Note: Descriptions are shown in the official language in which they were submitted.
~ 3 . ~ ~ ~
X-5255A -1-
AMINO-SUBSTITUTED 4,5,6,7-TETRAHYDRO-
lH (or 2H) INDAZOLES
This invention in one aspect provides a group of tetra-
hydro-lH (or 2~)-indazoles of the formulae
il 6~ R ~ ~ ~ 7a 6T-R
CH 3~ 3a\4~ \R
II
wherein
one of R and Rl is H and the other is
N(R )2;
where each R2 is individually allyl,
methyl, ethyl or n-propyl; and
pharmaceutically-acceptable acid addition
salts thereof.
These compounds and their salts are useful
as dopamine agonists for treating Parkinsonism and
for inhibiting prolactin secretion.
A process for preparing the tautomers of
formulae I and II comprises reacting tautomers of
the formulae
H
~( I ` HN/~I I
IB IIB
~L
~ 23~2
X-5255A -2-
wherein
2one of R and Rl is H and the other is
N(R )2; 2
where both R 's are H;
with an aldehyde in the presence of a metal hydride
reducing agent, or
with an alkyl halide or anhydride followed by
reduction; and where desired, forming the p~ar~aceu'ically
accepta~le acid addition salts of said tautomerS of
formLlae I and II. mis a ~ ct of the invention is also disclosed, and
is claimed Ln Canadian Patent Application No. 330,568 filed June 26, 1979,
of which the present application is a divisional~
Additionally, novel tautomer intermediates
are within the scope of this invention having the
formulae
R / , HN~ ~ I R
; IA IIA
wherein
one of R and Rl is H and the other is
N(R2)2 or NH-Co-R3; 2 3
where each R is H; and R is methyl,
ethyl, or n-propyl.
Compounds represented by I and II are
tautomers, i.e.~ in solution, they exist in dynamic
equilibrium with the percent of a given tautomer in
the mixture depending on both environment and
electronic forces. Formula I above represents a lH-
indazole and formula II a 2H-indazole. Many of the
intermediates used to prepare formulae I and II are
also tautomers.
z
X-5255A -3-
The pharmaceutically~acceptable acid
addition salts of the compounds of formulae I and
II include salts derived from non-toxic inorganic
acids such as: hydrochloric acid, nitric acid,
phosphoric acid, sulfuric acid, hydrobromic acid,
hydriodic acid, nitrous acid, phosphorous acid and
the like, as well as salts derived from non-toxic
organic acids such as aliphatic mono and dicar-
boxylic acids, phenyl-substituted alkanoic acids,
hydroxy alkanoic and alkandioic acids, aromatic
acids, aliphatic and aromatic sulfonic acids.
Such pharmaceutically-acceptable salts thus include
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
nitrate, phosphate, monohydrogenphosphate, dihydro-
genphosphate, metaphosphate, pyrophosphat~, chloride,bromide, iodide, fluoride, acetate, propionate,
decanoate, caprylate, acxylate, formate, isobutyrate,
caprate, heptanoate, propiolate, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate,
mandelate, butyne-l,4-dioate, hexyne-l,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitro-
benzoate, hydroxybenzoate, methoxybenzoate, phthalate,
terephthalate, ben~enesulfonate, toluenesulfonate,
chlorobenzenesulfonate, xylenesul~onate, phenyl-
acetate, phenylpropionate, phenylbutyrate, citrate,lactate, ~-hydroxybutyrate, glycollate, malate,
tartrate, methanesulfonate, propanesulfonate r
naphthalene-L-sulfonate, naphthalene-2-sulfonate and
the li~e salts.
3~
X-5255~ -4-
Illustrative compounds coming within the
scope of formula I above include:
dl-5-dimethylamino-4,5,6,7-tetrahydro-lH-
indazole methane sulfonate.
dl-5-diethylamino-4,5,6,7-tetrahydro-lH-
indazole maleate.
dl-6-diallylamino-4,5,6,?-tetrahydro-lH-
indazole sul~ate.
dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-
lH-indazole hydrochloride.
Illustrative compounds coming within the
scope of formula II include:
N-methyl-N-allyl dl-5-amino-4,5,6,7-
l; tetrahydro-2H-indazole methanesulfonate.
dl-6-dimethylamino-4,5,6,7-tetrahydro-
2H-indazole maleate.
