DE2423060A1 - AMINO DERIVATIVES OF PYRAZOLOPYRIDINKETONS - Google Patents

Description

D R. E Y S E N B A C H

PATEN ADVERTISER

Telegrams: PATENTEYSENBACH, PULLACH-ISARTAL

Telephone Munich (0811): 7930391 Dr. Hans Eysenbach, D-8023 Pulloch, Baumstra SSE n 6 tegn - reff Sq-59 / H-99-P (M-361 12Q-H)

Date: May 13, 1974

Description 2423060

to the
Patent application

"Amino derivatives of pyrazolopyridine ketones"

Applicant: Chemische Fabrik von Heyden GmbH, Munich

Claimed priority: May 17, 1973 from United States patent application 361.12O

The invention relates to specific amino derivatives of pyrazolopyridine ketones with a high anti-inflammatory effect without a simultaneous disruptive diuretic effect as well as those for the production of these Connection suitable manufacturing process.

The German Offenlegungsschrift issued on December 7, 1972 2,225,433 describes amino derivatives of pyrazolo (3,4-b) pyridine-5-ketones including their salts with anti-inflammatory therapeutic activity and the following general formula

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wherein R. is hydrogen, lower alkyl, phenyl or phenyl lower alkylene, R _{2 is} hydrogen or lower alkyl, R- and R _{4 are} each hydrogen, lower alkyl, lower alkanoyl, halo-lower alkanoyl, the group R_, Rg-phenyl with the meaning of hydrogen, halogen or tri fluorine thy 1 for R ₇ and R _R , pheny is Iniedrigalky len, di-lower alkylamino-lower alkylene or else R ₃ and R. together with the nitrogen atom carrying them denotes one of the following heterocyclic ring systems: R, R -aziridinyl, R ₉ , R ₁₀ -pyrrolidino, R ₉ , R ₁₀ -piperidino, "R ₉ , R ₁₀ -PyrazoIyI, ^R ₉ ' ^R ₁₀ ~ pyrimidinyl, R_, R -pyridanzinyl or R _q , R. -Piperazinyl each with the meaning of hydrogen, lower alkyl or hydroxy-lower alkyl for R_ and ^ ₁₀ / and finally R _{ß is} hydrogen, lower alkyl or phenyl, and the acid addition salts of these compounds.

It is stated in this publication that these substances are a Possess anti-inflammatory properties and as anti-inflammatory therapeutic agents are useful, such as for the reduction of local inflammatory conditions such as those more edematous Nature or from proliferation of connective tissue cells in various Mammalian species, such as rats, dogs, and the like, are indicated by the carageenan edema test in rats.

In Table I below, representative inflammatory inhibition data are given, which are in the above-mentioned German Offenlegungsschrift 2 225 433 as a result of the respective Carageenan edema tests have shown.

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TABEL

H f2 * NR ₃ R ₄ ^R 5 ^R 6 ' (D 38 (2) 1 H H NHj phenyl H 130 4th 2 H H NHj phenyl phenyl 150 2 3 H H NH ₂ p-Cl-phenyl H 85 4th H CH ₃ NH ₂ phenyl H 170 1 5 H H NH-n-butyl phenyl H 150 6th H H NH-n-butyl phenyl phenyl 150 0 7th H CH ₃ NH-sec-butyl phenyl H 150 0 8th ^C 2 ^H 5 H NH-phenyl phenyl H > 150 9 ^C 2 ^H 5 H NH-sec-butyl phenyl H 80 0 10 C ₂ H ₅ H NH-n-butyl phenyl H > 150 2 11 C ₂ H ₅ H NH-phenyl phenyl H 160 12th H H NH-phenyl methyl H 160 13th C ₂ H ₅ H NH (CHj) ₃ -N Me ₂ phenyl H 120 14th C ₂ H ₅ H NHj methyl H > 47 3 15th ^C 2 ^H 5 H NH-n-butyl methyl H > 47 3 16 benzyl H NH-sec-butyl methyl H 200 3 17th H H NH ₂ phenyl H 150 18th C ₂ H ₅ H NH ₂ p-Cl-phenyl H 115 19th G ₂ H ₅ H NH-sec-butyl ethyl H 39 1 20th C ₂ H ₅ H NH ₂ phenyl H 92 4th 21 H H NH-sec-butyl n-propyl H 100 0 22nd H H NH ₂ p-MeO-phenyl H > 150 2 23 H NHj p-CH ₃ -phenyl H 3 40984 9/1092

