Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-17
2001-12-25
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000
Reexamination Certificate
active
06333339
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
is 2- or 3-indolyl which is unsubstituted or mono- or disubstituted by Hal, CN, A, AO, OH, CONH
2
, CONHA, CONA
2
, COOH and/or COOA, or is 5H-1,3-dioxolo-[4,5-f]-7-indolyl,
R
2
is benzyl which is unsubstituted or mono-, di- or trisubstituted by A, AO, OH, Hal, CN, NO
2
, NH
2
, NHA, NA
2
, CF
3
, COA, CONH
2
, COOH, CONHA, CONA
2
, OSO
2
A and/or OSO
2
CF
3
or is phenylhydroxymethyl,
Hal is F, Cl, Br or I,
A is straight-chain or branched alkyl having 1-10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms or is cycloalkyl having 3-10 C atoms,
k is 0 or 1 and
m is 1, 2, 3 or 4
and their physiologically acceptable salts and solvates.
Compounds of similar structure are disclosed, for example, in the documents WO 95/02592 or WO 95/33743.
The invention is based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
It has now been found that the compounds of the formula I and their salts have particularly useful pharmacological properties together with good tolerability. They exhibit actions on the central nervous system and have potent anti-epileptic and especially antiischaemic properties (this was shown in the model of transient occlusion of the middle cerebral artery in rats and reduction of the neurological scores). These substances are potent &sgr; receptor ligands with neuroprotective properties (M. O'Neill et al., European J. Pharmacol. 283 (1995), 217-225). Compounds which act as &sgr; receptor ligands also affect the NMDA ion channel complex (see also H. Yamamoto et al., J. Neuroscience (1995), 15(1), 731-736). &sgr; Agonists additionally have a favourable effect on age-related memory disorders (cf. Maurice et al., Brain Research 733 (1996), 219-230). Some of the compounds of the formula I furthermore show a strong 5-HT reuptake-inhibiting action. For such compounds, a particularly good antidepressant, anxiolytic action, as well as a positive effect on obsessive-compulsive disorder (OCD), eating disorders such as bulimia, tardive dyskinesias, learning disorders, age-dependent memory disorders and psychoses are to be expected.
Compounds of the formula I and their physiologically acceptable acid addition salts have particularly useful pharmacological properties together with good tolerability. The compounds are suitable for the treatment of schizophrenia, cognitive deficits, anxiety, depression, nausea, tardive dyskinesia, gastrointestinal tract disorders or Parkinsonism. They exhibit actions on the central nervous system, especially 5-HT reuptake inhibiting actions. For the ex-vivo detection of serotonin reuptake inhibition, synaptosomal uptake inhibition (Wong et al., Neuropsychopharmacol. 8 (1993), 23-33 and p-chloroamphetamine antagonism (Fuller et al., J. Pharmacol. Exp. Ther. 212 (1980), 115-119) are used.
Since these substances, as &sgr; a ligands, have a neuroprotective action, they are also suitable, in particular, as therapeutics for the treatment of stroke, for the treatment of cerebral and bone marrow traumata, and also for the treatment of ischaemic conditions after a cardiac arrest.
The compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and of inflammations. They can be used for the prophylaxis and for the control of the sequelae of cerebral infarcts (cerebral apoplexia) such as stroke and cerebral ischaemias, and for the treatment of extrapyramidal motor side effects of neuroleptics and of Parksinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and also for the treatment of amyotrophic lateral sclerosis. They are also suitable as therapeutics for the treatment of cerebral and bone marrow traumata. However, they are also suitable as pharmaceutical active compounds for axiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and/or for positively affecting obsessive-compulsive disorder, sleep disorders, tardive dyskinesias, learning disorders, age-dependent memory disorders, eating disorders such as bulimia and/or sexual function disorders.
The invention thus relates to the compounds of the formula I and their physiologically acceptable acid addition salts.
