Piperazine and piperidine compounds

Details Piperazine and piperidine compounds Piperazine and piperidine compounds

1999-03-04

2001-05-01

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S253060, C514S254090, C514S254100, C514S254110, C544S105000, C544S362000, C544S363000, C544S369000, C544S376000, C544S377000

Reexamination Certificate

active

06225312

ABSTRACT:

The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties.
It has been found that compounds of the formula (a)
wherein
A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 heteroatoms from the group O, N and S are present,
R
1
is hydrogen or fluoro,
R
2
is C
1-4
-alkyl, C
1-4
-alkoxy or an oxo group, and p is 0, 1 or 2
Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Z is carbon,
R
3
and R
4
independently are hydrogen or C
1-4
-alkyl,
n has the value 1 or 2
R
5
is halogen, hydroxy, C
1-4
-alkoxy or C
1-4
-alkyl, and q is 0, 1, 2 or 3
Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, C
1-4
-alkoxy, C
1-4
-alkyl, cyano, aminocarbonyl, mono- or di-C
1-4
-alkylaminocarbonyl,
and salts thereof have interesting pharmacological properties.
Preferred compounds according to the invention are the compound formula (a) wherein A together with the phenyl group represents a group of the formula b-m
wherein
R
1
and (R
2
)p, n is 1, R
3
, R
4
, (R
5
)
q
, Y and Z have the above meaning, and salts thereof.
Especially preferred are the compounds of formula (a) wherein A together with the phenyl group represents a group of the formula (b), or a group of the formula (I) which is substituted in the hetero ring with an oxo group, and Y is phenyl which may be substituted as mentioned above and wherein n is 1, R
3
and R
4
are hydrogen, R
5
is hydroxy, methoxy or halogen, q is 0 or 1, Z is nitrogen, and salts thereof.
More especially preferred are the compounds of formula (a) wherein A together with the phenyl group is the group of formula (I) which is substituted in the heteroring with an oxo group, q is 0 and Y is phenyl, and salts thereof.
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 5-HT
1A
receptors (pKi range 7.0-9.5 for both receptor types). This combination is useful for the treatment of schizophrenia and other psychotic disorders and might allow for a more complete treatment of all disease symptoms (e.g. positive symptoms, negative symptoms and cognitive deficits).
The compounds show varying activities as either partial agonists or antagonists at dopamine D
2-
, D
3-
and D
4
-receptors. Some compounds show agonist-like effects at dopamine receptors, however they potently antagonize apomorphine-induced climbing behaviour in mice (ED
50
values<1 mg/kg p.o). The compounds show varying activity as 5-HT
1A
receptor agonists and induce aspects of the serotinin behavioural syndrome to differing intensities.
The 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), antidepressants (e.g. differential reinforcement of low rate responses; van Hest et al., Psychopharmacology, 1992, 107:474-479) and anxiolytics (e.g. suppresion of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147-148).
In contrast to clinically relevant dopamine D
2
receptor antagonists the 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 behavioural models sensitive to either antidepressants or anxiolytics.
The compounds are likely to be of value for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotinergic systems, for example: Parkinson's disease, 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 are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphtalene-sulphonic acid.
The compounds of the invention can be brought into forms for administration by means of usual processes using auxiliary substances such as liquid and solid carrier materials.
The compounds of the invention can be obtained according to a number of methods (A to E) which are described below. The piperazines, homopiperazines and piperidines used in these methods are indicated as I-H to XIX-H, wherein I to XIX represent the following groups:
The synthesis of the piperidines XVIII-H and XIX-H (FIG. A
1
) used in the preparations of the compounds of the invention is analogous to the procedure described in WO 94-GB 1507.
The synthesis of the piperazines (FIG. A1) used in the preparations of the compounds of the invention are described in EP0189612, with the exception of XI-H, XIII-H and XV-H (vide infra).
The homopiperazine XI-H and piperazines XIII-H and XV-H are new and their preparations are given below (schemes A.i-A.iii).
Preparation XI-H:
Preparation XIII-H:
Steps 1 to 3 (scheme A.ii):
7-nitro-indole has been described by S. M. Parmerter et al., J. Am. Chem. Soc. 80, (1958), 4621-2, Steps 1,2 and 3 were carried out similarly to the syntheses described in European patent publication no. 0650964.
Preparation XV-H:
Step 1 to 3 of Scheme A.i and step 1 of the scheme A.iii are described in detail in the Examples, and the procedures of step 2 and 3 of Scheme A.iii are similar to those described in EP0189612.
The H-atom of the N—H moiety of compounds I-H to XIX-H can be replaced by group Q in five different chemical ways (A, B, C, D and E, vide infra), eventually leading to the compounds of the invention. In FIG. A2 the meanings of Q1 to Q34 are given.
Synthesis Route A
The compounds A1-A14 and A16-A28 were prepared to the synthesis depicted in scheme A1 (vide infra). A piperazine (I-H to VI-H and VIII-H to XVII-H) was reacted with Q-X (X=Cl, Br, OMs) in acetonitrile with Et(i-Pr)
2
N acting as a base, in some cases KI were added. Et
3
N can be used instead of Et(iPr)
2
N.
The following synthesis routes B to E are not restricted to the preparation of piperazines, but can also be used for the preparation of piperidines.
Synthesis Route B
The compounds can also be prepared according to the synthesis depicted in scheme B1 (vide infra). Piperazine I-H was reacted with 2-phenyl-phenol and formaldehyde in EtOH.
Synthesis Route C
The compounds C1-C4 were prepared according to the synthesis depicted in scheme C1 (vide infra). Phenylpiperazines were reacted with several meta-subsituted phenyl-benzoic acid chlorides to yield the corresponding amides. The amides were subsequently reduced to compounds C1-C4 with the aid of LiAlH
4
.
Compounds C2 and C3 were prepared as depicted in scheme C2.
Synthesis Route D
The compounds D1-D18 and D21-D23 were prepared according to the synthesis depicted in scheme D1 (vide infra). An arylboronic acid was reacted with an aromatic bromide under basic conditions in the presence of a catalytic amount of Pd(PPh
3
)
4
. This so-called “Suzuki” reaction yields the C—C coupled endproducts D.
The compounds D19 and D20 were prepared according to a modified synthesis which is depicted in scheme D2:
After the above described Suzuki reaction has taken place, an additional hydrolysis step removes the protective benzyl gr

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