystallized from ethanol. (M.p. 250 °)

40 9 8.51 / 1 U 5

- 59 - 100-4004

Analogous to example 24 one obtains:

- 8-Dimethylaminoiuethyl-2,7-dimethyl-4-methylamino pyrazolotl / 5-a] -s-triazine
(Srap. Of the dihydrochloride: 256 °)

SJu. ™ ^! 4-Dimethylamino-2,7-dimethy_lp_y_razolo - [l ^ B-a ^ -s-triazine-S-carbaldehyde (Method c)

For the suspension of 1/91 g of 4-dimethylamino-2,7-dimethylpyrazolo [l, 5-a] -s-triazine 1.83 ml of phosphorus oxychloride are added dropwise to 20 ml of dimethylformamide, the temperature being increased rises to approx. 40 °. The solution is heated to a bath temperature of 90 ° for 1 hour. Then one drips while cooling 20 ml of water are added, the mixture is extracted with chloroform, and the chloroform solution is washed once with an ice-cold saturated solution Sodium hydrogen carbonate solution, dry it over magnesium sulfate and evaporate it in a vacuum. The product is crystallized from ethanol. (M.p. 156 °)

Analogous to example 25 one obtains:

- 2,7-Dimethyl-4-methylaminopyrazolo [1,5-a] -s-triazine-8-carbaldehyde (M.p. 205 °)

Example 26: 8ζ ^ 2 ^ ί5ΐί} ΐ ^ 2ΐ1ΐΐ2ίϊΐ2ί2.ϊ

i2ili§l§liszti: iazin (method e)

A solution of 8-amino-4-butylamino-2-methylpyreVzolo- [1,5-a] -s-triazine in pyridine, excess acetic anhydride is added with cooling and 16 hours

4098 51 / 1U5

- 54 - 100-4004

left to stand at room temperature. Then it is evaporated in vacuo, the residue with chloroform and ice-cold shaken saturated sodium hydrogen carbonate solution, the chloroform solution dried over magnesium sulfate, evaporated in vacuo and the product crystallized from ether. (M.p. 153 °)

Example ^^ 27; 2 _i 7-DimethYl ~ 4-methYlthiopvrazol.o_ [l _i 5-a] _ ^ s-triazine (type: formula lic)

To a solution, cooled to 0 °, of 3.2 g of sodium 25 g of 4-mercapto-2,7-dimethylpyrazolo [l, 5-a] -s-triazine are added to 265 ml of methanol. After everything has dissolved, 23.6 g of methyl iodide are added and the mixture is left for 16 hours Stand room temperature. Then it is evaporated in vacuo, the residue with methylene chloride and ice-cold 2 H Sodium hydroxide solution extracted, the methylene chloride solution dried over sodium sulfate and evaporated in vacuo. The product is crystallized from ether-petroleum ether. (M.p. 105 °)

The 4-mereapto-2,7-dimethylpyrazolo [1,5-a] -s-triazine can be made as follows

4-7uTtino-2, 7 "dimethylpyrazolo [l, 5-a] -s-triazine (see Example 9) is mixed with sodium hydroxide in aqueous methanol Solution at the boiling point to give 4 ~ hydroxy-2,7-dimethylpyrazolo [1,5-a] -s-triazine hydrolyzed (m.p. 260 °).

409851 / IUS

100-4004

The solution of 120 g of 4-hydroxy-2,7-dimethylpyrazole p 324 g of phosphorus pentasulfide are added and the mixture is 15 hours ara reflux heated to boiling. This is done in a vacuum evaporated, the residue taken up in 660 ml of water and left to stand at room temperature. After 2 The aqueous solution is extracted several times with chloro form for hours. The chloroform extracts are combined, dried with magnesium sulfate and evaporated in vacuo. The aqueous phase becomes after 24 hours Stand again extracted with chloroform to give an additional amount of product. The raw product is chromatographed on 10 times the amount of silica gel, where the 4 - mercapto-2, 7-dircethylpyrazoio [1,5-aj ~ s ~ triazine eluted with methylene chloride / ethanol (19: 1) will. After recrystallization from methylene chloride / Aetha ™ nol the compound melts at 235 °.

