Composition containing an oxoindole compound

The present invention relates to an oxindole compound having the formula 5-cyclohexyl-1,3-dihydro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-in dol-2-one for the prevention or treatment of cognitive dysfunctions.

FIELD OF THE INVENTION 
The present invention relates to novel compounds having therapeutic 
activity, intermediates for their preparation, processes for their 
preparation, pharmaceutical formulations containing said compounds and 
medicinal use of said compounds and similar known compounds. 
BACKGROUND OF THE INVENTION 
A major characteristic of Alzheimer's Disease (Senile Dementia, SDAT) is a 
marked central cholinergic dysfunction. This cholinergic deficit has been 
reported to correlate with cognitive impairment (P. T. Francis et al, New 
Engl. J. Med., 1985, 313, 7). Various attempts to increase central 
cholinergic activity and thereby reverse the cognitive deficits have, to 
date, met with only limited success. 
There is some evidence that use of the alkaloid physostigmine can, in some 
cases, be marginally beneficial, but the use of this compound in the 
clinic is compromised by a low therapeutic ratio, a short half-life and 
poor bioavailability. The cholinesterase inhibitor, 
9-amino-1,2,3,4-tetrahydroacridine (THA) has been reported to be of 
therapeutic value in the treatment of a small group of patients with SDAT 
(W. K. Summers et al, New Engl. J. Med., 1986, 315, 1241). Further 
clinical trials of THA have produced some encouraging results but have 
been hampered by the association of this drug with certain toxic side 
effects. 
Other compounds structurally related to either physostigmine or THA have 
been reported and are the subject of ongoing investigations. 
There remains an urgent need for a safe and clinically effective drug for 
the symptomatic treatment of Alzheimer's Disease and related conditions. 
A compound structurally similar to the compounds of the present invention, 
namely 1-[1-(4-benzyl-piperazinyl)methyl]isatin, is disclosed in Chemical 
Abstracts 98 (3):16650w referring to Boll Chim. Farm., 1992, 121 (5), pp. 
221-9. Said compound is said to have pharmacological activity. 
Japanese Patent Application No. 138443/86 (Publication No. KOKAI JP 
62-294654A2) discloses 1-[2-(4-benzyl-piperazinyl)ethyl]isatin as an 
intermediate for the synthesis of isatin derivatives which are useful as 
an agent for treating gastric or duodenal ulcer or mammals including human 
beings. Said single compound is deleted from the scope of the present 
invention by a disclosure in claim 1. 
Furthermore, European Patent Application EP 0 010 398 relates to isatin 
derivatives useful for treating allergic symptoms. Among all specific 
compounds disclosed therein is only one falling within the general formula 
I of the compounds of the present invention, namely 
1-[3-{4-(4-chlorobenzyl)-1-piperazinyl}propyl[-isatin. Said single 
compound is deleted from the scope of the present invention by a 
disclosure in claim 1 as well. 
THE PRESENT INVENTION 
A primary objective of the present invention is to provide structurally 
novel compounds which by virtue of their pharmacological profile enhance 
cholinergic function and are of value in the treatment of the cognitive 
dysfunctions which may be associated with ageing or with conditions such 
as Alzheimer's Disease, Senile and related Dementias, Parkinson's Disease, 
Down's Syndrome and Huntington's Chorea, and in the treatment of 
conditions such as glaucoma or myasthenia gravis. This utility is 
manifested, for example, by the ability of these compounds to inhibit the 
enzyme acetylcholinesterase. Further, the compounds of this invention are, 
in general, highly potent and selective, have an improved duration of 
action and are, in general, less toxic than hitherto known compounds. 
