CA1071207A - 4-amino derivatives of 2h-pyrazolo (3,4-b) pyridine-5-carboxylic acids and esters - Google Patents
4-amino derivatives of 2h-pyrazolo (3,4-b) pyridine-5-carboxylic acids and estersInfo
- Publication number
- CA1071207A CA1071207A CA249,256A CA249256A CA1071207A CA 1071207 A CA1071207 A CA 1071207A CA 249256 A CA249256 A CA 249256A CA 1071207 A CA1071207 A CA 1071207A
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- hydrogen
- alkyl
- methyl
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract Compounds of the formula and their pharmaceutically acceptable salts wherein R is hydrogen or alkyl; R1 is alkyl, phenyl or phenyl-alkyl;
R2 is hydrogen or alkyl; R3 and R4 are independently selected from hydrogen, alkyl, phenyl, phenyl-alkyl, substituted-phenyl, (substituted-phenyl)alkyl, and dialkylaminoalkylene, or R3 and R4 together with the N atom form a six membered heterocyclic ring; and R5 is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; are disclosed. These compounds are useful as central nervous system depressants and anti-inflammatory agents. Also disclosed are the 4-hydroxy and 4-alkoxy intermediates.
R2 is hydrogen or alkyl; R3 and R4 are independently selected from hydrogen, alkyl, phenyl, phenyl-alkyl, substituted-phenyl, (substituted-phenyl)alkyl, and dialkylaminoalkylene, or R3 and R4 together with the N atom form a six membered heterocyclic ring; and R5 is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; are disclosed. These compounds are useful as central nervous system depressants and anti-inflammatory agents. Also disclosed are the 4-hydroxy and 4-alkoxy intermediates.
Description
MT106 ~
4-Amino derivatives of lH-pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters are known to possess pharmaceutical activity as note Hoehn et al. U. S. Pat. Nos. 3,755,340, 3,833,594 and 3,856,799. This invention is directed to the discovery that various 4-amino derivatives of 2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acids and esters also possess useful pharmaceutical activity.
This invention relates to new amino derivatives of 2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and esters, and acid addition salts thereof. The new compounds are of the formula (I) R3~ ~,R4 R ~ ~ ~ COOR
R~ ~N ~ N ~ R5 The symbols have the following meaning in formula I
and throughout this specification.
R i9 hydrogen or lower alkyl.
Rl is lower alkyl, phenyl or phenyl-lower alkyl.
R2 is hydrogen or lower alkyl.
R5 is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl.
I _ 107~Z07 MT106 R3 and R4 are independently selected from hydrogen, lower alkyl, phenyl, substituted-phenyl, phenyl-lower alkyl, (substituted-phenyl)-lower alkyl, and di(lower alkyl)amino-lower alkylene or R3 and R4 taken together with the N atom to which they are attached form a six membered substituted or unsubstituted saturated heterocyclic ring which may contain a second nitrogen atom. Exemplary of the heterocyclic moieties are those of the formulae _ ~ 6 ~ R6 wherein R6 is hydrogen, lower alkyl or hydroxy-lower alkyl and R7 and R8 are independently selected from hydrogen and lower alkyl.
Also within the scope of this invention are the compounds of formula (II) OR
~ `~
Rl~N ~ R5 which are useful as intermediates in the preparation of the compounds of formula I.
R, Rl, R2 and R5 have the n~eanings set forth above and Rg is hydrogen or lower alkyl.
The lower alkyl groups referred to throughout this specification include str~ight or branched chain hydrocarbon groups of one to seven carbon atoms, preferably 1 to 4 carbons.
Examples of the type of groups contemplated are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, etc.
The term "phenyl-lower alkyl" refers to such lower alkyl groups attached to a phenyl radical, i.e. phenylmethylene,
4-Amino derivatives of lH-pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters are known to possess pharmaceutical activity as note Hoehn et al. U. S. Pat. Nos. 3,755,340, 3,833,594 and 3,856,799. This invention is directed to the discovery that various 4-amino derivatives of 2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acids and esters also possess useful pharmaceutical activity.
This invention relates to new amino derivatives of 2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and esters, and acid addition salts thereof. The new compounds are of the formula (I) R3~ ~,R4 R ~ ~ ~ COOR
R~ ~N ~ N ~ R5 The symbols have the following meaning in formula I
and throughout this specification.
R i9 hydrogen or lower alkyl.
Rl is lower alkyl, phenyl or phenyl-lower alkyl.
R2 is hydrogen or lower alkyl.
R5 is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl.
I _ 107~Z07 MT106 R3 and R4 are independently selected from hydrogen, lower alkyl, phenyl, substituted-phenyl, phenyl-lower alkyl, (substituted-phenyl)-lower alkyl, and di(lower alkyl)amino-lower alkylene or R3 and R4 taken together with the N atom to which they are attached form a six membered substituted or unsubstituted saturated heterocyclic ring which may contain a second nitrogen atom. Exemplary of the heterocyclic moieties are those of the formulae _ ~ 6 ~ R6 wherein R6 is hydrogen, lower alkyl or hydroxy-lower alkyl and R7 and R8 are independently selected from hydrogen and lower alkyl.
