Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-03
2003-01-21
Kifle, Bruck (Department: 1629)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253090, C514S254090, C544S357000, C544S364000, C544S373000
Reexamination Certificate
active
06509340
ABSTRACT:
The invention relates to amide and urea derivatives of the formula I
R
1
—(CH
2
)
n
—(Y)
q
—(Z)
r
—CO—NH—R
2
I
in which
R
1
is 3-indolyl which is unsubstituted or mono- or disubstituted by A, AO, OH, Hal, CN, NO
2
, NH
2
, NHA, NA
2
, COA, CONH
2
, CONHA, CONA
2
, CH
2
OH, CH
2
OA, CH
2
NH
2
, CH
2
NHA, CH
2
NA
2
, COOH and/or COOA,
R
2
is
m is 1 or 2,
n is 0, 1, 2, 3 or 4,
Y is a 1,4-cyclohexylene, 1,3-pyrrolidinylene, 1,4-piperazinylene or 1,4-piperidinylene ring, which can also be partially dehydrogenated,
Z is (CH
2
)
n
or (CH
2
)
n
NH—,
q is 0 or 1,
r is 0 or 1,
R
3
is A,
R
4
is AO,
Hal is F, Cl, Br or I,
A is straight-chain or branched alkyl having 1-6 C atoms,
with the proviso that q and r are not simultaneously 0, and their physiologically acceptable salts.
The invention was 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 been found that the compounds of the formula I and their physiologically acceptable acid addition salts have useful pharmacological properties together with good tolerability, since they have effects on the central nervous system. The compounds especially affect serotoninergic transmission by inhibiting the reuptake of serotonin (5-HT) and having a strong affinity for 5-HT
1B/1D
receptors. As a result of these combined activities, they are particularly suitable as antidepressants and anxiolytics.
The compounds exhibit 5-HT-agonistic and antagonistic properties as well as a 5-HT reuptake-inhibiting action. For the in-vitro demonstration of the inhibition of reuptake of 5-HT, inhibition of synaptosomal uptake is used (Wong et al., Neuropsycho-pharmacology 8 (1993), 22-33). Ex vivo, this property is investigated in mouse brain tissue according to a method of Waldmeier (European J. Pharmacol. 46 (1997), 387-392). The affinity for 5-HT
1B/1D
receptors can be determined, for example, by the methods described by Peroutka et al. (Synapse 3 (1983), 61-66) and Hoyer et al. (European J. Pharmacol. 118 (1985), 1-12) and 5-HT
1B/1D
-antagonistic properties can be determined by a method of Choppin et al. (British Journal of Pharmacology, 114 (1995), 309-314).
Similar compounds which likewise exhibit 5-HT
1B/1D
[sic] antagonistic [sic] actions are described, for example, in the Patent Applications WO 97/14689 or WO 97/41802.
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 inflammation. They can be used for the prophylaxis and for the control of the sequelae of cerebral infarcts (cerebral apoplexy) such as stroke and cerebral ischaemias, and for the treatment of extrapyramidal motor side effects of neuroleptics and also of Parkinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and also for the treatment of amyotrophic lateral sclerosis. They are likewise suitable as therapeutics for the treatment of cerebral and spinal cord traumata. In particular, however, they are suitable as pharmaceutical active compounds for anxiolytics, antidepressants, anti-psychotics, neuroleptics, antihypertensives and/or for positively affecting obsessive-compulsive disorder (OCD), anxiety states, panic attacks, psychoses, anorexia, delusional ideas, agoraphobia, migraine, Alzheimer's disease, sleep disorders, tardive dyskinesias, learning disorders, age-dependent memory disorders, eating disorders such as bulimia, drug abuse and/or sexual function disorders.
In addition, they are suitable for the treatment of endocrine disorders such as hyperprolactinaemia, and further in vasospasms, hypertension and gastro-intestinal disorders. They can furthermore be employed as intermediates for the production of other pharmaceutical active compounds.
The invention relates to amide and urea derivatives 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) N-[2-(5-fluoro-3-indolyl)ethyl]-N′-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]urea;
b) 4-(5-cyano-3-indolyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
c) 4-(6-fluoro-3-indolyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
d) 3-{1-[4-methoxy-3-(4-methyl-1-piperazinyl)phenylaminocarbonyl]-4-piperidyl}indole-5-carboxamide;
e) 4-(5-fluoro-3-indolyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
f) 4-[2-(3-indolyl)ethyl]-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
g) 4-(3-indolyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
h) 4-(4-fluoro-3-indolyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide;
i) 4-(7-methoxyindol-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-amide;
j) 4-[4-(5-fluoro-3-indolyl)butyl]piperazine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide;
k) 4-(5-cyanoindol-3-yl)-3,6-dihydro-2H-pyridine [lacuna] 1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide;
l) 3-(5-fluoroindol-3-yl)pyrrolidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-amide;
m) 4-(5-fluoroindol-3-yl)cyclohexanecarboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide;
n) N-[2-(5-hydroxy-3-indolyl)ethyl]-N′-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]urea;
o) N-{2-[4-(6-fluoro-3-indolyl)piperidin-1-yl]ethyl}-N′-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-urea;
p) N-[4-(5-cyano-3-indolyl)butyl]-N′-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]urea;
q) 4-[4-(5-cyano-3-indolyl)butyl]piperazine-1-carboxylic acid [4-methoxy-3-(4-methyl-1-piperazinyl)-phenyl]amide;
r) 4-(5-fluoroindol-3-yl)piperidine-1-carboxylic acid (2,3-dihydro-1′-methylspiro(benzofuran)-3,4-piperidin)amide;
s) N-{2-[4-(6-fluoro-3-indolyl)piperidin-1-yl]ethyl}-[2,3-dihydro-1-methylspiro(benzofuran)-3,4-piperidin]urea;
and their physiologically acceptable salts.
The invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to Claim
1
.
The preparation process is characterized in that
a) a compound of the formula II
H
2
N—R
2
II
in which R
2
has the meaning indicated in Claim
1
,
is reacted with a compound of the formula III
R
1
—(CH
2
)
n
—(Y)
q
—(Z)
r
—CO—L III
in which L is Cl, Br, I, OH or another reactively [sic] functionally modified OH group or easily nucleophilically substitutable leaving group and
R
1
, n, Y, q, Z and r have the meanings indicated in Claim
1
, or
b) the amine component of the formula II
H
2
N—R
2
II
is reacted with the component of the formula IV
R
1
—(CH
2
)
n
—(Y)
q
—(Z)
r
—H IV
in which R
1
, R
2
, n, Y, q, Z and r have the meanings indicated, with addition of coupling reagents such as N,N′-carbonyldiimidazole, diphosgene, triphosgene or alternatively chloroformic acid esters, and/or
c) in that one of the radicals R
1
, R
3
and/or R
4
is optionally converted into another radical R
1
, R
3
and/or R
4
by, for example, cleaving an OA group with formation of an OH group and/or derivatizing a CN, COOH or COOA group and/or in that, for example, a primary or secondary N atom is alkylated and/or in that a base or acid of the formula I which is obtained is converted into one of its salts by treating with an acid or base.
The invention likewise relates to medicaments comprising compounds of the formula I and their physiologically acceptable salts having 5-HT1B/D-antagonistic [sic] and 5-HT reuptake-i
Bartoszyk Gerd
Boettcher Henning
Greiner Hartmut
Harting Juergen
Matzen Lisa
Kifle Bruck
Merck Patentgesellschaft
Millen White Zelano & Branigan P.C.
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