The present invention relates to a compound having the general formula (1) 
##STR1## 
wherein: n is 1, 2 or 3; 
p is 1 or 2; 
q is 1 or 2; 
x represents one or more substituents independently selected from hydrogen, 
lower alkyl, aryl, aryloxy, CN, lower alkoxy, halogen, hydroxy, nitro, 
trifluoromethyl, alkylsulphonamido, 
NHCOR where R is lower alkyl or aryl, 
NR.sub.1 R.sub.2 where R.sub.1 and R.sub.2 are independently hydrogen or 
lower alkyl or together form a ring, 
CO.sub.2 R where R is lower alkyl, or cycloalkyl, cycloalkenyl or 
bicycloalkyl either optionally further substituted by lower alkyl; 
Y is CO or CR.sub.3 R.sub.4 where R.sub.3 and R.sub.4 are independently 
hydrogen, lower alkyl, lower alkoxy or together form a cyclic acetal; 
Z is N or CH; 
and 
##STR2## 
represents an optionally substituted phenyl or cyclohexyl group; wherein W 
represents one or more substituents independently selected from hydrogen, 
lower alkyl, lower alkoxy or halogen; 
stereo and optical isomers and racemates thereof where such isomers exist, 
as well as pharmaceutically acceptable acid addition salts thereof and 
solvates thereof; 
with the provisos that the compound wherein n=1, p=1, q=1, X.dbd.H, 
Y.dbd.CO, Z.dbd.N and 
##STR3## 
=unsubstituted phenyl and the compound wherein n=2, p=1, q=1, X.dbd.H, 
Y.dbd.CO, Z.dbd.N and 
##STR4## 
=4-chlorophenyl are excluded. 
Preferred embodiments of this invention relate to compounds having the 
general formula (2) 
##STR5## 
wherein p, X, W and Z are as previously defined above; 
or to compounds having the general formula (3) 
##STR6## 
wherein p, X, W and Z are as previously defined above. 
Throughout the specification and the appended claims, a given chemical 
formula or name shall encompass all stereo and optical isomers and 
racemates thereof where such isomers exist, as well as pharmaceutically 
acceptable acid addition salts thereof and solvates thereof such as for 
instance hydrates. 
The following definitions shall apply throughout the specification and the 
appended claims. 
Unless otherwise stated or indicated, the term "lower alkyl" denotes a 
straight or branched alkyl group having from 1 to 6 carbon atoms. Examples 
of said lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, 
iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and 
hexyl. 
Unless otherwise stated or indicated, the term "cycloalkyl" denotes a 
cyclic alkyl group having a ring size from C.sub.3 to C.sub.7, optionally 
additionally substituted by lower alkyl. Examples of said cycloalkyl 
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl 
and cycloheptyl. 
Unless otherwise stated or indicated, the term "cycloalkenyl" denotes a 
cyclic alkenyl group having a ring size from C.sub.3 to C.sub.7, 
optionally additionally substituted by lower alkyl. Examples of said 
cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, 
cyclohexenyl, methylcyclohexenyl and cycloheptenyl. 
Unless otherwise stated or indicated, the term "aryloxy" denotes a phenoxy 
group in which the phenyl ring is optionally further substituted by lower 
alkyl, lower alkoxy or halogen. 
Unless otherwise stated or indicated, the term "lower alkoxy" denotes a 
straight or branched alkoxy group having from 1 to 6 carbon atoms. 
Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, 
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and 
branched-chain pentoxy and hexoxy. 
Unless otherwise stated or indicated, the term "halogen" shall mean 
fluorine, chlorine, bromine or iodine. 
Unless otherwise stated or indicated, the term "aryl" denotes a phenyl, 
furyl or thienyl group in which the ring is optionally further substituted 
by lower alkyl, lower alkoxy or halogen. 
Unless otherwise stated or indicated, the term "bicycloalkyl" denotes a 
bicyclic alkyl group having a size from C.sub.6 to C.sub.9, optionally 
additionally substituted by lower alkyl. Examples of said bicycloalkyl 
include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[2.2.3]nonyl. 
Unless otherwise stated or indicated, the term "cyclic acetal" denotes a 
cyclic acetal group having a ring size from C.sub.5 to C.sub.7. Examples 
of said cyclic acetal include 1,3-dioxolanyl and 1,3-dioxanyl. 
Preferred compounds according to the invention are those of general formula 
(2) or general formula (3) in which: 
p is 1, 
W is hydrogen or F, especially 4-F, 
X is lower alkyl, especially methyl or ethyl, lower alkoxy, especially 
methoxy or ethoxy, cycloalkyl, especially C.sub.5 to C.sub.7 cycloalkyl, 
F, aryl, especially phenyl, or NR.sub.1 R.sub.2, especially 1-pyrrolidinyl 
or 1-piperidinyl. More preferred compounds according to the invention are 
those of general formula (2) or general formula (3) in which the X 
substituent is at the 5-position. 
