Compounds with analgesic effect

Details Compounds with analgesic effect Compounds with analgesic effect

2001-01-18

2002-09-24

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S314000, C514S319000, C514S326000, C514S330000, C514S331000, C514S235500, C514S237200, C544S130000, C546S205000, C546S207000, C546S208000, C546S234000, C546S175000, C546S190000, C546S196000, C546S213000, C546S226000, C546S227000, C546S229000, C546S232000

Reexamination Certificate

active

06455545

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
BACKGROUND AND PRIOR ART
The &dgr; receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the &dgr; receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the &dgr; receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (&mgr;, &dgr; and &kgr;) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid &dgr; ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic &dgr; antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e., <10-fold) selectivity for the &dgr; receptor vs. &mgr; receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic &dgr; ligands.
Thus, the problem underlying the present invention was to find new compounds having improved analgesic effects, but also with an improved side-effect profile over current &mgr; agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages such as that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has been solved by developing novel compounds which possess a piperidine ring with an exocyclic double bond, as will be described below.
OUTLINE OF THE INVENTION
The novel compounds according to the present invention are defined by the general formula (I)
wherein
R
1
is selected from hydrogen, a branched or straight C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
3
-C
8
cycloalkyl, C
4
-C
8
(alkyl-cycloalkyl) wherein alkyl is C
1
-C
2
alkyl and cycloalkyl is C
3
-C
6
cycloalkyl;
C
6
-C
10
aryl; or heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH
3
, —(CH
2
)
p
CF
3
, halogen, —CONR
5
R
4
, —COOR
5
, —COR
5
, —(CH
2
)
p
NR
5
R
4
, —(CH
2
)
p
CH
3
(CH
2
)
p
SOR
5
R
4
, —(CH
2
)
p
SO
2
R
5
, and —(CH
2
)
p
SO
2
NR
5
, wherein R
4
and R
5
is each and independently as defined for R
1
above and p is 0, 1 or 2;
(C
1
-C
2
alkyl)-(C
6
-C
10
aryl); or (C
1
-C
2
alkyl)heteroaryl, the heteroaryl moieties having from 5 to 10 atoms selected from any of C, S, N and O, and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH
3
, —(CH
2
)
q
CF
3
, halogen, —CONR
5
R
4
, —COOR
5
, —COR
5
, —(CH
2
)
q
NR
5
R
4
, —(CH
2
)
q
CH
3
(CH
2
)
q
SOR
5
R
4
, —(CH
2
)
q
SO
2
R
5
, —(CH
2
)
q
SO
2
NR
5
and —(CH
2
)
p
OR
5
, wherein R
4
and R
5
is each and independently as defined for R
1
above and q is 0, 1 or 2; and
wherein R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
and R
25
is each and independently hydrogen, C
1
-C
6
alkyl or C
1
-C
6
alkenyl;
R
2
and R
3
is each and independently hydrogen or C
1
-C
6
alkyl;
A is selected from
wherein R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
is each and independently as defined for R
1
above, and wherein the phenyl ring of each A substituent may be optionally and independently substituted at any position of the phenyl ring by 1 or 2 substituents Z
1
and Z
2
which are each and independently selected from hydrogen, CH
3
, —(CH
2
)
q
CF
3
, halogen, —CONR
6
R
7
, —COOR6, —COR
6
, —(CH
2
)
r
NR
6
R
7
, —CH
2
)
r
CH
3
(CH
2
)
r
SOR
6
, —(CH
2
)
r
SO
2
R
6
and —(CH
2
)
r
SO
2
NR
6
R
7
wherein R
6
and R
7
is each and independently as defined for R
1
above and r is 0, 1, or 2;
Q is C
5
-C
6
hydroaryl or heterohydroaromatic having 5 or 6 atoms selected from anyone of C, S, N and O; C
5
-C
6
cykloalkyl, or heterocycloalkyl having 5 or 6 atoms selected from anyone of C, N, O and S; and where each Q may optionally be substituted by a substituent Z
1
and Z
2
as defined above;
B is a substituted or unsubstituted aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH
3
, —(CH
2
)
t
CF
3
, halogen, —(CH
2
)
t
CONR
5
R
4
, —(CH
2
)
t
NR
5
R
4
, —(CH
2
)
t
COR
5
, —(CH
2
)
t
COOR
5
, —OR
5
, —(CH
2
)
t
SOR
5
, —(CH
2
)
t
SO
2
R
5
, and —(CH
2
)tSO
2
NR
5
R
4
, wherein R
4
and R
5
is each and independently as defined for R
1
above, and t is 0, 1, 2 or 3; and
R
4
and R
5
is each and independently as defined for R
1
above.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula (I) wherein
A is selected from
wherein R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
is each and independently as defined for R
1
above, and wherein the phenyl ring of each A substituent may be optionally and independently substituted at any position of the phenyl ring by 1 or 2 substituents Z
1
and Z
2
which are each and independently selected from hydrogen, CH
3
, —(CH
2
)
q
CF
3
, halogen, —CONR
6
R
7
, —COOR
6
, —COR
6
, —(CH
2
)
r
NR
6
R
7
, —(CH
2
)
r
CH
3
(CH
2
)
r
SOR
6
, —(CH
2
)
r
SO
2
R
6
and —(CH
2
)
r
SO
2
NR
6
R
7
wherein R
6
and R
7
is each and independently as defined for R
1
above, and r is 0, 1, or 2;
Q is selected from morpholine, piperidine and pyrrolidine;
R
1
, R
4
, and R
5
is each and independently selected from hydrogen, a branched or straight C
1
-C
4
alkyl, C
3
-C
5
cycloalkyl, C
4
-C
8
(alkyl-cycloalkyl) wherein alkyl is C
1
-C
2
alkyl and cycloalkyl is C
3
-C
6
cycloalkyl; C
6
-C
10
aryl; and heteroaryl having from 5 to 6 atoms selected from any of C, S, N and O; and where the aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents independently selected from any of hydrogen, CH
3
, —(CH
2
)
p
CF
3
, halogen, —CONR
5
R
4
, —COOR
5
, —COR
5
, —(CH
2
)
p
NR
5
R
4
, —(CH
2
)
p
CH
3
(CH
2
)
p
SOR
5
R
4
, —(CH
2
)
p
SO
2
R
5
, and —(CH
2
)
p
SO
2
NR
5
, wherein R
4
and R
5
is each and independently as defined for R
1
above and p is 0, 1 or 2;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH
3
, CF
3
, halogen, —(CH
2
)
q
CONR
5
R
4
, —(CH
2
)
q
NR
5
R
4
, —(CH
2
)
q
COR
5
, —(CH
2
)
q
CO
2
R
5
, and —OR
5
, wherein q is 0 or 1, and wherein R
4
and R
5
are as defined above;
R
2
and R
3
is each and independently hydrogen or methyl.
Especially preferred compounds according to the invention are compounds of the formula (I) wherein
A is
wherein R
8
and R
9
are both ethyl, and where the phenyl ring optionally and ind

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