DE2225433A1 - Aminopyrazolo (3,4-b) pyridine-5-ketones with their salts, manufacturing processes therefor and pharmaceuticals therefrom - Google Patents

Description

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Patent application

Aminopyrazolo (3,4-b) pyridine-5-ketones with their salts, manufacturing process for it and medicines made from it

Applicant: Chemische Fabrik von Heyden GmbH, Munich

Priority: May 25, 1971 U.S.A. No. 146 812

The invention relates to new amino derivatives of pyrazolo (3,4-b) -pyridine-5-ketones with their salts, suitable processes for their preparation and those from the new, anti-inflammatory, the central nervous system calming and the intracellular concentration of adenosine-3 ¹ , 5'-cyclomonophosphate. Compounds having an increasing effect to produce therapeutic agents.

The new compounds have the general formula I.

(D

wherein R, hydrogen, lower alkyl, phenyl or phenyl lower alkylene is,

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R _{0 is} hydrogen or lower alkyl,

R- and R _{4 are} each hydrogen, lower alkyl, lower alkanoyl, halo-lower alkanoyl, phenyl-lower alkylene, di-lower alkylamino-lower alkylene or R ₇ , R _Q -phenyl with the meanings of each hydrogen, halogen or trifluoromethyl for R_ and R _g , or R ₃ and R ₄ together with the nitrogen atom bearing one of the following heterocyclic radicals, namely R _g , R _lo -aziridinyl, R ₉ / R ₁₀ -pyrrolidino, R ₉ , R ₁₀ -piperidino, R ^ R ^ -pyrazolyl, R ₉ , R ₁₀ -pyrimidinyl , R ₉ , R _1Q -pyridazinyl or R, R ₁₀ -piperaζinyl, each with the meanings of hydrogen, lower alkyl or hydroxy-lower alkyl for R- and R _1Q ,

Rc lower alkyl, cycloalkyl, phenyl or R ₇ , R_-phenyl with the meanings of each hydrogen, halogen or trifluoromethyl for R- and Rg,

R _{6 is} hydrogen, lower alkyl or phenyl, and the acid addition salts of these compounds.

The meanings given above for the general formula I. of the symbols also apply to the entire further description text as a symbol meaning.

The basic nitrogen-containing group -N-R_ is

1 - -J

^R 4

is an acyclic amino radical, in which, if R_ and R. ^ e mean a substituted phenyl group, this pe £ my! group can have one or two simple sulfostituents, i.e. halogen or trifluoromethyl aea-ή as indicated, where chlorine is preferred as halogen; if the meaning for R-, and R ₄ is phenyl-lower alkylene or Bi-lower alkylairtinone-lower alkylene, then it is preferred to provide only e; Lne of these two substituents, with the exception of the case

/ That these substituents are lower alkyl.

The basic group can, however, also be a 3ζ5- or 6-membered, / heterocyclic ring system in which the ring can contain an additional nitrogen atom, for example aziridinyl, pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl, where each can also carry substituents again, such as, for example, a hydroxynxedrigalkyl group or one to two lower alkyl groups.

209850/1220 original inspected

For the meanings given for R ^ and R _ß , namely lower alkyl, cycloalkyl, phenyl, substituted phenyl or hydrogen, lower alkyl or phenyl, the following should be noted: The lower alkyl and lower alkylene groups are straight or branched-chain hydrocarbon groups with up to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. The first four representatives mentioned are preferred. Benzyl and phenethyl are preferred phenyl lower alkylene groups. All four halogens can serve as substituents, but chlorine is preferred.

The lower alkanoyl groups are, for example, acyl radicals lower fatty acids with up to 8 carbon atoms. The four representatives with the fewest carbon atoms are preferred.

The cycloalkyl groups are acyclic ring systems with 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, cycloheptyl, the 5- to 6-membered rings being preferred are.

