Compounds useful in pain management

Details Compounds useful in pain management Compounds useful in pain management

1999-12-14

2002-12-24

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Sulfur, selenium or tellurium compound

C568S018000, C568S038000, C568S058000

Reexamination Certificate

active

06498196

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to compounds that exhibit analgesic activity and in particular compounds exhibiting analgesia due to their opioid receptor affinity.
BACKGROUND OF THE INVENTION
Many natural alkaloids and related analogs bind to specific opioid receptors and elicit an analgesic response similar to classic narcotic opiates. Many different types of opioid receptors have been shown to coexist in higher animals. For example, see W. Martin et al.,
J. Pharmacol. Exp. Ther
197, p. 517 (1975); and J. Lord et al.,
Nature
(London), 257, p.495 (1977). Three different types of opioid receptors have been identified. The first, &dgr;, shows a differentiating affinity for enkephalin-like peptides. The second, &mgr;, shows enhanced selectivity for morphine and other polycyclic alkaloids. The third, &kgr;, exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin. In general, the &mgr; receptors seem to be more involved with analgesic effects. The &dgr; receptors appear to deal with behavioral effects, although the &dgr; and the &kgr; receptors may also mediate analgesia.
Each opioid receptor, when coupled with an opiate, causes a specific biological response unique to that type of receptor. When an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects. The less specific and selective an opiate may be, the greater the chance of causing increased side effects by the administration of the opiate.
Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd,
In
International Encyclopedia of Pharmacology and Therapeutics;
N. E. Williams and H. Wilkinson, Eds., Pergammon: (Oxford), 112, p.51 (1983). It is therefore an object of the present invention to provide compounds having analgesic effects but having as few side-effects as possible.
DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides novel thio aminotetralin compounds represented by formula (I):
and pharmaceutically acceptable derivatives thereof;
wherein;
Z is S, SO or SO
2
,
X is selected from anyone of
(i) a bond;
(ii) —CR
7
R
8
— wherein R
7
and R
8
are independently selected from the group consisting of H, OH, halogen, CN, COOH, CONH
2
, amino, nitro, SH, C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COOR
C
wherein R
c
is C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl; R
7
and R
8
can also be connected to form C
3-8
cycloalkyl, a C
3-8
cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
R
1
is selected from the group consisting of H, C
1-12
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-12
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-12
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
6-12
aryl, C
6-12
aralkyl, C
6-12
aryloxy, C
1-12
acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl;
R
2
and R
3
are independently selected from the group consisting of C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
6-12
aryl, C
6-12
aralkyl, heteroaryl having from 6 to 12 atoms, and H; or
R
2
and R
3
may together form a saturated heterocycle of from 3 to 8 atoms;
R
4
and R
5
are independently selected from the group consisting of C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H;
R
4
and R
5
can also be connected to form C
3-8
cycloalkyl, a C
3-8
cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
R
6
is hydrogen, OH, C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C
2-6
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C
2-6
alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C
2-6
alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH
2
, amino, nitro, or SH;
with the provisos that:
1) not both R
4
and R
5
are H; and
2) at least one of R
2
and R
3
is H or C
1-6
alkyl.
The compounds of the present invention are useful in therapy, in particular as analgesics.
In another aspect, there is provided a method of treating pain in a mammal, comprising administering to said mammal an analgesic amount of a compound or composition of the invention.
Still another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of pain.
In another aspect, there is provided pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers, diluents or adjuvants.
X is preferably —CR
7
R
8
— wherein R
7
and R
8
are independently selected from the group consisting of OH, halogen, CN, COOH, CONH
2
, amino, nitro, SH, C
1-6
alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, H, and COOR
c
wherein R
c
is C
1-6
alkyl; R
7
and R
8
can also be connected to form a C
3-8
cycloalkyl.
X is more preferably —CR
7
R
8
— wherein R
7
and R
8
are independently selected from the group consisting of C
1-6
alkyl, and H.
X is most preferably —CH
2
—.
R
1
is preferably selected from the group consisting of H, C
1-12
alkyl, C
6-12
aryl, and C
6-12
aralkyl.
R
1
is more preferably selected from the group consisting of C
1-6
alkyl, C
6-12
aryl, and C
6-12
aralkyl.
R
1
is most preferably C
1-6
alkyl.
R
1
can also be
 wherein n is an integer between 1 to 5, Rx and Rx
1
are independently H, C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl. More preferably, n is 1 or 2 and Rx and Rx
1
are C
1-6
alkyl. Most preferably, Rx and Rx
1
are methyl or ethyl.
In an alternative embodiment, R
1
is selected from the group consisting of CH
3
, —(CH
2
)
n
—CH
3
, and —(CH
2
)
n
—O—CH
3
wherein n is an integer selected between 1 and 5. In an alternative preferred embodiment R
1
is C
6-12
aryl or heteroaryl having from 6 to 12 atoms.
In a further preferred embodiment, R
1
is selected from the group consisting of
wherein A is selected from the group consisting of C
1-6
alkyl, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, O—C
1-6
alkyl, O—C
2-6

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