Note: Descriptions are shown in the official language in which they were submitted.
Case 100-4263
10653~6
HEXAHYDRO-4-PHENYL- 4-HYDROXY-I~DOLINE
The present invention relates to hexahydro-
indolinols.
The present invention provides compounds of
formula I,
~ R
HO ~ H
~:`
N
~3 X2
wherein R1 is hydrogen, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms,
fluorine, chlorine or hydroxy, and
R2 is i) alkyl of 1 to 4 carbon atoms,
ii) alkenyl or alkynyl of 3 to 7
carbon atoms, wherein the
multiple bond is located in a
position other than a to the
nitrogen atom to which R2 is
bound,
iii) cycloalkyl of 5 to 7 carbon atoms,
iv) alkyl of 1 to 4 carbon atoms mono-
substituted by cycloalkyl of
3 to 7 carbon atoms,
~, .
1065326 100-4263
v) hydroxyalkyl of 2 to 4 carbon
atoms, wherein the hydroxy
moiety is attached to a carbon
atom other than a carbon atom a to the
nitrogen atom to which ~2 is bound,
vi) a group -(CH2)p-C0-A, wherein p
is a whole number from 1 to 3
and A is alkyl of 1 to 4 carbon
atoms or alkoxy of 1 to 4 carbon
atoms, or
vii) a group -(CH2)n-X ~ 3 wherein
R3 and R4, independently, are
hydrogen, alk~l of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon
atoms, or halogen, and either
X is a direct bond, vinylene
or carbonyl and n is a whole
number from 1 to 5 or X is -0-,
-S-, -S0-, -S02- or -~R5-, wherein
R5 is hydrogen, phenyl, alkyl of 1 to
4 carbon atoms or alkanoyl of 2 to 4
carbon atoms, and n is a whole number
from 2 to 5, and pharmaceutically
acceptable acid addition salt
forms thereof.
The alkyl and alkoxy moieties preferably have 1 to 2
carbon atoms, especially 1. Rl preferably is hydrogen, alkyl,
alkoxy, fl~orine or chlorine. R2 is
--2--
~0653Z6 l00-4263
preferably alkyl, alkenyl, hydroxyalkyl, -(CH2)p-CO-A
( 2)n X ~ 3 . When R2 is hydroxyalkyl, this
preferably has 2 or 3 carbon atoms. The significance
p is preferably 2 or 3. When R2 is cycloalkylalkyl,
S this is preferably cyclopropylmethyl.
A is preferably alkyl.
~ 3 is preferably hydrogen, halogen or alkyl.
R4 is preferably hydrogen. ~Ihen R3 and/or R4 is
halogen, this is fluorine, chlorine or bromine,
preferably fluorine or chlorine.
When X is a direct bond or vinylene, n is
preferably a whole number from 1 to 4. When X is -O-,
-S-, -SO-, -S02-, -CO- or -NR5-, n is preferably 2
or 3. ~hen R5 is alkanoyl, this preferably has 2 or 3
carbon atoms.
X is preferably a direct bond, -CO-, -O-, -S-,
-S02-, especially a direct bond or -CO-.
The present invention provides a process
a) for the production of a compound of formula I, as
2C defined above, which comprises introducing by N-alkylation
a group R2, as defined above, into the l-position of a
compound of formula II,
O - 3 -
~,sil
~065326 100-4 2 6 3
~---RL
~l N J
wherein Rl is as defined above, or
b) for the production of a compound of formula Ia,
~ Rl
~ -_ ~ H Ia
1H2E
wherein R1 is hydrogen, alkyl or alkoxy of 1 to
4 carbon atoms, fluorine or chlorine,
S and
E is hydrogen, alkyl of 1 to 3 carbon
atoms, cycloalkyl of 3 to 7 carbon
atoms, alkyl of 1 to 3 carbon atoms
mono-substituted by cycloalkyl of 3 to
7 carbon atoms, or a group
-(CH2)m ~ R4
10653Z6
wherein m is a whole number from O to
4 and R3 and R4 are as defined above,
which comprises reducing the -C03 group to a -CH2E
group in a compound of formula III,
~ R
f~O ~
,Y~ III
- COD
S wherein Rl is as defined above, and
D is alkoxy of 1 to 4 carbon atoms or
E, as defined above, and isolating
the resulting compound of formula I in free form or in
acid addition salt form.
