Compounds with analgesic effect

Details Compounds with analgesic effect Compounds with analgesic effect

2000-08-02

2004-01-20

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...

C514S253010, C514S252130, C514S254010, C514S254100, C544S360000, C544S372000, C544S379000, C544S393000, C544S396000

Reexamination Certificate

active

06680321

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 used 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 posess 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; agonists.
Recently, a non-peptidic &dgr; agonist, BW 373U86, was described by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267: 852-857., as the first &dgr;-selective non-peptide with analgesic activity, however, it shows significant affinity for the &mgr; receptor.
Thus, the problem underlying the present invention was to fund new analgesics having excellent 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 in 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.
In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethylpiperidine compounds, including BW 373U86, are disclosed, but these prior art compounds are structurally distinct from the compounds according to the present invention.
The problem mentioned above has been solved by developing novel piperazine and piperidine compounds, as will be described below.
OUTLINE OF THE INVENTION
The novel compounds according to the present invention are defined by the formula (I)
wherein
G is a carbon atom or a nitrogen atom;
A is selected from
(i) phenyl substituted by any of —COOH, —CONH
2
, COOCH
3
, —CN, NH
2
or —COCH
3
;
(ii) naphtyl, benzofuranyl, and quinolinyl; and
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH
3
, (CH
2
)
o
CF
3
, halogen, CONR
7
R
8
, CO
2
R
7
, COR
7
, (CH
2
)
o
NR
7
R
8
, ( CH
2
)
o
CH
3
(CH
2
)
o
SOR
7
, (CH2)
o
SO
2
R
7
and (CH
2
)
o
SO
2
NR
7
R
8
wherein o is 0, 1, or 2, and R
7
and R
8
are as defined below;
R
1
is selected from hydrogen; a branched or straight C
1
-C
6
alkyl, C
1
-C
6
alkenyl, —CO(C
1
-C
6
allyl); (C
1
-C
6
alkyl)-B wherein B is as defined below; C
3
-C
8
cycloallyl, C
4
-C
8
(alkyl-cycloalcyl) 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 5-10 atoms selected from any of C, S, N and O; and whereby the C
6
-C
10
aryl and the heteroaryl may optionally be substituted by 1 or 2 substituents selected from hydrogen, CH
3
, (CH
2
)
o
CF
3
, halogen, CONR
7
R
8
, CO
2
R
7
, COR
7
, (CH
2
)
o
NR
7
R
8
, (CH
2
)
o
CH
3
(CH
2
)
o
SOR
7
, (CH
2
)
o
SO
2
R
7
and (CH
2
)
o
SO
2
NR
7
R
8
;
wherein o is 0, 1, or 2, and R
7
and R
8
are as defined below:
R
7
and R
8
is each and independently as defined for R
1
above;
R
2
is selected from hydrogen, CH
3
, OR
1
, CO
2
R
1
, and CH
2
CO
2
R
1
wherein R
1
is as defined above;
R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, and R
18
, is each and independently as defined for R
1
above;
B is a substituted or unsubstituted aromatic; an optionally substituted C
5
-C
10
hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety, each having from 5 to 10 atoms selected from any of C, S, N and O, and each being optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH
3
, CF
3
, halogen, (CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
NR
7
R
8
, (CH
2
)
p
COR
7
, (CH
2
)
p
CO
2
R
7
, OR
7
, (CH
2
)
p
SOR
7
, (CH
2
)
p
SO
2
R
7
, and (CH
2
)
p
SO
2
NR
7
R
8
;
wherein p is 0, 1, 2 or 3 and wherein R
7
and R
8
are as defined above;
R
3
, R
4
, R
5
and R
6
is each and independently selected from R
7
, (CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
NR
7
R
8
, (CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
CO
2
R
7
, (CH
2
)
p
Ph, (CH
2
)
p
(p-OH Ph), (CH
2
)
p
-3-indolyl, (CH
2
)
p
SR
7
, and (CH
2
)
p
OR
7
;
wherein p is 0, 1, 2, 3, or 4, and R
7
and R
8
are as defined above;
with the proviso that when A is a phenyl ring substituted by a —CN group or by a —NH
2
group, B may not be
 wherein
Z
1
is hydroxy, and esters thereof;
hydroxymethyl, and esters thereof; or
amino, and carboxamides and sulfonamides.
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
G is a carbon atom or a nitrogen atom;
A is selected from
(i) phenyl substituted by any of —COOH, —CONH
2
, COOCH
3
, —CN, NH
2
or —COCH
3
;
(ii) naphtyl, benzofuanyl, and quinolinyl; and
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH
3
, (CH
2
)
o
CF
3
, halogen, CONR
7
R
8
, CO
2
R
7
, COR
7
, (CH
2
)
o
NR
7
R
8
, (CH
2
)
o
CH
3
(CH
2
)
o
SOR
7
, (CH
2
)
o
SO
2
R
7
and (CH
2
)
o
SO
2
NR
7
R
8
, wherein o is 0, 1, or 2, and R
7
and R
8
are as defined below;
R
1
, R
7
and R
8
is each and independently selected from hydrogen; a branched or straight C
1
-C
4
alkyl, allyl, —CO—(C
1
-C
6
alkyl); (C
1
-C
6
alkyl)-B wherein B is as defined below; 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; and phenyl;
R
2
is hydrogen, methyl, or OR
1
wherein R
1
is as defined above;
R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, and R
18
, is each and independently as defined for R
1
above;
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, indazolinyl, and
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH
3
, CF
3
, halogen, (CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
NR
7
R
8
, (CH
2
)
p
COR
7
, (CH
2
)
p
CO
2
R
7
, and OR
7
;
wherein p is 0 or 1, and wherein R
7
and R
8
are as defined above; and
R
3
, R
4
, R
5
and R
6
is each and independently selected from hydrogen, CH
3,
CH(Me)
2
, CH
2
CH(Me)
2
, CH(Me)CH
2
CH
3
(CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
NR
7
R
8
, (CH
2
)
p
CONR
7
R
8
, (CH
2
)
p
CO
2
R
7
, (CH
2
)
p
Ph, (CH
2
)
p
(p-OH Ph), (CH
2
)
p
-3-indolyl, (CH
2
)
p
SR
7
, and (CH
2
)
p
OR
7
, wherein p is 0, 1, 2, or 3, and wherein R
7
and R
8
are as defined above;
with the proviso that when A is a phenyl ring substituted by a —CN group or by a —NH
2
group, B may not be
 wherein
Z
1

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