In column (1) of this table the ID ₅₀ number of the anti-inflammatory effect is given and in column (2) the diuretic effect is given. The following explanations:

(1) The anti-inflammatory activity was measured according to the standard test, the carrageenan edema test, in rats. The numerals given each mean ID ₅₀ in mg / kg. The ID ₅ dosage elicits 50% reversal of the edema.

(2) The diuretic effectiveness was measured with a rating scale from 0 to 4; O means none Effectiveness; 1 means up to 40% of the theophylline effect; 2 means 40 to 80% of the theophylline effect; 3 means as great an effect as with theophylline and 4 means that the effectiveness of theophylline is greater than Effect.

It can be seen from Table I that all compounds which have the lowest possible substitution in the various positions have the highest level of anti-inflammatory activity. For example, the compound (1) in which R ^ is phenyl and there is the least possible substitution in the other possible positions, ie, R, R ₃ , R_. R ₄ and R are each hydrogen, which is by far the most effective anti-inflammatory active substance according to the measurement in the ... standardized carrageenan edema test in rats and the compound 20, which is derived from this compound 1 only by an ethyl substitution in the R position deviates is also most effective. However, other substitutions in the various positions generally result in a remarkable decrease in the anti-inflammatory effectiveness, to the extent that the levels of effectiveness make these substances uninteresting as anti-inflammatory substances in competition with other known active substances.

The therapeutic value of these compounds with the fewest substitutions in the series, i.e. Compounds No. 1 and No. 20, which would be of interest because of their high anti-inflammatory effects, but is diminished by the fact that

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precisely these compounds have remarkably high diuretic activity exercise. Substitution is used to reduce the diuretic effectiveness to tolerable values (on the rating scale from 0 to 2) displayed in the various positions. Allerdinqs unfortunately goes with this decrease in diuretic activity a remarkably large reduction in anti-inflammatory potency hand in hand. That underlying the invention The problem is therefore / to produce such compounds which are still high with a tolerable diuretic effectiveness exert anti-inflammatory effects.

If, in the general formula given at the outset, R _{5 is} phenyl and all other possible substitution positions are unsubstituted, that is to say the following general formula I

present or only a very small group in the R. position of branched-chain substituents of the general formula II

(ID

are present, in which R ¹ and R ″ are each independently hydrogen or methyl and the dashed line is either one bond closing the cyclopropyl ring or two

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Represents hydrogen atoms, there are compounds which a still have tolerably low levels of diuretic activity and at the same time have a high level of anti-inflammatory activity that is comparable to the activity of the Effect level of the unsubstituted compound no. 1 or its R -ethyl-substituted derivative compound no. 20 from Table I, or even exceeds it. It has also been found that, in contrast to what is shown in Table I in general This desirable combination of low diuretic activity with high anti-inflammatory activity is also trending is still retained when the R -phenyl ring in the above given formula I is substituted with a haloene, a lower alkyl or a lower alkoxy.

The problem on which the invention is based therefore becomes the invention solved by the provision of amino derivatives of pyrazole (3,4-b) pyridine-5-ketones, the following general Formula III correspond

NH

wherein R ^f and R "are each independently either hydrogen or methyl, R ^f " is hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -lower alkoxy and the dashed line is a bond closing the cyclopropyl ring or two Means hydrogen atoms.