Also within the scope of this invention are the compounds of formula (II) OR
~ `~
Rl~N ~ R5 which are useful as intermediates in the preparation of the compounds of formula I.
R, Rl, R2 and R5 have the n~eanings set forth above and Rg is hydrogen or lower alkyl.
The lower alkyl groups referred to throughout this specification include str~ight or branched chain hydrocarbon groups of one to seven carbon atoms, preferably 1 to 4 carbons.
Examples of the type of groups contemplated are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, etc.
The term "phenyl-lower alkyl" refers to such lower alkyl groups attached to a phenyl radical, i.e. phenylmethylene,
2-phenylethylene, etc.
The terms "substituted-phenyl" and "(substituted-phenyl)-lower alkyl" refer to a phenyl group having one or two lower alkyl substituents or one trifluoromethyl or carboxy substituent. Examples of the type of groups contemplated are 2-, 3- or 4-methylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl-methylene, (3-trifluoromethyl)phenyl, 4-carboxyphenyl, 2-[(4-trifluoromethyl)phenyl]ethylene, etc.
The term "lower alkylene" refers to straight or branched chain alkylene of 1 to 7 carbons, preferably 1 to 4 carbons, such as -(CH2)n~ wherein n is 1 to 7, -CH2-CH-, -CH2-fH-(CH2)2-, etc.
Thus, the term di(lower alkyl)amino-lower alkylene refers to groups such as H3C~ H3C ~
~ N-(CH2)3-, N-CH2-CH-, etc.
The preferred compounds of formula I wherein the substituent at the 4-position is an acyclic amino group are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R3 is hydrogen, alkyl of 1 to 4 carbons or dialkylamino-alkylene wherein alkyl and alkylene are of 1 to 4 carbons, especially alkyl of 1 to 4 carbons~
~07~Z07 R4 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R5 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
The preferred compounds of formula I wherein the substituent at the 4-position is a heterocyclic group are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R6 is hydrogen, alkyl of 1 to 4 carbons, or hydroxy-alkyl of 1 to 4 carbons, especially hydrogen.
R7 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R~ is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen or methyl.
R5 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
Among the intermediates of formula II preferred are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R5 is hydrogen or alkyl of l to 4 carbons, especially hydrogen.
Rg is hydrogen or alkyl of 1 to 4 carbons.
1071207 MTl06 The new compounds of formula I are prepared by the following series of reactions.
A 3-aminopyrazole of the formula (III) R2~L.
R / ~N 2 [produced analogously to the procedure described in Angew.
Chem. 86, 237 (1974)1 is reacted with an alkoxymethylene malonic acid dialkylester of the formula (IV) ~ COOalkyl alkyl-O-C=C
R Cooalk to produce a compound of the formula (V) R2 ¦ ¦ ~COOalkyl R~ ~N ~ I ~ COOalkyl The compound of formula V is cyclized in an inert organic solvent such a-q diphenylether by heating at about 240-260C to produce the intermediate of the formula (IIa) OH
R21 ~ COOalkyl Rl ~ N R5 The intermediate of formula IIa is treated with an inorganic acid chloride or bromide such as phosphorous oxy-chloride, thionyl chloride, thionyl bromide, etc. to yield a compound of the formula (VI) X
R2 ~ COOalkyl R ~ ~ N ~ N~ R
wherein X is Cl or Br.
Treatment of the compound of formula VI with an amino compound of formula ~ VII) H-N ~ 3 at reflux temperature for several hours yields the final products of formula I.
Alternatively, the compound of formula VI can be treated with an alcohol of formula (VIII) . HO-alkyl to yield the intermediate of formula (IIb) Oalkyl COOalkyl R2~ ~
R'~N N R5 which is treated with an amino compound of formula VII at reflux temperature for several hours to yield the final products of formula I.
1071207 ~ -The esters (i.e. R is lower alkyl) of formulas I and II
can be converted to the free acid by conventional means such as treatment with an organic acid such as acetic acid.
The compounds of formulas I and II form pharmaceutically acceptable acid addition salts by reaction with equivalent amounts of the common inorganic and organic acids. Such salts include the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate oxalate, tartrate, malate, succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, etc. It is frequently convenient to purify or isolate the product by forming an insoluble salt. The base may be obtained by neutralization and another salt then formed by treat-ment with the appropriate acid.
The new compounds of formula I are central nervous system depressants and may be used as tranquilizers or ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species, in the same manner as chlordiazepoxide.
