Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-14
2003-04-15
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S198000, C546S187000, C546S201000, C540S485000, C514S322000, C514S323000
Reexamination Certificate
active
06548516
ABSTRACT:
The invention relates to piperidine derivatives of the formula I
in which
X is 0, NR
1
, S or (CH
2
)
n
,
Y is CH,
Z is CH,
where Y and Z together can also be C═C,
R
1
, R
2
and R3 each independently of one another are H or A,
R
4
is H, Hal, A or OA,
A is alkyl having 1-6 carbon atoms,
Hal is F, Cl, Br or I and
n is 1, 2 or 3,
and their physiologically acceptable salts.
Benzylpiperidine derivatives having a high affinity for binding sites of amino acid receptors are known, for example, from EP 0 709 384 A1.
The object of the invention was to discover novel compounds having useful properties, especially compounds which can be used for preparing medicaments.
It has been found that the compounds of the formula I and their salts are not only well tolerated but also have very useful pharmacological properties. In particular, they have a very high affinity for binding sites of amino acid receptors, especially for the ifenprodil binding site on the NMDA receptor (NMDA=N-methyl-D-aspartate), which modulates the polyamine binding site allosterically.
The binding test for [
3
H]-ifenprodil can be conducted by the method of Schoemaker et al., Eur. J. Pharmacol. 176, 249-250 (1990). The compounds are suitable for treating neurodegenerative disorders, including cerebrovascular diseases. The novel compounds can also be used as an analgesic or anxiolytic and in the treatment of epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischaemias or infarcts. Furthermore, they are suitable for treating psychoses caused by excessively high amino acid levels.
The [
3
H]-CGP-39653 binding test for the glutamate binding site of the NMDA receptor can be conducted, for example, by the method of M. A. Stills et al., described in Eur. J. Pharmacol. 192, 19-24 (1991). The test for the glycine binding site of the NMDA receptor can be conducted by the method of M. B. Baron et al., described in Eur. J. Pharmacol. 206, 149-154 (1991).
The activity against Parkinson's disease, i.e. the potentiation of the L-DOPA-induced contralateral pivoting in hemiparkinsonian rats, can be detected by the method of U. Ungerstedt and G. W. Arbuthnott, Brain Res. 24, 485 (1970).
The compound is particularly suitable for treatment or prophylaxis of strokes and for protection against and treatment of cerebral oedemas and states of undersupply of the central nervous system, especially hypoxia or anoxia.
The activities referred to can, moreover, be detected or checked by methods such as those described in the following literature references:
J. W. McDonald, F. S. Silverstein and M. V. Johnston, Eur. J. Pharmacol. 140, 359 (1987); R. Gill, A. C. Foster and G. N. Woodruff, J. Neurosci. 7, 3343 (1987); J. B. Bederson et al., Stroke, 17, 472-476 (1986); S. Brint et al., J. Cereb. Blood Flow Metab. 8, 474-485 (1988).
The literature references listed below disclose a variety of antagonists which are able to block different binding sites of the NMDA receptor:
W. Danysz, C. G. Parsons, I. Bresink and G. Quack, Drug, News & Perspective 8, 261 (1995), K. R. Gee, Exp. Opin. Invest. Drugs 3, 1021 (1994) and J. J. Kulagowski and L. L. Iversen, J. Med. Chem. 37, 4053 (1994).
Ifenprodil and eliprodil, of the formulae IIIa and IV respectively, are able to block the NMDA receptor by interacting with the modulatory polyamine binding site (C. J. Carter, K. G. Lloyd, B. Zivkovic and B. Scatton, J. Pharmacol. Exp. Ther. 253, 475 (1990)).
Since ifenprodil and eliprodil interact with the polyamine binding site on the NMDA receptor, the antagonistic activity of the compounds of the invention can be determined using a spermine-stimulated [
3
H]-MK-801 (dizocilpine) binding test.
In the presence of saturation concentrations of glycine and NMDA, spermine is still able to increase the binding of MK-801, which is inhibited by ifenprodil, eliprodil and, very effectively, by the compounds of the invention.
In addition, the compounds of the invention can be tested in a [
3
H]-GABA (&ggr;-aminobutyric) release test, in analogy to J. Dreijer, T. Honoré and A. Schousboe, J. Neurosci. 7, 2910 (1987), which is an in vitro model describing the antagonistic function in the cell.
The invention provides, accordingly, the compounds of the formula I according to claim 1 and/or their physiologically acceptable salts as antagonists to receptors of excitatory amino acids, such as glutamic acid or its salts.
The invention provides, in particular, the compounds of the formula I according to claim 1 and/or their acceptable salts as excitatory amino acid antagonists for combating neurodegenerative disorders including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischaemias, infarcts and psychoses.
The invention also provides for the use of the compounds of the formula I according to claim 1 and/or their physiologically acceptable salts for preparing a medicament for combating neurodegenerative disorders including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischaemias, infarcts and psychoses.
The compounds of the formula I can be employed as an active principle of medicaments in human and veterinary medicine.
The invention additionally provides a process for preparing the compounds of the formula I according to claim 1 and their physiologically acceptable salts, characterized in that
a) a compound of the formula II
in which
L is Cl, Br, I, OH or a reactively esterified OH group,
and X, Y, Z, R
1
, R
2
and R
3
are as defined in claim 1
is reacted with a compound of the formula III
in which R
4
is as defined in claim 1, or
b) a compound of the formula I in which X, R
1
, R
2
, R
3
and R
4
are as defined in claim 1, and Y and Z together are C═C is hydrogenated, or
c) water or L′H is eliminated from a compound of the formula I in which X, R
1
, R
3
and R
4
are as defined in claim 1,
Y is CH,
Z is CH and
R
2
is OH or L′, in which L′ is Cl, Br, I, or a reactively esterified OH group, and/or
d) a compound of the formula I is converted by treatment with an acid into one of its salts.
Accordingly, the invention provides in particular those compounds of the formula I in which at least one of the stated radicals has one of the preferred definitions indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ia to Ic, which correspond to the formula I and in which those radicals not identified in any more detail are as defined for the formula I, but in which
in Ia
R
1
is H;
in Ib
R
1
is H and
X is O, NR
1
or S;
in Ic
R
1
is H,
X O, NR
1
or S,
R
2
is H,
R
3
is H or A and
R
4
is Hal.
Alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, and also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) under reaction conditions which are known and suitable for the stated reactions. In this context it is also possible to make use of variants which are known per se but are not mentioned in any greater detail here.
If desired, the starting materials can also be formed in situ such that they are not isolated from the reaction mixture but instead are immediately reacted further to give the compound of the formula I.
The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
The starting compounds of the formula II are generally novel. However, the
Barber Andrew
Bartoszyk Gerd
Leibrock Joachim
Prücher Helmut
Merck Patent GmbH
Robinson Binta M.
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