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As already mentioned, compounds of the formula III given above have a unique combination of effects, namely a high anti-inflammatory effect and a negligibly low diuretic effect, this novel combination of effects probably declining and being characteristic of the branched-chain alkyl substitution in the R. position with the general formula II given above

(II)

MR"

thus includes the following residual groups: isopropyl, secondary butyl, 3-pentyl, Cyclopropyl, 2-methylcyclopropyl and 2,3-dimethylcyclopropyl.

Table II, presented below, gives the results of a comparison of the anti-inflammatory activities of representative ones Compounds of formula III with the anti-inflammatory activity of compounds which are only in the relationship differ from this general formula III that they have other alkyl groups in the R. position, even though they are Homologues to 'the alkyl groups according to formula II; these results thus show that this constellation of effects is unique and that the range of connections that these are desired Have effects, is very close.

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RLL

II

NH R

# ' ^R 4 R ^IW m.p. inflammatory
Effect
^ID 50 24 * -CH (CHg) -C ₂ H ₅ H 174-175 39 25 * -CH (CHg) -C ₂ H p-Cl 216-218 42 26 * -CH (CHg) -C ₂ H ₅ p-CHg 203-204 65 27 * -CH (CH ₃ ) -C ₂ H ₅ P-CHgO 196-197 47.5 28 -CH ₂ CH (CHg) ₂ H 237-239 150 29 -CH (CH ₃ ) C (CHg) ₃ H 247-250 150 30th -CH ₂ C (CH ₃ ) 3 H 291-292 150 31 - (CH ₂ J ₃ CH (CHg) ₂ H 178-182 170 32 -CH (CH ₃ J ¹ C ₃ H ₇ * HCl H 137-141 83 33 π H 248-250 150 34 * VJ H 256-258 26th 35 A. H 274-276 130 36 Sl H 133-135 110 37 * H 191-193 14.5 -CH (CHg) CH ₂ CH (CH ₃ ) ₂ -CH (CH ₃ J ₂ 'H ₂ O

compounds according to the invention

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The subject matter of the invention accordingly also consists in the preparation of the compounds of the general formula III given above, the is characterized in that one is an S-benzoyl-4-alkoxy or Halo-1H-pyrazolo (3,4-b) pyridine of the general formula IV

in which X is chlorine, bromine or alkoxy and R ¹ ″ has one of the meanings given above, reacted with an amine of the formula V

CR ¹
ι

C-R "

wherein R ¹ and R "have the same meanings already given above. This reaction is carried out by treating the reactants either at room temperature or at elevated temperatures. In some cases it may be advantageous to make use of an autoclave. The preparation of the starting materials of the formula IV, in which R ¹ "is hydrogen and X is alkoxy, the alkoxy group being ethoxy, is illustrated in more detail by way of example 1 with process steps (a) to (d). The R ¹ "group

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can be varied by using an ethoxymethylene substituted one Ethyl benzylacetate in the procedure according to Example 1 (a). The alkoxy group (X) can be varied by using other alkyl halides instead of that in Example, 1 (c) ethyl iodide used. In addition, the hydroxy product des Example 1 (b) can be reacted with a suitable phosphorus halide such as phosphorus oxychloride to optionally provide a starting material to be prepared according to formula IV, in which X is chlorine or bromine.

The compounds of the formula III form salts, which also belong to the invention. The salts are, for example, acid addition salts, and in particular the non-toxic, physiologically acceptable representatives. The bases of the formula III form salts through reaction with a large number of inorganic and organic acids and thus form acid addition salts such as e.g. the hydrogen halides (especially hydrogen chloride), sulfates, nitrates, phosphates, oxalates, tartrates, malates, citrates, acetates, axcorbates, Succinates, benzenesulfonates, toluenesulfonates, cyclohexanesulfonates, Cyclohexanesulfamate, etc. The acid addition salts are often is also a convenient means of isolating the product, that is, allowing salts to form and precipitate which are in suitable Solvents are insoluble as a salt, whereupon they are separated off and neutralized with a base such as barium hydroxide or sodium hydroxide; after the free base of the formula III released again in this way, other salts which are therapeutically desirable are formed are, by reaction with an equivalent weight of the desired acid.

