Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-01
2002-04-23
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S001810, C424S001850, C424S001890, C514S634000, C549S058000, C564S316000
Reexamination Certificate
active
06376534
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. Also intermediates to the compounds of the present application are claimed. 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 substituted phenyl 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
R
1
is selected from anyone of
(i) a straight or branched C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents;
(ii) C
3
-C
7
cycloalkyl optionally substituted by anyone of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy;
(iii) hydrogen, halogen or C
1
-C
6
alkoxy;
(iv) C
6
-C
10
aryl;
(v) 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;
Q is selected from any of CH
3
;
wherein
R
2
, R
3
and R
4
is each and independently selected from any of
(i) C
6
-C
10
aryl; or
(ii) heteroaryl 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;
(iii) hydrogen;
(iv) a straight or branched C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl;
(v) saturated or unsaturated C
3
-C
10
cycloalkyl, 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;
Y is each and independently selected from any of hydrogen, CH
3
; —(CH
2
)
p1
CF
3
; halogen; C
1
-C
3
alkoxy; hydroxy; —NO
2
; —OCF
3
; —CONR
a
R
b
; COOR
a
; —COR
a
; —(CH
2
)
p2
NR
a
R
b
; —(CH
2
)
p3
CH
3
, (CH
2
)
p4
SOR
a
R
b
; —(CH
2
)
p5
SO
2
R
a
; —(CH
2
)
p6
SO
2
NR
a
; C
4
-C
8
(alkyl-cycloalkyl) wherein alkyl is C
1
-C
2
alkyl and cycloalkyl is C
3
-C
6
cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein
R
a
and R
b
is each and independently selected from hydrogen, a branched or straight C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
3
-C
8
cycloalkyl; and wherein
p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2.
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
Q is
wherein
R
2
and R
4
is each and independently selected from any of
(i) C
6
-C
10
aryl; or
(ii) heteroaryl 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 above;
(iii) a straight or branched C
1
-C
6
alkyl or C
2
-C
6
alkynyl;
(iv) saturated or unsaturated C
3
-C
6
cycloalkyl, 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 above;
Particularly preferred compounds according to the invention are compounds of the formula I wherein
R
1
is
(i) phenyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(ii) naphthyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(iii) heteroaryl 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 above;
Q is
wherein
R
2
is
(i) phenyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; or
(ii) naphthyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above.
By “halogen” we mean chloro, fluoro, bromo and iodo.
By “aryl” we mean an aromatic ring having 6 or 10 carbon atoms, such as phenyl and naphthyl.
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 “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 in the relative physical arrangement of molecules by crystal lattice, such that isoforms refer to various crystalline compounds 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 an active form of the drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated by reference.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, fo
Delorme Daniel
Gregor Vlad
Roberts Edward
Sun Eric
AstraZeneca Canada Inc.
Pillsbury & Winthrop LLP
Solola T. A.
Wright Sonya
LandOfFree
Compounds useful in pain management does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds useful in pain management, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds useful in pain management will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2909065