Among the most preferred compounds of formula (1) according to the present 
invention are 
1,3-Dihydro-5-methyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-indol-2 
-one, 
5-Cyclohexyl-1,3-dihydro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-ind 
ol-2-one, 
1,3-Dihydro-1-[2-[4-[(4fluorophenyl)methyl]-1-piperazinyl]ethyl]-5-methyl-2 
H-indol-2-one, 
5-Cyclohexyl-1,3-dihydro-1-[2-[4-[4-fluorophenyl)methyl]-1-piperazinyl]ethy 
l]-2H-indol-2-one, 
5-Methyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indol-2,3-dione, 
1-[2-[4-[(4-Fluorophenyl)methyl]-1-piperazinyl]ethyl]-5-methyl-1H-indole-2, 
3-dione, 
5-Cyclohexyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dion 
e, 
5-Fluoro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione, 
1,3-Dihydro-5-fluoro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-indol-2 
-one, 
1,3-Dihydro-5-phenyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-indol-2 
-one, 
1,3-Dihydro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-5-(1-piperidinyl)-2 
H-indol-2-one, 
5-Cyclohexyl-1,3-dihydro-1-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-2H-ind 
ol-2-one 
and pharmaceutically acceptable acid addition salts or solvates thereof. 
The present invention also relates to processes for preparing the compound 
having formula (1). Said compound may be prepared by 
(a) reacting a compound of the general formula (4) or an acid addition salt 
thereof 
##STR7## 
wherein Z, W, n, p and q are as defined above and Hal is halogen, with a 
compound of the general formula (5) 
##STR8## 
wherein X and Y are as defined above, or, in the case where Z.dbd.N, by 
(b) treating a compound of the general formula (5) 
##STR9## 
wherein X and Y are as defined above, with a 1, (n+1)-dihaloalkane to 
obtain a compound of the general formula (6) 
##STR10## 
wherein X, Y and n are as defined above and Hal is halogen, and reacting 
the compound of the general formula (6) with a compound of the general 
formula (7) 
##STR11## 
wherein W, p and q are as defined above. 
The process (a) can be achieved, for example, by reacting together a 
compound of structure (4) or an acid addition salt thereof with a compound 
of structure (5) in a suitable solvent such as toluene or 
3-methyl-2-butanone or dimethylsulphoxide or dimethylformamide in the 
presence of a base such as potassium hydroxide or triethylamine or 
anhydrous potassium carbonate, optionally with the addition of a catalytic 
amount of potassium iodide. Said reaction should be conducted at a 
suitable temperature, normally between 0.degree. C. and 100.degree. C., 
optionally in an inert atmosphere. In a preferred variation, a solution of 
the compound of structure (5) in dimethylformamide at 0.degree. C. is 
treated with a strong base, preferably sodium hydride. After a suitable 
period of time the compound of structure (4) or an acid addition salt 
thereof is added to the reaction mixture and the process is then allowed 
to proceed at ambient temperature or above. The required product (1) may 
then be isolated and purified and characterised using standard techniques. 
The process (b) can be achieved, for example, by treating a compound of 
structure (5) with a 1,.omega.-dihaloalkane, typically 
1-bromo-2-chloroethane, in a suitable solvent such as toluene or 
3-methyl-2-butanone or dimethylsulphoxide or dimethylformamide in the 
presence of a base such as triethylamine or anhydrous potassium carbonate. 
Such reaction should be conducted at a suitable temperature, normally 
between 0.degree. C. and 100.degree. C., optionally in an inert 
atmosphere. Some compounds of type (6) are known in the literature. The 
intermediate (6) may either be isolated and purified and characterised 
using standard techniques or else may be reacted in a crude form with a 
compound of structure (7). Such reaction is preferably conducted in a 
suitable solvent such as dimethylformamide in the presence of a base such 
as triethylamine or anhydrous potassium carbonate, optionally with the 
addition of a catalytic amount of potassium iodide. The reaction should be 
conducted at a suitable temperature, normally between 0.degree. C. and 
100.degree. C., optionally in an inert atmosphere. The required product 
(1) may then be isolated and purified and characterised using standard 
techniques. 
Compounds of structure (4) wherein Hal represents a halogen substituent, 
preferably either chloro or bromo, are, depending on the nature of the 
substituent W, either known compounds or compounds which can be prepared 
using known methods. The application of such methods to the synthesis of 
compounds of structure (4) will be readily understood by those skilled in 
the art. 
Compounds of structure (5) wherein Y is CO are known as isatins (systematic 
name 1H-indole-2,3-diones). The isatins of structure (5) are, depending on 
the nature of the substituent(s) X, either compounds which have been 
previously described in the literature, or compounds which can be prepared 
by the straightforward application of known methods. The Sandmeyer 
procedure (Organic Syntheses, Coll. Vol. I., p 327), in which an aniline, 
chloral hydrate and hydroxylamine are reacted together to give an 
intermediate isonitrosoacetanilide which is then cyclised to the isatin on 
treatment with strong acid, is a particularly useful method. 