The basic, nitrogen-containing group -N-R_ is, as mentioned,

ι -3

^R 4

an acyclic amino group in which R ₃ and R. are each hydrogen, lower alkyl, phenyl, substituted phenyl (ie the phenyl ring contains one to two simple substituents such as halogen or trifluoromethyl), phenyl lower alkylene or di-lower alkylamino lower alkylene (these substituents are preferably present if there are is not lower alkyl, only one substituent is present). This basic group can also be a heterocyclic radical with 3, 5 or 6 ring members, in which an additional nitrogen is present in the ring system, in particular aziridinyl, pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl, each also including one Substitueiie-n, namely a hydroxy-lower alkyl group or one to two lower alkyl groups. It should be said that R_ and R _{4 can} each be hydrogen, lower alkyl, R ₇ , Rg-phenyl (with the meaning of hydrogen, halogen or trifluoromethyl for R ₇ and R _g ), phenyl-lower alkylene, or di-lower alkylamino-lower alkylene

r -. - 2 0 98 50/12 20

or the two radicals R- and R. together with the nitrogen atom carrying them can also be heterocycles, as already mentioned above, but also the R _n -monosubstituted or '

the R-, R. -disubstituted derivatives, with the substituents lower alkyl, hydroxynxedrigalkyl or hydrogen for R _g and ^ ₁₀ *

To explain the invention in more detail, individual examples will be given later. The preferred meaning for R and R is hydrogen, especially when R- is a cyclic substituent or a substituted or unsubstituted acyclic group. Particular preference is given to compounds of the formula I in which R ^ are phenyl and all other radicals are hydrogen or in which R _{1 is} the ethyl group, R _{2 is} hydrogen or methyl, R_ butyl, phenyl, substituted phenyl and tertiary

■ 3 are

Are amine, R, and R, each hydrogen / and R ₁ . either the methyl or the phenyl group.

The new compounds of formula I are prepared by the series of process steps described below. Are there the symbols given in these structural formulas have the same meaning as the symbols already described.

A 5-aminopyrazole of the formula II is reacted with one another

(II)

(prepared analogously to that described in Z.?. Chemie 10, page 386 (1970) Procedure) with an alkoxymethylene acetoacetic acid ester of the general formula III

Alky1-0-C = C-COR ₅ (III)

RgCOO-alkyl 209850/1220

with heating at a temperature of about 120 to 130 ⁰ C.

The resulting compound of formula IV

^R 2 I ¹

.COR.

COO-alkyl

^R l. ■.

is in an inert organic solvent such as diphenyl ether, cyclized at temperatures in the range of about 230 ° C to 260 ° C, whereby the alcohol formed is distilled off and a compound of the formula V is formed:

(V)

with a hydroxyl group in the 4-position.

This 4-hydroxy compound is refluxed for several times Hours with a phosphorus halide such as phosphorus oxychloride for the purpose of preparing the intermediate of the general formula VI

(VI)

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The compounds of the formula I are then obtained by reacting the compounds of the formula VI with a suitable primary or secondary amine of formula VII

HN-R ,,
^ (VII)

This reaction is carried out by treating the reactants either at room temperature or at elevated temperatures. In some cases it is advisable to use an autoclave for this.

The compounds according to the invention can also be obtained in another way, namely by treating a compound the given formula V with. an AJ_kylating agent, for example an alkyl halide such as ethyl iodide, being found as an intermediate forms a compound of formula VIII:

O-

(VIII)

The intermediates according to formula VIII can then with an amine be treated as it is already described above to achieve the same end products.

Such compounds of the formula I in which R is hydrogen, are expediently produced by a modification of the procedure described above.

In this modification, a 5-aminopyraiiol of the formula II is used, where R is an arylmethyl group or a heheromethyl group is. This starting material has the general formula Ha

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■ V

1 (Ha)

CH ₂

wherein R-. an aromatic or heterocyclic ring system such as Phenyl, naphthyl, furyl, pyridyl, pyrimidyl, pyrazinyl, or the like is.

This material is, as already mentioned, by a reaction with the alkoxymethylene acetoacetic acid ester of the formula III treated, the product cyclized according to Formula V to form a compound of the formula V and finally by alkylation for the preparation of a compound of formula VIII.

In this process step is oxidized with an oxidizing agent such as selenium dioxide at a temperature of about 160 ⁰ C in a high boiling solvent such as Hiäthylenglycoldimethyläther this compound of formula VIII, which has in the setting the -CH ₂ -R-, substituents of formula Ha; a compound of the formula VIII in which R 1 is hydrogen is obtained, and this product can then be reacted with a primary or secondary amine of the type described.