As stated, the compounds according to the invention have an anti-inflammatory effect Property and are therefore suitable means for alleviating inflammatory processes, for example enable they reduce local inflammatory processes such as those of an edematous nature or those resulting from proliferation of connective tissue cells in various mammals such as rats, dogs and the like show when these agents are given orally at dosages of about 5 to 50 mg / kg / day, preferably 5 to 25 mg / kg / day, in a single dose or in 2 to 4 doses divided into the day, like the carageenan-tfdem test indicated in rats £ ^ giJi> lets ^

j. - 11 - ■

The active substance can be used in compositions such as tablets, capsules, Solutions or suspensions are used which contain up to about 300 mg per dosage unit of one of the compounds or also on a mixture of these compounds of the formula I or physiologically acceptable acid addition salts or quaternary ammonium salts of which can be used, they can also be used in the usual way with a physiologically compatible carrier or vehicle, be mixed with excipients, binders, stabilizers, flavoring agents, etc., as in the pharmaceutical Practice has proven useful. Preparations that can be used externally contain about 0.01 to 3 percent by weight of active substance in a lotion, ointment, or cream.

The following examples explain the invention in more detail.

example 1
5-Benzoyl-4-sec-butylamino-1 H -pyrazolo (3,4-b) pyridine

a) (((1- (2-Furyl) methylpyrazolyl) amino) methylene) benzoyl acetic acid ethyl ester

163 g of l- (2-furyl) methyl-5-aminopyrazole (1 mol) and 248 g of ethyl ethoxymethylene benzoyl acetate (1 mol) are heated to 130 C and kept at this temperature until no alcohol more distilled off (about an hour). The oily residue crystallizes and on cooling and recrystallization from hexane gives a Amount of 310 g (((1- (2-furyl) methyl-5-pyrazolyl) amino) methylene) -benzoyl acetic acid ethyl ester (85% of theory), melting point 75 to 77 ° C.

b) S-Benzoyl ^ -hydroxy-lU-furyllmethyl-lH-pyrazoloQ ^ -bipyridln

36.5 g (((1- (2-furyl) methyl-5-pyrazolyl) amino) methylene benzoy1-acetic acid ethyl ester are dissolved in 50 ml of diphenyl ether and refluxed at 260 ° C. for 30 minutes. After distilling of the solvent, a dark oil is obtained, which crystallizes out after adding methanol. By recrystallization 20 g of 5-benzoyl-4-hydroxy-1- (2-furyl) -methyi-1H-pyrazolo (3,4-b) pyridine are obtained from butyl alcohol (61% of theory), melting point 102 ° C.

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c) 5-Benzoyl-4-ethoxy-1- (2-fury1) methyl-1H-pyrazolo (3,4-b) pvridine

3.3 g of 5-benzoyl-4-hydroxy-1- (2-furyl) methyl-1H-pyrazolo (3,4-b) pyridine (0.01 mol) are dissolved in 20 ml of dimethylformamide. 2.8 g of potassium carbonate and 3.1 g of ethyl iodide are added and the mixture is heated the mixture at 60 ° C for 12 hours. The excess potassium carbonate is filtered off and water is added. Man receives the above substance as a precipitate and recrystallizes it from hexane; Yield 3 g (86% of theory), melting point 70 ° C.

d) 5-Benzoyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine

1.7g of 5-benzoyl-4-ethoxy-1- (2-furyl) methyl-1H-pyrazolo (3,4-b) pyridine (0.005 mol) are dissolved in 5 ml of diethylene glycol dimethyl ether, 1.1 g of selenium dioxide are added and the mixture is heated to 160 ° C. with stirring. After adding a drop of water the temperature is maintained for one hour. The mixture is filtered off while hot and a precipitate is obtained of the above substance when cooled. Recrystallization from butanol gives 1 g (77% of theory). with a melting point from 195 to 197 ° C.