-- ,
Processes a) and b) may be effected in analogous
manner to known methods.
Process a) may be effected in conventional manner,
e.g. for the alkylation of a secondary amir.e. For
example as alkylating agent a compound of formula V,
R2_Y V
wherein R2 is as defined above, and
Y is a group capable of leaving under
SN2 conditions,
may be used. Other known alkylating agents ma~ be used,
for example those mentioned hereinafter.
Y is conveniently an acid radical of a reactive
ester, e.g. a halide such as a chloride, bromide or iodide,
_ 5 _
.
10653Z6 100-~263
preferably a chloride or bromide, or an acid radical
of an organic sulphonic acid, e.g. alkylsulphonyl-
OXy~ such as methylsulphonyloxy,or arylsulphonyloxy
such as phenylsulphonyloxy or p-tolylsulphonyloxy.
The alkylation is conveniently effected in
an organic solvent, for example in a solvent which is
an amide of an aliphatic carboxylic acid, such as
dimethyl formamide or in an aromatic hydrocarbon solvent,
such as toluene. Preferably a basic condensation agent,
e.g. an alkaline metal carbonate, such as potassium
carbonate is present. The reaction temperature may
be from room temperature to about 120C; preferably
it is the reflux temperature.
Alternatively other known alkylating agents
may be used,e.g. a compound obtainable from a compound
of formula V, as defined above, by splitting off HY.
For the production of compounds of formula I wherein
R2 is -(CH2)2~CO~A or -~CH2)2-C0 ~ , wherein
A, R3 and R4 are as defined above, a,~ unsaturated
carbonyl compounds may be used. For example methyl
vinyl ketone or an appropriate alkyl ester of acrylic
acid may be used. Conveniently a suitable organic
solvent is present, e.g. ethyl acetate or a lower
alcohol such as methanol, ethanol. Conveniently the
1065326 1 oo--4263
reaction mixture is stirred. The reaction temperature
may vary from room temperature to the reflux temperature;
preferably it is from 20 to 80C.
Alternatively a 1,2-alkylene oxide may be used
to produce a compound of formula I, wherein R2 is
2-hydroxyalkyl. The reaction may be carried out under
conventional conditions, e.g. a reaction temperature
of from -10 to 100C may be used.
It will be appreciated that those
significances of R2 which contain a moiety which is
not completely inert under the conditions of process a)
may be introduced using an alkylating agent having
the moiety in protected form and then the protecting
group is split off. Thus one can produce particularly
conveniently compounds of formula Ib,
- R
Ib
(C~2)r-co ~ R3
R4
wherein Rl, R3 and R4 are as defined above, and
r is a whole number from 1 to 5l
by using in the above described alkylation processes
alkylating agents capable of introducing a moiety of
100-4263
10653Z6
formula
- - (CH2) r~co~R3
wherein R3, R4 and r are as defined above,
wherein the carbonyl group is in ketal protected form
to produce a compound with the carbonyl group in ketal
S protected form, e.g the compound of formula VI,
~1
~0~
-- VI
(Cil ) --C ~R~3
wherein Rl, R3, R4 and r are as defined above, and
Rk and Rk are independently alkyl of
1 to 4 carbon atoms, or together
an alkyl chain of 2 to 4 carbon atoms,
and then removing the protecting group or groups
present to produce the compound of formula Ib with the
carbonyl group in free form.