Instead of an alkylation of the compound according to formula V with the 4-IIydroxygruppe one can also first oxidize this compound, to remove the substituent in one position and then alkylate in the 4-position.

These compounds according to formula I form salts, which likewise Are part of this invention. The salts include the acid addition salts, especially those with nontoxic, physiological salts compatible representatives, oils bases according to formula I form the

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Salts by reacting with a number of inorganic and organic acids with the formation of acid addition salts such as * · '.

wise hydrogen halides (especially halogen chlorides), sulfates, nitrates, phosphates, oxalates, tartrates, malates, citrates, acetates, ascorbates, succinates, benzenesulfonates, toluenesulfonates, cyclohexanes & ■ ' sulfonates, cyclohexanesulfamates and the like. The acid additionj ?? salts are often convenient means of isolating products _f ; that is, the salts are formed and left to precipitate in a suitable medium in which the salt in question is insoluble "..; is, then the salt is separated off, it is neutralized with a base, ©, Y such as barium hydroxide or sodium hydroxide, in order to recover the free base of the λ formula! Other salts can then be obtained from this ge · ^

purified free base by reacting with an equivalent weight ^ the desired acid can be produced.

'f ■ · · ■ ■.'

The new compounds of this invention have inflammation- ^ inhibiting property and are therefore useful as anti-inflammatories, _r example for local inflammatory conditions such as

* 'Of an edematous nature, or those which are caused in various mammalian species by connective tissue cell proliferation, to improve, for example in rats, dogs and the like ^ by oral administration in doses of about 5 to

■ 50 mg / kg / day, preferably from 5 to 25 mg / kg / day; one gives the Medium in a single daily dose or divided into 2 to 4 daily dosages, as in the carageenan edema experiment proves useful in rats. The active substance can be used in

■ 'are used as in tablets, capsules, or solutions Suspensions containing up to about 300 mg per dosage unit

'..: contain one of the compounds according to the invention or a mixture of such compounds of the formula I or physiologically acceptable salts or quaternary ammonium salts. They can be formulated in the usual way with physiologically compatible carriers or lead substances, that is to say with such excipients, binders, preservatives, stabilizers, flavorings, etc., as they have proven themselves in pharmaceutical practice. Preparations for surface treatment can also be used in a lotion, ointment or cream with about 0.01 to 3 percent by weight of active substance.

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The new compounds of the invention are also sedatives for the central nervous system and can be used as a tranquilizer or ataractic means to relieve anxiety and tension can be used, e.g. in mice, cats, rats, dogs and other mammalian species in a manner similar to that of chlordiazepoxide. For this purpose, a compound or a mixture of the compounds according to formula I, or non-toxic, is physiological acceptable acid addition salts thereof, given orally or parenterally in a customary dosage form, for example as Tablets, capsules, injections or the like. A single dose, or preferably 2 to 4 daily dividing doses, prepared on the basis of about 1 to 50 mg per kg per day, preferably about 2 to 15 mg per kg per day, is considered suitable. It can be conventionally formulated in an oral or parenteral dosage form by formulation in about 10 to 250 mg per dosage unit with the usual carrier, excipient, binding agent, preservative, stabilizing agent, flavoring agent agents and the like, as is customary in pharmaceutical practice. . . '

The new compounds are also able to increase the intracellular concentration of adenosine-3 ¹ , S'-cyclomonophosphate and in this way the symptoms of asthma can be alleviated by administration of about 1 to 100 mg / kg / day, preferably about 10 to 50 mg / kg, in a single daily dose or divided into 2 to 4 daily doses in the usual conventional oral or parenteral dosage forms as already described.

The following examples serve to further illustrate the invention.