N-methyl-N-ethyl dl-5-amino-4,5,6,7-
tetrahydro-2H-indazole hydrochloride.
N-methyl-N-n-propyl dl-5-amino-4,5,6,7-
tetrahydro-2H-indazole sulfate~
N-allyl-N-n-propyl dl-5-amino-4,5,6,7-
tetrahydro-2H-indazole tartrate.
The presence of a substituent at C-5 or
C-6 in the indazole ring introduces a center of
asymmetry into thosP molecules. Thus, compounds
represented by formulae I and II include .wo optical
isomers occurring as a dl pair or racemate. Resolu-
tion of a dl pair of this invention into its optical
antipodes can be accomplished by procedures known to
those skilled in the art.
~.23~
X-5255A _5_
The compounds of formulae I and II wherein
R1 is H and R is N (R2)2 are prepared according to
the following Reaction Scheme I.
X--5255A --6--
Reaction Scheme I
O O
Il 11
(CH30)2CH-N(CH3)2 ~ ~ ~H N(CH3)2
NH-CO-CH3 NH-CO-CH3
¦ N2H4-H20
MeOH
\ /
V 2HCI IV ~
'I` I ~,
\ / / HCI ~N==~ t
\ H20 HN\ l l
N ~ / \ 4 =~\ / -NH-CO-CH3
Iva
~--r\ / -NH2
Va \ 2HCI
NaOAC \ R3CHo
MeOH ~ BH3CN
~ N(CH2R4)2
VI ~ 2HCI
\ /
~ D~ /1-N (CH2R4)2
VIa 2HCL
wherein R4 is H, CH3, C2H5 or CH=CH2.
~ ~ 23~
X-5255A -7_
In accordance with Reaction Scheme I, 4-
acetamidocyclohexanone is reacted with dimethylfor-
mamide dimethylacetal. The product of this reaction,
4-acetamido-2-dimethylaminomethylenecyclohexanone
(III), reacts with hydrazine hydrate in a suitable
inert mutual solvent such as methanol to yield
directly dl-5 acetamido-4,5,6,7-tetrahydro-lH
indazole (IV) and its 2H tautomer (IVa), ordinarily
isolated as an acid addition salt such as the
methane sulfonate or hydrochloride because of the
lack of crystallinity of the free base. Hydrolysis
of IV and IVa, with aqueous hydrochloric acid for
example, yields directly dl-5-amino-4,5,6,7-
tetrahydro-lH-indazole and its 2H tautomer as the
dihydrochlorides salts (V and Va), compounds of
formulae IA and IIA above in which R is NH2 and
is H. Transformation of this primary amine to
compounds of formulae I and II in which R is N-
(methyl)2, N~ethyl)2, N(n-propyl)2, or N(allyl)2 is
readily accomplished by reaction with an aldehyde,
R4CHo wherein R4 is H, vinyl, meth~l or ethyl, in a
reductive alkylation in the presence of sodium
cyanoborohydride or other suitable metal hydride
reducing agent.
Compounds according to formulae I and II
above in which the R2 groups are dissimilar are
prepared by, for example, reducing a C-5 acetamide
such as IV or IVa to yield an N-ethyl derivative.
AlXylation of this secondary amine by standard
procedures such as use of an alkyl halide, for
i~.23
X-5255A -8-
example methyl iodide, yields an N-methyl-N-ethyl
amine group at C-5. Additionally, the secondary
amine can be acylated as with propionic anhydride,
and the resulting propionamide reduced with a metal
hydride, such as LiAlH4, to yield an N-ethyl-N-n-
propylamine group at C-5. Acylation of the indazole
nitrogen, if any, can be selectively reversed.
Compounds of formulae I and II in which
is N(R )2 and R is H are prepared by a slightly
different, though similar, synthetic procedure
illustrated in Reaction Scheme II below. In Re-
action Scheme II R2 has the same meaning as before
and wherein R5 is (Cl-C3)alkyl or benzyl. The term
(Cl-C3)alkyl includes methyl, ethyl, n-propyl and
isopropyl.