For this purpose a compound or mixture of compounds of formula I or a pharmaceutically acceptable acid addition salt thereof is administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 1 to 50 mg/kg/day, preferably about 2 to 15 mg/kg/day, is appropriate. These can be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like, and ~()7~Zo7 MTl06 if necessary sterilized, all as called for by accepted pharmaceutical practice.
The compounds of formula I are also useful as antlinflammatory agents and are effectlve in the prevention and inhibition of granuloma tissue formation in warm blooded animals, for example, in a manner similar to indomethacin.
For example, about 150 mg/kg/day is effective in reduced paw swelling in rats. They can be used to decrease joint swelling tenderness, pain and stiffness, in various mammalian species, e.g., in conditions such as rheumatoid arthritis. A
compound of formula I or a pharmaceutically acceptable salt thereof is compounded according to accepted pharma-ceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably lO0 mg. to l gm.
per day, in two to four divided doses.
The following examples constitute preferred embodiments and also illustrate how these and other members of this group are produced. Simple variation of the reactants and substitution in the reaction sequences described below, readily yield other compounds within the scope of the invention. All temperatures are in degrees centigrade.
~7~207 MT106 Example 1 4-Hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, .
eth~l ester a) [[(l-Methyl-lH-pyrazol-3-yl)amino]methylene]propane-dicarb~xylic acid, ethyl ester 194 g. (2 moles) of 3-amino-1-methyl-pyrazole and 432 g.
of ethoxymethylene malonic acid, diethyl ester are stirred together for one hour at 100. The alcohol formed is re-moved in vacuo and the resulting product crystallized from ether to yield 425 g. of [[(l-methyl-lH-pyrazol-3-yl)amino~-methylene]propane-dicarboxylic acid, ethyl ester; m.p. 60-63.
b) 4-Hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester 534 g. of the ester from part (a) are added to about
The terms "substituted-phenyl" and "(substituted-phenyl)-lower alkyl" refer to a phenyl group having one or two lower alkyl substituents or one trifluoromethyl or carboxy substituent. Examples of the type of groups contemplated are 2-, 3- or 4-methylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl-methylene, (3-trifluoromethyl)phenyl, 4-carboxyphenyl, 2-[(4-trifluoromethyl)phenyl]ethylene, etc.
The term "lower alkylene" refers to straight or branched chain alkylene of 1 to 7 carbons, preferably 1 to 4 carbons, such as -(CH2)n~ wherein n is 1 to 7, -CH2-CH-, -CH2-fH-(CH2)2-, etc.
Thus, the term di(lower alkyl)amino-lower alkylene refers to groups such as H3C~ H3C ~
~ N-(CH2)3-, N-CH2-CH-, etc.
The preferred compounds of formula I wherein the substituent at the 4-position is an acyclic amino group are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R3 is hydrogen, alkyl of 1 to 4 carbons or dialkylamino-alkylene wherein alkyl and alkylene are of 1 to 4 carbons, especially alkyl of 1 to 4 carbons~
~07~Z07 R4 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R5 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
The preferred compounds of formula I wherein the substituent at the 4-position is a heterocyclic group are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R6 is hydrogen, alkyl of 1 to 4 carbons, or hydroxy-alkyl of 1 to 4 carbons, especially hydrogen.
R7 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R~ is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen or methyl.
R5 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
Among the intermediates of formula II preferred are those wherein:
R is hydrogen or alkyl of 1 to 4 carbons.
Rl is alkyl of 1 to 4 carbons, especially methyl.
R2 is hydrogen or alkyl of 1 to 4 carbons, especially hydrogen.
R5 is hydrogen or alkyl of l to 4 carbons, especially hydrogen.
Rg is hydrogen or alkyl of 1 to 4 carbons.
1071207 MTl06 The new compounds of formula I are prepared by the following series of reactions.
A 3-aminopyrazole of the formula (III) R2~L.
R / ~N 2 [produced analogously to the procedure described in Angew.
Chem. 86, 237 (1974)1 is reacted with an alkoxymethylene malonic acid dialkylester of the formula (IV) ~ COOalkyl alkyl-O-C=C
R Cooalk to produce a compound of the formula (V) R2 ¦ ¦ ~COOalkyl R~ ~N ~ I ~ COOalkyl The compound of formula V is cyclized in an inert organic solvent such a-q diphenylether by heating at about 240-260C to produce the intermediate of the formula (IIa) OH
R21 ~ COOalkyl Rl ~ N R5 The intermediate of formula IIa is treated with an inorganic acid chloride or bromide such as phosphorous oxy-chloride, thionyl chloride, thionyl bromide, etc. to yield a compound of the formula (VI) X
R2 ~ COOalkyl R ~ ~ N ~ N~ R
wherein X is Cl or Br.
Treatment of the compound of formula VI with an amino compound of formula ~ VII) H-N ~ 3 at reflux temperature for several hours yields the final products of formula I.