Example 28; 2

triazine (type: formula lic)

For the solution, cooled to 0 °, of 1.4 g of sodium in 110 10 g of 4-mercapto-2-methylpyrazolo- [1,5-a} - s-triazine are added to ml of methanol. After everything has dissolved, 10.2 g of methyl iodide are added and the mixture is left at room temperature for 16 hours stand. Then it is evaporated in vacuo, the residue with chloroform and ice-cold 2N sodium hydroxide solution Shaken out the chloroform solution over sodium sulfate dried and evaporated in vacuo. The product is crystallized from ether-petroleum ether. Snip. 91 °

409 85 17 1U5

■ ■ 100-4004

The 4-mercapto-2-methylpyrazolo [1,5-a] -s-triazine can manufactured as follows:

4-Amino-2-methylpyrazolo [l, 5-a] -s-triazine (see example

6) with aqueous-methanolic sodium hydroxide solution in the Boiling heat to give 4-hydroxy-2-methylpyrazolo [1,5-aj -s-triazine hydrolyzed (m.p. 274 °).

A pot of 88 g of 4-hydroxy-2-methylpyrazolo [1,5-a] -s-triazine, 2.5 l of dioxane and 156 g of phosphorus pentasulfide is refluxed for 15 hours. It is then evaporated in vacuo and the residue is heated on a water bath with 850 ml of water for 1 1/2 hours. After cooling, it is extracted with chloroform, the chloroform solution is dried with magnesium sulfate and evaporated in vacuo. The viscous product is extracted with boiling methanol and the crude product obtained after evaporation of the methanol is chromatographed on a 20-fold amount of silica gel. The 4-mereapto-2-methyI- · pyrazolo [l, 5-a] -s-triazine is eluted with chloroform-ethanol (19: 1). It is recrystallized from ethanol. M.p. 257 °

Example 29: 4-methylthio £ y_razolo | 1 _x 5-a3_-S2triazine

This compound is prepared from 4-mercaptopyrazolo [l, 5-a] -triazine analogously to that described in Examples 27 and 28 Process made and crystallized from ether. (M.p. 108 °)

The 4-mercaptopyrazolo [1,5-a] -s-triazine can be as follows getting produced:

409851/1 145

- 9? - 100-4004

5-Amino-1-pyrazolecarboxamidine is used with an excess of the mixed anhydride of formic and acetic acid to form 4-Formyiaminopyra7.olo [1, 5-a] -s ~ triazine (Snip. 235 °) cyclized. A mixture of 220 g of 4-foi-mamidopyrazolo [l, 5-a] - s-triazine, 620 ml of formic acid and 1860 ml of water are refluxed for 7 hours. Then v / ird the solution cooled, whereby the 4-hydroxypyrazolo [1,5-a] · s-triazine (m.p. 26 8 °) crystallized.

The suspension of 100 g of 4-hydroxypyrazolo [1,5-a] -triazine in 1.5 l of pyridine is mixed with 327 g of phosphorus pentasulfide added and the mixture heated to boiling under reflux for 15 hours. The dark solution is in vacuo evaporated and the residue treated with 1 l of water., As soon as the initially strong foaming subsides, is. Heated for 4 hours in an oil bath at 50 °, then the solution by adding a little concentrated hydrochloric acid to approx. Set pH 3 and filtered. The filtrate is in vacuo evaporated and the syrup obtained in the separating funnel extracted with chloroform. That obtained after evaporation of the chloroform solution dried over magnesium sulfate The crude product is chromatographed on a 20-fold amount of silica gel. The 4-mercaptopyrazolo [1,5-a] -s-triazine is eluted with chloroform / ethanol (S: 1). The substance is recrystallized from chloroform / methanol. M.p. 275 °

Example 30: i ^ A

s ~ triazine

The procedure is analogous to Example 27 and, using ethyl iodide as the alkylating agent, the title is obtained rb i nöung. (M.p. 55 °)

% 0 9 8 5 1/1 U5

100-4004

Example 31: 4-Hydroxy_-2-rue i-l2YlpYrazolo_tl _z 5-a] _- s ~ triaj.i2 (Type: Formula VI)