-
~.23~at2
X-5255A -9-
Reaction Scheme II
o
b ~. a
VII ~I~ I VIII
/ I \1/
~ ~ ~ / H ~ I I
¦ ~I~ NH4AcVIIIa
\ MeOH H
I x ~
H O IXa
/N-~ N(CH2R4) ~4CHo~ t/ \~-NHz
~ \ HN\o_
XI NaBH CN \
~l\ NaOAc Xa
\ / I MeOH
25N ~ / ¦-N(CH~R4)
XIa
-~.23~
X-525SA -10-
In accordance with Reaction Scheme II, a
3-enol ether-6-hydroxymethylene-2-cyclohexenone, for
example 3-ethoxy-6-hydroxymethylene-2-cyclohexenone,
prepared by the method of Wenkert et al. J. Or~. Chem.,
27, 2278 (1962), is reacted with hydrazine hydrate
in a mutual inert solvent such as ethanol to yield
dl-6-ethoxy-4,5-dihydro-lH-indazole (VIII) and its
2H tautomer (VIIIa). The intermediate compounds of
formulae VIII and VIIIa are also novel. Hydrolysis
with acid, preferably a strong, highly ionized acid
such as p-toluenesulfonic, trifluoroacetic, hydro-
chloric and others, yields dl-6-oxo-4,5,6,7-
tetrahydro-lH-indazole (IX) and the 2H tautomer
(IXa). The intermediate compounds of formulae
IX and IXa are also novel. Reductive amination of
this oxo compound with ammonium acetate and sodium
cyanoborohydride, or other suitable metal hydride
reducing agents of sufficient reducing power, in the
presence of a mutual inert solvent yields the
corresponding dl-6-amino-4,5,6,7-tetrahydro-lH-
indazole, (X) and dl-6-amino-4,5,6,7-tetrahydro-2H-
indazole, compounds coming within the scope of
formulae IA and IIA above wherein R is H and Rl is
NH2 .
The present invention, then, in one aspect,
resides in a process for preparing intermediate tautomers
of the formulae
~CH~ CH=I~ I
IX IXa
3~Z
-1 Oa-
which comprises reacting compounds of the formulae
VIII VIIIa
wherein R5 is (Cl-C3)alkyl or benzyl with acid
hydrolysis.
Preparation of compounds of formulae I
and II wherein R is H and Rl is N(CH3)2, N(C2H5)
or N(n-propyl)2 is carried out by reductively
alkylating the 6-amino ~ompound (X) and (Xa) with an
aldehyde in the presence of a metal hydride re-
ducing agentl such as sodium cyanoborohydride,
3~
X-5255A -11-
in accordance with the procedure set forth in
connection with Reaction Scheme I above, to yield
the dl-6-dialkyl(or diallyl)amino-4,5,6,7-tetra-
hydro-lH-indazole (XI) and the corresponding 2H
tautomer (XIa). The preparation of compounds in
which the 6-amino group is unsymmetically substi-
tuted can be accomplished by reacting the primary
amine (X and Xa) with one mole of an acid chloride
or anhydride to yield the 6-acylamino derivative,
reducing the acyl group to an alkyl group (e.g.,
acetyl ~ ethyl) with a metal hydride, such as
LiAlH4 and then alkylating the thus-formed secondary
amlne at C-6 with an alkylating agent containing a
different alkyl group (e.g., methyl or n-propyl in
the above example.)
The novel intermediates represented by
formulae VIII and VIIIa and IX and IXa in Reaction
Scheme II are prepared by formylating at C-6 an
R
enolether of cyclohexane-1,3-dione. ~ 5 where-
in R is (Cl-C3)alkyl or benzyl, using the pro-
cedure of Wenkert/ et al (loc. cit.~ ~o yield a
compound of formula VII. Reaction of VII with
hydrazin~ hydrate yields the tautomers VIII and
VIIIa, de-enolization of which with acid gives the
keto compounds IX and IXa.
3~
X-5255A -12-
The compounds of formulae I and II have
all been named as dl-5~or 6)-dialkylamino-4,5,6,7-
tetrahydro-lH-indazoles and dl-S(or 6)-dialkylamino-
4,5,6,7-tetrahydro-2H-inda~oles. The presence of
the amino group at C-5 or C-6 of the indazole ring
produces a center of asymmetry and thus the com-
pounds of formulae I and II are prepared as a
racemate or dl mixture. These racemates can be
revolved into their respective d and l-isomers bv
methods available in the art. It is believed that
the dopamine agonist activity shown by the racemakes
of formulae I and II may reside chiefly, if not
entirely, in a single stereoisomer. Thus, this
invention provides not only dl racemates having
dopamine agonist activity but also substantially
pure stereoisomers having dopamine agonist activity.