Alternatively, the compound of formula VI can be treated with an alcohol of formula (VIII) . HO-alkyl to yield the intermediate of formula (IIb) Oalkyl COOalkyl R2~ ~
R'~N N R5 which is treated with an amino compound of formula VII at reflux temperature for several hours to yield the final products of formula I.
1071207 ~ -The esters (i.e. R is lower alkyl) of formulas I and II
can be converted to the free acid by conventional means such as treatment with an organic acid such as acetic acid.
The compounds of formulas I and II form pharmaceutically acceptable acid addition salts by reaction with equivalent amounts of the common inorganic and organic acids. Such salts include the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate, nitrate, phosphate, acetate, citrate oxalate, tartrate, malate, succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, etc. It is frequently convenient to purify or isolate the product by forming an insoluble salt. The base may be obtained by neutralization and another salt then formed by treat-ment with the appropriate acid.
The new compounds of formula I are central nervous system depressants and may be used as tranquilizers or ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species, in the same manner as chlordiazepoxide.
For this purpose a compound or mixture of compounds of formula I or a pharmaceutically acceptable acid addition salt thereof is administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 1 to 50 mg/kg/day, preferably about 2 to 15 mg/kg/day, is appropriate. These can be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like, and ~()7~Zo7 MTl06 if necessary sterilized, all as called for by accepted pharmaceutical practice.
The compounds of formula I are also useful as antlinflammatory agents and are effectlve in the prevention and inhibition of granuloma tissue formation in warm blooded animals, for example, in a manner similar to indomethacin.
For example, about 150 mg/kg/day is effective in reduced paw swelling in rats. They can be used to decrease joint swelling tenderness, pain and stiffness, in various mammalian species, e.g., in conditions such as rheumatoid arthritis. A
compound of formula I or a pharmaceutically acceptable salt thereof is compounded according to accepted pharma-ceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably lO0 mg. to l gm.
per day, in two to four divided doses.
The following examples constitute preferred embodiments and also illustrate how these and other members of this group are produced. Simple variation of the reactants and substitution in the reaction sequences described below, readily yield other compounds within the scope of the invention. All temperatures are in degrees centigrade.
~7~207 MT106 Example 1 4-Hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, .
eth~l ester a) [[(l-Methyl-lH-pyrazol-3-yl)amino]methylene]propane-dicarb~xylic acid, ethyl ester 194 g. (2 moles) of 3-amino-1-methyl-pyrazole and 432 g.
of ethoxymethylene malonic acid, diethyl ester are stirred together for one hour at 100. The alcohol formed is re-moved in vacuo and the resulting product crystallized from ether to yield 425 g. of [[(l-methyl-lH-pyrazol-3-yl)amino~-methylene]propane-dicarboxylic acid, ethyl ester; m.p. 60-63.
b) 4-Hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester 534 g. of the ester from part (a) are added to about
3 liters of 240 diphenylether (oil-bath temperature of 280-290) with stirring causing the temperature of the solvent to drop. The mixture i9 kept at 220 for 30 minutes while the alcohol which forms is continuously removed by distillation.
The solution is cooled to about 100 and the solvent is dis-tilled off (b.p.o 04 90-95) The oily residue is treated with 500 ml. of acetonitrile and after standing overnight the ringclosed product c~ystallizes. Recrystallization from n-propylalcohol yields 235 g. (67%) of 4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p.
222-224.
.
~07~207 MT106 Example 2
The solution is cooled to about 100 and the solvent is dis-tilled off (b.p.o 04 90-95) The oily residue is treated with 500 ml. of acetonitrile and after standing overnight the ringclosed product c~ystallizes. Recrystallization from n-propylalcohol yields 235 g. (67%) of 4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p.
222-224.
.
~07~207 MT106 Example 2
4-Ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic ~ ._ acid, ethyl ester .
221 g. (0.1 mole) of 4-hydroxy-2-methyl-2H-pyrazolo-[3,4-b~pyridine-5-carboxylic acid, ethyl ester from Example 1 is refluxed with stirring for 15 hours in 1 liter of thionyl chloride. The thionyl chloride is distilled off and the residue is dissolved in about 1 liter of ethyl alcohol. On cooling, a precipitate of 270 g. of 4-ethoxy-2-methyl-2H-pyrazolol3,4-b]pyridine-5-carboxylic acid, ethyl ester, hydrochloride; m.p. 162-164, is obtained.
The free base is obtained quantitatively by dis-solving the hydrochloride in water and suhsequently neutralizing with sodium hydroxide. The 4-ethoxy-2-methyl-2H-pyrazoio-13,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 163-165 (methanol); precipitates and is removed by filtration.
Examples 3-7 Following the procedure of example 2 but substituting for the ethyl alcohol the following alcohols:
methyl alcohol, i-propyl alcohol, n-butyl alcohol, and t-butyl alcohol one obtains:
4-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, 4-i-propoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, ~7~z07 MT106 4-n-butoxy 2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, and 4-t-bu.toxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester respectively.