In an alternative variant, a reductive alkylation
using the appropriate aldehyde or ketone may be used to
produce compounds of formula I, wherein R2 has an a-carbon
atom carrying a hydrogen atom and wherein the moieties attached
tv tne a-carbon are suitably inert under the conditions
106S3Z6 100-4263
of a reductive alkylation. This variant may be effected
in conventional manner, e.g. hvdrogenolytically or
according to the Leuckart-Wallach method.
Process b) may be effected in conventional
manner for such reductions, e.g. for the reduction of
a tert. amide or an N,N-disubstituted-urethane to a
tert. amine. As reducing agent a metal or metalloid
hydride, conveniently in complexed form may be used,
for example diborane or the aluminium hydrides, such as
aluminium hydride, dialkylaluminium hydride, lithium-
aluminium hydride or a mixture of lithium aluminium
hydride and aluminium chloride.
Conveniently an inert solvent is used, e.g.
cyclic or open-chain ethers, such as diethyl ether
and tetrahydrofuran.
The reaction temperature may be from about
room temperature to about 100C, for example from
about 30C up to the reflux temperature. Reduction
of tert.-amides is conveniently effected at from 40
to 60C; whereas the reduction of urethanes is
conveniently effected at the reflux temperature.
It will be appreciated that when a chlorine
or a bromine substituent is present in the compound of
formula III aluminium hydride, dialkyl aluminium
hydride, or diborane is conveniently used.
_ g _
100-4263
10653Z6
Preferred variants of process b) include the
reduction of a compound of formula III wherein -COD is
alkyloxycarbonyl~ to produce a corresPonding compound
of formula Ia, wherein -CEI2E is methyl. Process b) is
also particularly suitable for the production of compounds
of formula Ia, wherein -CH2E is cyclopropylmethyl.
Free base forms of compounds of formula I may
be converted into acid addition salt forms in
conventional manner and vice versa. Suitable acids
include naphthalene-1,5-disulphonic acid, malonic acid,
fumaric acid, hydrochloric acid and maleic acid.
The compounds of formulae II and III are new
and may be produced in analogous manner to known methods.
For example compounds of formula IXa,
~I
~0 ~ IIa
wherein Rl is as defined above,
mav be produced by splitting off the alkoxvcarbonyl
group present in the l-position of a compound of
formula IIIa,
-- 10 --
100-4263
10653Z6
RI
~~
~Q IIIa
COOB
wherein R1 is as defined above, and
B is alkyl of 1 to 4 carbon atoms.
A compound of formula II, wherein Rl is hydroxy
may be produced by splitting the ether group of a
compound of formula IIa, wherein Rl- is alkoxy of 1 to
4 carbon atoms. A suitable agent for splitting the
ether group is a Lewis acid or a mixtl~re of an
alkali metal hydride and a mercaptan such as sodium
hydride/methyl mercapian.
A compound of formula IIIa as defined above
may be produced by means of a Grignard Synthesis from
a comPound of formula IV,
H
IV
~NJ
COOB
10653Z6 oo-~ 2~)3
wherein B is as defined above,
which proceeds in general stereospecifically.
Compounds of formula IV, wherein B ia ethyl are
known. Other compounds of formula IV may be ?repared
in analogous manner to known processes.
Compounds of formula III, wherein D ~s E as
defined above, may be produced by N-acylatirg or
N-formylating the corresponding compounds of formula II
as defined above.
Insofar as the production of any sta~ting
material is not particu'arly described thece compo~lds
are knownr or may be produced and pu~ified in accordance
with known processes, or in a manner analogcis to
processes described herein, e.g. in the E~am~les, or
to kncwn processes.
In the following Examples all temperG'ures are
in degrees Centigrade, and are uncorrected.
