Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-08-31
2001-04-10
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S363000
Reexamination Certificate
active
06214829
ABSTRACT:
The present invention relates to a group of new piperazine compounds having interesting and advantageous pharmacological properties.
The inventors have discovered that compounds of the formula (a)
wherein
R
1
is hydrogen or fluoro,
R′ is H or C
1-4
-alkyl,
R
2
is H, C
1-4
-alkyl or an oxo group, or R′ and R
2
together represent a single bond,
R″ is H or C
1-4
-alkyl, and the dotted lines represent a single or double bond,
p has the value 0, 1, or 2,
Y represents C, O, N or S,
T represents N or C,
R
3
and R
4
independently are hydrogen or C
1-4
-alkyl,
n has the value 1 or 2,
Q is a group of the formula —CH
2
—C(R
5
R
6
)—Z—R
7
, wherein R
5
and R
6
represent H or C
1-7
-alkyl, C
1-3
-alkylphenyl; Z represents —C(R
8
R
9
)—O—, —C(R
8
R
9
)—C(═O)—, —C(R
8
R
9
)—C(=NOR
10
)—, —NH—C(═O)— or —O—CH
2
—, wherein R
8
, R
9
, and R
10
represent H or C
1-4
-alkyl; and R
7
is a 5- or 6-membered cyclic group, aromatic group or hetero-aromatic group, or the 1- or 2-adamantyl group, which R
7
group can be substituted with O—C
1-4
-alkyl, CN, halogen or C-
1-4
-alkyl, with the proviso that R
7
cannot be 1-alkylcycloalkyl, and the proviso that the compounds of formula (a) wherein Z is the group —NH—C(═O)—, R
5
=R
6
=H, T is nitrogen, and the bicyclic group is 1,4-benzoxazin-8-yl, quinoxalin-5-yl, quinolin-5-yl, indol4-yl, benzoxazol-7-yl, benzimidazol-4-yl, or benzothiazol-7-yl are not included, and salts thereof have interesting and advantageous pharmacological properties.
Preferred compounds according to the invention are compounds having formula (a) wherein T represents nitrogen, R′ is hydrogen, and the other symbols have the above meanings.
Especially preferred are compounds of formula (a) wherein Y is carbon and T is nitrogen, p=1, n=1, R
1
, R′, R
2
, R″, R
3
and R
4
are hydrogen, the dotted lines are single bonds, and Q is a group of the formula —CH
2
—C(R
5
R
6
)—Z—R
7
wherein R
5
and R
6
represent H, C
1-4
-alkyl or benzyl, Z is —C(R
8
R
9
)—C(═O)—, —C(R
8
R
9
)—O— or —NH—C(═O)—, wherein R
8
and R
9
represent hydrogen or methyl, and R
7
is phenyl optionally substituted with halogen, CN, CH
3
or OCH
3
. In these especially preferred compounds, if Z is —NH—C(═O)— or —CH
2
—O—, R
5
=H and R
6
is alkyl or alkylphenyl, then the R-configuration at the chiral C-atom carrying R
5
and R
6
is preferred.
It is known from EP 0650964 that compounds of the formula
wherein R
0
is C
1-4
-alkyl, which compounds can be substituted in the phenyl group and/or heterocyclic group and/or the piperazine group, act on the central nervous system by binding to 5-HT receptors. In particular, these compounds bind to subtypes of the 5-HT-receptor, i.e. 5-HT
1A
and 5-HT
1D
receptors.
It has now surprisingly been found that the compounds according to the invention show high affinity for both the dopamine D
2
and serotonin 5HT
1A
receptors (pKi range 7.0-9.5 for both receptor types). Affinity for this combination of receptors is useful for the treatment of schizophrenia and other psychotic disorders and allows for a more complete treatment of all disease symptoms, e.g., positive symptoms, negative symptoms and cognitive deficits.
The compounds according to the invention show varying activities as either partial agonists or antagonists at dopamine D
2
-, D
3
-, and D
4
-receptors. Some of the inventive compounds show agonist-like effects at dopamine receptors, however they potently antagonize apomorphine-induced climbing behavior in mice (ED
50
values<1 mg/kg p.o). The inventive compounds also show varying activity as 5-HT
1A
receptor agonists and induce aspects of the serotonin behavioral syndrome to differing intensities.
The inventive compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g., the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67, the disclosure of which is incorporated herein by reference), antidepressants (e.g., differential reinforcement of low rate responses; van Hest et al., Psychopharmacology, 1992, 107:474-479, the disclosure of which is incorporated herein by reference), and anxiolytics (e.g., suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989,97:147-148, the disclosure of which is incorporated herein by reference).
In contrast to clinically relevant dopamine D
2
receptor antagonists, the presently described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.
The 5-HT
1A
receptor agonism inherent in these compounds may be responsible for the reduced tendency to induce extrapyramidal effects and the therapeutic effects observed in behavioral models sensitive to either antidepressants or anxiolytics.
The inventive compounds are additionally expected to be of value for the treatment of affective disorders or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotinergic systems, for example, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia, and other psychotic disorders.
Suitable acids with which the compounds can form pharmaceutically acceptable acid addition salts include hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, succinic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene-sulphonic acid.
The compounds of the invention can be brought into forms appropriate for administration by means of the usual processes known to the skilled artisan using auxiliary substances such as liquid and solid carrier materials.
The compounds of the invention can be obtained according to a number of synthetic routes (A to D) as described hereafter. The piperazines and homopiperazines used in these methods are indicated as I-H to XVIIl-H, wherein I to XVIII represent the following groups (FIG. 1):
The syntheses of the piperazines I-H, IV-H, V-H, VI-H, VIII-H, XI-H, XII-H and XVIII-H have been described in EP 0189612 and/or EP 0138280, the disclosures of both of which are incorporated herein by reference, or can be prepared in an analogous manner. The syntheses of the remaining piperazines is given below (schemes i to vii).
Step 1 (scheme iii)
This step can be carried out according to the procedure described in: C. K. Ingold, H. A. Piggott,
J. Chem. Soc.(II),
(1923),1469, the disclosure of which is incorporated herein by reference.
Step 2 (scheme iii)
This step can be carried out according to the procedure described in: M. Tomita, S. Minami,
J. Chem. Soc. (C),
(1969), 183, the disclosure of which is incorporated herein by reference.
Steps 3 and 4 (scheme iii)
Steps 3 and 4 can be carried out according to procedures described in EP 0189612.
Moiety of X-H
X-H was not used as an intermediate in the synthesis. The fragment was built in a different manner, see “Remark about D3” in the last part of the examples (vide infra).
Synthesis of XII-H
Step 1 (scheme v)
Transforming the aniline (see also scheme iv) into the corresponding piperazine XII-H can be carried out according to the procedure described in EP 0189612.
The H-atom of the N-H moiety of compounds I-H to XVII-H can be replaced by group Q in four different chemical ways (A, B. C, and D, vide infra), ultimately leading to the compounds of the invention.
A number of Q-Cl or Q-Br compounds are commercially available, others can be obtained according to standard chemical procedures as illustrated in the examples showing the preparation of these intermediates.
Synthesis routes A to D
The compounds listed in Table A, except for A
11
, A
14
and A
16
, were prepared via the synthesis depicted in scheme A
1
(vide infra): a piperazine (see FIG. 1) was reacted with Q-X (X=Cl, Br, OMs, OTos) in e.g., acetonitrile with Et
Feenstra Roelof W.
Kruse Cornelis G.
Long Stephen K.
Tulp Martinus T. M.
Visser Gerben M.
Duphar International Research B.V.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Raymond Richard L.
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