A mixture of 115 g of 4 ~ amino ~ -2-methylpyra.zolo [1, 5-a] -striazine, 580 ml of 2W sodium hydroxide solution and 290 ml of methanol are heated to boiling under reflux for 2 hours, then in an ice bath cooled down. The crystallized sodium salt of the product is filtered off with suction and dried in vacuo. Then it is taken up in 300 ml of water and with 411 ml 2N hydrochloric acid is added, whereupon it dissolves and the 4-hydroxy compound crystallizes out. It will be fil- trated and dried in vacuo. (M.p. 275 °)

The following compounds were prepared analogously to this or to that in Example 1 for the preparation of 4-hydroxy-2,7-dimethylpyrazolo ti, 5-a] -s-triazine Process made:

- 4-Hyd3: oxy ~ 2-methylpyrazolo [1,5-a] -s-triazine (M.p. 274 °)

- 7-Ethyl-4-hydroxy-2-methylpyrazolo [1,5-a] -s-triazine (M.p. 192 °)

2-Ethyl-4-hydroxy-7-methylpyrazolotl, 5-a] -s-triazine (M.p. 243 °)

4-Hydroxy-2,8-diinethylpyrazolo [1,5-a] -s-triazine (M.p. 316 °)

- 4-Hydroxy-7-methyl-2-phenylpyrazolo [1,5-a] -s-triazine

- 2-Ethyl-4-hydroxypyrazolo [l _f 5-a] -s-triazJn

4 0 9 8 5 1 / IUS

- 5-9 · 100-400'i

- 4-Hydroxy-2, 7, 8-trimethylpyrazolo [1,5-a] -s-tri.azine

- 7-Cyclohexyl-4-hydroxy-2-methylpyrazo3.o ti , 5-a] -s-triazine

- 2-Cyclohexyl-4-hydroxy-7-methylpyrazolo [1,5-a] - s-triazine

- 8-Bromo - 4-hydroxy-2-rcethylpyrazolo ti , 5-a] -s-triazine

- 8-Bromo-4-hydroxy-2,7-dimethy.lpyrazolo ti, 5-a] -s-triazine

- 4-Hydroxy-2-methyl-8-nitropyrazolo [1,5-a] -s-triazine

- 8 ~ chloro-4-hydroxy ~ 2 ~ methylpyrazolo ti, 5 ~ a] -s-triazine (M.p. 308 °) ..

4-Hydroxy-2-methyl-7-phenylpyrazolo [1,5-a] -s-triazine

- 2-Aethyl-4-hydroxypyrasoloti, 5-a] -s-triazine (M.p. 264 °)

- 8-Ethyl-4-hydroxy-2-ynethylpyrazolo [1,5-a] -s-triazine (M.p. 295 °)

- 8-Chloro-4-hydroxy-2 _/ 7-dimethylpyrazolo [I ₇ 5-a] -s-trictzine

Example 32; (.Type: Formula VI)

In Example 29 is a method of making compounds of the formula VI (4-hydroxypyrazolo [l, 5-a] -s-triazine) explained. The following connections were made analogous to manufactured using this process:

409851/1145

100-4004

- 4-Hydroxy-7-methylpyrazolo [l, 5-a} ~ s-triaziri (m.p. 293 °)

- 4-Hydroxy-7 , 8-dimethylpyrazolo [1,5-a] -s-triazine (melting point 330 °)

Example 33:

One for oral administration according to the invention Representative pharmaceutical form suitable for compounds is, for example, a tablet.

Such a tablet can contain, for example, the following ingredients contain:

2, V-Dimethyl - ^ - niethylaminopyrazolo- [1,5-aj-s-triazine 25 mg

Tragacanth 10 mg

Milk sugar 222.5 mg

Talc 15 mg

Corn starch 25 _{mgmagnesium stearate 2 r} 5 nig

Production can be carried out using known tableting techniques take place.

The tablets can be used, for example, in a dosage of 3x1 or 4x1 tablets daily.

