Benzonitriles and benzofluorides

Details Benzonitriles and benzofluorides Benzonitriles and benzofluorides

1996-04-05

2001-10-30

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S373000

Reexamination Certificate

active

06310068

ABSTRACT:

The invention relates to compounds of the formula I
in which
Ar is a phenyl radical which is mono- or disubstituted by CN and/or F,
Q is C
n
H
2n
and
n is 3 or 4
and their salts, 3-[4-(4-(4-fluorophenyl)-1-piperazinyl)butyl]-5-cyanoindole and 3-[4-(4-(2-fluorophenyl)-1-piperazinyl)-butyl]-5-cyanoindole, with the exception of their salts, being excluded.
BACKGROUND OF THE INVENTION
Similar compounds have been disclosed in EP 0 376 607, BE 771285, GB 1 075 156, FR 1,551,082 and in particular in DE 41 01 686 A1 (corresponding to EP 0496 222 A1).
As regards the last-mentioned patent application, the compounds according to the invention are distinguished in comparison to the known compounds substituted by methoxy groups by an improved oral bioavailability. They are considered as a selection invention, expecially with respect to DE 41 01 686.
SUMMARY OF THE INVENTION
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. Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art. It was found that the compounds of the formula I and their physiologically acceptable acid addition salts have very useful pharmacological properties together with good tolerability. Thus they show, in particular, actions on the central nervous system, especially 5-HT
1A
-agonistic and 5-HT-reuptake-inhibiting actions. They inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155). In addition, changes in DOPA accumulation in the striatum and 5-HTP accumulation in N. raphe occur (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). Furthermore, analgesic and hypotensive actions occur; thus in conscious, spontaneously hypertensive rats bearing catheters (SHR strain/Okamoto/NIH-MO-CHB-Kisslegg; method cf. Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648) the blood pressure measured directly after oral administration of the compounds is lowered. They are also suitable for prophylaxis and for the control of the sequelae of cerebral infarcts (apoplexia cerebri) such as stroke and cerebral ischaemias, and also for the treatment of extrapyramidal motor side effects of neuroleptics and of Parkinson's disease.
The compounds of the formula I and their physiologically acceptable acid addition salts can therefore be used as pharmaceutical active substances, in particular for anxiolytics, antidepressants, antipsychotics, neuroleptics and/or antihypertensives and also as intermediates for the production of other pharmaceutical active compounds.
The invention thus relates to the medicaments of the formula I and to their physiologically acceptable acid addition salts.
The invention also relates to pharmaceutical preparations, characterized in that they contain at least one compound of the formula I and/or one of its physiologically acceptable acid addition salts.
The invention relates in particular to pharmaceutical preparations comprising at least one compound selected from the group consisting of
a) 3-[4-(4-(4-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole;
b) 3-[3-(4-(4-cyanophenyl)-1-piperazinyl)propyl]-5-cyanoindole;
c) 3-[4-(4-(4-fluorophenyl)-1-piperazinyl)butyl]-5-cyanoindole, methanesulfonate;
d) 3-[4-(4-(2-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole;
e) 3-[4-(4-(3-fluoro-4-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole.
f) 3-[4-(4-(4-fluorophenyl)-1-piperazinyl)butyl]-5-cyanoindole-hydrochloride.
The invention also relates to the medicaments of the formula I and to their physiologically acceptable acid addition salts as 5-hydroxytryptamine agonists and antagonists.
The radical Ar is a phenyl radical which is mono- or disubstituted by CN and/or F.
The radical Q is —(CH
2
)
3
— or —(CH
2
)
4
—.
The invention relates in particular to the compounds:
a) 3-[4-(4-(4-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole;
b) 3-[3-(4-(4-cyanophenyl)-1-piperazinyl)propyl]-5-cyanoindole;
c) 3-[4-(4-(2-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole;
d) 3-[4-(4-(3-fluoro-4-cyanophenyl)-1-piperazinyl)butyl]-5-cyanoindole
and to the acid addition salts of the compounds mentioned.
A preferable object of the invention is 3-[4-(4-(4-fluorophenyl)-1-piperazinyl)butyl]-5-cyanoindole-hydrochloride.
The invention further relates to a process for the preparation of compounds of the formula I according to claim
1
, and to their salts, characterized in that a compound of the formula II
in which
X
1
is X or NH
2
and
X is Cl, Br, I, OH or a reactive functionally modified OH group, and
Q has the meaning indicated, is reacted with a compound of the formula III
X
2
—CH
2
—CH
2
NAr—CH
2
—CH
2
X
3
  III
in which
X
2
and X
3
can be identical or different and, if X
1
=NH
2
, are each X, or if X
1
is X, then X
2
and X
3
together are NH to form a cyclic compound,
Ar has the meaning indicated,
or in that a compound of the formula IV
in which
X and Q have the meanings indicated, is reacted with a compound of the formula V
Ar—NH
2
  V
in which
Ar has the meaning indicated,
or in that a base of the formula I which is obtained is converted into one of its acid addition salts by treating with an acid.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart; but in particular in DE 4101686), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds 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.
In the compounds of the formula II, X
1
is preferably X; accordingly in the compounds of the formula III X
2
and X
3
are preferably together NH. The radical X is preferably Cl or :Br; however, it can also be I, OH or a reactive modified OH group such as alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
Accordingly, the compounds of the formula I are obtainable in particular by reaction of compounds of the formula II, in which X
1
is Cl or Br, with piperazine derivatives of the formula III, in which X
2
and X
3
together are an NH group (designated below as IIIa).
The compounds of the formulae II and in particular III are known in some cases; the unknown compounds of the formulae II and III can easily be prepared analogously to the known compounds.
Compounds of the formula II in which X
1
is OH are obtainable, for example, by reduction of the corresponding carboxylic acids or their esters. Treating with thionyl chloride, hydrogen bromide, phosphorus trichloride or similar halogen compounds gives the corresponding compounds of the formula II in which X
1
is Cl or Br. The corresponding sulfonyloxy compounds are obtainable from the compounds of the formula II in which X
1
is OH by reaction with the corresponding sulfonyl chlorides.
The iodine compounds of the formula II are obtainable, for example, by the action of potassium iodide on the associated p-toluenesulfonic acid esters. The compounds of the formula II in which X
1
is NH
2
can be prepared, for example, from the halides using potassium phthalimide.
The piperazine derivatives IIIa are in the main known and obtainable, for example, by

Affiliated with

Also associated with

Rating

Benzonitriles and benzofluorides does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzonitriles and benzofluorides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzonitriles and benzofluorides will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2587380