Heterocycle-condensed morphinoid derivatives (II)

Details Heterocycle-condensed morphinoid derivatives (II) Heterocycle-condensed morphinoid derivatives (II)

1999-02-22

2002-04-02

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S281000, C514S282000, C546S039000, C546S040000, C546S041000, C546S043000, C546S044000, C546S045000, C546S046000, C546S047000, C546S048000, C546S049000, C546S050000, C546S056000, C546S057000

Reexamination Certificate

active

06365594

ABSTRACT:

The present invention is concerned with novel morphinoid compounds, processes for their preparation and their use in medicine.
The presence of at least three populations of opioid receptors (mu, delta and kappa) is now well established and documented and all three appear 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. Nos. 5,223,507 and 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.
WO 94/07896 (Toray Ind. Inc.) discloses indole-condensed morphinoid compounds useful as immunosuppressants, anti-allergic and anti-inflammatory agents.
We have now discovered a novel class of substituted monoheterocycle-condensed morphinoid derivatives which are potent and selective delta opioid agonists and antagonists which may therefore be of potential therapeutic utility as analgesics, immunosuppressants to prevent rejection in organ transplant and skin graft, anti-allergic and anti-inflammatory agents, brain cell protectant, agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness and epilepsy and, in general, for the treatment of those pathological conditions which customarily can be treated with agonists and antagonists of the delta opioid receptor.
According to the present invention, there is provided a compound, or a solvate or salt thereof of formula (I):
in which,
R
1
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
COR wherein m is 0 to 5 and R represents linear or branched C
1-6
alkyl, hydroxy, C
1-5
alkoxy, OC
3-6
alkenyl or alkylaryl, NR
10
R
11
where R
10
and R
11
may be the same or different, and each is hydrogen, linear or branched C
1-6
alkyl, C
4-6
cycloalkylalkyl, C
3-5
alkenyl, aryl or aralkyl; or R
1
is a group A-B wherein A represents C
1-10
alkylene and B represents substituted or unsubstituted aryl or heteroaryl;
R
2
is hydrogen, hydroxy or C
1-5
alkoxy, preferably methoxy, halogen, nitro, NR
10
R
11
, SR
10
, where R
10
and R
11
have the same meaning described above and in addition R
10
is COR
1
, preferably acetyl;
R
3
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
COR where m and R have the same meaning described above, SR
10
, nitro, NR
10
R
11
, NHCOR
10
, NHSO
2
R
10
, where R
10
and R
11
, have the same meaning described above, preferably hydrogen or methyl;
R
4
and R
5
, 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
4
together with R
3
may form a methylendioxy group (—OCH2O—); R
6
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
3
in which R
3
has the same meaning described above, there being up to three R
3
groups in the ring,
or R
6
is a group C(Z)R
12
, in which Z is oxygen or sulphur, R
12
is linear or branched C
1-18
alkyl, hydroxy, linear or branched C
1-18
alkoxy, aralkyloxy or NR
13
R
14
, where R
13
and R
14
, 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
13
and R
14
may form together a C
3-6
alkyl ring which may be interrupted by an oxygen or a NR
1
where R
1
has the same meaning described above,
or R
6
is a CH
2
WA group, where W is oxygen, sulphur or NR
14
, and A is hydrogen, linear or branched alkyl or COR
14
, where R
14
is defined above and is preferably methyl; or R
6
is a COCOR
12
group, where R
12
has the same meaning described above, and is preferably C
1-18
alkoxy;
or R
6
is a NR
13
R
14
group, where R
13
and R
14
have the same meaning described above, or R
13
may be a (CH2)mCOR group where m and R have the same meanings defined above;
or R
6
is a P(Z)R
12
group where Z and R
12
have the same meaning described above, and preferably Z=O and R12=C
1-18
alkoxy;
or R
6
is a S(O)
i
R
12
group where i=1,2 and R
12
has the same meaning described above. R
7
is hydrogen, C
1-18
alkyl, C
2-18
alkenyl, halogen, halogen-C
1-6
alkyl, (CH
2
)
m
COR where m and R 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
3
in which R
3
has the same meaning described above,
R
8
is hydrogen, C
1-6
alkyl preferably methyl;
n is 0 or 1;
when n=0, then X and Y are independently oxygen, sulphur, CH or a R6- or R7-substituted carbon atom, and NR
9
, where R
9
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
, or may contain a NR
10
R
11
group where R
10
and R
11
have the same meaning described above, C
3-5
alkenyl, aryl, aralkyl or (CH
2
)
m
COR wherein m is 0 to 5 and R represents hydroxy, C
1-5
alkoxy, OC
3-6
alkenyl or alkylaryl, NR
10
R
11
where R
10
and R
11
may be the same or different, are each hydrogen, linear or branched C
1-6
alkyl, C
4-6
cycloalkylalkyl; and when n=1, then X and Y are both N, or N and CH.
When R
1
is aryl, it is preferably phenyl and when it is aralkyl, it is preferably phenyl-C
1-6
alkyl.
Examples of R
1
are hydrogen, methyl, ethyl, propyl, i-propyl, allyl, benzyl, phenyl-ethyl, CH
2
CH
2
OH, CH
2
COOH, CH
2
COOEt, CH
2
CONH
2
, and COMe.
Examples of R
2
are hydrogen, hydroxy and methoxy.
Examples of R
3
are hydrogen, hydroxy, ethyl, bromine, hydroxy, methoxy, ethoxy, i-propoxy, COMe and OCH
2
COOH.
Examples of R
4
and R
5
are hydrogen, hydroxy, acetyloxy, methoxy, O-phenyl, together as an oxy group or R
4
together with R
3
is a methylendioxy group.
Examples of R
6
are CONH
2
, CONMe
2
, CONEt
2
, CON(i-Pr)
2
, CON(i-Pr)CH
2
Ph, CON(i-Pr)(CH
2
)
2
OH, CON(CH
2
CF
3
)(i-Pr), COOMe, COOEt, COO-n-Pr, COO-i-Pr, and COO-i-Bu, COOCH(i-Pr)
2
, CSNEt
2
, CSN(i-Pr)
2
, COOH, COMe, CO-i-Pr, CO-i-Bu, CO-t-Bu, CO-3-pentyl, COPh,
and PO(OEt)
2
.
Examples of R
7
are methyl, i-propyl, trifluoromethyl, CH
2
COOH and CH
2
COOEt.
An example of R
8
is hydrogen.
Examples of R
9
are hydrogen, methyl, CH
2
COOH, CH
2
COOEt, CH
2
CONHCH
2
Ph, CH
2
CONHMe, CH
2
CONMe
2
.
Examples of X are NR
9
, where R
9
are the same of the examples described above, and S.
Examples of Y are CR
7
, where R
7
are the same of the examples described above.
A group of preferred compounds of formula (I) is that in which n=0, X is NH and Y is CH or a R
6
- or R
7
-substituted carbon atom, where R
6
is a group —C(Z)—R
12
where R
12
is C
1-6
alkyl, C
1-4
alkoxy or NR
13
R
14
where R
13
and R
14
are as defined above and Z is oxygen; and R
7
is methyl or halogen-C
1-2
alkyl.
Particularly preferred compounds of formula (I) are those in which R
6
is CONEt
2
, CON(i-Pr)
2
or COO-i-Bu, R
7
is methyl,

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