Substituted cycloheptenes, their preparation and use

Details Substituted cycloheptenes, their preparation and use Substituted cycloheptenes, their preparation and use

1999-12-14

2001-11-27

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S443000, C514S646000

Reexamination Certificate

active

06323369

ABSTRACT:

The invention provides substituted cycloheptenes of the general formula I
in which
R
1
represents OH, O—(C
1
-C
6
) -alkyl, O—(C
3
-C
7
) -cycloalkyl, O-aryl, C
1
-C
6
alkyl-COO—, aryl-COO—,
R
2
represents C
1
-C
6
-alkyl, (CH
2
)
(1-2)
-aryl, C
2
-C
6
-alkenyl-aryl and
R
3
represents (CH
2
)
(0-1)
—C
5
-C
7
-cycloalkyl, (CH
2
)
(0-2)
-aryl, heterocyclyl, C
1
-C
6
-alkyl-heterocyclyl,
either as a racemate or in the form of the pure enantiomers, each as a base or as a salt with a pharmaceutically acceptable acid, a process for their preparation and their use as medicaments.
Classical opioids such as morphine are very effective during the treatment of severe to very severe pain. However, their use is restricted due to the known side-effects, e.g. respiratory depression, vomiting, sedation, obstipation and the development of tolerance. In addition they are less effective in the case of neuropathic or incidental pains such as those suffered in particular by tumour patients.
opioids develop their analgesic effect by bonding to receptors located in the membrane, these belonging to the family of so-called G-protein coupled receptors. The biochemical and pharmacological characterisation of subtypes of these receptors has now led to the hope that subtype-specific opioids may provide a different effect/side-effect profile from e.g. morphine. Whereas morphine bonds selectively to the so-called &mgr;-receptors, endogenous encephalines have been characterised as &dgr;-selective peptides. Further pharmacological tests have now demonstrated the probable existence of more subtypes of these opioid receptors (&mgr;
1
, &mgr;
2
, &kgr;
1
, &kgr;
2
, &kgr;
3
, &dgr;
1
and &dgr;
2
).
Knowledge relating to the physiological significance of &dgr;-receptor selective substances has been substantially extended by the discovery of the non-peptidic antagonist naltrindol. It has now been demonstrated that &dgr;-agonists have an intrinsic antinociceptive potential. In addition to a number of animal experimental studies, there have also been trials with the peptidic agonists D-alanine
2
-D-leucine
5
-encephalin (DADL) in cancer patients for whom morphine was no longer having an analgesic effect. Following intrathecal administration, DADL exhibited a long-lasting analgesic effect.
Obviously &dgr;-agonists differ from &mgr;-agonists in their interaction with the “endogenous opioid antagonist” cholecystokinin (CCK). In addition to this different mode of action, the actual side-effects profile of &dgr;-agonists and &mgr;-agonists may differ, e.g. by reducing the respiratory depression or obstipation. These compounds have great potential as analgesics and, quite generally, for all pathological conditions which can normally be treated with &dgr;-opiate receptor agonists.
The object on which the invention is based therefore comprises providing analgesically effective substances whose biological effectiveness is partly or largely promoted via &dgr;-opiate receptor agonists.
It has now been found that these requirements are satisfied by the substituted cycloheptene compounds of the general formula I.
The present invention provides new substituted cycloheptenes of the general formula I
in which
R
1
represents OH, O—(C
1
-C
6
)-alkyl, O—(C
3
-C
7
)-cycloalkyl, O-aryl, C
1
-C
6
-alkyl-COO—, aryl-COO—,
R
2
represents C
1
-C
6
-alkyl, (CH
2
)
(1-2)
-aryl, C
2
-C
6
-Alkenyl-aryl and
R
3
represents (CH
2
)
(0-1)
—C
5
-C
7
-cycloalkyl, (CH
2
)
(0-2)
-aryl, heterocyclyl, C
1
-C
6
-alkyl-heterocyclyl
which are present in the form of their enantiomers, diastereomers, racemates or bases or as salts of physiologically acceptable acids.
Compounds of the general formula I in which R