Examples 8-19 Following the procedure of Example 1 but employing the substituted pyrazole shown below in Col. I and the alkoxymethylene malonic acid dialkyl ester shown be~low in Col. II, one obtains the hydroxy compounds shown in Col. III
which are converted by the process set forth in Example 2 to the alkoxy compounds of Col. IV.
~ o7~ Z07 MTl O 6 ~1 $ ~ ~ $ $ ~ I $ ~ 5~ $ $
l ~ t,) N U t~ 3 8 ~ ~ u ~ u c~ u ~, v u u u $u~
0~
~1 ~
U :~
~ ~ .
$ $ $ $ ~ C $ ~ 3 N
O ' U ~`1 '1 O U') U ~ --~; I O ~
H ~
ul ~
~ $ ~ $ $,~ $,~, C~ Z U
O
U
H ~
. I U-~
U
, ~; I $ :C $ :r: $ :r: m $ $ $ ~c $
U~ U~ U~ o~ y~ U ~ U ~ U U~ U
$
~ .
~o~ iZ 0 7 MT106 Similarly by employing the alcohols of examples 3-7 other compounds within the scope of the invention are obtained.
Example 20 4-Ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 28.5 g. of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-
221 g. (0.1 mole) of 4-hydroxy-2-methyl-2H-pyrazolo-[3,4-b~pyridine-5-carboxylic acid, ethyl ester from Example 1 is refluxed with stirring for 15 hours in 1 liter of thionyl chloride. The thionyl chloride is distilled off and the residue is dissolved in about 1 liter of ethyl alcohol. On cooling, a precipitate of 270 g. of 4-ethoxy-2-methyl-2H-pyrazolol3,4-b]pyridine-5-carboxylic acid, ethyl ester, hydrochloride; m.p. 162-164, is obtained.
The free base is obtained quantitatively by dis-solving the hydrochloride in water and suhsequently neutralizing with sodium hydroxide. The 4-ethoxy-2-methyl-2H-pyrazoio-13,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 163-165 (methanol); precipitates and is removed by filtration.
Examples 3-7 Following the procedure of example 2 but substituting for the ethyl alcohol the following alcohols:
methyl alcohol, i-propyl alcohol, n-butyl alcohol, and t-butyl alcohol one obtains:
4-methoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, 4-i-propoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, ~7~z07 MT106 4-n-butoxy 2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, and 4-t-bu.toxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester respectively.
Examples 8-19 Following the procedure of Example 1 but employing the substituted pyrazole shown below in Col. I and the alkoxymethylene malonic acid dialkyl ester shown be~low in Col. II, one obtains the hydroxy compounds shown in Col. III
which are converted by the process set forth in Example 2 to the alkoxy compounds of Col. IV.
~ o7~ Z07 MTl O 6 ~1 $ ~ ~ $ $ ~ I $ ~ 5~ $ $
l ~ t,) N U t~ 3 8 ~ ~ u ~ u c~ u ~, v u u u $u~
0~
~1 ~
U :~
~ ~ .
$ $ $ $ ~ C $ ~ 3 N
O ' U ~`1 '1 O U') U ~ --~; I O ~
H ~
ul ~
~ $ ~ $ $,~ $,~, C~ Z U
O
U
H ~
. I U-~
U
, ~; I $ :C $ :r: $ :r: m $ $ $ ~c $
U~ U~ U~ o~ y~ U ~ U ~ U U~ U
$
~ .
~o~ iZ 0 7 MT106 Similarly by employing the alcohols of examples 3-7 other compounds within the scope of the invention are obtained.
Example 20 4-Ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 28.5 g. of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-
5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 15 g. of potassium hydroxide are refluxed in 100 ml. of ethanol for 10 hours. The solvent is then distilled off and the residue is dissolved in 20 ml. of water. Acetic acid is added and a precipitate of 16 g. of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid; m.p. 222-225 (DMF);
is obtained.
Similarly, the esters of examples 3-7 and of Col. IV
of examples 8-19 can be converted to the free acid.
Example 21 4-[(3-Dimethylaminopropyl)amino]-2-methvl-2H-pyrazolo[3,4-b]
pyridine-5-carboxylic acid, ethyl ester 2.9 (0.01 mole) of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 10 ml. of (3-dimethylaminopropyl)amine are re-fluxed for 3 hours. The excess of amine is removed in vacuo and the residue is treated with 10 ml. of cold water. 2.3 g.
of 4-[(3-dimethylaminopropyl)amino]-2-methyl-2H-pyrazolo[3,4-b]-pyridine~5-carboxylic acid, ethyl ester; m.p. 61-63 (methanol/
water); is removed by filtration.
- - - . .. : - - . . . .
. . .
~71Z07 MT106 Example 22 4-(Methylamino)-2-methyl-2~-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of Example 21 but substituting methylamine for the (3-dimethylaminopropyl)amine, one obtains 4-methylamino-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 178-180 (methanol/water).