This invention is further illustrated by
the following specific examples:
Example A
Preparation of 4-Acetamido-2-dimethylaminomethylene-
cyclohexanone
A reaction mixture was prepared from
15.S g. of 4-acetamidocyclohexanone [prepared by the
procedure of Fraser and Swingle~ Con. J. Chem., 48,
2Q65 (1970)l, 80 g. of the dimethylacetal of
dimethylformamide, 1.5 ml. of triethylamine and 500
ml. of benzene. The benzene was distilled therefrom
over a 1.5 hour period until the volume was reduced
to about 1/2 of the original volume. An additlonal
X-5255A -13-
250 ml. of benzene were added. The reaction mixturewas heated just below the boiling point of benzene
for about 2 hours and was then distilled again until
the volume was about one-half of that originally
present (250 ml.). The above process was repeated
once more except that the volume was reduced to
one-third of the original volume (167 ml.). The
reaction mixture was then cooled and filtered. The
filter cake consisted of 4-acetamido-2-dimethyl-
lQ aminomethylenecyclohexanone formed in the abovereaction; weight = 6.45 g. Evaporation of the
filtrate to dryness yielded a residue, chromatog-
raphy of a chloroform solution of which over 200 g.
of''Florisil~* using chloroform containing increasing
amounts Or methanol (0-5~) as an eluant, yielded
pure 4-acetamido-2-dimethylaminomethylenecyclo-
hexanone; m.p. = 132-133C. (from benzene); yield =
5.55 g.; total yield = 12 g.
Analysis Calc.: C, 62.83; H, 8.63; N, 13.32;
Found: C, 63.07; H, 8.38; N, 13.12.
Example B
Preparation of dl-5-Acetamido-4,5,6,7-tetrahydro-
lH-indazole and dl-5-Acetamido-4,5,6,7-tetrahydro-
2H-indazole
A solution was prepared by dissolving
1.46 g. of 4-acetamido-2-dimethylaminomethylene-
cyclohexanone in 25 ml. of methanol. 0.35 ml. of
hydrazine hydrate were added and th~ resulting
mixture stirred at room temperature for about 16
* Trademark for activated magneium silicate in the form of
hard, porous, stable white granules, used as a highly
selectlve adsorbent in chromatographic separations.
1 3~ Lf~
X-5~55A -14-
hours. The reaction mixture was concentrated by
evaporation ln vacuo and a chloroform solution of the
residue was chromatographed over 30 g. Of"Florisil"*
using chloroform containing increasing amounts
(2-5%) of methanol as the eluant. Fractions shown by
TLC to contain a major component different from
starting material were combin~d and the solvent
evaporated therefrom in vacuo. 1.5 g. of dl-
5-acetamido-4,5,6,7-lH-indazole and its 2H ~automer
were obtained. The material was dissolved in an-
hydrous ethanol to which was added 0.5 ml. of methane
sulfonic acid: dl-5-Acetamido-4,5,6,7-tetrahydro-
lH-indazole methane sulfonate and dl-5-acetamido-
4,5,6,7-tetrahydro-2H-indazole methane sulfonate thus
prepared melted at about 190-2C.; yield equal 1.61 g.
Analysis Calc.: C, 43.62; H, 6.22; N, 15.26;
S, 11.65
Found: C, 43.83; H, 6.37; N, 15.15;
S, 11.39.
Example C
Preparation of dl-5-Amino-4,5,6,7-tetrahydro-lH-
indazole and dl-5-Amino-4,5,6,7-tetrahydro-2H-
indazole
A solution of 950 mg. of a mixture of dl-
5-acetamido-4,5,6,7-tetrahydro-lH-indazole methane
sulfonate and the 2H-tautomer methane sulfonate in
50 ml. of 6N aqueous hydrochloric acid was refluxed
under a nitrogen atmosphere for sixty minutes. The
reaction mixture was cooled and the volatile con-
* Trademark
~.23~
X-5255A -15-
stituents removed by evaporation ln vacuo. The
resulting residue was dissolved in ethanol, and the
ethanol solution concentrated and cooled. dl-
5-Amino-4,5,6,7-tetrahydro-lH-indazole dihydro-
chloride and dl-5-amino-4,5,6,7-tetrahydro-2H-
inda7ole dihydrochloride formed in the above reaction
crystallized and were separated by filtration; m.p. =
260-70C.: yield = 380 mg.
