DE2453305A1 - NEW HYDRAZINES, HYDRAZIDES AND HYDRAZONES OF PYRAZOLO (3,4-B) PYRIDINE-6-CARBONIC ACIDS AND CARBONIC ACID ESTERS AND THEIR SALTS - Google Patents

Description

DR. EYSENBAGH

PATENT ADVOCATE

Telegrams: PATENTEYSENBACH, PULLAGH-ISARTAL

Telephone Munich (0811): 7930391 Dr. Hans Eysenbach, D-8023 Pullach, Baumstraße 6 Ze ichen - ref .: Sq-62 / H-102-P (P-421879 -H)

Date: November 11, 1974

Describes 2453305

to the
Patent application

New hydrazines, hydrazides, and hydrazones of pyrazolo (3,4-b) pyridine-6-carboxylic acids and carboxylic acid esters and their salts

Applicant: Chemische Fabrik von Heyden GmbH, Munich

The priority is claimed December 5, 1973 from U.S.A. Patent application 421,879

The invention relates to new hydrazines, hydrazides and hydrazones of Pyrazolo (3,4-b) pyridine-6-carboxylic acids and carboxylic acid esters and their salts. These connections are called central nervous system soothing Means and also for increasing the intracellular concentration of adenosine 3 ·, 5'-cyclomonophosphate concentration therapeutically useful.

The utility of hydrazines, hydrazides and hydrazones of pyrazolo (3,4-b) pyridine-5-carboxylic acids and their esters as Central nervous system sedatives are described in U.S. Patent 3,761. The compounds according to this US patent are in their 6-position either by hydrogen or by a Lower alkyl occupied, surprisingly it was discovered that compounds which are substituted in their 6-position with a carboxylic acid or acid ester are also therapeutic are useful. The compounds of the invention possess i.e. one of the general formulas I or II

509824/0921

or

wherein R is hydrogen or lower alkyl; O

R ₁ hydrogen, lower alkyl, phenyl, phenyl lower alkyl, phenyl-C-

Il

or a mono- or di-substituted phenyl-C- with the meanings of lower alkyl, halogen or lower alkoxy for the substituents;
R_ hydrogen, lower alkyl, phenyl or phenyl lower alkyl;

R _{3 is} hydrogen, lower alkyl, lower alkyl-C-, phenyl or phenyl-lower alkyl;

Il

R _{4 is} hydrogen, lower alkyl or lower alkyl-C-; R _{5 is} hydrogen, lower alkyl, phenyl, lower alkylphenyl or halogen;

X is hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, phenyl lower alkyl or mono- or di-substituted phenyl or phenyl-lower alkyl with the meaning of lower alkyl, halogen or Lower alkoxy for the substituents;

Y lower al & yl, phenyl, hydroxy lower alkyl, phenyl lower alkyl or mono- or di-substituted phenyl or phenyl-lower alkyl with the meaning of lower alkyl, halogen or lower alkoxy for the substituents or

X and Υ together represent a cycloalkyl with three to seven carbon atoms,
and their pharmaceutically acceptable acid addition salts.

That which is suitable according to the invention for the production of these substances The process is characterized by the reaction of a compound of the formula

S09824 / 0921

2 ^ 53305

ο- lower alkyl

(VI)

wherein R, R

1'

and R _{5 has} the meanings given in claim 1

possess, with a compound of formula VIII

H ₂ NN

(VIII)

in which R ₃ and R. have the meanings given in claim -1 / and that, if desired, the compound of formula I formed in the above reaction, provided that R 1 and R ₄ therein are hydrogen, further reacted with a carbonyl compound for preparation a compound of the formula II or else that one can use a compound of the following general formula

0OR

wherein Z is halogen and R, R., R ₃ and R _{5 have} the meanings given in claim 1, reacted with a compound of the formula VIII

H ₀ NN

(VIII)

wherein R- and R _{4 are} each defined as given above, for the purpose of preparing a compound of the formula II and, if further desired, that a compound of the formula I or the

S09SU70921

Formula II, where R is lower alkyl, hydrolyzed for conversion into a compound of formula I or II in which R is hydrogen.

The lower alkyl groups listed in the description are all straight-chain or branched-chain hydrocarbons groups with 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Examples of the type of such groups are methyl, ethyl, propyl and isopropyl. The lower alkoxy groups include those lower alkyl groups attached to an oxygen atom are bound, for example methoxy, ethoxy, propoxy and isopropoxy.