409851 / 1U5

- 100-4004

-ty

The active ingredient mentioned by way of example can be replaced by other active ingredients of the formula I ₁ lic or Vi or physiologically acceptable acid addition salts thereof.

Inhalation therapy _y __z ^ B ^ _Aerosol

The compounds according to the invention can also be used in the form of inhalation therapy. For the nasal implication is generally expedient aqueous solutions of the substances according to the invention are used, which are then instilled by means of an applicator or sprayed with a kebulizer.

Compositions for use in the form of inhalation therapy can be prepared by known methods and contain the additions for such additions usual ingredients.

An aerosol formulation representative according to the invention contains e.g. the following components:

2,7-Diinc'thyl-4-methylarainopyrazolo- [1,5-a] -s-triazine 0.8-20%

Ethanol ^ 10/0 - 40 %

Ascorbic acid 1.0 ~ 10 %

Fri on 11 10.0 - 30 %

Freon 114 10.0 ~ 30% Freon 12 . 30.0 to 60%

Buffer system q.s.

Aromants' q.s.

The active ingredient listed by way of example can be replaced by other active ingredients of the formula I, lic or VI or physiologically Compatible acid addition salts replaced therefrom will. 409851 / 1U5

Claims (4)

100-40C4 i /. Process for the preparation of new compounds of the formula wherein _R1 is hydrogen, lower alkyl, phenyl, substituted by halogen, lower alkoxy or lower alkyl phenyl, or cycloalkyl having 3-6 · KohJ.enstofratomen, R is hydrogen, lower alkyl, chlorine, bromine, formyl, acetyl, nitro _r Di (lower) alkylaminomethyl, amino or a group A-CO-KH- in which A is hydrogen, lower alkyl or lower alkyl substituted by halogen, R 1 is hydrogen, hydroxy, lower alkyl, cycloalkyl with 3-6 carbon atoms , Denotes phenyl or a phenyl group substituted by lower alkyl, lower alkoxy or halogen, either R ₄ denotes hydrogen, lower alkyl, lower / alkenyl or lower alkynyl, the multiple bonds of which are not in the α, β position to the nitrogen atom, where the alkenyl or alkynyl radical is bonded, a hydroxy (lower) alkyl or (lower) alkoxy (lower) alkyl group, in which the oxygen atom is replaced by at least 2 carbon atoms from the nitrogen atom to which the alkyl radical is bonded, is separated, di (lower) alkylamino- (lower) alkyl, whose nitrogen is replaced by at least 2 409851 / 1U5 «■ 9 - 100-4004 -Or Carbon atoms are separated from the nitrogen atom to which "this radical is bonded, cycloalkyl with 3-7 carbon atoms or cycloalkyl (lower) alkyl with 4-10 carbon atoms, pyridyl, pyrimidyl, benzyl, one in the phenyl radical by lower alkoxy, lower alkyl, halogen or." Hydroxy-substituted benzyl group, amino, di (lower) alkylamino or an alkyleneimino group with 2-7 carbon atoms and R _n . Hydrogen, lower alkyl, lower alkenyl or lower alkynyl, the multiple bond of which is not in α, β-position to the nitrogen atom, where the Alkenyl or alkynyl radical is bonded, is a hydroxy (lower) alkyl or (lower) alkoxy (lower) alkyl group, in which the oxygen atom is separated from the nitrogen atom to which the alkyl radical is bonded by at least 2 carbon atoms, Di (lower) alkylamino (lower) alkyl, the nitrogen of which is separated by at least 2 carbon atoms from the nitrogen atom to which this radical is attached, cycloalkyl with 3-7 carbon atoms omen or cycloalkyl (lower) alkyl with 4-10 carbon atoms or the group ΝίΓ '^ for piperidino, pyrrolidino, morpholino, thiomorpholino or the N. ~ B-piperazino group in which E (lower) alkyl, hydroxy (lower ) alkyl, the hydroxyl radical of which is separated from N by at least 2 carbon atoms, phenyl or phenyl monosubstituted by lower alkyl, lower alkoxy or halogen, where, if R. and R ^ are hydrogen, a possible group A is hydrogen, methyl or Means ethyl, and its acid