Example 23 4-~n-Butylamino)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-car~oxylic acid, ethyl ester Following the procedure of Example 21 but substituting n-butylamine for the (3-dimethylaminopropyl)amine, one obtains 4-(n-butylamino)-2-methyl-2H-py~azolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 95-97 (methanol/water).
Example 24 4-[(l-Methylpropyl)amino]-2-methYl-2H-pyrazolo[3~4-b]pyridine-5 carboxylic acid, ethyl ester Following the procedure of Example 21 but substituting (l-methylpropyl)amine for the (3-dimethylaminopropyl)amine, one obtains 4-[(1-methylpropyl)amino~-2-methyl-2H-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 132-134 (methanol/water).
MTlO6 Example 25 4-[(l-Méthylethyl)amino]-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of example 21 but substituting (l-methylethyl)amine for the (3-dimethylaminopropyl)amine, one obtains 4-[(l-methylethyl)amino]-2-methyl-2H-pyrazolo-13,4-b]pyridine-5-carboxylic acid, ethyl ester m.p. 168-170 (methanol/water).
Examples 26-49 Following the procedure of example 21 but substituting the amines shown below in Col. I for the (3-dimethylaminopropyl)-amine, one obtains the products shown below in Col. II.
Col. I Col. II
N-N~ ~ COOC2H5 H3C~ ~
Ex. R3 R4 29 n C5Hll H
31 -C-(CH3)3 H
n-C4Hg CH3 -~071Z07 MTl 0 6 Ex. R3 R4 36 ~ H
37 ~C2H5 CH3 38 ~ N
~ 3 CH3 4 0 ~COOH H :
41 ~ ~) 4 2 CH2~ H
43 CH2~) H
44- (CH2) Z~) H
45- (CH2) 2~ H
4 6- (CH2) 2-N~ 3 H
4 7-CH2-cH-cH2-N~ 2 5 H
CH3 C2H5 .
4 82 \C H CH3 4 9 - (CH2 ) 4 -N ~ 3 H
107~Z07 Similarly, by also employing the compounds of Col. IV
of examples 8-19 in the procedure of examples 21-49, other compounds within the scope of the invention are obtained.
Example 50 2-Methyl-4-(1-piperidinyl)-2~-pyrazolo[3,4-b]pyridine-5-car~oxylic acid, ethyl ester Following the procedure of example 21 but substituting piperidine for the (3-dimethylaminopropyl)amine, one obtains 2-methyl-4-~1-piperidinyl)-2H-pyrazolo~3,4-b]pyridine-5-10carboxylic acid, ethyl ester; m.p. 185-188 (methanol/water).
Example 51 2-Methyl-4-(4-methyl-1-piperazinvl)-2~-pYrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of example 21 but substituting N-methylpiperazine for the (3-dimethylaminopropyl)amine, one obtains 2-methyl-4-(4-methyl-1-piperazinyl)-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester; m.p. 142-143 (ethyl acetate).
Examples 52-69 Following the procedure of Example 21 but substituting the heterocyclic compound listed below for the (3-dimethylamino-propyl)amine, one obtains final products of the formula 3~ N~ 4 H ~ 2 5 C ~N~ N~ h 1~71Z07 EX. . / R3 52 HN hH
HN N-C4Hg 57 HN~
59 H ~ C4H9 HN ~ CH2H
61 ~
62 ~ ON
63 ~ ~
~07~Z07 Ex. ~ R3 ~`
66 HN ~ -H
H
~i .
C~2O~
r--68 H~ N-CH3 ~H3 Similarly, by also employing the compounds of Col. IV
of examples 8-19 in the procedure of examples 50-69, other compounds within the scope of the invention are obtained.
~.
is obtained.
Similarly, the esters of examples 3-7 and of Col. IV
of examples 8-19 can be converted to the free acid.
Example 21 4-[(3-Dimethylaminopropyl)amino]-2-methvl-2H-pyrazolo[3,4-b]
pyridine-5-carboxylic acid, ethyl ester 2.9 (0.01 mole) of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 10 ml. of (3-dimethylaminopropyl)amine are re-fluxed for 3 hours. The excess of amine is removed in vacuo and the residue is treated with 10 ml. of cold water. 2.3 g.
of 4-[(3-dimethylaminopropyl)amino]-2-methyl-2H-pyrazolo[3,4-b]-pyridine~5-carboxylic acid, ethyl ester; m.p. 61-63 (methanol/
water); is removed by filtration.
- - - . .. : - - . . . .
. . .
~71Z07 MT106 Example 22 4-(Methylamino)-2-methyl-2~-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of Example 21 but substituting methylamine for the (3-dimethylaminopropyl)amine, one obtains 4-methylamino-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 178-180 (methanol/water).
Example 23 4-~n-Butylamino)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-car~oxylic acid, ethyl ester Following the procedure of Example 21 but substituting n-butylamine for the (3-dimethylaminopropyl)amine, one obtains 4-(n-butylamino)-2-methyl-2H-py~azolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 95-97 (methanol/water).
