Spirooxindole derivatives that act as analgesics

Details Spirooxindole derivatives that act as analgesics Spirooxindole derivatives that act as analgesics

2000-10-27

2004-08-10

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S017000, C546S019000

Reexamination Certificate

active

06774132

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel spirooxindole derivatives, and pharmaceutically acceptable salts thereof, with an analgesic effect. The compounds of the invention can thus be used in the prevention and treatment of pain. In further aspects, the invention relates to compounds for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above. The invention also relates to new intermediates for use in the preparation of the novel compounds.
BACKGROUND ART
Certain spirooxindole derivatives are known as intermediates in the syntheses of vasopressin receptor ligands from U.S. Pat. No. 5,728,723 (Elf Sanofi). Patent applications WO 9741125 (SKB), WO 9711697 (MSD), WO 9527712 (CEMAF), and WO 9315051 (Elf) also discloses spirooxindoles as synthetic intermediates.
Certain spirooxindole derivatives are known as local anesthetics from Komet and Thio,
Journal of Medicinal Chemistry
1976, 19, 892-8. This publication discloses racemic mixtures and biological studies were limited to toxicity (LD
50
) in mice and local anesthetic activity (rat sciatic nerve blocking) in which test the compounds were found inferior to lidocaine. No analgesic effects of the spirooxindole derivatives are mentioned.
However, there remains a need for new therapeutic agents to treat chronic pain. Chronic pain can be caused by injury to nerves or by a variety of lesions. As of today there is no clear understanding why some, more or less visible injuries may elicit pain. Medical doctors often find even strong analgesics, such as opioids, distressfully inefficacious when the pain state is involving the nervous system itself, peripheral as well as central. These pain states are often referred to as neuropathic pain. As a final resort clinicians often prescribe drugs which are not considered true analgesics but which by trial and error have been found partly useful. Such agents include tricyclic antidepressants, for example amitriptylin, anticonvulsants like carbamazepine and gabapentin, and some local anesthetics and antiarrhythmics, especially mexiletine.
It has surprisingly been found that certain spirooxindole derivatives exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.
DISCLOSURE OF THE INVENTION
It has surprisingly been found that compounds of the Formula I, which are spirooxindole derivatives, are particularly effective analgesic compounds and thereby suitable in the treatment of pain.
In one aspect, the present invention thus relates to compounds of the general Formula I
or a pharmaceutically acceptable salt thereof, wherein
R
1
is
a) H,
b) substituted or unsubstituted C
1
-C
6
alkyl,
c) C
1
-C
6
alkoxy C
2
-C
6
alkyl,
d) C
1
-C
6
alkylthio C
2
-C
6
alkyl,
e) halogenated C
1
-C
6
alkyl,
f) aryl C
1
-C
6
alkyl,
g) C
1
-C
6
alkenyl, or
h) C
1
-C
6
cycloalkyl C
1
-C
2
alkyl;
R
2
is
a) H,
b) C
1
-C
6
alkyl,
c) C
2
-C
4
alkynyl,
d) halogen,
e) substituted or unsubstituted carbamoyl,
f) substituted or unsubstituted carbamoyloxy,
g) C
1
-C
6
alkylcarbonyl,
h) C
1
-C
6
alkoxycarbonyl,
i) C
1
-C
6
alkylcarbonyloxy,
j) hydroxy-substituted C
1
-C
6
alkyl,
k) cyano,
l) nitro,
m) amino,
n) halogenated C
1
-C
6
alkyl,
o) halogenated C
1
-C
6
alkoxy,
p) halogenated C
1
-C
6
alkylthio,
