Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-09
2001-07-10
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252180, C514S252140, C514S253010, C514S253110, C514S255030, C514S252130, C544S295000, C544S357000, C544S360000, C544S364000, C544S392000
Reexamination Certificate
active
06258813
ABSTRACT:
The invention relates to piperazine derivatives of the formula I
in which
R
1
is pyridyl or phenyl, each of which is monosubstituted by Ph or by 2- or 3-thienyl,
R
2
is Ph′ or Het,
Ph and Ph′ in each case independently of one another are phenyl, it being possible for both radicals to be in each case unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, I, OH, OA, A, CF
3
, NO
2
, CN, COA, CONH
2
, CONHA, CONA
2
or 2- or 3-thienyl,
Het is a saturated, partially or fully unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, it being possible for 1 or 2 N and/or 1 or 2 O atoms to be present and it being possible for the heterocyclic radical to be mono- or disubstituted by F, Cl, Br, I, OA, CF
3
, A or NO
2
, and
A is alkyl having 1 to 6 C atoms,
and to the physiologically acceptable salts thereof.
The invention was based on the object of finding novel compounds which can be used for the preparation of pharmaceuticals.
It has been found that the compounds of the formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. The compounds of the formula I are dopamine ligands with a selectivity for the D4 receptor, in comparison with D2 and D3 receptors (method analogous to Creese et al., European J. Pharmacol. 46, 377-381 (1977); with
3
H-spiroperidol as ligand for dopamine receptors and cloned, human dopamine D4, D3 and D2 receptors (available from: Receptor Biology Inc., Baltimore Md. 21227, USA). The compounds are suitable for the treatment of schizophrenia, cognitive deficiencies, anxiety, depressions, nausea, tardive dyskinesia, disturbances of the gastro-intestinal tract, or Parkinson's disease. They have effects on the central nervous system, mainly additional 5-HT
1A
-agonistic and 5-HT reuptake-inhibitory effects. Furthermore, the compounds have serotonin-agonistic and -antagonistic properties. They inhibit the binding of tritiated serotonin ligands to hippocampus receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155). Changes in DOPA accumulation in the striatum and changes in 5-HTP accumulation in the nuclei raphes are observed as well (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). Moreover, analgetic and antihypertensive effects are observed; thus, in catheterized conscious spontaneously hypertonic rats (strain SHR/Okamoto/NIH-MO-CHB-Kisslegg; Methods, cf. Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648), the directly measured blood pressure is lowered after administering the compounds orally. They are also suitable for prophylaxis and for controlling the sequelae of cerebral infarctions (apoplexia cerebri), such as apoplexy and cerebral ischaemias.
Compounds of the formula I and their physiologically acceptable acid addition salts can therefore be used as pharmaceutically active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics and/or antihypertonics, and also as intermediates for the preparation of other pharmaceutically active ingredients.
The invention relates to piperazine derivatives of the formula I and to their physiologically acceptable acid addition salts.
The radical A is alkyl having 1, 2, 3, 4, 5 or 6, in particular 1 or 2, C atoms, preferably methyl, furthermore also ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. OA is preferably methoxy, furthermore also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is preferably methylamino, furthermore ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA
2
is preferably dimethylamino, furthermore N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. As a result, CO-NHA is preferably N-methylcarbamoyl or N-ethylcarbamoyl; CO—NA
2
is preferably N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.
The radical R
1
is preferably phenyl which is unsubstituted or monosubstituted by 3-thienyl, biphenyl which is unsubstituted or monosubstituted by OA, CN, CF
3
, F, Br or Cl, or 2-, 3- or 4-pyridyl which can be especially preferably substituted by 3-thienyl, phenyl or p-, m- or o-F-phenyl. If R
1
is substituted or unsubstituted pyridyl, then the 3-pyridyl radical is preferred.
The radical R
2
is preferably phenyl which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, OH, OA, A, CONH
2
, COA, CF
3
, CN and/or NO
2
, or Het which is substituted analogously, it being possible for Het to be preferably 1,4-benzodioxane, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, 2- or 3-pyrazinyl.
The rule that all radicals such as, for example, Ph which can occur more than once in a molecule can be identical or different applies to the entire invention.
Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the abovementioned radials has one of the meanings given above as being preferred. Some preferred groups of compounds can be expressed by the formulae Ia to Ik below, which correspond to the formula I and in which the radicals which are not detailed further have the meanings given in the formula I, but in which,
in Ia, R
1
is 3-pyridyl which is substituted in the 5-position;
in Ib, R is 2-pyrimidinyl;
in Ic, R
1
is phenyl and R
2
is pyridyl or pyrimidinyl, each of which is unsubstituted or monsubstituted;
in Id, R
1
is biphenyl and R
2
is unsubstituted or mono-, di- or trisubstituted phenyl;
in Ie, R
1
is biphenyl and R
2
is unsubstituted or monosubstituted 1,4-benzodioxanyl, benzofuranyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
in If, R
1
has a meaning given in Ia or Ib and R
2
is mono-, di- or trisubstituted phenyl;
in Ig, R
1
has a meaning given in Ia or Ib and R
2
is monosubstituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
in Ih, R
2
is 2-pyrimidinyl and R
1
is meta-susbtituted phenyl or is pyrid-3-yl which is substituted in the 5-position;
in Ii, R
2
is 2-pyrimidinyl and R
1
is substituted phenyl or substituted pyrid-3-yl, the substituents preferably being OCH
3
, F or 2- or 3-thienyl;
in Ik, R
1
has a meaning given in Ia and the substituent is phenyl or o- or p-fluorophenyl.
The invention furthermore relates to a process for the preparation of piperazine derivatives of the formula I and of salts thereof, characterized in that a compound of the formula II
in which R
2
has the abovementioned meaning is reacted with a compound of the formula III
R
1
—CH
2
—L III
in which
L is Cl, Br, I, OH, O—CO—A, O—CO—Ph, O—SO
2
—Ar, Ar representing phenyl or tolyl and A representing alkyl, or another OH group which is reactively esterified, or a leaving group which is readily nucleophilically substitutable, and
R
1
has the abovementioned meaning,
or in that a compound of the formula IV
H
2
N—R
2
IV
in which
R
2
has the abovementioned meaning
is reacted with a compound of the formula V
in which
X
1
and X
2
can be identical or different and are Cl, Br, I, OH or a reactive, functionally modified OH group and R
1
has the abovementioned meaning,
or in that a compound of the formula VI
in which
R
2
, X
1
and X
2
have the meanings which have already been given
is reacted with a compound of the formula VII
R
1
—CH
2
—NH
2
VII
in which
R
1
has the abovementioned meaning,
or in that a compound which otherwise corresponds to the formula I but which contains one or more reducible group(s) and/or one or more additional C—C and/or C—N bond(s) instead of one or more hydrogen atom is treated with a reducing agent,
or in that a compound which otherwise corresponds to the formula I but which contains one or more solvolysable group(s) instead of one or more hydrogen atom is treated with a solvolysing agent,
and/or in that, if appropriate, a radical R
1
and/or R
2
is converted into another radical R
1
and/or R
2
, for example by cleaving an OA group with the formation of an OH group and/or derivatizing a CN, COOH or COOA group and/or, for example, in that a primary or secondary N atom is
Arlt Michael
Bartoszyk Gerd
Bottcher Henning
Seyfried Christoph
Bernhardt Emily
Merck Patent Gesellschaft mit
Millen White Zelano & Branigan P.C.
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