Morphinoid compounds

Details Morphinoid compounds Morphinoid compounds

2002-04-02

2004-02-24

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...

C546S044000, C546S045000, C546S046000

Reexamination Certificate

active

06696457

ABSTRACT:

The present invention is concerned with novel compounds, in particular novel morphinoid compounds, processes for their preparation and their use in medicine.
The presence of three populations of opioid receptors (mu, delta and kappa) is now well established and documented and all three are reported to be present in the central and peripheral nervous system of many species including man (Lord J. A. H. et al.,
Nature
1977, 267, 495).
Activation of all three opioid receptor subtypes can lead to antinociception in animal models. In particular, studies with peptidic delta agonists have indicated that activation of the delta receptor produces antinociception in rodents, primates and can induce clinical analgesia in man (D. E. Moulin et al.
Pain
, 1985, 23, 213). Evidence exists that suggest a lesser propensity of delta agonists to cause the usual side-effects associated with mu and kappa activation (Galligan et al,
J. Pharm. Exp. Ther
., 1984, 229, 641).
U.S. Pat. No. 5,223,507 and U.S. Pat. No. 5,225,417 (G. D. Searle & Co.) disclose bicycle-condensed morphinoid compounds which are said to be delta opioid agonists having therapeutic utility as analgesics agents.
International Application Publication Number WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti-inflammatory agents.
International Application Publication Numbers WO 96/02545 and WO 97/25331 (SmithKline Beecham S.p.A.) disclose a novel class of substituted monoheterocycle-condensed morphinoid derivatives which are stated to be potent and selective delta opioid agonists and antagonists. They are stated to have potential therapeutic utility as inter alia analgesics.
The contents of WO 96/02545 are incorporated herein by reference, including compounds of formula (IA) as defined below and the specific Examples disclosed therein:
wherein;
R
1A
is hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, C
3-5
alkenyl, aryl, aralkyl or furan-2 or 3-yl alkyl or (CH
2
)
m
A
COR
A
wherein m
A
is 1 to 5 and R
A
represents hydroxy, C
1-5
alkoxy, OC
3-6
alkenyl or alkylaryl or R
1A
is a group A
A
-B
A
wherein A
A
represents C
1-10
alkylene and B
A
represents substituted or unsubstituted aryl or heteroaryl;
R
2A
is hydrogen, hydroxy or C
1-5
alkoxy, preferably methoxy, halogen, nitro, NR
8A
R
9A
, SR
8A
, where R
8A
and R
9A
, which may be the same or different, are each hydrogen, C
1-6
alkyl, COR
1A
preferably acetyl.
R
3A
is hydrogen, hydroxy, C
1-5
alkoxy, preferably methoxy, halogen, SR
8A
, preferably hydrogen, nitro, NHR
10A
, NR
10A
R
11A
, NHCOR
10A
, NHSO
2
R
10A
, where R
10A
and R
11A
which may be the same or different, are each hydrogen or C
1-6
alkyl, preferably methyl;
R
4A
and R
5A
, which may be the same or different, are each independently hydrogen, hydroxy, C
1-5
alkoxy, preferably methoxy, or together may form an oxy group (—O—);
R
6A
is a group
 in which R
3A
has the same meaning described above, there being up to three R
3A
in the phenyl ring, or R
6A
is a group C(Z
A
)R
12A
, in which Z
A
is oxygen or sulphur, R
12A
is C
1-18
alkyl, C
1-18
alkoxy or NR
13A
R
14A
, where R
13A
and R
14A
, which may be the same or different, are hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, C
3-6
alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring or may form together a C
3-6
alkyl ring which may be interrupted by an oxygen or a nitrogen.
R
7A
is hydrogen, C
1-18
alkyl, C
2-18
alkenyl, or is a group
 in which R
3A
has the same meaning described above;
n
A
is 0 or 1;
when n
A
=0, then X
A
and Y
A
are independently NH, oxygen and sulphur or CH or a R
6A
- or R
7A
-substituted carbon atom; and when n
A
=1, then X
A
and Y
A
are both N, or N and CH or a R
6A
- or R
7A
-substituted carbon atom.
