Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-13
2004-08-03
Kifke, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S254110, C514S255040, C544S374000, C544S379000, C544S400000
Reexamination Certificate
active
06770649
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel 1-[1-(hetero)aryl-1-perhydroxyalkylmethyl]-piperazine compounds which are tachykinin receptor antagonists and to medicaments containing these compounds. Furthermore, the invention relates to a process for preparing the novel piperazine compounds and intermediate products of this process.
The tachykinins include the naturally-occurring neuropeptides substance P, neurokinin A and neurokinin B. The tachykinins act as agonists of receptors occurring in larger mammals and humans, such as the neurokinin (=NK)-1 receptor, the NK-2 receptor and the NK-3 receptor. Artificially prepared compounds which are tachykinin receptor antagonists are usually classified according to their relative ability to bind to one or more of the aforementioned three receptor subtypes. In the physiological process the tachykinins play e.g. an important part in the transmission of pain, emesis, neurogenic inflammations, bladder inflammation, inflammatory joint diseases or asthmatic complaints.
Inter alia, piperazine derivatives which act as antagonists to the NK-2 receptor are already known from published European Patent application no. EP 474,561.
Further piperazine derivatives which can act as antagonists to tachykinin receptors are known from published PCT Patent application no. WO 96/10568.
SUMMARY OF THE INVENTION
It was an object of the present invention to provide novel active substances having properties antagonistic to tachykinin receptors and an improved activity profile.
Another object of the invention is to provide new active compounds which are suitable for treating peripheral disorders.
A particular of object of the invention was to provide active compounds which are useful to treat functional and inflammatory disorders of the gastrointestinal tract.
These and other objects are achieved in accordance with the present invention by providing a compound corresponding to the formula I:
wherein
A is naphthyl, phenyl optionally substituted by hydroxy, mono- or bicyclic heteroaryl or C
3-6
-alkenyl optionally substituted by phenyl,
Z is a subgroup corresponding to the formula
wherein
R
1
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
2
, R
3
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
2
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
3
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
3
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
4
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
3
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
5
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
3
and R
4
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
k is 0 or 1,
l is 0 or 1,
m is 0 or 1 and
n is 0 or 1,
R
6
is halogen or hydrogen, and
R
7
is halogen or hydrogen,
or a physiologically compatible acid addition salt thereof.
In accordance with a further aspect of the invention, the objects are achieved by providing a method of inhibiting a functional or inflammatory disorder of a lower intestinal tract of a mammal which involves increased sensitivity to pain or impaired stool passage in the colon region, said method comprising administering to said mammal a pharmaceutically effective amount of a piperazine compound as described above.
In yet another aspect of the invention, the objects are achieved by providing a process for the preparation of a compound corresponding to formula I:
wherein
A is naphthyl, phenyl optionally substituted by hydroxy, mono- or bicyclic heteroaryl or C
3-6
-alkenyl optionally substituted by phenyl,
Z is a subgroup corresponding to the formula
wherein
R
1
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
2
, R
3
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
2
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
3
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
3
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
4
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
R
4
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
3
and R
5
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-
-alkylene,
R
5
is hydrogen or lower alkanoyl, or together with another substituent, selected from the group consisting of R
1
, R
2
, R
3
and R
4
, may form a 5- or 6-member ring bridged by carbonyl, thiocarbonyl or by methylene optionally substituted by lower alkyl or C
4-5
-alkylene,
k is 0 or 1,
l is 0 or 1,
m is 0 or 1 and
n is 0 or 1,
R
6
is halogen or hydrogen, and
R
7
is halogen or hydrogen,
or a physiologically compatible acid addition salt thereof, said process comprising reacting a compound of formula II:
wherein R
6
and R
7
have the above meanings,
with a compound of formula III:
A—B(OH)
2
III
wherein A has the above meaning,
and with a compound of formula IV:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, k, l, m und n have the above meanings, and
optionally acylating a resulting compound of Formula I,
wherein at least one substituent selected from R
1
, R
2
, R
3
, R
4
and R
5
is hydrogen, in the subgroup Z by reacting with a compound corresponding to formula VIII:
R
8
—COOH (VIII)
wherein R
8
is a straight-chain or branched alkyl with 1 to 3 carbon atoms, or
optionally carbonylating or thiocarbonylating a resulting compound of Formula I, wherein at least two substituents selected from R
1
, R
2
, R
3
, R
4
and R
5
are hydrogen, in the subgroup Z by reacting the compound of formula I with a reactive carbonyl- or thiocarbonyl synthesis equivalent, or optionally converting a resulting compound of Formula I, wherein at least two substituents, selected from R
1
, R
2
, R
3
, R
4
and R
5
are hydrogen, to a 5- or 6-member ring derivative bridged by methylene and optionally substituted by lower alkyl or C
4-5
-alkylene by reacting the compound of Formula I in the subgroup Z with a di-lower alkylketone or a C
5-6
-cycloalkylketone, and
optionally converting compound of Formula I into a corresponding acid addition salt, or
optionally converting an acid addition salt into a free compound of Formula I.
A still further aspect of the invention involves the provision of a compound compound corresponding to formula II:
wherein
R
6
is halogen or hydrogen, and
R
7
is halogen or hydrogen.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It has now been found, surprisingly, that a group of novel 1-[1-(hetero)aryl-1-perhydroxyalkylmethyl]-piperazine compounds is distinguished by properties antagonistic to tachykinin receptors, in particular to NK-2 receptors, and has a marked action component directed at the peripheral region. Accordingl
Antel Jochen
Brueckner Reinhard
David Samuel
Eeckhout Christian
Jasserand Daniel
Kifke Bruck
Solvay Pharmaceuticals GmbH
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