Example 24 4-[(l-Methylpropyl)amino]-2-methYl-2H-pyrazolo[3~4-b]pyridine-5 carboxylic acid, ethyl ester Following the procedure of Example 21 but substituting (l-methylpropyl)amine for the (3-dimethylaminopropyl)amine, one obtains 4-[(1-methylpropyl)amino~-2-methyl-2H-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester; m.p. 132-134 (methanol/water).
MTlO6 Example 25 4-[(l-Méthylethyl)amino]-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of example 21 but substituting (l-methylethyl)amine for the (3-dimethylaminopropyl)amine, one obtains 4-[(l-methylethyl)amino]-2-methyl-2H-pyrazolo-13,4-b]pyridine-5-carboxylic acid, ethyl ester m.p. 168-170 (methanol/water).
Examples 26-49 Following the procedure of example 21 but substituting the amines shown below in Col. I for the (3-dimethylaminopropyl)-amine, one obtains the products shown below in Col. II.
Col. I Col. II
N-N~ ~ COOC2H5 H3C~ ~
Ex. R3 R4 29 n C5Hll H
31 -C-(CH3)3 H
n-C4Hg CH3 -~071Z07 MTl 0 6 Ex. R3 R4 36 ~ H
37 ~C2H5 CH3 38 ~ N
~ 3 CH3 4 0 ~COOH H :
41 ~ ~) 4 2 CH2~ H
43 CH2~) H
44- (CH2) Z~) H
45- (CH2) 2~ H
4 6- (CH2) 2-N~ 3 H
4 7-CH2-cH-cH2-N~ 2 5 H
CH3 C2H5 .
4 82 \C H CH3 4 9 - (CH2 ) 4 -N ~ 3 H
107~Z07 Similarly, by also employing the compounds of Col. IV
of examples 8-19 in the procedure of examples 21-49, other compounds within the scope of the invention are obtained.
Example 50 2-Methyl-4-(1-piperidinyl)-2~-pyrazolo[3,4-b]pyridine-5-car~oxylic acid, ethyl ester Following the procedure of example 21 but substituting piperidine for the (3-dimethylaminopropyl)amine, one obtains 2-methyl-4-~1-piperidinyl)-2H-pyrazolo~3,4-b]pyridine-5-10carboxylic acid, ethyl ester; m.p. 185-188 (methanol/water).
Example 51 2-Methyl-4-(4-methyl-1-piperazinvl)-2~-pYrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester Following the procedure of example 21 but substituting N-methylpiperazine for the (3-dimethylaminopropyl)amine, one obtains 2-methyl-4-(4-methyl-1-piperazinyl)-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester; m.p. 142-143 (ethyl acetate).
Examples 52-69 Following the procedure of Example 21 but substituting the heterocyclic compound listed below for the (3-dimethylamino-propyl)amine, one obtains final products of the formula 3~ N~ 4 H ~ 2 5 C ~N~ N~ h 1~71Z07 EX. . / R3 52 HN hH
HN N-C4Hg 57 HN~
59 H ~ C4H9 HN ~ CH2H
61 ~
62 ~ ON
63 ~ ~
~07~Z07 Ex. ~ R3 ~`
66 HN ~ -H
H
~i .
C~2O~
r--68 H~ N-CH3 ~H3 Similarly, by also employing the compounds of Col. IV
of examples 8-19 in the procedure of examples 50-69, other compounds within the scope of the invention are obtained.
~.
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R is hydrogen or lower alkyl; R1 is lower alkyl; and R3 and R4 are independently selected from the group consisting of hydrogen, lower alkyl, di(lower alkyl)amino-lower alkylene or R3 and R4 taken together with the nitrogen atom to which they are attached are piperazino or piperidino; and pharmaceutically acceptable salts thereof, characterized by reacting a compound of the formula wherein X is chloro or bromo or alkoxy with an amine of the formula HNR3R4.
2. The process of claim 1 wherein R is hydrogen or C1-C4 alkyl; R1 is C1-C4 alkyl; R3 is hydrogen, C1-C4 alkyl or di-(C1-C4 alkyl)amino-(C1-C4)alkylene; and R4 is hydrogen or C1-C4 alkyl.
3. The process of claim 1 wherein R is hydrogen or C1-C4 alkyl; R1 is methyl; R3 is hydrogen, C1-C4 alkyl, or di(C1-C4 alkyl)amino-(C1-C4)alkylene; and R4 is hydrogen.
4. The process of claim 1 wherein R is ethyl; R1 is methyl;
R3 is dimethylamino-propyl and R4 is hydrogen.
R3 is dimethylamino-propyl and R4 is hydrogen.