Example 1 5-Acetyl-4-n-butylamino-1-ethylpyrazolo (3,4-b) pyridine

a) (l-Ethyl-5-pyrazolyl) aminomethylene acetoacetate 222 g of l-ethyl-5-aminopyrazole (2 mol) with 372 g of ethoxymethylene acetoacetate (2 mol) are heated together at 120 to 130 C with stirring until the theoretical yield of alcohol is distilled off. Obtained after cooling and recrystallization from methanol

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a yield of 375 g of the ether indicated in the title (74% of theory), melting point 53 to 55 ° C.

b) 5-Acetyl-1-ether-4-hydroxypyrazolo (3,4-b) pyridine

300 g of ethyl (l-ethyl-5-pyrazolyl) aminomethylene acetoacetate (1.2 moles) are placed in a vessel which is immersed in an oil bath during 5 minutes at 260 ° C is held, wherein the split off alcohol is distilled off. After this time the vessel will be as fast as only possible cooled. The residue is recrystallized from ethanol and gives 148 g of the above product (60% of theory) from melting point 155 to 157 ° C.

c) 5-Acetyl-4-ethoxy-1-ethylpyrazolo (3,4-b) pyridine

102 g of 5-acetyl-1-ethyl-4-hydroxypyrazolo (3,4-b) pyridine (0.5 mol) are dissolved in 500 ml of dimethylformamide and mixed with 100 g of potassium carbonate (0.71 mol) and 117 g of ethyl iodide (0 , 75 mol) added. The mixture is maintained for 10 hours with continued stirring at 60 to 70 ⁰ C. The excretion is filtered off and the liquid phase is concentrated to about 100 ml. After adding 500 ml of water, the product specified above separates out and after filtering off 92 g (73% of theory) with a melting point of 136 ° C. are obtained.

d) 5-acetyl-4-butylamino-1-ethylpyrazolo (3,4-b) pyridine

2.5 g of 5-acetyl-4-ethoxy-l-ethylpyrazlo (3,4-b) pyridine (0.01 mol) and 2.2 g (0.03 mol) of n-butylamine in 15 ml of ethanol are during 5 Refluxed for hours.

After this time, 50 ml of water are added and the white precipitate is filtered off. By recrystallization from ligroin if 2.3 g of the product indicated above (88% of theory) with a melting point of 73 ° C.

The hydrochloride salt is produced from this by treating the Product with ver ti «2 ηnimv ethanolic hydrogen chloride solution.

5-acetyl-4-sec.-butylamino-l-ethylpyrazolo (3,4-b) pyridine is through the above procedure produced by the fact that instead of the

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there used n-butylamine in process step d) the corresponding see.-butylamine used.

Example 2 4-Anilino-5-benzoyl-1-ethy / pyrazole- (3., 4-b) pyridine

a) 5-Benzoyl-1-ethyl-4-hydroxypyrazolo (3,4-b) pyridine

222 g of 5-amino-1-ethylpyrazole (2 mol) and 496 g of ethyl ethoxymethylene benzoyl acetate (2 mol) are heated with stirring at about 140 ° C until no more alcohol is distilled off. The temperature is then increased to 240 ° C. The alcohol which is split off is distilled off in vacuo. The reaction takes about an hour completed and the residue is cooled to room temperature, whereupon 500 ml of methanol are added. The above Product crystallizes out and is filtered off. 360 g (67% of theory) with a melting point of 15 ° C. are obtained.

b) 5-Benzoyl-4-chloro-1-ethylpyrazolo (3,4-b) pyridine

53.5 g (p, 2 moles) of 5-benzoyl-1-ethyl-4-hydroxypyrazolo (3,4-b) pyridine and 150 ml of phosphorus oxychloride are refluxed at 150 ° C. for 5 hours. The excess of phosphorus oxychloride is im Stripped vacuum and the residue with saturated sodium bicarbonate solution neutralized. The product specified above, which separates out in the form of pale yellow crystals, is filtered off and recrystallized from ethyl acetate, 35 g (61% of theory) with a melting point of 140 ° C. are obtained.

c) 4-Anilino-5-benzoyl-1-ethylpyrazolo (3,4-FeQ pyridine

2.85 g (0.01 mol) of 5-benzoyl-4-chloro-1-ethylpyrazolo (3,4-b) pyridine and 2 g (0.021 mol) of aniline are suspended in 20 ml of butanol and heated at 130 ° C. for 5 hours. The solvent is distilled off and the residue is treated with 10 ml of water. Included the above product crystallizes out with cooling and a yield of 2.5 g (73% of theory) of the product is obtained a melting point of 137 to 138 ° C.