Analysis Calc.: C, 40.02; H, 6.24; N, 20.00;
Cl, 33.75
Found: C, 40.29; H, 5.99; N, 20.12;
Cl, 33.63.
Example D
Preparation of dl-6-Ethoxy-4,5-dihydro-lH-indazole
and dl-6-Ethoxy-4,5~dihydro-2H-indazole
A solution was prepared from 5 g. of 3-
ethoxy-6-hydroxymethylene-2-cyclohexenone [prepared
by the method of Wenkert et al., J. Org. Chen., 27,
2278, (1962)] and 150 ml. of ethanol. 1.9 ml. of
hydrazine hydrate were added and the resulting
mixture stirred at room temperature under nitrogen
atmosphere for 18 hours. The reaction mixture was
evaporated in vacuo and the residue dissolved in
chloroform. The chloroform solution was chromato-
graphed over 100 g. of "Florisil" using chloroformcontaining increasing amounts (0-2%) of ethanol as
the eluant. Fractions shown by T~C to contain a
major spot different from starting material were
combined and the solvents evaporated from the
~.Z3~2
X-5255A -16-
combined fractions in vacuo. The resulting residue
was crystallized from a mixture of ether and hexane.
dl-6-Ethoxy-4,5-dihydro-lH-indazole and its 2H tau-
tomer thus prepared melted at 118-120C.; yield =
3.64 g.
Analysis Calc.: C, 65.83; H, 7.37; N, 17.06
Found: C, 66.03, H, 7.25; N, 16.81.
Example E
Preparation of dl-6-Oxo-4,5,6,7-tetrahydro-lH-
indazole and dl-6-Oxo-4,5,6,7-tetrahydro-2H-indazole
A mixture of 3.2 g. of dl-6-ethoxy-4,5-
dihydro-lH-indazole and its 2H tautomer and 150 ml.
of lN aqueous hydrochloric acid were stirred at
am~ient temperature under a nitrogen atmosphere for
1.25 hours. TLC indicated that a new major spot (not
starting material) was present. An infrared spectrum
of this major spot showed absorption at 1710 cm. 1
indicating formation of a keto group. The reaction
mixture was saturated with solid sodium bicarbonate
and the aqueous alkaline mixture extracted several
times with chloroform. The chloroform solutions were
combined and the combined solutions washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the chloroform yielded a residue which
was dissolved in chloroform and chromatographed over
30 g. of "Florisil" using chloroform containing 2%
methanol as the eluant. Fractions shown to contain
dl-6-oxo-4,5,6,7-tetrahydro-lH-indazole and dl-6-
oxo-4,5,6,7-tetrahydro-2H-indazole formed in the
~ ~.Z3~
X-5255A -17-
above reaction were combined and dissolved in
methanol. 0.7 ml. of methane sulfonic acid were
added and the resulting mixture diluted to a volume
of about 125 ml. with ether. The solution was cooled
and the volatile constituents were removed by evap-
oration in vacuo. The residue was dissolved in
ethanol, and the ethanol solution diluted with ether.
On cooling an oil formed. ~he oil was redissolved in
ethanol, ether added to the poin~ of incipient
precipitation and the mixture allowed to cool.
Crystalline dl-6-oxo-4,5,6,7-tetrahydro-lH(and
2H)-indazole methane sulfonate was obtained which
melted in the range 95-105C. after recrystallization
from an ether/ethanol solvent mixture; yield =
1.86 g.
Analysis Calc.: C, 41.37; H, 5.21; N, 12.06,
S, 13.81
Found: C, 41.57; H, 5.38; N. 11.77;
S, 13.53.
Example F
Preparation of dl-6-Amino-4,5,6,7-tetrahydro-lH-
indazole and dl-6-amino-4,5,6,7-tetrahydro-2H-
indazole
Eight grams of dl-6-oxo-4,5,6,7-tetra-
hydro-lH-indazole hydrochloride plus the hydro-
chloride of the 2H-tautomer (formed by metathesis
from the above methane sulfonate of Example E) and
30 g. of ammonium acetate were dissolved in 400 ml.