5. The process of claim 1 wherein R is hydrogen or C1-C4 alkyl; R1 is methyl; R3 is C1-C4 alkyl and R4 is hydrogen.
6. The process of claim 1 wherein R is ethyl; R1 is methyl;
R3 is methyl and R4 is hydrogen.
R3 is methyl and R4 is hydrogen.
7. The process of claim 1 wherein R is ethyl; R1 is methyl;
R3 is isopropyl and R4 is hydrogen.
R3 is isopropyl and R4 is hydrogen.
8. The process of claim 1 wherein R is ethyl, R1 is methyl;
R3 is butyl and R4 is hydrogen.
R3 is butyl and R4 is hydrogen.
9. The process of claim 1 wherein the group -NR3R4 is piperidino.
10. The process of claim 1 wherein the group -NR3R4 is piperazino.
11. A compound of the formula wherein R is hydrogen or lower alkyl; R1 is lower alkyl; and R3 and R4 are independently selected from the group consisting of hydrogen, lower alkyl, di(lower alkyl)amino-lower alkylene or R3 and R4 taken together with the nitrogen atom to which they are attached are piperazino or piperidino; and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 1.
12. The compound of claim 11 wherein R is hydrogen or C1-C4 alkyl; R1 is C1-C4 alkyl; R3 is hydrogen, C1-C4 alkyl or di-(C1-C4 alkyl)amino-(C1-C4)alkylene; and R4 is hydrogen or C1-C4 alkyl, whenever prepared by the process of claim 2.
13. The compound of claim 11 wherein R is hydrogen or C1-C4 alkyl; R1 is methyl; R3 is hydrogen, C1-C4 alkyl, or di(C1-C4-alkyl)amino-(C1-C4)alkylene; and R4 is hydrogen, whenever prepared by the process of claim 3.
14. The compound of claim 11 wherein R is ethyl; R1 is methyl; R3 is dimethylamino-propyl and R4 is hydrogen, whenever prepared by the process of claim 4.
15. The compound of claim 11 wherein R is hydrogen or C1-C4 alkyl; R1 is methyl; R3 is C1-C4 alkyl and R4 is hydrogen, whenever prepared by the process of claim 5.
16. The compound of claim 11 wherein R is ethyl; R1 is methyl; R3 is methyl and R4 is hydrogen, whenever prepared by the process of claim 6.
17. The compound of claim 11 wherein R is ethyl; R1 is methyl; R3 is isopropyl and R4 is hydrogen, whenever prepared by the process of claim 7.
18. The compound of claim 11 wherein R is ethyl; R1 is methyl; R3 is butyl and R4 is hydrogen, whenever prepared by the process of claim 8.
19. The compound of claim 11 wherein the group -NR3R4 is piperidino, whenever prepared by the process of claim 9.
20. The compound of claim 11 wherein the group -NR3R4 is piperazino, whenever prepared by the process of claim 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA330,683A CA1077485A (en) | 1975-04-30 | 1979-06-27 | 4-amino derivatives of 2h-pyrazolo (3,4-b) pyridine-5-carboxylic acids and esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57319575A | 1975-04-30 | 1975-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071207A true CA1071207A (en) | 1980-02-05 |
Family
ID=24291008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA249,256A Expired CA1071207A (en) | 1975-04-30 | 1976-03-31 | 4-amino derivatives of 2h-pyrazolo (3,4-b) pyridine-5-carboxylic acids and esters |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS51146495A (en) |
| CA (1) | CA1071207A (en) |
| DE (1) | DE2617157A1 (en) |
| FR (2) | FR2309225A1 (en) |
| GB (1) | GB1531598A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5300498A (en) * | 1993-06-04 | 1994-04-05 | Hoechst-Roussel Pharmaceuticals Incorporated | 6-piperazinyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acids, esters, amides and related compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE787249A (en) * | 1971-08-05 | 1973-02-05 | Squibb & Sons Inc | AMINO DERIVATIVES OF PYRAZOLOPYRIDINE CARBOXYLIC ACIDS, THEIR ESTERS AND THE SALTS OF SUCH COMPOUNDS, AS WELL AS THEIR PREPARATION PROCESSES |
-
1976
- 1976-03-31 CA CA249,256A patent/CA1071207A/en not_active Expired
- 1976-04-20 DE DE19762617157 patent/DE2617157A1/en active Pending
- 1976-04-26 GB GB1687876A patent/GB1531598A/en not_active Expired
- 1976-04-30 FR FR7612966A patent/FR2309225A1/en active Granted
- 1976-04-30 JP JP5073676A patent/JPS51146495A/en active Pending
- 1976-11-03 FR FR7633091A patent/FR2344556A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB1531598A (en) | 1978-11-08 |
| FR2344556A1 (en) | 1977-10-14 |
| FR2309225A1 (en) | 1976-11-26 |
| FR2309225B1 (en) | 1979-04-13 |
| JPS51146495A (en) | 1976-12-16 |
| DE2617157A1 (en) | 1976-11-11 |
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