100-4263
10653Z6
EXP~IPLE 1: (3aRS 4SR, 7aRS)-~exahydro~ henethyl-
__ _ __L___ __ _________ __ _ ___ __ _ _ __ __ _ ___
4-~henyl-4-indolinol [process variant a)]
_ _ _~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
14.8 g-of (3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-
4-indolinol, 18.9 g of phenethyl bromide and 18 g of
potassium carbonate in 170 ml of dimethylformamide
were heated at reflux for 15 hours. After cooling, the
reaction mixture was concentrated by evaporation and
the concentrate was partitioned between water and ethyl
acetate. The organic extract was dried over sodium
sulphate, filtered, and concentrated to afford the
title compound (M.P. of the hydrogen malonate from
ethanol/ethyl acetate 133 - 135).
The starting material was produced as follows:-
a) Pnenylmagnesium bromide (produced from 40 g of
bromobenzene and 5 g of magnesium) was reacted with
30 g of cis-hexahydro-4-oxo-1-indoline carboxylic
acid ethyl ester in tetrahydrofuran. After the
reaction mixture had been stirred for 4 hours at
room temperature,100 ml of 2N hydrochloric acid
and 200 ml diethyl ether were added. The organic
phase was separated off, washed with water and
dried over sodium sulphate. (3aRS, 4SR, 7aRS)-hexa-
hydrG-4-hydroxy-4-phenyl-1-indoline carboxylic
acid ethyl ester remained as an oil after
concentration by evaporation.
- 13 -
100-4263
~0653~6
b) To 30 g of (3aRS, 4SR, 7aRS)-hexahydro-~-hydroxy-
4-phenyl-1-indoline carboxylic acid ethyl ester
in 300 ml of methanol, 300 ml of 2N sodium hydroxide
was added and the mixture was stirred overnight under
reflux. After cooling the mixture was exhaustively
extracted with methylene chloride. The organic
extracts were extracted with 2N tartaric acid solution.
The tartaric acid extract was made alkaline and
extracted with methylene chloride. After working
up the organic phase in conventional manner,
(3aRS, 4SR, 7aRS)-hexahydro-4-phenyl-4-indolinol
- was obtained (M.P. of the hydrogen naphthalene-
1,5-disulphonate from ethanol 228 - 230).
EX~PLE 2: (3aRS, 4SR, 7aRS~-~-fluoro-4-[hexahydro-
__________________ ______ _________ ____
4-hydroxy-4-m-methoxy~henyl-1-indolinyl]
butyro~henone tprocess variant a) )
6 g of (3aRS, 4SR, 7aRS)-hexahydro-4-m-methoxy-
phenyl-4-indolinol and 3 g of 2-(3-choropropyl)-2-~-
fluorophenyl-1,3-dioxolanewere heated at 150 for
1 hour. After cooling, the solidified residue
containing {(3aRS, 4SR, 7aRS)-1-[3-(2-~-fluorophenyl-
1,3-dioxolan-2-yl~propyl~-4-m-methoxyphenyl-4-indolinol}
was made alkaline with 2N sodium hydroxide and the
mixture was exhaustively extracted with methylene
chloride. After working up in conventional manner,
- 14 -
1065~Z6 100-4263
an oily residue was obtained which was dissolved in
165 ml of acetone. 16.5 ml of 2N hydrochloric acid
was added and the mixture was maintained at room
temperature for 48 hours. After concentration to
dryness, the title compound was obtained as the
hydrochloride (M.P. 168 - 170 from acetone/diethyl
ether).
_ ~PLE 3: (3aRSL 4SRL 7aP~S)-4-~-chloro~henyl-hexa-
hydro-l-methyl-4-indolinol
_ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _
[process variant b)~
15 g of (3aRS, 4SR, 7aRS)-4-~-chlorophenyl-
hexahydro-4-hydroxy-1-indoline carboxylic acid ethyl
ester and 4 g of lithium aluminium hydride in 100 ml
of tetrahydrofuran were heated at reflux for 15 hours.
Any remaining lithium aluminium hydride was destroyed
by the addition of water. Partition between water
and diethyl ether afforded after separation and
working up of the organic phase the title compound a5
an oil (M.P. of the free ba.se fxom diethyl ether/
petroleum ether 98 - 101).