e) 5-Benzoy1-4-sec-butylamino-1H-pyrazolo (3,4-b) pyridine

2.6 g of 5-benzoyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine (0.01 mol) and 10 ml of sec-butylamine are refluxed for 10 hours. After this time, the excess amine is evaporated off in vacuo and the residue, namely the substance indicated above, is recrystallized; Melting point 174 to 175 ° C, yield 87% of theory

Example 2
5-p-Chlorobenzoyl-4-sec-butylamino-1 H -pyrazolo (3,4-b) pyridine

By using an equimolar amount of ethoxymethylene-p-chlorobenzoyl acetic acid ethyl ester instead of the ethoxymethylene benzoyl acetic acid ethyl ester used in Example 1 (a) and also the following The procedure of Example 1 up to process step (d) gives 5-p-chlorobenzoyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine.

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By using this substance instead of the 5-benzoyl-4-ethoxy-1H-pyrazolo- (3,4-b) pyridine used in Example 1, process step (e), the substance indicated in the heading, namely 5-p-chlorobenzoy, is obtained .l-4-sec-butylamino-lH-pyrazolo (3,4-b) pyridine having a melting point 216-218 ⁰ C, yield 88% of theory

Example 3
5-p-Toluy1-4-sec-butylamino-1 H -pyrazolo (3,4-b) pyridine

By using ethoxymethylene-p-toluylessigsäureäthylester according to Process step (a) of Example 1 and the following execution This example gives the substance given above with a melting point of 203 to 204 ° C., yield 91% of theory.

Example 4
5-p-Methoxyenzoyl-4-sec-butylamino-1 H -pyrazolo (3,4-b) pyridine

By using ethoxymethylene-p-methoxybenzoyl acetic acid ethyl ester In process stage (a) of Example 1 and subsequent further implementation of the remaining process stages, the above are obtained specified substance with a melting point of 196 to 197 ° C. with a yield of 90% of theory

Example 5
5-Benzoyl-4-cyclopropylamino-1H-pyrazolo (3,4-b) pyridine ¹

2.6 g of 5-benzoyl-4-ethoxy-1H-pyrazolo (3,4-b) pyridine are dissolved in 50 ml · n-butyl alcohol, 10 ml cyclopropylamine is added and the mixture is heated in an autoclave at 160 ° C. for 10 hours. After this time the excess solvent will be distilled off in vacuo and the residue is crystallized out; the above-mentioned substance with a melting point is obtained from 256 to 258 ° C with a yield of 84% of theory

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Example 6
5-Benzoyl-4-isopropylamino-1H-pyrazolo (3 , 4-b) pyridine monohydrate

By substituting isopropylamine for that used in Example 5 Cyclopropylamine is obtained the above substance with a melting point of 191 to 19 3 C with a yield of 84% of theory

Example 7

5-Benzoyl-4-cyclopropylamino-1H-pyrazolo (3,4-b) pyridine hydrochloride (1: 1)

0.1 mole of 5-benzoyl-4-cyclopropylamino-1 H -pyrazolo (3,4-b) pyridine is suspended in 100 ml of methanol saturated with hydrogen chloride. The mixture is refluxed for one hour, the Solvent is evaporated in vacuo and the residue dissolved in a small amount of methanol. By adding from ether the substance given above is obtained as an excretion with a melting point of 250 to 252 C.