Example 3 5-Benzoyl-4- (chloroacetylamine) -1-ethylpyrazlo (3,4-b) pyridine

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a) 4-Amino-5-benzoyl-1-ethylpyrazolo (3,4-b) pyridine

28.5 g (0.1 mol) of 5-benzoyl-4-chloro-1-ethylpyra ± o (3,4-b) pyridine vzerden dissolved in 100 ml of butanol and mixed with 50 ml of a concentrated aqueous ammonia solution at 150 ° C for 5 hours in a Autoclave treated. The solvent is removed and the residue washed with 100 ml of water, recrystallization from a A methanol-water mixture gives 15 g of 4-amino-5-benzoyl-1-ethylpyrazolo (3,4-b) pyridine (56% of theory) from melting point 152 to 153 ° C.

b) 5-Benzoyl-4- (chloroacetylamino) -l-ethylpyrazolo (3,4-b) pyridine 2.66 g (0.01 mol) of 4-amino-5-benzoyl-1-ethylpyrazolo (3,4-b ) pyridine are dissolved in 50 ml of dry dimethylene glycol dimethyl ether. A quantity of 0.31 g (0.013 mol) of sodium hydride is poured in and stirring is continued for 30 minutes. The yellow suspension is then cooled to -50 ° C. At this temperature, an amount of 1.12 g (0.01 mol) of chloroacetyl chloride is added dropwise. Stirring is continued for one hour. The mixture is then ^{warmed to 0} ° C. and mixed with water (100 ml). Crystals of 5-benzoyl-4- (chloroacetylamino) -1-ethylpyrazolo (3,4-b) pyridine separate out and are filtered off. You get

1.9 g (55% of theory) with a melting point of 135 ° C.

Examples 4A, 4B, 4C _f 4P

a) By treating the product from Example 1 (b) with phosphorus oxychloride following the procedure of Example 2 gives 5-acetyl-4-chloro-1-ethylpyrazolo (3,4-b) pyridine from Melting point 55 ° C.

b) The following additional compounds according to the invention are obtained from this product of process step a according to the procedure of Example 2 (c) with the same Use of suitable starting materials, as described in the following Table are given. '.

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/ * ³

^R 4o

2225A33

CR ₅

^Ε ι ■ ■ - ■ -. '-

1 χ / 3 5 -

-C ₀ H- -NH-CH- ^ ^J -CH ₀ . 65-68 °

2 5 \ ^

^C 2 ^H 5

-C ₀ H- -NH-C, H _Q -C 1 H-155-156 °

Zo 4 y ob

-C ₂ H ₅ -NH-C ₆ H ₅ -CH ₃ 73 °

/ ^C 2 ^H 5

-C _O H _C -NH-CH -CcPa ■■ 87 °

Zd ^. ■ o5

CH ^

For games 5 to 28

The additional products listed in the following table can be produced by exchanging the suitably substituted Starting materials for the 5-aminopyrazole or the ethoxymethylene benzoyl acetic acid ethyl ester in part a or by aniline in part c of example 2:

209850/1220

If

Ri

R,

I! ⁵ O

example

5 6

R-,

^C 6 ^H 5

R,

C ₂ H ₅

CH

In-C ₃ H ₇

NH

-N

C ₂ H ₅
CI-L

CH

8 9

10 11

C ₂ H ₅

^C 2 ^H 5

C ₂ H ₅

C ₂ H ₅

CH

CH

CH

NHC ₄ H ₉ (H)

eye 1obutyl -NHC.H _n (η)

cyclopentyl

cyclohexyl

-N

example

12th

^C 2 ^H 5

CH.

CH.

R>

-N

13th

^C 2 ^H 5

^C 2 ^H 5

-N

/ ί

Λ I

14th

^C 2 ^H 5

CH.

CH.

-N

Ό
CO
00
Cn
O

15th

16

^C 2 ^H 5

^C 2 ^H 5

CH.

CH.

CH.

CH.

N NH
y NH

-N

17th

^C 2 ^H 5-

CH.

CH.

