Substituted urea compounds useful in pain management

Details Substituted urea compounds useful in pain management Substituted urea compounds useful in pain management

2000-06-01

2002-05-14

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S231200, C514S248000, C514S277000, C514S426000, C544S224000, C544S106000, C546S304000, C548S557000, C564S057000, C564S435000

Reexamination Certificate

active

06387949

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
The present application represents U.S. national stage of international application PCT/SE99/01077 which has an international filing date of Jun. 16, 1999 and which was published in English under Article 21(2) of the PCT on Dec. 29, 1999 as No. 9/67206. The international application claims priority to Swedish application 9802208-0, filed on Jun. 22, 1998.
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 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 now been solved by developing novel 1,4-substituted cyclohexyl compounds, 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 and n is each and independently an integer of from 0-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of C
1
-C
6
alkyl C
1
-C
6
alkoxy or hydroxy; or
one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S;
R
1
is selected from hydrogen, a branched or straight C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
8
cycloalkyl, C
4
-C
8
(alkyl-cycloalkyl) wherein the alkyl is C
1
-C
2
alkyl and the cycloalkyl is C
3
-C
6
cycloalkyl;
R
2
is selected from any of
(i) hydrogen;
(ii) a straight or branched C
1
-C
6
alkyl C
2
-C
6
alkenyl or C
2
-C
6
alkynyl;
(iii) —[(CH
2
)
q
— aryl];
(iv) —((CH
2
)
r
-heteroaryl) where the heteroaryl has from 5 to 10 atoms and the heteroatom is selected from any of S, N and O;
 and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; and wherein q and r is each and independently an integer of from 0 to 3;
(v) C
3
-C
10
cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C
6
-C
10
aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
or
R
1
and R
2
may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
R
3
is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl;
(iii) C
6
-C
10
arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteroaryl-(C
5
-C
10
alkyl) where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C
3
-C
10
cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) —[C
3
-C
6
cycloalkyl-(CH
2
)
q
] wherein q is an integer of from 1 to 3;
R
4
is selected from
(i) hydrogen;
(ii) a straight or branched C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl;
(iii) C
6
-C
10
arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteroaryl-(C
5
-C
10
alkyl) where the heteroaryl has from 5 to 10 atoms, the heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C
3
-C
10
cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C
6
-C
10
aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms, the heteroatom being selected from any of S, N and O; wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
R
5
is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl;
(iii) C
6
-C
10
arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein

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