The contents of WO 97/25331 are incorporated herein by reference, including compounds of formula (IB) as defined below and the specific Examples disclosed therein:
wherein;
R
1B
is hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, each of the latter three groups being optionally substituted by a hydroxy group when C
≧2
, C
3-5
alkenyl, aryl, aralkyl or furan-2 or 3-yl alkyl or (CH
2
)m
B
COR
B
wherein m
B
is 0 to 5 and R
B
represents linear or branched C
1-6
alkyl, hydroxy, C
1-5
alkoxy, OC
3-6
alkenyl or alkylaryl, NR
10B
R
11B
where R
10B
and R
11B
may be the same or different, and each is hydrogen, linear or branched C
1-6
alky, C
4-6
cycloalkylalkyl, C
3-5
alkenyl, aryl or aralkyl; or R
1B
is a group A
B
-B
B
wherein A
B
represents C
1-10
alkylene and B
B
represents substituted or unsubstituted aryl or heteroaryl;
R
2B
is hydrogen, hydroxy or C
1-5
alkoxy, preferably methoxy, halogen, nitro, NR
10B
R
11B
, SR
10B
, where R
10B
and R
11B
have the same meaning described above and in addition R
10B
is COR
1B
, preferably acetyl;
R
3B
is hydrogen, linear or branched C
1-6
alkyl, preferably ethyl, hydroxy, C
1-5
alkoxy, preferably methoxy, halogen, preferably bromine, or (CH
2
)
m
B
COR
B
where m
B
and R
B
have the same meaning described above, SR
10B
, nitro, NR
10B
R
11B
, NHCOR
10B
, NHSO
2
R
10B
, where R
10B
and R
11B
, have the same meaning described above, preferably hydrogen or methyl;
R
4B
and R
5B
, which may be the same or different, are each independently hydrogen, hydroxy, C
1-5
alkoxy, preferably methoxy, O-phenyl or together may form an oxy group (—O—); or R
4B
together with R
3B
may form a methylendioxy group (—OCH
2
O—);
R
6B
is a group
 or a five- or six-membered heteroaromatic group, containing up to three heteroatoms such as O, S and N, substituted with R
3B
in which R
3B
has the same meaning described above, there being up to three R
3B
groups in the ring,
or R
6B
is a group C(Z
B
)R
12B
, in which Z
B
is oxygen or sulphur, R
12B
is linear or branched C
1-18
alkyl, hydroxy, linear or branched C
1-18
alkoxy, aralkyloxy or NR
13B
R
14B
, where R
13B
and R
14B
, which may be the same or different, are hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, each of the latter three groups being optionally substituted by up to three fluorine atoms or hydroxy group when C
≧2
, C
3-6
alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring or R
13B
and R
14B
may form together a C
3-6
alkyl ring which may be interrupted by an oxygen or a NR
1B
where R
1B
has the same meaning described above,
or R
6B
is a CH
2
W
B
D
B
group, where W
B
is oxygen, sulphur or NR
14B
, and D
B
is hydrogen, linear or branched alkyl or COR
14B
, where R
14B
is defined above and is preferaby methyl;
or R
6B
is a COCOR
12B
group, where R
12B
has the same meaning described above, and is preferably C
1-18
alkoxy;
or R
6B
is a NR
13B
R
14B
group, where R
13B
and R
14B
have the same meaning described above, or R
13B
may be a (CH
2
)
m
B
COR
B
group where m
B
and R
B
have the same meanings defined above;
or R
6B
is a P(Z
B
)R
12B
group where Z
B
and R
12B
have the same meaning described above, and preferably Z
B
=O and R
12B
=C
1-18
alkoxy;
or R
6B
is a S(O)
i
R
12B
group where i=1,2 and R
12B
has the same meaning described above;
R
7B
is hydrogen, C
1-18
alkyl, C
2-18
alkenyl, halogen, halogen-C
1-6
alkyl, (CH
2
)
m
B
COR
B
where m
B
and R
B
have the same meanings defined above or is a group
 or a five- or six-membered heteroaromatic group, containing up to three heteroatoms such as O, S and N, substituted with R
3B
in which R
3B
has the same meaning described above;
R
8B
is hydrogen, C
1-6
alkyl preferably methyl;
n
B
is 0 or 1;
when n
B
=0, then X
B
and Y
B
are independently oxygen, sulphur, CH or a R
6B
- or R
7B
-substituted carbon atom, and NR
9B
, where R
9B
is hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, each of the latter three groups being optionally substituted by

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