N NC ₂ H ₄ OH

'18

^C 2 ^H 5

CH.

-NH,

19th

20th

C ₆ H ₅ C ₂ H ₄ -

CH.

Jl

NHC ₄ H ₉

-NHCH.

ro ro ro

Ü3 M W UUU

in

cm

W U

a υ

pi

in in W. CM ' CM U U

in

ο
U

in

CM

CM in in in η in η in W. K W. W. W. U CM CM CM U CM U CM in U U U U U VO U

QJ • H Pi

•H

H CM

cn

CM

CM

in

CN

CM

CM

209850/1220

Examples 29 to

According to the modified procedure outlined, the following products according to the invention are produced, where R is hydrogen:

example

29 30 31 32 33 3- ¹ I 35

^ 2 ^H 5 cyclohexyl H cyclopentyl

4 g

CH.

3 Br

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Claims (12)

Chemische Fabrik von Heyden GmbH Reference: Sq-26 / H-63-P Date: May 25, 1972 Claims . AminopyrazoloO ^ -b ^ pyridine-S-ketones of the general formula I. (I) wherein R, hydrogen, lower alkyl, phenyl or phenyl lower alkylene _{3 F} R _{0 is} hydrogen or lower alkyl, R, and R, each hydrogen, lower alkyl, lower alkanoyl, halo-lower alkanoyl, phenyl-lower alkylene, di-lower alkylamino-lower alkylene or R ₇ , R _ft -phenyl with the meanings of each hydrogen, halogen or trifluoromethyl for R _{7 and R 1} , or R 3 and R ₄ together with the nitrogen atom carrying them, ^{one of} the following heterocyclic radicals, namely R ₀ . , R, --Aziridinyl, R ₉ fR ₁₀ -pyrrolidino, R _gi R ₁₀ -piperidino, R _{9 #} R ₁₀ -pyrazolyl _# R ₉₇ R ₁₀ -pyrimidinyl, R _g , R. , .- pyridazinyl or R _g , R -piperazinyl each having the meanings of hydrogen, lower alkyl or hydroxy-lower alkyl for R _Q and R _1n , R ₅ lower alkyl, cycloalkyl, phenyl or R ", R ₈ ~ phenyl, each with the meanings of hydrogen, halogen or trifluoromethyl for R ₇ and R _g , Rg is hydrogen, lower alkyl or phenyl, and the acid addition salts of these compounds. 2. A compound according to claim 1, in which R, R ₃ and Rj- are each lower alkyl and Rp, R. and R _{fi are} each hydrogen. 3. \ erbverbindungen according to claim 1, wherein R is lower alkyl, R _? R ₃ and R are each hydrogen and R, R are each phenyl. 209850/1220 4. A compound according to any one of claims 1, 2 or 3 in which the lower alkyl is the ethyl group. 5. A compound according to claim 1, in which R _{1 is} ethyl, R ₃ , R _{g are} each hydrogen, R _{4 is} the butyl group and R _{5 is} the methyl group. 6. A compound according to claim 5, in which R. is a see-butyl group is. 7. A compound according to claim 1, in which R. is an ethyl group, R ₂ , R ₄ and Rg are each hydrogen, R- is acetyl and R _{5 is} phenyl. 8. A compound according to claim 1, in which R is ethyl, R ₂ / R ₄ , R _{fi are} each hydrogen, R- is phenyl and R _{5 is} methyl. 9. A compound according to claim 1, wherein R, R ₂ , R ₃ , R ₄ , R _{g are} each hydrogen and R _{5 is} phenyl. 10. Acid addition salt of one of the compounds after the preceding Claims. 11. A compound according to claim 1, in which an O-lower alkyl group is present instead of the -NR - group. R ₄ 12. Process for the preparation of compounds according to the in Claim 1 given formula I, characterized in that a primary or secondary amine of the formula VII ^H ? " ^R 3 (VII) ^R 4 implements with one of the roder VIII compounds of the general formulas VI listed below, where the symbols R-, R-, R_, R ₄ , Rj- and Rg inserted in these formulas have the meanings given in claim 1 ^ 209850/1220 ίο (VI). (VIII) O -Lower alkyl .Cl 209850/1220