Compounds of structure (5) in which Y is CH.sub.2 are known as oxindoles 
(systematic name 1,3-dihydro-2H-indol-2-ones). The oxindoles of structure 
(5) are, depending on the nature of the substituent(s) X, either known 
compounds or compounds which can be prepared using known methods. The 
Gassman reaction (P. G. Gassman et al, J. Amer. Chem. Soc., 1974, 96, 5508 
and 5512) constitutes a well-known and general synthesis of oxindoles. 
Compounds of structure (5) wherein Y represents an acetal or cyclic acetal 
can be prepared from compounds of structure (5) wherein Y is CO by the 
straightforward application of known methods in a manner that will be 
readily understood by those skilled in the art. 
Thus, the present invention also refers to some new intermediates of 
formulas (4) and (5), respectively, namely: 
##STR12## 
wherein Z and Hal are as defined above, n=p=q=1 and W=Me, OMe or F or 
##STR13## 
=cyclohexyl, with the proviso that the compound where Z=N and 
##STR14## 
=2-methylphenyl is excluded, and 
##STR15## 
wherein X is cycloalkyl, cycloalkenyl or bicycloalkyl, either optionally 
further substituted by lower alkyl or 
X is 
##STR16## 
where n=4 to 7 and Y is CH.sub.2 or CO or 
##STR17## 
where m=2 to 4, with the proviso that the compound where X=5-cyclohexyl 
and Y=CO is excluded. 
In certain circumstances it is advantageous to prepare oxindoles from the 
corresponding isatins. This transformation may be achieved using such 
known methods as: 
a) catalytic hydrogenation/hydrogenolysis; 
b) formation of the corresponding 3-hydrazone followed by reductive 
elimination under basic conditions (Wolff-Kischner procedure); 
or 
c) formation of the corresponding 3-dithioacetal followed by reduction 
using Raney nickel or nickel boride. 
Method (c) represents a preferred process for the conversion of certain 
isatins (1;Y.dbd.CO) or (5;Y.dbd.CO) into the corresponding oxindoles 
(1;Y.dbd.CH.sub.2) or (5;Y.dbd.CH.sub.2) respectively. 
The present invention also relates to pharmaceutical formulations 
containing a compound according to claim 1 as active ingredient and a 
pharmaceutically acceptable carrier. 
Another object of the present invention is a compound according to claim 1 
for use in therapy. 
Still another object of the present invention is the use of a compound 
having the general formula (1) 
##STR18## 
wherein: n is 1, 2 or 3; 
p is 1 or 2; 
q is 1 or 2; 
X represents one or more substituents independently selected from hydrogen, 
lower alkyl, aryl, aryloxy, CN, lower alkoxy, halogen, hydroxy, nitro, 
trifluoromethyl, alkylsulphonamido, 
NHCOR where R is lower alkyl or aryl, 
NR.sub.1 R.sub.2 where R.sub.1 and R.sub.2 are independently hydrogen or 
lower alkyl or together form a ring, 
CO.sub.2 R where R is lower alkyl, 
or cycloalkyl, cycloalkenyl or bicycloalkyl either optionally further 
substituted by lower alkyl; 
Y is CO or CR.sub.3 R.sub.4 where R.sub.3 and R.sub.4 are independently 
hydrogen, lower alkyl, lower alkoxy or together form a cyclic acetal; 
Z is N or CH; and 
##STR19## 
represents an optionally substituted phenyl or cyclohexyl group; wherein 
W represents one or more substituents independently selected from 
hydrogen, lower alkyl, lower alkoxy or halogen; 
stereo and optical isomers and racemates thereof where such isomers exist, 
as well as pharmaceutically acceptable acid addition salts thereof and 
solvates thereof, for the manufacture of a medicament for the treatment of 
conditions such as glaucoma and myasthenia gravis and more particularly, 
for the prevention or treatment of cognitive dysfunctions which may be 
associated with ageing or with conditions such as Alzheimer's Disease, 
Senile and related Dementias, Parkinson's Disease, Down's Syndrome and 
Huntington's Chorea. 
Moreover, the present invention relates to a method for the treatment of 
cholinergic dysfunction whereby a pharmacologically effective amount of a 
compound according to claim 1 is administered to a host in need of said 
treatment. 