The substituted Phenyl groups! There are those that are occupied by one or two substituents, namely, lower alkyl, halo (F, Cl, Br or I, preferably Cl or Br) _r or lower alkoxy. Examples of such types of groups are chlorophenyl, ie o-, m- or p-chlorobenzyl, 3,5-dimethylphenyl, 3,4-dimethoxyphenyl, o-, m- or p-chlorobenzyl, 3,5-dichlorobenzyl, p-methoxyphenyl and 3,5-dichlorophenethyl.

Il

The lower alkyl-C groups are aryl radicals of lower fatty acids with up to 8 carbon atoms, for example Acetyl, propionyl, butyryl and isobutyryl etc.

The cycloalkyl groups are cycloalphatic Ring systems with 3 to 7 carbon atoms (cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl and cycloheptyl).

Among the preferred representatives of the compounds according to the invention It is a question of those in which the representing symbols have the following meanings:

R is hydrogen or lower alkyl of up to 4 carbon atoms ,

R. is hydrogen, lower alkyl with up to 4 carbon atoms, phenyl, benzyl or phenethyl,

R ₂ is hydrogen, lower alkyl with up to 4 carbon atoms, phenyl, benzyl or phenethyl,

SQ3824 / 0921

R ₃ is hydrogen, lower alkyl with up to 4 carbon atoms / phenyl, benzyl or phenethyl,

R. is hydrogen or lower alkyl of up to 4 carbon atoms ,

R_ is hydrogen, lower alkyl with up to 4 carbon atoms, Phenyl, ToIy1 or halogen,

X is hydrogen, lower alkyl with up to 4 carbon atoms, Hydroxy lower alkyl with up to 4 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, phenethyl or s ubs ti tuie rte s Phene thy1,

Y is. Lower alkyl of up to 4 carbon atoms, hydroxy lower alkyl with up to 4 carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, phenethyl or substituted Phenethyl, or

X and Y together form a cycloalkyl ring having 5 to 7 carbon atoms .

The most preferable ones are those in which the following Meanings exist:

R is lower alkyl of up to 4 carbon atoms, in particular Ethyl;

R ₁ is hydrogen or lower alkyl with up to 4 carbon atoms, in particular hydrogen or ethyl;

R ₂ is hydrogen or lower alkyl with up to 4 carbon atoms, in particular hydrogen or methyl;

R_ or R. is hydrogen, but in particular both are representatives Hydrogen;

R ₅ is hydrogen, halogen or lower alkyl with up to 4 carbon atoms, in particular hydrogen, chlorine, bromine or methyl; X and Y are each lower alkyl, especially methyl.

The reaction sequence for the preparation of the compounds according to the invention is explained in more detail below. The symbols in the
Structural formulas have the meanings already given above.

A 5-aminopyrazole of formula III

509824/0921

Λ.

(III)

(prepared analogously to the description, as described in Z. f. Chemie 10 , page 386 (19 70)), is reacted with a oxalacetic acid ester of the formula IV

Alkyl-OOC-CH-C-COOalkyl ^iIV)

by heating to a temperature of about 100 to 120 ° C in an acidic solvent such as acetic acid (analogous to the procedure described in Pharmazie, 2 £, page 732 (19 71) is) to obtain a compound of the formula V:

COOR

This compound of formula V is then alkylated by treatment with an alkyl halide in an inert organic solvent such as dimethylformamide in the presence of an alkali metal carbonate to produce a compound of formula VI

(VI)

■ S0982A / 0921

2A53305

_ "7 -

Instead of the alkylation of the 4-hydroxy compound of the formula V, it is also possible to proceed in such a way that the 4-hydroxy compound is during reflux for a few hours with a phosphorus halide such as phosphorus oxychloride, thereby forming an intermediate of formula VII

(VII) COOR

wins, wherein Z is a halogen atom, preferably chlorine or Bromine.

The compounds of the formula I are then prepared either from compounds of the formula VI or of the formula VII by reaction with an equivalent amount of the suitable hydrazines of the formula VIII

/ R-3 (VIII)

This reaction is carried out by treating the reactants in an inert, preferably dry organic Solvent, either at room temperature or at a slightly elevated temperature. In some cases it may be useful to carry out the reaction in an autoclave.