10~53Z6 100-4263
EXAMPIE 4: ~3aRS, 4SR~ 7aRS)-4-~-chloro~henyl-1-
_________ ______ _ ___________ ____
cyclopro~ylmethyl-hexahydro~4-indolin
[process variant b)]
A solution of 5 2 g (3aRS, 4SR, 7aRS)-4-p-chloro-
phenyl-l-cyclopropylcarbonyl -hexahydro-4-indolinol in
300 ml of tetrahydrofuran was produced by warming,
and was added to a suspension of 1.3 g of lithium aluminium
hydride in 30 ml of tetrahydrofuran. The mixture was
stirred at 50 for 30 minutes. A saturated solution ofamonium
sulphate was added. The mixture was filtered. The
filtrate was concentrated and reacted with a concentrated
solution of naphthalene~l,5-disulphonic acid. Diethyl
ether was added, and bis-[(3aRS, 4SR, 7aRS)-4-~-chloro-
phenyl-l-cyclopropylmethyl-hexahydro-4-in~olinol~-
naphthalene-1,5-disulphonate (M.P. 240-242).
The starting material was produced as follows:-
2.74 g of Cyclopropanecarboxylic acid chloride was
added dropwise to a solution of 7.2 g of (3aRS, 4SR,
7aRS)-4-p-chlorophenylhexahydro-4-indolinol and
2.5 ml of pyridine in 30 ml of methylene chloride
at 0 to 10. ~he mixture was stirred at room
temperature for 1 hour, and then was washed first
with a 10% tartaric acid solution, then with a
sodium bicarbonate solution, t~len with a saturated
salt solution.
- 16 -
1065326 100-4263
The orsanic phase was dried over sodi U.T, C ~lphate
and concentrated to afford (3aP~S, 4SR, 7zRS)-4-_-
chlorophenyl-l-cyclopropylcarbonylhe~ahy~.o-4-
indolinol. (M.P. 167 - 169).
The compounds of formula I listed in the Table
below are also obtained.
10653Z6 100-4263
__ _ _
Example ¦ 1 j R2 M . P .
~) Usin~ process a) analo~ous to Example 1_
S m-OCH3 -CH2-CH=CH2 ns140-144
6 p-F - (CH2) 2 ~~~ h f162 -163
7 m-OCH3 ~ (CH2) 3-S~ C1 ns210-212
8 m-OCH 3 - ( CH2) 3-S02 ~C 1 n s139 -141
9 m-OCH 3 - (CH2) 2 -CH--CH~F b102 -103
p-Cl -CH2-CH=CH2 ns120-122
11 p-C1 -CH2-C - CH b92 - 94
12 p-Cl - (CH2) 2-OH ns233-235
13 m-OCH3 ~ (CH2) 3 ~ ns236-237
14 m-OCH3 ( 2) 3 3 ns 130
p-Cl -CH2COCH3 b 90-92~
16 m-OCH3 - (CH2) 3-CO~F hcl 168-170
17 p-Cl -CH2~ ns 240-242
18 p-Cl -CH2-CH-CH~ b 80-82
~ (CH2) 2 ~~
- 18 -
10653Z6 loO-~1 263
.
Example Rl ¦ R2 ~I.P.
l .
~) Using process a) analogous to Ex. 1 and 2:
m-OCH3 -(CH2)3-CO ~ Cl b 97-99
21 m-OCH3 -(CH2)3-CO ~ ns 237-239
22 p-Cl -(CH2)3-CO ~ F hcl 224-226
23 m-OCH3 -CH -CO ~ b 125-126
24 m-OCH3 -(CH2)3-CO ~ C 3 ns 196-198
m-OCH3 -(CH2)3-CO ~ OC 3 ns 206-208
OCH3
26 H -(CH2)3-Co ~ OC 3
~) Usina process a)~ laloaous to Ex. 1 and process b) analoqous
I to Example 4ii):
27 m-OCH3 -(CH2)2 ~ b 102-104
28 p-Cl -CH3 b 98-101
29 m-OCH3 -CH2 ~ hf 173
H -(CH2)3 ~ ns 211-213
31 m-OCH3 ( 2)3 ~ ns 240-241
32 p-Cl -(CH2)2 ~ b 105-107
33 m-OCH3 -(CH2)4 ~ hme 142-144
34 p-Cl -CH2 ~ b 92-94
10653Z6 loo-~ 263
. _
ExNOm,ple Rl OCH~ M.P. .
