Diarylalkenylamine derivatives

Details Diarylalkenylamine derivatives Diarylalkenylamine derivatives

1998-06-05

2001-07-17

Oswecki, Jane C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S210010, C514S211010, C514S231200, C514S239500, C514S277000, C514S357000, C514S374000, C514S378000, C514S472000, C514S617000, C514S618000, C514S620000, C514S624000, C540S484000, C540S544000, C546S106000, C546S152000, C546S162000, C546S329000, C546S337000, C548S215000

Reexamination Certificate

active

06262104

ABSTRACT:

This application is a 371 of PCT/EP96/03988 filed Sep. 9, 1996.
This invention is concerned with novel diarylalkenylamine derivatives, 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 al 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).
Substituted diarylalkenylamines useful as analgesics (moffet R. B. and Everson G. N.
Org. Prep. and Procedures,
53, 11, 1979), antidepressant agents [Jones et al.
J. Med. Chem.
161, 14, 1971; Astra Lakemedel AB (Jpn. Kokai, Tokkyo Koho, 80/11, 563); Astra Lakemedel AB (Jpn. Kokai, Tokkyo Koho, 79/39,057)] and as potential inhibitors of adrenal corticosteroid biogenesis (blank B. et al.
J. Med. Chem.,
271, 12, 1969) have been already described.
We have now discovered a novel class of diarylalkenylamine 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 protectants, agents for treating drug and alcohol abuse, gastritis, diarrhoea, cardiovascular and respiratory diseases, cough, mental illness, epilepsy and, in general, agents 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
and R
2
, which can be the same or different, are each hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkenyl, C
4-6
cycloalkylalkyl, C
3-6
alkenyl, C
3-5
alkenyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C
3-7
alkyl ring which may be interrupted by oxygen.
R
3
and R
4
, which can be the same or different, are each hydrogen, linear or branched C
1-6
alkyl;
R
5
is hydroxy, C
1-6
alkoxy, thiol or alkythio;
R
6
is a —C(Z)—R
8
group, in which Z is oxygen or sulphur, R
8
is C
1-8
-alkyl, C
1-8
-alkoxy or NR
9
R
10
, wherein R
9
and R
10
, which may be the same or different, are hydrogen, straight or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
4-6
cycloalkylalkyl, C
3-6
alkenyl, aryl or aralkyl,
in which R
11
and R
12
have the same meaning as R
9
and R
10
or together form an optionally substituted heterocyclic ring and Z is as defined above, and
R
7
is hydrogen, straight or branched C
1-8
alkyl or halogen, preferably chlorine.
Preferably, R
6
is in the para or meta position.
Examples of R
1
and R
2
are methyl and, taken together, pyrrolidinyl.
Examples of R
3
and R
4
are hydrogen.
Examples of R
5
are hydroxy and methoxy.
Examples of R
6
are CONEt
2
, CON(—NH
2
—)
4
and CON(i-Pr)
2
.
An example of R
7
is hydrogen.
A first group of preferred compound of formula (I) are those in which each of R
3
and R
4
is hydrogen or C
1-6
alkyl, preferably methyl and R
1
, R
2
, R
5
, R
6
and R
7
are as defined above for formula (I).
A second preferred group of compounds of formula (I) are those in which R
5
is an hydroxy or C
1-6
alkoxy group, preferably methoxy, R
1
, R
2
, and R
6
and R
7
are as defined above for formula (I) and each of R
3
and R
4
is hydrogen or C
1-6
alkyl.
A particularly preferred group of compounds of formula (I) are those in which R
6
is a group —C(Z)—R8 where R
8
is NR
9
R
10
, R
9
and R
10
being as defined above for formula (I), Z is oxygen, R
1
, R
2
and R
7
are as defined above for formula (I), each of R
3
and R4 is hydrogen or C
1-6
alkyl, and R
5
is hydroxy or C
1-6
alkoxy.
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromis, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
The compounds of formula (I) exist in tow geometric isomer forms, E and Z, and the invention extends to all such forms as well as to their mixtures thereof.
In addition, the compounds of formula (I) may exist in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
The invention also provides a process for the preparation of a compound of formula (I) which comprises reacting a compound of general formula (IV)
in which R′
5
to R′
7
are R
5
to R
7
as defined for formula (I) or a group or atom convertible to R
5
to R
7
, with an ylide of general formula R
1
R
2
NCH
2
CH
2
P
+
Rh
3
Br
−
(A) or with a phosphonate of general formula (EtO)
2
POCH(R
4
)—COOEt (B) or (EtO)
2
POCH2—COR
3
(C) in the presence of a base to form a compound of general formula (Ia)
in which R′
1
to R′
4
are R
1
to R
4
as defined in formula (I), or a group or atom convertible to R
1
to R
4
; with the following provisos:
when a compound of general formula (IV) is treated with the phosponate of general formula (B), the resulting ester derivative undergoes a subsequent reduction to the corresponding alcohol which, after activation with a suitable leaving group, is treated with an amine of general formula NHR
1
R
2
in which R
1
and R
2
are as defined above to give a compound of general formula (Ia);
when a compound of general formula (IV) is treated with a phosponate of general formula (C), the resulting ketone intermediate undergoes a subsequent reductive amination using an amine of general formula NHR
1
R
2
in which R
1
and R
2
are as defined above to give a compound of general formula (Ia),
and optionally thereafter, performing one or more of the following steps:
a) where R′
1
to R′
7
are R
1
to R
7
, converting anyone of R′
1
to R′
7
to R
1
to R
7
to obtain a compound of general formula (I);
b) where R′
1
to R′
7
are other than R
1
to R
7
, converting anyone of R
1
to R
7
to another R
1
to R
7
to obtain compound of general formula (I);
c) forming a salt and/or solvate of the compound of formula (I)
In general, compounds of formula (I) may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing react

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