The free acid, i.e. a compound with hydrogen for R, can be obtained from the ester by hydrolysis, i.e. by treatment with an aqueous sodium hydroxide solution.

The compounds of the formula I in which R. is hydrogen, can be prepared in another way, using a 5-aminopyrazole of the formula III as starting material, in which

-60982 ^ / 092 1

R is a heteromethyl group. This starting material possesses the formula IHa

R ₂ .

_s NH ₂ ^(IIIa)

^H 2

R ₉

where R «is a heterocyclic ring such as Fury1, pyridyl? Pyrimidyl, Is pyrazinyl or the like.

A compound of the formula IHa is then reacted with a compound of the formula IV, as already described above to produce a compound of Formula Va

> H

R ₂ .

^CH 2

The compound of the formula Va is then alkylated as already described, whereupon a compound of the formula VIa is obtained.

, - lower alkyl
^R 5
COOR (VIa)

60982470921

The compound of the formula Via is made with an oxidizing agent such as Selenium dioxide in a high boiling solvent such as diethylene glycol dimethyl ether oxidized at about 160 ° C. A compound of the formula VI in which R. is hydrogen is obtained.

The hydrazones of the formula II are obtained from the hydrazines of the formula I, in which R and R are each hydrogen, by reaction with a carbonyl compound, namely an aldehyde or ketone, in an organic solvent such as an alcohol. Such carbony compounds are, for example: acetaldehyde, Propionaldehyde. Butyraldehyde, benzaldehyde, acetaldehyde, phenylpropionaldehyde ,; p-chlorobenzaldehyde, m-bromobenzaldehyde, 2,5-dichlorobenzaldehyde, p-methoxybenzaldehyde, acetone, dihydroxyacetone, Methyl ethyl ketone, methyl propyl ketone, acetophenone, phenyl propyl ketone, Acetophenone, phenylpropy! Ketone, p-chlorophenyl ethy! Ketone, Cyclopropanone, cyclobutanone, cyclohexanone and the like.

The bases of the formula I and II form pharmaceutically acceptable acid addition salts by reacting with an equivalent weight on the known inorganic or organic acids. Such salts are the hydrogen halide salts, for example Hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate, oxalate, tartrate, malate, succinate, benzoate, ascorbate, but also alkanesulfonates such as methanesulfonate, arysulfonates such as Benzoisulfonate, etc.

It is often convenient to facilitate the purification or isolation of the products by first adding an insoluble salt forms. The base can then be recovered by neutralization and the other salt can then be treated with the suitable acid partners are produced.

The inventive compounds and their acid addition salts have a central nervous system sedative activity and can be used as tranquilizers or als.ataractische means of relief from fear "and stress conditions, • for example, in mice, Katsen, rats, dogs & t nä Anue & xmn mammals? in the similar way, wl ©

A compound or a mixture of compounds is used for this purpose according to formula I or formula II, or one of the acid addition salts of these compounds, orally or parenterally in a conventional dosage form such as tablets, Capsules, injection preparations, etc. as a single dose, but preferably as two to four doses divided into the day, on an amount of about 1 to 50 mg / kg / day, preferably about 2 to 15 mg / kg / day »

These active ingredients can be formulated as usual in an oral or parenteral dosage form by adding about 10 to 250 mg per dosage unit with customary carriers, excipients, binders, stabilizers, flavorings or the like, as / as they are used in pharmaceuticals Have proven themselves in practice.

The novel compounds and their SSureadditionssalse also have the Wirkwagjr u increase the intracellular concentration of adenosine-3 ^1, 5'-eyciQmonophQsphat ^ and man'erhält this effect by administration of about 1 to 100 mg per kg per day,! Preferably about 10 to 50 mg / kg / day, and swar as a single dose or as two to four subdivided daily partial doses in the usual oral or parenteral preparation forms as already described above. With these agents, the symptoms of asthma can be alleviated »

The invention will be explained in more detail with the aid of a number of examples.