H -(CH2)2 ~ OCH3
36 p-OCH3 -(C~2)2 ~
g) Using process a) ar alogous to Example 1 and p~ ~ocess b)
analoqous to Examples 3 ) and 4 ):
37 m-OCH3 -CH3 hf 156-158
38 H -CH3 ns 229-231
39 p-F -CH3 nf 159-161
p-CH3 -CH3 hf 130
41 o-CH3 -CH3 hf 121-123
42 p-OCH3 -CH3
43 o-Cl -CH3
~) Using process b) analogous to Example 4 :
. 44 ¦ H ¦ ( 2)2 ~ hmo 133-135
In the table:
= decomposition.
ns = bis [base] naphthalene-1,5-disulphonate
nf = hydrogen fumarate
b = base
hmo = hydrogen malonate
hcl = hydrochloride
hme = hydrogen maleate
i) from corresponding compounds of formula III wherein
D is ethoY.y
ii) from corresponding compounds of formula III wherein
D is E as~defined above.
- 20 -
100-4263
10653Z6
Compounds of formula I exhibit interesting
pharmacological activity. In particular they exhibit
antiarrhythmic activity as indicated in standard tests,
for example by a prolongation of the functional
refractory period of the isolated albino guinea pig
left atria according to the method of N. Reuter,
E. Heeg and U. Haller [Arch. Pharmacol., 268, 323-333,
(1971)].
The compounds are therefore indicated for
use as anti-arrhythmic agents. For this use an
indicated daily dose is from about 1 to about 100 mgr
conveniently administered in divided doses 2 to 4
times a day in unit dosage form containing from about
0.25 to about 50 mg, or in sustained release form.
Preferred compounds have Rl hydrogen, 3~methoxy,
4-methyl, 4-fluorine or 4-chlorine. Preferably R2 is
methyl, allyl, a group -(CH2)p CO CH3, wherein p is
as defined above, phenylalkyl of 7 to 10 carbon atoms,
phenoxyalkyl with 8 - 9 carbon atoms, 3-~-chlorophenyl-
thiopropyl, 3-~-chlorophenylthiopropyl, 3-~-chloro-
phenylsulphonylpropyl or a group
~ (CH2 ) r~CO~Rx3
10653~6 100-4263
wherein r is as defined above,
RX3 is hydrogen, fluorine, chlorine or
methyl, and
R4x is hydrogen or methyl.
The Example 1 compound is the most interesting
compound.
Compounds of formula I additional7y exhibit
anti-depressant activity as indicated in standard tests.
For example in one standard test in accordance with
the method of G~ Stille [Arz. Forsch. 14, 534-7 (19641
an antasonism of the ptosis and catalepsy induced in
rats by tetrabenazine is observed.
The compounds of formula I are therefore
indicated for use as anti-depressants. An indicated
suitable daily dosage is from 5 mg to 300 mg, prefera~ly
administered in divided dosages of from 1.5 mg to 150 mg,
or in sustained release form.
For the anti-depressant use Rl preferably is
4-chlorine. Preferably R2 is methyl, allyl or
2-hydroxyalkyl.
- 22 -
- ~0653Z6 "~ 3
The compounds of formula I may be adsinistered
in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the sa.e order
of activity as the free base forms and are readily
prepared in conventional manner. The present invention
also prc,vides a pharmaceutical composition cc,~prising
a compound o' formula I, in free base form or in
pharmaceutically accep~able acid addition salt form,
in association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for exa~ple,
a solution or a tablet.