1
represents OH, O—(C
1
-C
6
)-alkyl, O—(C
3
-C
7
)-cycloalkyl, O-aryl, C
1
-C
6
-alkyl-COO—, or aryl-COO— and R
2
and R
3
are defined in accordance with the definition for general formula I, or
R
1
represents OH, O—(C
1
-C
6
)-alkyl or O—(C
3
-C
7
)-cycloalkyl, R
2
represents C
1
-C
6
-alkyl or (CH
2
)
(1-2)
-aryl and R
3
is defined in accordance with the definition for general formula I, or
R
1
represents OH, R
2
represents C
1
-C
6
-alkyl or (CH
2
)
(1-2)
-aryl and R
3
is defined in accordance with the definition for general formula I, or
R
1
represents OH, R
2
represents C
1
-C
6
-alkyl and R
3
is defined in accordance with the definition for general formula I are preferred.
Particularly preferred compounds include the following:
3-[6-(4-chlorophenyl)-2-dimethylaminomethyl-cyclohept-1-enyl]-phenol hydrochloride
3-(2-dimethylaminomethyl-6-phenyl-cyclohept-1-enyl)-phenol hydrochloride
3-(2-dimethylaminomethyl-6-naphth-1-yl-cyclohept-1-enyl)-phenol hydrochloride
3-(2-dimethylaminomethyl-6-naphth-2-yl-cyclohept-1-enyl]-phenol hydrochloride
3-[2-dimethylaminomethyl-6-(4-hydroxyphenyl)-cyclohept-1-enyl]-phenol hydrochloride
3-(2-dimethylaminomethyl-6-m-toluyl-cyclohept-1-enyl]-phenol hydrochloride
3-[6-(3-tert-butyl-phenyl)-2-dimethylaminomethyl-cyclohept-1-enyl]-phenol hydrochloride
6-[4-dimethylaminomethyl)-3-(3-hydroxyphenyl)-cyclohept-3-enyl]-naphth-2-ol hydrochloride
3-[2-dimethylaminomethyl-6-(3-fluoro-4-hydroxyphenyl)-cyclohept-1-enyl]-phenol hydrochloride
3-[2-dimethylaminomethyl-6-(2-hydroxyphenyl)-cyclohept-1-enyl]-phenol hydrochloride
3-(6-cyclohexyl-2-dimethylaminomethyl-cyclohept-1-enyl)-phenol hydrochloride
3-(6-cyclohexylmethyl-2-dimethylaminomethyl-cyclohept-1-enyl)-phenol hydrochloride
3-(6-benzyl-2-dimethylaminomethyl-cyclohept-1-enyl)-phenol hydrochloride
3-[2-dimethylaminomethyl)-6-(3-hydroxybenzyl)-cyclohept-1-enyl]-phenol hydrochloride
3-(2-dimethylaminomethyl)-6-phenethyl-cyclohept-1-enyl)-phenol hydrochloride
3-[2-dimethylaminomethyl)-6-(3,5-dimethyl-4-hydroxyphenyl)-cyclohept-1-enyl]-phenol hydrochloride
3-[2-dimethylaminomethyl-6-(3-hydroxyphenyl)-cyclohept-1-enyl]-phenol hydrochloride
3-[2-(methylphenethylaminomethyl)-6-phenyl-cyclohept-1-enyl]-phenol hydrochloride and
[2-(3-methoxyphenyl)-4-naphth-1-yl-cyclohept-1-enyl-methyl]-dimethylamine hydrochloride.
The expression “C
1
-C
6
-alkyl” in the present invention means straight chain or branched hydrocarbons with 1 to 6 carbon atoms. The following may be mentioned by way of example:
methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.
In the context of the present invention the expression “C
2
-C
6
-alkenylene” means straight chain or branched hydrocarbons with 2 to 6 carbon atoms which contain one or more double bonds. Examples are 2-propenyl, 2-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl or 1,3-dimethyl-3-butenyl.
The expression “aryl” in the context of the present invention means unsubstituted phenyls or phenyls which are substituted once or several times by OH, F, Cl, CF
3
, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, C
1
-C
7
-cycloalkoxy, C
3
-C
7
-cycloalkyl, C
2
-C
6
-alkenylene or heterocyclyl units. The heterocyclyl or phenyl groups may optionally be fused. The expression may optionally also mean naphthyl.
The expression “heterocyclyl” in the context of the present invention is understood to mean 5- or 6-membered saturated or unsaturated, optionally provided with a fused aryl system, heterocyclic compounds which contain one or two hetero atoms from the group nitrogen, oxygen and/or sulfur.
Examples of saturated heterocyclyl compounds are 1,4-dioxan, tetrahydrofuran and 1,4-thioxan.
The following may be mentioned by way of example from the group of unsaturated heterocyclyl compounds; furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine and quinazoline.
The expression “C
1
-C
6
-alkylheterocyclyl” in the context of the present invention means that

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