1-ethyl-4-isopropylidene-hydra2ino-10-pyrazolo (3,4-b) pyridine-6 carboxylic acid ethers

Ui g 5-lÄ «£ ffiO- = l = ethyl pfrasol (1 mol)« ad 210 g sodium oxaline acetic acid

© £ it - <! 2 Cl. K © 3.)%? @ Ε "α © Ώ la 1 3Litos? Acetic acid for 5 hours am lüS gj & oefeio Hacli dl © s © r time the acetic acid is in a vacuum

driven off and the residue treated with water. Solidified in the process the ester given above, it is filtered off and recrystallized from methanol; Melting point 178 to 180 ° C, Yield 198 g (84% of theory).

b) 1-Ethyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester

23.5 g of 1-Ethy1-4-hydroxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.1 mol) are dissolved in 150 ml of dimethylformamide; To this solution, 23 g of ethyl iodide (0.15 mol) are added and 21 g of potassium carbonate (0.15 mole). The mixture is stirred at 60 ° C. for 10 hours. After this time it is filtered Potassium iodide and the excess potassium carbonate and add water to the filtrate. 19 g of the above are obtained Esters as a precipitate (72% of theory), which are recrystallized from petroleum ether: melting point 39 to 41 ° C.

c) 1-Ethy1-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester

5.2 g of 1-ethyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.02 mol) and 1 g of hydrazine hydrate (0.02 mol) are refluxed together with 50 ml of butyl alcohol for 6 hours cooked. After this time, the solvent is evaporated off in vacuo and the residue, namely the ester specified above, is recrystallized from methanol. Yield 4.2 g (83% of theory) with melting point 154 to 155 ° C.

d) 1-Ethyl ^ -isopropylidene-hydrazino-1H-pyrazolot3,4-b) pyridln-6-carboxylic acid ethyl ester

5 g of 1-Ethy1-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.02 mol) are dissolved in 20 ml of butyl alcohol and 1 ml of acetone is added. The mixture is for 3 hours on After this time, the solvent is evaporated off in vacuo and the residue is recrystallized from butyl alcohol; 4.2 g (72% of theory) with a melting point of 174 to 176 ° C. of the desired end substance mentioned at the beginning are obtained.

509824/0921

- 4.2 -

Example 2

4-Isopropylidene-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester

a) 1 ~ furfuryl-4-hydroxy-1H-pyra2Olo (3y4 - b) pyridine-6-carborx5 acid ethyl ester

163 g of 5-amino-1-furfuryl-pyrazole (1 mol) and 188 g of ethyl oxaloacetate (1 mol) are refluxed in 750 ml of acetic acid for 4 hours. The solvent is distilled off and the residue is recrystallized from methanol; 190 g of the above ester (73% of theory) are obtained with a Melting point from 220 to 221 ° C.

b) 1-Furfuryl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ester

57.4 g of 1-furfuryl-4-hydroxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.2 mol), 42 g of potassium carbonate (0.3 mol) and 37.2 g of ethyl iodide (0.24 mol) are dissolved in 300 ml of dimethylformamide heated at 70 ° C for 10 hours with continued stirring. The mixture is filtered hot and the filtrate is with about 50 ml of water are added. The above-mentioned ester is crystallized out by cooling. Yield 43 g (68% of theory) with a melting point of 45 to 47 ° C.

c) 4-Ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester

31.6 g of 4-ethoxy-1-furfuryl-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.1 mol) and 13.4 g of selenium dioxide (0.12 mol) are dissolved in 150 ml of diethylene glycol dimethyl ether for 1 1/2 hours heated to 160 ° C. The selenium formed is filtered off hot and the filtrate is cooled in an ice bath. Crystallizes " the initially precipitated product, the ester specified above, and is recrystallized from butyl alcohol; Yield 15 g, melting point 135-137 ° C.

d) 4-hydrazine - 1H-pyrazolo (3 , 4- b) pyridine ^ 6 ~ carboxylic acid ethy ester

4.7 g of ethyl 4-ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylate (0> 02 mol) and 0.2 g of hydrazine hydrate (0.04 mol) are in 50 ml

2A53305

Dissolved butanol and refluxed for 8 hours. The solvent is distilled off and the remaining ester specified above is recrystallized from acetic acid; Exudation 2.8 g (63% of theory) with a melting point of 213 to 214 ° C.

e) 4-Isopropylidene-hydrazino-1H-pyrazolo (3 _f 4-b) pyridine-6-carboxylic acid ethyl ester

2.2 g of ethyl 4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylate (0.01 mol) are dissolved in 20 ml of butyl alcohol. 1 ml of acetone and a few drops of acetic acid are added and that The mixture is refluxed for one hour. It is then concentrated to dryness and the residue is recrystallized from butanol; 2.2 g (84.5% of theory) of the abovementioned substance with a melting point of 202-2O3 ° C. are obtained.

