Note: Descriptions are shown in the official language in which they were submitted.
MT106 ~
1071Z07
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
R2 1 COOR
~ `~
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.
--2--
MT106
1071Z07
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.
C2H5
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~
--3--
~07~Z07
MT106
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.
--4--
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
1071Z07 MT106
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
R4
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.
--6--
MT106
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--
~()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.
--8--
~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
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,
--10--
~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
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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
$
~ .
--12--
~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).
-14-
107127
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
26 H H
27 C2H5 H
28 3 7 H
29 n C5Hll H
CH2-CH-CH3 H
IH3
31 -C-(CH3)3 H
32 CH3 CH3
2 5 CH3
34 C2H5 C2H5
n-C4Hg CH3
-
-15-
~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
H3
44- (CH2) Z~) H
45- (CH2) 2~ H
CF3
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
MT106
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
-17-
1~71Z07
MT106
EX. . / R3
52 HN hH
53 HN N-C2H5
N N C3H7
HN N-C4Hg
56 HN 3 CH3
57 HN~
C3H7
58 HN
C2H5
59 H ~ C4H9
HN ~ CH2H
CH3
61 ~
H2-CH20H
62 ~ ON
63 ~ ~
64 HN N-CH3
C2H5
~07~Z07
MT106
Ex. ~ R3
R4
~`
HN N-CH3
2H5
66 HN ~ -H
H
67 HN NH
~i .
C~2O~
r--
68 H~ N-CH3
H2-CH2OH
~H3
69 HN N-CH3
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.
--19--
~.