addition salts, characterized in that one 409851/1 145 - m - 100-4004 a) for the preparation of compounds of the formula ^R 3 ^R 2 wherein R,, R. and R _n . have the above meaning, R. ' represents hydrogen, lower alkyl, chlorine, bromine or ritro and R 'represents hydrogen, lower alkyl, cycloalkyl with 3-6 carbon atoms, phenyl or a phenyl group substituted by lower alkyl, lower alkoxy or halogen, compounds of the formula' - II, wherein R-, R 'and R' have the above meaning and X stands for the acid residue of a reactive ester, with compounds of the formula HNR ₄ R ₅ III, wherein R. and R _{c have the} above meaning, converts or 409851/1 145 100-4004 -CV b) for the preparation of compounds of the formula Ib, in which R,, R-, R. and R _{r have the} above meanings and R "represents hydrogen or lower alkyl, compounds of the formula NO. R _c ι 4 b IV, ^R 2 wherein R ₁ , R ", R and R _{r have the} above meaning, with reactive derivatives of the compounds of the formula R ₃ COOH V, wherein R has the above meaning, cyclizes, or c) for the preparation of compounds of the formula ■ N 3 'N Ic, Rl, " A09851 / TU5 100-4004 wherein R ₁ , R_, R. and R ₁ . have great importance JL «J τ. J and R " ¹ chlorine, bromine, Foriayl, acetyl, di (lower) alkyiaminomethyl, nitro, 7unino or an A-CQ-NH - group, - in which A has the above meaning, means the radical R"' in compounds of formula wherein R, R-, R ₄ and R _{r have the} above meaning, introduces d) for the preparation of compounds of the formula wherein R ₁ , R ₃ , R. and R, have the above meaning, compounds of the formula Ic " 409851 / 1U5 --66a - 100-4004 reduced, or ■ '.-... e) for the preparation of compounds of the formula Ic " ¹ NH-COA where E., R-, R., R ₅ and A have the above meaning, acylated compounds of the formula Ic ¹ \ and the compounds of formula 1 thus obtained are obtained as bases or in the form of acid addition salts. 2. Process for the preparation of new compounds of the formula ^s v ^R 2 409851/114 6 100-400-i wherein R ₁ , R 'and R' have the meaning given in claim 1 and R stands for lower alkyl, cycloalkyl with 3-6 carbon atoms, benzyl or a benzyl group substituted in the phenyl radical by lower alkoxy, lower alkyl, halogen or hydroxy stands _f and its acid addition salts, characterized in that compounds of the formula IX, wherein R, R 'and R' have the above meanings, alkylated and the compounds of the formula lic obtained in this way are obtained as bases or as acid addition salts. 3. Process for the preparation of new compounds of the formula OH Y N VI, where R ,, Ri and R 'have the above meaning, characterized in that compounds of the form]. 4 0 9 8 5 1/1 145 100-4004 NHRg χ, in which R, / R 'and R' have the above meaning and R "is hydrogen and, if RJ, is hydrogen, can also be formyl, hydrolyzed, and if desired in the 8-position of the compound of the formula VI ₁ thus obtained in which RJ. represents hydrogen, introduces a chlorine, bromine or nitro substituent. A09851 / 1U5 100-4004 Germany West 4. Compounds of the formula wherein R ,, R ", R ^, R and R are as recited in claim 1 JL £ m "J TX * J have given meaning, and their acid addition salts. 5. Compounds of the formula SR lic, v.'orin R,, Ri and R 'have the meaning given in claim 2 own and their acid addition salts. 6. Compounds of the formula OH R ' ^R 2 4098 5 1/1 U5 VI, ■ 100-4004 wherein R, R 'and R' are as defined above, and acid addition salts thereof. 7. Medicinal products containing compounds of the formula I.
or acid addition salts thereof as defined in claim 4. 8. Medicinal products containing compounds of the formula JI or acid addition salts thereof as defined in claim 5. 9. Wedge agents containing compounds of the formula VI as defined in claim 6. S A N D O Z AG 4 0 9 8 5 1/1 1 A 5