Example 3

5-chloro-1-ethyl-4-cyclohexylidene-hydrazino-1H-pyrazolo (3,4-b) -pyridine-6-carboxylic acid ethyl ester

a) 5-Chloro-1-ethyl-4-hydroxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester

111 g of 5-amino-1-ethylpyrazole (1 mol) and 222 g of ethyl chloroxaloacetate are refluxed in 1 liter of acetic acid for 4 hours. The acetic acid is evaporated in vacuo and the filter residue recrystallized from methanol. Yield 211 g (78% of theory), melting point 183 to 184 ° C of the above Esters.

b) Ethyl ether 5-chloro-4-ethoxy-1-ethyl-1H-pyrazolo (3,4-b) pyrldine-6-carboxylic acid

26.9 g of 5-chloro-1-ethyl-4-hydroxy-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.1 mol) are dissolved in 100 ml of dimethylformamide. 21 g of potassium carbonate (0.15 mol) and 18 ', 6 g of ethyl iodide (0.12 mol) are added and the mixture is ^{kept at a temperature of 60 °} C. for 10 hours with stirring. The undissolved material is filtered off and the filtrate is added water is added. The substance indicated above is obtained as a solid

509824 / Q821

Residue and recrystallized it from petroleum ether; yield 20.5 g (69% of theory), melting point 36 to 37 ° C.

c) 5-chloro-1-ethyl-4-hydrazino-1H-pyrazolo (3 _y 4-b) pyridine-6-carboxylic acid ethyl ester

14.8g of S-chloro-4-ethoxy-l-ethy1-lH-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.05 mol) and 2.5 g of hydrazine hydrate are dissolved in 50 ml of butanol and refluxed for 48 hours. To During this time the solvent is distilled off and the residue is recrystallized from alcohol. Yield 9 g (64% of theory), melting point 166 to 169 ° C, of the ester given above.

d) -5-chloro-1-ethyl-4-cyclohexylidene -hydrazino-1H-pyrazolo (3 _f 4-b) -pyridine-6-carboxylic acid ethyl ester

7.05 g of 5-chloro-1-ethyl-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester (0.025 mol) are dissolved in 10 ml of butanoi. 2.65 g of cyclohexanone (0.025 mol) are added and the mixture is boiled Mixture refluxed for one hour. The solvent is distilled off and the residue is recrystallized from butanoi. Man obtained a yield of 6 g (66% of theory) of the substance indicated above, melting point 200 to 2O2 ° C.

Example 4

5-chloro-4-dimethyl-hydrazino-1-ethyl-1H-pyrazolo (3 _y 4-b) pyridine-6-carboxylic acid ethyl ester

2.9 g of 5-chloro-1-ethyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine-6-carbon ~ acid ethyl ester (0.01 mol) from Example 3 (a) and 0.6 g of N, N-dimethyl hydrazine are refluxed in 10 ml of butanol for 48 hours. The solvent is removed and the crystalline residue recrystallized from methanol / ethyl acetate. Yield of the above product is 2.2 g (71% of theory) with a Melting point from 214 to 217 ° C.

Example 5

The following additional compounds are made according to Example 1 manufacturable

504824/0921

! 3 - Pi

in pi-

ro

CN

pi

ro ro .in 8th 8th ro 8th 8th 8th O O 8th O ro O O OJ OJ OJ O J? 8th Ό 8th 8th 8th O O O Oil
O

8th- 8th ro ro OJ O 8th 8th ro O O O 8th K * ■ O O

η W U

ra

TO m 8th 8th O OJ O

ιη

ro
8th
O

O = O

ro

in in in in cn 8th 8th 8th 8th 8th OJ OJ OJ OJ O O O O O • r «

509824/0921

CO co ro co η οο id S3 υ υ U U U U

co u

m CO co co CO ro υ W. K H SJ SS U U U ϋ U O

in

i U

H U

ffi

ffi

id

id "