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Claims (26)

Chemische Fabrik von Heyden GmbH Reference: Sq-49 / H-99-P (M-361120-H) '""'"''" ^: ""^:> ~ ■ "'■''Date:" 13. May 1974 " Claims Amino derivatives of pyrazolopyridine ketones of the general formula III H NH CH ' ..CR ¹ R " (III) I Il wherein R 'and R "are each independently either hydrogen or methyl, R " ^{1 is} hydrogen, halogen, C -C alkyl or C -C alkoxy and the dashed line denotes a bond closing a cyclopropyl ring or two hydrogens. 2. A compound according to claim 1, characterized by the following general formula , " wherein R ¹ and R "are each independently either hydrogen 4098A9 / 1092 or methyl and R ¹ "denotes hydrogen, halogen, C ₃ -C ₄ -AlJCyI or C.-C.-ralkoxy, I Il 3. A compound according to claim 2, wherein R is hydrogen. 4. A compound according to claim 2, wherein R ¹ , R "and R ¹ " are hydrogen. 5. A compound according to claim 2, wherein R ^{1 is} methyl and R "is hydrogen. 6. A compound according to claim 2, wherein R ^{1 is} methyl, R "is hydrogen and R ¹ " is hydrogen. 7. A compound according to claim 2, wherein R ^{1 is} methyl, R "hydrogen and R!" is para-methyl. 8. A compound according to claim 2, wherein R ^{1 is} methyl, R "is hydrogen and R ¹ " is para-chlorine. 9. A compound according to claim 2, wherein R ^{1 is} methyl, R "is hydrogen and R ¹ " is para-methoxy. 10. Compound of the general formula given below CHR ¹ wherein R ¹ and R "are each independently either hydrogen or methyl and R ¹ "is hydrogen, halogen, C, -C ₄ -alkyl or C, -C ₄ -AlkOXy. 409849/1092 - 11. A compound according to claim 10, characterized in that therein R ¹ "is hydrogen. 12. A compound according to claim 10, characterized in that therein R ¹ and R "are each hydrogen. 13. A compound according to claim 10, characterized in that therein R ¹ , R "and R ¹ " are each hydrogen. 14. Process for the preparation of a compound of the general formula III given in claim, characterized in that a compound of formula IV I Il (IV) wherein X is chlorine, bromine or alkoxy and R ¹ "has the meanings given in claim 1, reacted with an amine of the general formula V I.
C-R ' H ₂ NC (V) C-R " I.
H wherein R ¹ and R "have the meanings given in claim 1. 15. A method for producing a compound according to claim 1, characterized in that for the purpose of producing a connection the general formula given in claim 2 is a compound of the general formula IV given in claim 14 reacts with an amine of the following general formula 409849/1092 H ₂ N-CH. CH ₂ R " wherein R ¹ and R "have the meanings given in claim 1. 16. The method according to claim 15, characterized / that therein R ¹ "is hydrogen. 17. The method according to claim 15, characterized in that therein R ¹ , R "and R ¹ " are each hydrogen. 18. The method according to claim 15, characterized in that therein R ^{1 is} methyl and R "is hydrogen. 19. The method according to claim 15, characterized in that therein R ^{1 is} methyl, R "is hydrogen and R ¹ " is hydrogen. 20. The method according to claim 15, characterized in that therein R ^{1 is} methyl, R "is hydrogen and R ¹ " is para-methyl. 21. The method according to claim 15, characterized in that therein R ^{1 is} methyl, R "is hydrogen and R" ^{1 is} para-chlorine. 22. The method according to claim 15, characterized in that therein R ^{1 is} methyl, R "is hydrogen and R ¹ " is para-methoxy. 23. A method for the preparation of a compound according to claim 1, characterized in that for the purpose of preparing the in claim The general formula given reacts a compound of the general formula IV given in claim 15 with an amine the following general formula CHR ¹ h ₂ n-ch: 'CHR " 409849/1092 wherein R "and R" have the meanings given in claim 1. 24. The method according to claim 13, characterized in that therein R ¹ "is hydrogen. 25. The method according to claim 23, characterized in that therein R ¹ and R "are each hydrogen. 26. The method according to claim 23, characterized in that therein R ¹ , R "and R ¹ " are each hydrogen. 409849/1092