The invention relates in particular to compounds of the formula I, selected from the group consisting of
a) 3-[4-(3-benzylpiperidin-1-yl]butyl}indole;
b) 3-[4-(3-phenylhydroxyphenylpiperidin-1-yl)butyl]-indole
c) 3-[4-(3-benzylpiperidin-1-yl)butyl]-5-fluoro-indole;
d) 3-benzyl-1-[4-(5-fluoroindol-3-yl)butanoyl]-piperidine;
e) 3-benzyl-1-[4-(5-chloroindol-3-yl)butanoyl]-piperidine;
f) 3-[4-(3-benzylpiperidin-1-yl)butyl]-5-carboxy-indole;
g) methyl 3-[4-(3-benzylpiperidin-1-yl)butyl]indole -5-carboxylate;
h) methyl (−)-3-{4-[3-(3R′)-benzylpiperidin-1-yl]-butyl}indole-5-carboxylate;
i) methyl (+)-3-{4-[3-(3S′)-benzylpiperidin-1-yl]-butyl}indole-5-carboxylate;
j) 3-{4-[3-(3R′)-benzylpiperidin-1-yl]butyl}-6-methoxyindole;
k) 3-{4-[3-(3S′)-benzylpiperidin-1-yl]butyl}-6-methoxyindole;
l) (+)-3-[4-(3-benzylpiperidin-1-yl)butyl]indole;
m) (−)-3-[4-(3-benzylpiperidin-1-yl)butyl]indole;
n) 3-[4-(3-benzylpiperidin-1-yl)butyl]-5-chloro -indole;
o) 3-[4-(3-benzylpiperidin-1-yl)butyl]-5-methoxy -indole;
p) 3-{4-[3-(4-fluorobenzyl)piperidin-1-yl]butyl}-5-fluoroindole;
q) 7{4-[(3R)-3-benzylpiperidin-1-yl]butyl}-5H-1,3-dioxolo[4,5-f]indole;
r) 7{4-[(3S)-3-benzylpiperidin-1-yl]butyl}-5H-1,3-dioxolo[4,5-f]indole;
s) 3-{4-[(3R)-3-benzylpiperidin-1-yl]butyl}-5-fluoroindole;
t) 3-{4-[(3S)-3-benzylpiperidin-1-yl]butyl}-5fluoroindole;
u) 3-{4-[(3R)-3-benzylpiperidin-1-yl]butyl}indole-5-carbonitrile;
v) 3-{4-[(3S)-3-benzylpiperidin-1-yl]butyl}indole-5-carbonitrile;
w) 3-{4-[3-(4-fluorophenylhydroxymethyl)piperidin-1-yl]butyl}indole-5-carbonitrile;
and their salts and solvates.
The compounds (d), (e) and (f) are used as intermediates.
For all radicals which occur several times, such as, for example, A, it applies that their meanings are independent of one another.
The term solvates means for example the hemi- mono- or dihydrates or for example addition compounds with alcohols.
The radical A is alkyl and has 1 to 10, preferably 1, 2, 3, 4, 5 or 6, in particular 1 or 2, C atoms. Alkyl is therefore in particular, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl -propyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-tri-methylpropyl, additionally also fluoromethyl, difluoro-methyl, trifluoromethyl, 1,1,1-trichloroethyl or penta-fluoroethyl.
Cycloalkyl is in particular, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-adamantyl.
OA is preferably methoxy, additionally also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is preferably methylamino, additionally ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA
2
is preferably dimethylamino, additionally N-ethyl-N-methylamino, diethylamino, di-n-propyl-amino, diisopropylamino or di-n-butylamino. Resulting from this, CO—NHA is preferably N-methylcarbamoyl or N-ethylcarbamoyl; CO—NA
2
is preferably N,N-dimethyl-carbamoyl or N,N-diethylcarbamoyl.
Hal is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. k is 0 or 1, preferably 0. If k is 1, inte
Barber Andrew
Boettcher Henning
Greiner Hartmut
Martinez Joseph Maria
Pruecher Helmut
Chang Ceila
Merck Patent Gellschaft mit Beschrankter
Millen White Zelano & Branigan
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