VO U

id

O = U

ο — υ o =

ro O id 'ro U B. U

CM

in tn in in M. id H W. CM U U U U

in

id

in in m m W. Si SJ SJ Sd CO CN CN CN CN U U U U Ü

CN

S09824 / 0921

VO

to

ιη

r-t in m in pi 8th 8th CM CN | CN O O U

tn 8

SNJ

CN U

in 8th

CJ

ιη

in

SSi

in in in in in 8th 8th 8th 8th 8th CNl CN | CN | CNl CNl L) O U U O

2470821

cn KO

(Π ro κ ϊΰ υ Ό

tfä

tn

ORiGfNAL iiSlSPECTED

cn
K η
X η η
X (O υ U O O τ " I. η ■ Η X Ό

X X ro U U I. I. • Η ■ Α

-H

σι

U ί

• Γ «

ιη ιη X K OJ O ü

O in

CM

CJ

- 19 -

do

ffl

in in in in in W. B. a OJ Oil Oil Oil Oil O U CJ U O

<M

in in in in in in W. a M. a a CM eg Oil CM Oil CN U U CJ CJ U U

Examples

The following additional compounds according to formula I are prepared by the procedure according to Example 4:

ro ro ro in ro B. ftf B. B. B. B. B. O O O CN O

U CQ

do

S3

in

a <"* ■

cn a

O O

in

ffi

O = O

( O

f)

VD W SJ UO

O ro ro r

ro iü W IU

a υ o o

O = O

ro ro

ro ro ro in ro in a a B. B. O O O CN O vo O O I. 'CN a O ro in 1 a a
O a VO
O (Ω) a

O = O

ro

ro ro
OO

O = O I

ro ro ro

a a a

O O U

a a a a a

in in in in in m IS) in in in a a a a a a a a a a CN CN CN CM CN CN CN CN CN O O O O O O O O O O

in in in in in in in in in in a a a a a a. a a a a a ro CN CN CN CN CN CM CN CN CN CN O O O O O O O O O O O •H

609824/0921

• rt

* r

η O

• Η

-H

in

OJ

in

CN

in

OJ

in in (N OJ O O

S0S824 / 0921

Example 7

l-ftthyl-ft ^ hydrazi no-lH-pyrazolo (3 , 4-b) pyridine-e-carboxylic acid ethyl ester hydrochloride

By treating the 1-ethyl-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester from Example 1 (c) with an equivalent amount of HCl, the acid addition salt given above is obtained.

Example 8

1-ethyl-4-isopropylidene-hydrazino-1H-pyrazolo (3 _f 4-b) pyr: ldin-6-carboxylic acid ethyl ester hydrochloride

By treating the 1-ethyl-4-isopropylidene-hydrazino-1H-pyrazolo- (3,4-b) pyridine-6-carboxylic acid ethyl ester from Example 1 (d) with an equivalent amount of hydrogen chloride, the above is obtained Hydrogen chloride addition salt.

Claims (15)