of methanol to which was added 2.9 g. of sodium
~-~.Z3~
X-5255A -18-
cyanoborohydride. The reaction mixture was stlrred
at room temperature under a nitrogen atmosphere for
about 1 day after which time it was poured into an
excess of lN aqueous hydrochloric acid. The aqueous
layer was extracted with ether and the ether extract
discarded. The aqueous layer was ~hen made basic
- with dilu~e aqueous sodium hydroxide and the basic
layer extracted several times with a chioroform-
isopropanol solven~ mixture. The organic extracts
were combined and the combined extracts washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a residue com-
prising dl-6-amino-4,5,6,7-tetrahydro-lH-indazole and
dl-6-amino-4,5,6,7-tetrahydro-2H-indazole. The
lS residue was dissolved in 200 ml. of ethanol and the
ethanol solution added dropwise with stirring to 7.7 ml.
of 12N aqueous hydrochloric acid. The resulting
mixture was concentrated in vacuo to yield an equi-
librium mixture of dl-6-amino-4,5,6,7-tetrahydro-
lH-indazole dihydrochloride and dl-6-amino-4,5,6,7-
tetrahydro-2H-indazole dihydrochloride melting at
275-280C. with decomposition after recrystallization
from ethanol. Yield = 4.20 g~
Analysis Calc.: C, 40.02. H, 6.24; N, 20.00
Found: C, 39.74; H, 6.04 N, 19.80.
~3.Z3~
X-5255~ -19-
FINAL PRODUCTS
Exam~le 1
Preparation of dl-5-Dimethylamino-4,5,6,7-tetra-
hydro-lH-indazole and dl-5-Dimethylamino-4,5,6,7-
tetrahydro-2H-indazole.
A reaction mixture was prepared containing
630 mg. of dl-5-amino-4,5,6,7-tetrahydro-lH-indazole
dihydrochloride and its 2H tautomer dihydrochloride
410 g. of sodium acetate, and 75 ml. of ethanol. To
this mixture was added 380 mg. of sodium cyanoboro-
hydride followed by 1 ml. of 37% aqueous formalin.
The resulting mixture was stirred at ambient temper-
ature for about 17 hours, after which ~ime it was
poured into an ice-lN aqueous hydrochloric acid
mixture. The agueous layer was extracted with
chloroform and the chloroform extract discarded. The
a~ueous layer was then made basic with 14N aqueous
ammonium hydroxide and the resulting alkaline
solution extracted several times with a chloro-
form-isopropanol solvent mixture. The extracts were
combined and the combined extrac~s washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded 0.43 g. of a
residue comprising dl-5-dimethylamino-4,5,6,7-
tetrahydro-lH-indazole and dl-5-dimethylamino-
4,5,6,7-tetrahydro-2H-indazole formed in the above
reaction. N.~R of the tautomeric mixture gave
characteristic peaks at 142 cps (singlet-aminomethyl)
432 and 440 cps (broad singlet C-3H) using CDC13.
The compounds were further purified by dissolving the
3~
X-5255A -20-
residue in 10 ml. of lN aqueous hydrochloric acid and
diluting this mixture with anhydrous ethanol. This
solution was evaporated to dryness in vacuo and the
resulting residue crystallized from a methanol/ether
solvent mixture. dl-5-Dimethylamino-4,5,6,7-
tetrahydro-lH-indazole dihydrochloride and dl-
- 5-dimethylamins-4,5,6,7-tetrahydro-2H-indazole
dihydrochloride thus prepared melted at 230-38 with
foaming; yield = 430 mg.
Analysis Calc.: C, 45.39; H, 7.20; N, 17.64
Found: C, 45.26; H, 7.13; N, 17.46.
Example 2
Preparation of dl-S-di(n-propyl)amino-4,5,6,7-
tetrahydro-lH-indazole and dl-5-di~n-propyl)amino-
4,5,6,7-tetrahydro-2H-indazole
Following the procedure of Example 1, but
substituting propionaldehyde for formaldehyde, there
was prepared a mixture of dl-5-di~n-propyl)amino-
4,5,6,7-tetrahydro-lH-indazole and its 2H-tautomer.
NMR in CDC13 gave characteristic peaks at 52 cps
(triplet-propyl CH3) and 432 (singlet -C-3H). The
dihydrochloride salts of the tautomeric mixture were
prepared, melting at 154-60C. with foaming; yielded
= 2.97 g. (from 2.15 g. of starting material).
Analysis Calc.: C, 53.06; H, 8.56; N, 14.28
Found: C, 52.83; H, 8.83; N, 14.30.