q) C
1
-C
6
alkylsulfinyl,
r) C
1
-C
6
alkylsulfonyl,
s) C
1
-C
4
alkylsulfinylalkyl,
t) C
1
-C
4
alkylsulfonylalkyl,
u) C
1
-C
6
alkylsulfonylamino,
v) halogenated C
1
-C
6
alkylsulfonylamino,
w) halogenated C
1
-C
2
alkylsulfonyloxy,
x) aminosulfonyl,
y) aminosulfonyloxy,
z) aryl,
aa) heteroaryl,
bb) arylcarbonyl,
cc) heteroarylcarbonyl,
dd) arylsulfinyl,
ee) heteroarylsulfinyl,
ff) arylsulfonyl,
gg) heteroarylsulfonyl, in which any aromatic moiety is optionally substituted,
hh) C
1
-C
6
alkylcarbonylamino,
ii) C
1
-C
6
alkoxycarbonylamino,
ii) C
1
-C
6
alkyl-thiocarbonyl,
kk) C
1
-C
6
alkoxy-thiocarbonyl,
ll) formyl, or
mm)alkoxysulfonylamino;
R
3
is
a) H,
b) C
1
-C
6
alkyl,
c) halogen,
d) C
1
-C
6
alkoxy,
e) halogenated C
1
-C
4
alkyl,
f) halogenated C
1
-C
6
alkoxy,
g) halogenated C
1
-C
6
alkylthio,
h) C
1
-C
4
alkylsulfinyl,
i) C
1
-C
4
alkylsulfonyl,
j) C
1
-C
4
alkylsulfinyl C
1
-C
6
alkyl,
k) C
1
-C
4
alkylsulfonyl C
1
-C
6
alkyl,
l) C
1
-C
4
alkylsulfonylamino,
m)halogenated C
1
-C
4
alkylsulfonylamino,
n) aminosulfonyl, or
o) aminosulfonyloxy;
R
4
is
a) H,
b) C
1
-C
4
alkyl, or
c) halogen;
R
2
and R
3
may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, CF
3
, OH, cyano, amino, C
1
-C
6
alkyl-NH—, (C
1
-C
6
alkyl)
2
—N—, CN, NH
2
SO
2
, NH
2
CO—, or C
1
-C
6
alkyl-CO—;
Any amino moiety in R
2
-R
4
can optionally be substituted with one or two C
1
-C
6
alkyl groups which may be part of a ring;
Ar is
a) benzene,
b) pyridine,
c) thiophene,
d) pyrazine,
e) pyrimidine,
f) oxazole,
g) thiazole,
h) pyrrole,
i) pyrazole, or
j) furan;
X is
a) —NHCO—,
b) —CONH—,
c) —NH—SO
2
—,
d) —SO
2
NH—,
e) —OCH
2
—,
f) —NHCH
2
—, or
g) —NHCOCH
2
—;
Y is
a) —CH
2
—,
b) —CH(C
1
-C
6
alkyl)—,
c) —C(C
1
-C
6
alkyl)
2
—, or
d) a single bond;
Z is
a) —CH
2
CH
2
CH
2
—,
b) —CH
2
CH
2
CH
2
CH
2
—,
c) —CH═CHCH
2
—,
d) —CH═CHCH
2
CH
2
—, or
e) —CH
2
CH═CHCH
2
—;
provided that when X is —NHCOCH
2
— then Y cannot be —CH
2
—; and excluding the racemic compounds wherein Ar is benzene, R
2
-R
4
is hydrogen, X is NHCO, Y is a single bond, Z is —CH
2
CH
2
CH
2
—, and R
1
is ethyl or n-propyl.
The pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that also all the diastereomeric forms possible are within the scope of the invention.
It will also be appreciated by those skilled in the art, although derivatives of compounds of formula I may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives, of which the N-oxide is one example, may therefore be described as “prodrugs”. All prodrugs of compounds of formula I are included within the scope of the invention.
Depending on the process conditions the final products of the Formula I are obtained either in neutral or salt form. Salt forms include hydrates and other solvates and also crystalline form polymorphs. Both the free base and the salts of these end products are within the scope of the invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitably pharmaceutically acceptable salts. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic carboxylic or sulfonic acids, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, ethanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, alogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. All crystalline form polymorphs are within the scope of the invention.
Preferred compounds of the invention are those of Formula I wherein
R
1
is
a) H,
b) C
1
-C
4
alkyl,
c) C
1
-C
4
alkoxy C
1
-C
4
alkyl,
d) C
1
-C
4
alkylthio C
1
-C

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