Pharmacology 
The compounds of general formula (1) of the present invention are useful in 
the treatment of various cognitive dysfunctions, such as those occurring 
in Alzheimer's disease. This utility is manifested by the ability of these 
compounds to inhibit the enzyme acetylcholinesterase. 
Acetylcholinesterase Inhibition Assay 
The ability of compounds in general to inhibit the acetylcholinesterase 
activity of rat brain homogenate was determined using the 
spectrophotometric method of Ellman et al, Biochem. Pharmacol., 1961, 7, 
88. Results are expressed as IC.sub.50 nanomolar (i.e. the nanomolar 
concentration of test compound required to inhibit enzyme activity by 
50%). 
Further the compounds of this invention potentiate cholinergic function in 
the brain such that when administered to rodents these compounds induce 
marked cholinergic effects such as tremor. These utilities are further 
demonstrated by the ability of these compounds to restore cholinergically 
deficient memory in a delayed non-matched to sample task. 
Delayed Non-Matched to Sample Assay 
Rats were trained on a delayed non-matched to sample task similar to that 
described by Murray et al, Psychopharmacology, 1991, 105, 134-136. 
Scopolamine, an anticholinergic that is known to cause memory impairment, 
induces an impairment in performance of this task. This impairment is 
reversed by compounds of the type described in the present invention. 
Pharmaceutical formulations 
The administration in the novel method of treatment of this invention may 
conveniently be oral, rectal, or parenteral at a dosage level of, for 
example, about 0.0001 to 10 mg/kg, preferably about 0.001 to 1.0 mg/kg and 
especially about 0.01 to 0.2 mg/kg and may be administered on a regimen of 
1 to 4 doses or treatments per day. The dose will depend on the route of 
administration, a preferred route being by oral administration. It will be 
appreciated that the severity of the disease, the age of the patient and 
other factors normally considered by the attending physician will 
influence the individual regimen and dosage most appropriate for a 
particular patient. 
The pharmaceutical formulations comprising the compound of this invention 
may conveniently be tablets, pills, capsules, syrups, powders or granules 
for oral administration; sterile parenteral administration; or as 
suppositories for rectal administration. 
To produce pharmaceutical formulations containing a compound according to 
the present invention in the form of dosage units for oral application the 
active substance may be admixed with an adjuvant/a carrier e.g. lactose, 
saccharose, sorbitol, mannitol, starches such as potato starch, corn 
starch or amylopectin, cellulose derivatives, a binder such as gelatine or 
polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium 
stearate, polyethylene glycol, waxes, paraffin, and the like, and then 
compressed into tablets. If coated tablets are required, the cores, 
prepared as described above, may be coated with a concentrated sugar 
solution which may contain e.g. gum arabic, gelatine, talcum, titanium 
dioxide, and the like. Alternatively, the tablet can be coated with a 
polymer known to the man skilled in the art, dissolved in a readily 
volatile organic solvent or mixture of organic solvents. Dyestuffs may be 
added to these coatings in order to readily distinguish between tablets 
containing different active substances or different amounts of the active 
compounds. 
For the preparation of soft gelatine capsules, the active substance may be 
admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine 
capsules may contain granules of the active substance using either the 
above-mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, 
mannitol, starches (e.g. potato starch, corn starch or amylopectin), 
cellulose derivatives or gelatine. Also liquids or semisolids of the drug 
can be filled into hard gelatine capsules. 
Dosage units for rectal application can be solutions or suspensions or can 
be prepared in the form of suppositories comprising the active substance 
in admixture with a neutral fatty base, or gelatine rectal capsules 
comprising the active substance in admixture with vegetable oil or 
paraffin oil. 
Liquid preparations for oral application may be in the form of syrups or 
suspensions, for example solutions containing from about 0.02% to about 
20% by weight of the active substance herein described, the balance being 
sugar and mixture of ethanol, water, glycerol and propylene glycol. 
Optionally such liquid preparations may contain colouring agents, 
flavouring agents, saccharine and carboxymethylcellulose as a thickening 
agent or other excipients known to the man in the art. 
Solutions for parenteral applications by injection can be prepared in a 
aqueous solution of a water-soluble pharmaceutically acceptable salt of 
the active substance, preferably in a concentration of from about 0.5% to 
about 10% by weight. These solutions may also contain stabilizing agents 
and/or buffering agents and may conveniently be provided in various dosage 
unit ampoules.