3~Z
X-5255A -21-
Example 3
Following the procedure of Example 1,
dl-6-amino-4,5,6,7-tetrahydro-lH(and 2H)-indazole was
alkylated with propionaldehyde and NaBH3CN to yield
dl-6-di-(n-propyl)amino-4,5,6,7-tetrahydro-lH(and
2H)-indazole. The free base was a non-crystalline
glass; mass spectrum, molecular ion ~M ) at 221.
As evidence of the utility of the compounds
of formulae I and II in the treatment of Parkinson's
Syndrome, it has been found ~hat they affect turning
behavior in a test procedure utilizing 6-hydroxy-
dopamine-lesioned rats. In this test, nigro-neo-
striatal-lesioned rats, prepared by the procedure of
Ungerstedt and Arbuthnott, Brain Res, 24, 485 (1970)
are employed. A compound having dopamine agonist
activity, upon injection, causes the rats to turn in
circles contralateral to the side of the lesion.
After a latency period, which varies from compound to
compound, the number of turns is counted over a
15-minute period. The compounds are dissolved in
water and the resulting aqueous solution injected
into the rat by the intxaperitoneal route at a series
of dose levels. Table 1 which follows gives the
results of these tests. In Table 1, column 1 gives
the name of the compound, column 2 the dose, column 3
the percent of rats exhibiting turning behavior and
column 4 the average numbPr of turns.
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X-5255A -22-
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X-525SA -23-
The compounds of formulae I and II are
also useful as prvlactin inhibitors and as such can
be employed in the treatment of inappropriate lacta-
tion, such as postpartum lactation and galactorrhea.
As evidence of their utility in the treatment of
diseases in which it is desirable to reduce the
prolactin level, the compounds of formulae I and II
have been shown to inhibit prolactin according to the
following procedure.
Adult male ra~s of the Sprague-Dawley
strain weighing about 200 g. were housed in an
air-conditioned room with controlled lighting (lights
on 6 a.m. - 8 p.m.) and fed lab chow and water ad
libitum. Each rat received an intraperitoneal
injection of 2.0 mg. of reserpine in aqueous sus-
pension 18 hours before administration of the
indazole. The purpose of the reserpine was to keep
prolactin levels uniformly elevated. The compounds
under tes were dissolved in water and were injected
intraperitoneally at doses ranging from 5 mg/kg down
to 50 mcg/kg. Each compound was administered at each
dose level to a group of 10 rats, and a control group
of 10 intact males received an equivalent amount of
solvent. One hour after treatment all rats were
killed by decapitation, and 150 ~1 aliquots of serum
were assayed for prolactin.
The difference between the prolactin level
of the treated rats and prolactin level of the
control rats divided by the prolactin level of the
control rats gives the percent inhibition of pro-
~.23~
X-5255A -24-
lactin secretion attributable to the compounds of
formulae I and II. These inhibition percentages are
given in Table 2 below. In the table, column 1 gives
the name of the compound; and columns 2-4 the percent
prolactin inhibition at the given dose level.
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X-5255A -25-
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X-5255~ -26-
In using the compounds of formulae I and
II to inhibit prolactin secretion or to treat Park-
inson's syndrome or for other pharmacologic action, a
compound according to formulae I and II above, or a
salt thereof with a pharmaceutically-acceptable acid,
is administered to a subject suffering from Parkin-
sonism, or in need of having their prolactin level
reduced, in an amount e~fective to all~viate some of
the symptoms of Parkinsonism or to reduce an elevated
prolactin level. Oral administration is preferred~
If parenteral administration is used, the injection
is preferably by the subcutaneous route using an
appropriate pharmaceutical formulation. Other modes
of parenteral administration such as intraperitoneal,
intramuscular, or intravenous routes are equally
effective. In particular, with intravenous or intra-
muscular administration, a water soluble pharmaceu-
tically-acceptable salt is employed. For oral admin-
istration, a compound according to formulae I and II
either as the free base or in the form of a salt
thereof can also be mixed with standard pharma-
ceutical excipients and loaded into empty telescoping
gelatin capsules or pressed into tablets. The oral
dosage should be in the range 0.01-10 mg/kg of
mammalian body weight and the parenteral dose in the
range 0.0025 to 2.5 mg/kg. The LD50 of dl-5-
di(n-propyl)amino-4,5,6,7-tetrahydro-lH(and 2H)-
indazole dihydrochloride is between 100 and 300 mg/kg
by the intraperitoneal route in the mouse. Doses of
10 and 30 mg/kg are not fatal but a 30 mg/kg dose
produces some undesirable side effects~
