Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-19
2002-11-05
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S139000
Reexamination Certificate
active
06476047
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the use of anellated dihydropyridines and the salts thereof with physiologically acceptable acids for preparing agents for the treatment of chronic pain.
BACKGROUND OF THE INVENTION
EP 0 491 441 A1, describes the compound of Formula
wherein ZR
6
denotes para-phenoxy. There is no reference therein to the treatment of chronic pain.
British Patent 2236674 describes compounds for treating pain and/or CNS-diseases in which R
4
and R
5
denote hydrogen, Z denotes a bond and R
6
denotes a C
1
-C
5
alkyl, aryl or aryl-lower alkyl group. These compounds act as GABA antagonists on GABA-autoreceptors.
Diseases connected with chronic or chronically recurring pain include, inter alia, migraine, neuralgia, muscle pain and inflammatory pain. They have mechanisms in common with chronically recurring pain [Dray, A. Urban L. and Dickenson, A. Trends in Pharmacological Sciences 1994; 15:190-197].
The chronic neuronal pains include inter alia postoperative pain, shingles, phantom pain, diabetic neuropathy, pain after chronic nerve compression as well as AIDS and cancer in their final stages.
The aim of the present invention is to provide an active substance for treating chronic pain, particularly chronic neuronal pain, with good bioavailability and a powerful antinociceptive activity.
BRIEF SUMMARY OF THE INVENTION
In one general aspect, the present invention is directed to a method of treating chronic pain by the administration of a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein A is benzo or thieno,
and if A is benzo
R
1
, R
2
and R
3
independently of one another denote
H, OH, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, —O—(CH
2
)
1-5
—OCH
3
or R
2
and R
3
together form the group
—O—CH
2
—O—, and
if A is thieno, R
1
, R
2
and R
3
denote hydrogen;
R
4
and R
5
independently of one another denote
H, C
1
-C
5
alkyl or
Together with the central atom to which they are bonded form a C
3
-C
7
ring.
R
6
denotes C
1
-C
12
alkyl or a phenyl or benzyl group substituted by the groups R
7
and R
8
,
wherein R
7
and R
8
independently of one another denote hydrogen, halogen (F, Cl, Br, I), C
1
-C
5
alkyl, C
1
-C
5
alkoxy or C
1
-C
5
fluoroalkyl group.
Z denotes O, S or an NHCO— group or, if at least one of the groups R
4
and R
5
is other than hydrogen, Z may also denote a single bond.
In a second general aspect, the present invention is directed to a compound of formula I above, or a pharmaceutically acceptable salt thereof, with the proviso that the compound of the following formula:
wherein ZR
6
=para-phenoxy is excluded. The present invention is also directed to pharmaceutical compositions comprising these compounds of formula I or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, the compounds according to the present invention exhibit a powerful antinociceptive activity based on the blockade of voltage-dependent N-type Ca
+2
-channels.
The invention therefore relates to the use of the compounds of Formula I, or the salts thereof with physiologically acceptable acids, for the preparation of a pharmaceutical composition for treating chronic pain:
wherein A is benzo or thieno,
and if A is benzo
R
1
, R
2
and R
3
independently of one another denote
H, OH, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, —O—(CH
2
)
1-5
—OCH
3
or R
2
and R
3
in positions 6 and 7 together form the group
—O—CH
2
—O—, and
if A is thieno, R
1
, R
2
and R
3
denote hydrogen;
R
4
and R
5
independently of one another denote
H, C
1
-C
5
alkyl or
together with the central atom to which they are bonded form a C
3
-C
7
ring.
R
6
denotes C
1
-C
12
alkyl or a phenyl or benzyl group substituted by the groups R
7
and R
8
,
wherein R
7
and R
8
independently of one another denote hydrogen, halogen (F, Cl, Br, I), C
1
-C
5
alkyl, C
1
-C
5
alkoxy or C
1
-C
5
fluoroalkyl group.
Z denotes O, S or an NHCO— group or, if at least one of the groups R
4
and R
5
is other than hydrogen, Z may also denote a single bond.
The invention further relates to the compounds of Formula I above, with the proviso that the compound of the following formula:
wherein ZR
6
=para-phenoxy is excluded.
Preferred compounds are the compounds of Formula IA and their use as described above,
wherein R
1
, R
2
and R
3
preferably independently of one another denote hydrogen, methyl or methoxy, particularly wherein R
2
and R
3
denote methoxy and R
1
is methoxy or hydrogen.
Also preferred are compounds of general Formula I and their use as specified above wherein R
4
and R
5
independently of each other denote hydrogen or a methyl group.
Particularly preferred are compounds of general Formula I and their use as described above, wherein Z—R
6
denotes a group of general Formula II, III or IV:
Particularly preferred are compounds of general Formula I and their use as described above wherein R
6
denotes C
6
-C
10
alkyl.
Additional embodiments are compounds of general Formula I and their use as described above, wherein Z—R
6
denotes a phenoxy group of formula II in the ortho or para-position;
Additional embodiments are compounds of general Formula I and their use as described above, wherein at least one of the groups R
7
and R
8
denotes a CF
3
group or an F atom.
Additional embodiments are compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula:
wherein R
4
and R
5
simultaneously denote hydrogen or methyl, and R
6
denotes a group of formula V, VI or VII:
Additional embodiments are compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula:
wherein R
1
denotes methyl or methoxy, R
4
and R
5
simultaneously denote hydrogen or methyl, and R
6
denotes a group of formula V or VII:
An additional embodiment is compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula:
Another general aspect of the invention is directed to a compound of the following formula I, or a pharmaceutically acceptable salt thereof:
wherein A is benzo or thieno,
and if A is benzo
R
1
, R
2
and R
3
independently of one another denote
H, OH, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, —O—(CH
2
)
1-5
—OCH
3
,
or R
2
and R
3
together form the group
—O—CH
2
—O—, and
if A is thieno, R
1
, R
2
and R
3
denote hydrogen;
R
4
and R
5
independently of one another denote
H, C
1
-C
5
alkyl or together with the atom to which they are bonded form a C
3
-C
7
ring;
R
6
denotes C
1
-C
12
alkyl, or denotes a phenyl or benzyl group each substituted by the groups R
7
and R
8
,
wherein R
7
and R
8
independently of one another denote hydrogen, halogen, C
1
-C
5
alkyl, C
1
-C
5
alkoxy or C
1
-C
5
fluoroalkyl group;
Z denotes O, S or an NHCO— group or, if at least one of the groups R
4
and R
5
is other than hydrogen, Z may also denote a single bond.
with the proviso that the compound of the following formula is excluded:
wherein ZR
6
=para-phenoxy.
One embodiment is directed to a compound of formula I above, or a pharmaceutically acceptable salt thereof, wherein Z—R
6
denotes a group of formula II or IV:
Another embodiment is directed to a compound of formula I above, wherein R
4
and R
5
simultaneously denote hydrogen or methyl, and R
6
denotes a group of formula V, VI or VII:
Another embodiment is directed to a compound of formula I above, wherein the compound has the following formula:
wherein R methyl or methoxy, R
4
and R
5
simultaneously denote hydrogen or methyl and R
6
denotes a group of formula V or VII:
Another embodiment is directed to a pharmaceutical composition comprising a compound of formula I described above.
Acids suitable for forming the salts of the compounds according to the invention include, for example, hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, cit
Arndts Dietrich
Blech Stefan Matthias
Draheim Henning
Gaida Wolfram
Klinder Klaus
Boehringer Ingelheim Pharma KG
Datlow Philip I.
Davis Zinna Northington
Raymond Robert P.
Stempel Alan R.
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