Chemische Fabrik von Heyden GmbH Reference: Sq-62 / H-102-P (P-421879-H) Date: November 11, 1974 Claims 1. New hydrazines, hydrazides and hydrazones of pyrazolo (3,4-b) -pyridine-6-carboxylic acids and carboxylic acid esters and their salts, characterized by one of the following general ones Formulas I and II HN-N or (II) wherein R is hydrogen or lower alkyl; R. hydrogen, lower alkyl, phenyl, phenyl lower alkyl, phenyl-C- or a mono- or di-substituted PhenyJ-C- with the meanings lower alkyl, halogen or lower alkoxy for the substituents; . R ₂ hydrogen, lower alkyl, phenyl or phenyl lower alkyl; R_ "is hydrogen, lower alkyl, lower alkyl-C-, phenyl or phenyl-lower alkyl; R _{4 is} hydrogen, lower alkyl, or lower alkyl-O; R _{5 is} hydrogen, lower alkyl, phenyl, lower alkyl phenyl or halogen; X is hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, phenyl lower alkyl or mono- or di-substituted phenyl or phenyl 609824/0921 ' 2Ä53305 lower alkyl with the meaning of lower alkyl, halogen or lower alkoxy for the substituents; Y lower alkyl, phenyl, hydroxy lower alkyl, phenyl lower alkyl or mono- or di-substituted phenyl or phenyl-lower alkyl with the meaning of lower alkyl, halogen or lower alkoxy for the substituents or X and Y together represent a cycloalkyl with three to seven carbon atoms,
and their pharmaceutically acceptable acid addition salts. 2. A compound according to claim I ₁ according to formula I, wherein R and R. are each hydrogen or lower alkyl having 1 to 4 carbon atoms; R, R- and R _{3 are} each hydrogen, lower alkyl having 1 to 4 carbon atoms, phenyl, benzyl or phenethyl; and R _{5 is} hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, tolyl or halogen. 3. A compound according to claim 2 according to formula I, wherein R is lower alkyl having 1 to 4 carbon atoms; and R. and R- are each hydrogen or lower alkyl having 1 to 4 carbon atoms, at least one of the substituents R ₃ and R. being hydrogen and the meaning for R _{g being} hydrogen, lower alkyl having 1 to 4 carbon atoms or halogen. 4. A compound according to claim 3 according to formula I, consisting of 5-chloro-4-dimethyl-hydrazino-1-ethyl-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester. 5. A compound according to claim 3 according to formula I, wherein R is ethyl, R is hydrogen or ethyl, R, hydrogen or methyl, R- and R. are each hydrogen and R _{5 is} hydrogen, chlorine, bromine or methyl. 6. A compound according to claim 5 according to formula I, consisting of 1-ethyl-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester. 7 .. Compound according to claim 5 according to formula I, consisting of 4-hyd'razino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester. SO9824 / Ö921 8. A compound according to claim 5 according to formula I, consisting of 5-chloro-1-ethyl-4-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethylacetate. 9. A compound according to claim 1 according to formula II, wherein R is hydrogen or lower alkyl with 1 to 4 carbon atoms, R. and R- are each hydrogen, lower alkyl with 1 to 4 carbon atoms, phenyl, benzyl or phenyl, R _{5 is} hydrogen, lower alkyl with 1 to 4 carbon atoms, phenyl, ToIy 1 or halogen and X is hydrogen, lower alkyl with 1 to 4 carbon atoms, phenyl, benzyl, phenethyl or substituted phenyl, substituted benzyl or substituted phenethyl, and Y is lower alkyl with 1 to 4 carbon atoms, hydroxy lower alkyl with 1 up to 4 carbon atoms, phenyl, benzyl, phenethyl or substituted phenyl, substituted benzyl or substituted phenethyl, or X and Y together are a cycloalkyl ring having 5 to 7 carbon atoms. 10. A compound according to claim 9, according to formula II, consisting of 5-chloro-1-ethyl-4-cyclohexylidene-hydrazino-1H-pyrazolo (3,4-b) -pyridine-6-carboxylic acid ethyl ester .. 11. A compound according to claim 9 according to formula II, wherein R is lower alkyl having 1 to 4 carbon atoms, R ₁ and R _{3 are} each hydrogen or lower alkyl having 1 to 4 carbon atoms, R _{5 is} hydrogen, lower alkyl having 1 to 4 carbon atoms or. Is halogen and X and Y are each lower alkyl of 1 to 4 carbon atoms. . 12. A compound according to claim 11 according to formula II, wherein R is ethyl, R. is hydrogen or ethyl, R, hydrogen or methyl, R _{5 is} hydrogen, chlorine, bromine or methyl and X and Y are each methyl. 13. A compound according to claim 12 according to formula II, consisting of 1-ethyl-4-isopropylidene-hydrazino-1H-pyrazolo (3,4-b) pyridine-6-carboxylic acid ethyl ester. SÖ9824 / Ö 14. A compound according to claim 12 according to formula II, consisting of 4-isopropylidene-hydrazino-1H-pyrazolo (3,4r-b) pyridine-6-carboxylic acid ethyl ester. 15. A process for the preparation of a compound according to claim 1 according to the general formulas defined in this claim 1 I or II including their acid addition salts by reacting a compound of formula VI o-lower alkyl (VI) 0OR wherein R, R., R ₂ and R _{5 have} the meanings given in claim 1, with a compound of the formula VIII H ₉ NN R ₃ wherein R ₃ and R _{4 have} the meanings given in claim 1, and that, if desired, the compound of the formula I formed in the above reaction, provided that R ₃ and R are hydrogen therein, are further reacted with a carbonyl compound to produce a Compound of the formula II or else that one is a compound of the following general formula OOR IL ' wherein Z is halogen and R, R-, R ₂ and R _{5 have} the meanings given in claim 1, reacts' with a compound of the formula VIII H ₂ NN (VIII) ^R 4. wherein R ₃ and R _{4 are} each defined as given above «for the purpose of preparing a compound of the formula II and, if further desired, that a compound of the formula I or of the formula II, in which R is lower alkyl, is hydrolyzed to convert it into a compound of Formula I or II in which R is hydrogen. 309824/0921