Compounds with analgesic effect

Details Compounds with analgesic effect Compounds with analgesic effect

2002-04-15

2004-03-23

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S224000, C548S557000, C540S606000, C424S001650, C424S001810, C424S009440, C424S009450, C424S009100, C514S329000, C514S426000, C514S217110

Reexamination Certificate

active

06710179

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to novel nitrogen ring 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 analgesics 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 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.
The problem mentioned above has been solved by developing novel compounds which possess a piperidine ring, which may be a 5-membered, a 6-membered or a 7-membered nitrogen ring, 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
m is 0 or 1;
n is 1 or 2;
R
1
is selected from
hydrogen;
a branched or straight C
1
-C
6
alkyl;
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;
benzyl;
 where G is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, and where the heteroatoms are selected from O, S and N; and
 and wherein n=0 or 1;
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
, 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
5
, (CH
2
)
q
SO
2
R
4
, (CH
2
)
q
SO
2
NR
5
, and (CH
2
)
q
OR
4
, wherein R
4
and R
5
is each and independently as defined for R
1
above and q is 0, 1 or 2;
A is
 wherein R
6
, R
7
, R
8
, 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 and wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents Z
1
and Z
2
which are each and independently selected from hydrogen, CH
3
, (CH
2
)
r
CF
3
, halogen, CONR
2
R
3
, CO
2
R
2
, COR
2
, (CH
2
)
r
NR
2
R
3
, (CH
2
)
r
CH
3
(CH
2
)
r
SO
2
R
2
, (CH
2
)
r
SO
2
R
2
and (CH
2
)
r
SO
2
NR
2
R
3
wherein R
2
and R
3
is each and independently as defined for R
1
above and wherein r is 0, 1, or 2; X is O, S or NR
19
where R
19
is as defined for R
1
, 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
)
t
SO
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;
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
R
1
is selected from benzyl;
 where G is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, and where the heteroatoms are selected from O, S and N; and
 and wherein n=0 or 1;
A is selected from anyone of
 wherein R
6
, R
7
, R
8
, R
9
, R
16
, R
17
and R
18
is each and independently as defined for R
1
above; and Z
1
, Z
2
and X is each and independently as defined 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, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH
3
, 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
CO
2
R
5
, and —OR
5
, wherein t is 0 or 1, and wherein R
4
and R
5
are as defined above.
Especially preferred compounds are compounds of the formula (I) wherein
R
1
is (C
1
-C
2
alkyl)phenyl and hydrogen;
A is
 wherein R
6
, R
7
, R
8
, R
9
, is each an ethylene group; and Z
1
and Z
2
, are as defined above;
B is phenyl or naphtalene; and
m and n is each 1, or m is 1 and n is 0.
The substituents A and B respectively, may optionally be substituted at any position of the ring.
By “halogen” we mean chloro, fluoro, bromo and iodo.
By “aryl” we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
By “heteroaryl” we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By “hydroaromatic” we mean a partly or fully saturated aromatic ring structure having from 5-10 carbon atoms in the ring.
By “heterohydroaromatic” we mean a partly or fully saturated aromatic ring structure in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By “isomers” we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By “orientation” we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By “isoforms” we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
By “prodrug” we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGr

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