Acridin derivatives

Details Acridin derivatives Acridin derivatives

2000-03-30

2001-08-14

Huang, Evelyn Mei (Department: 1625)

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

Organic compounds

Amino nitrogen containing

C564S305000, C549S330000, C546S104000

Reexamination Certificate

active

06274768

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to acridin derivatives of general formula I
or pharmaceutically acceptable salts thereof, and relates to a method of producing them and to their use as drugs.
Classical opioids such as morphine are used for the therapy of severe and very severe pain. Their use is limited, however, by their known side effects, e.g. respiratory depression, vomiting, sedation and obstipation, and by the development of tolerance. Moreover, they are less effective for neuropathic or incidental pain, from which tumour patients suffer in particular.
Opioids develop their analgesic effect by binding to membrane receptors, which form part of the family of what are termed G protein-coupled receptors. The biochemical and pharmacological characterisation of subtypes of these receptors has shown that subtype-specific opioids exhibit a spectrum of effects and side-effects which is different to that of morphine for example. Whereas morphine binds selectively to what are termed &mgr;-receptors, endogenous enkephalins have been characterised as &dgr;-selective peptides. In the meantime, other pharmacological investigations have indicated that a plurality of subtypes of these opioid receptors (&mgr;
1
, &mgr;
2
, &kgr;
1
, &kgr;
2
, &kgr;
3
, &dgr;
1
and &dgr;
2
) probably exist.
Knowledge of the physiological importance of &dgr;-receptor-selective substances has essentially been widened by the development of the non-peptidic antagonist naltrindol. In the meantime, it has been ascertained that &dgr;-agonists exhibit an autonomous antinociceptive potential. In addition to a multiplicity of experimental studies on animals, an investigation has also been performed in which the peptidic agonist D-alanine
2
-D-leucine
5
-enkephalin (DADL) was used on cancer patients on whom morphine no longer had an analgesic effect. When administered intrathecally, DADL exhibited a long-term analgesic effect. Moreover, &dgr;-agonists differ from &mgr;-agonists as regards their interaction with the “endogenous opioid antagonist” cholecystokinin (CCK).
SUMMARY OF THE INVENTION
The underlying object of the present invention was to provide substances having an analgesic effect which exhibit an affinity for &dgr;-opiate receptors.
This object has been achieved by the acridin derivatives according to the present invention. These new compounds exhibit a considerable affinity for &dgr;-opiate receptors.
The present invention relates to acridin derivatives corresponding to the general formula I:
wherein
R
1
denotes A, if
R
2
denotes H or OR
12
, or R
2
and R
3
form a double bond together,
R
3
denotes H, or R
e
and R
2
form a double bond together,
R
4
denotes CH
2
NR
14
R
15
;
R
5
denotes H or C
1-6
alkyl;
R
6
denotes H or C
1-6
alkyl;
R
7
denotes H;
R
8
denotes H;
or
R
3
denotes A, if
R
1
denotes H or R
1
R
4
form a double bond together;
R
2
denotes H;
R
4
denotes H or OR
12
, or R
4
and R
1
form a double bond together or R
4
and R
5
form a double bond together;
R
5
denotes H, or R
5
and R
4
form a double bond together;
R
6
denotes CH
2
NR
14
R
15
;
R
7
denotes H;
R
8
denotes H;
or
R
5
denotes A, if
R
1
denotes H;
R
2
denotes H;
R
4
denotes H;
R
6
denotes H or OR
12
, or R
6
and R
3
form a double bond together, or R
6
and R
7
form a double bond together;
R
7
denotes H, or R
7
and R
6
form a double bond together;
R
8
denotes CH
2
NR
14
R
15
;
and
A denotes
R
9
and R
10
are identical to or different from each other and denote H, OH, C
1-6
alkoxy, Cl, F, CF
3
, CN, COOH, CONR
17
R
18
or COOR
16
;
R
11
denotes H, OH, C
1-6
alkoxy, O—C
3-7
cycloalkyl, O-aryl or O- heterocyclyl;
R
12
denotes H, C
1-6
alkyl, aryl or COR
13
R
13
denotes C
1-6
alkyl or aryl,
R
14
, R
15
are identical to or different from each other and denote C
1-6
alkyl, aryl or C
3-7
-cycloalkyl;
R
16
denotes C
1-6
alkyl or aryl,
R
17
, R
18
are identical to or different from each other and denote C
1-6
alkyl or aryl; and
X represents N if Y represents C, or X represents C if Y represents N, or pharmaceutically acceptable salts thereof.
The preferred compounds of formula I are those in which R
14
and R
15
are identical to or different from each other and denote C
1-6
alkyl, and R
1
to R
13
, R
16
to R
18
, X and Y have the above meanings, or in which
R
11
denotes OH or C
1-6
alkoxy, and R
1
to R
10
, R
12
to R
18
, X and Y have the above meanings, or in which
R
1
denotes A, R
11
denotes OH or C
1-6
alkoxy, R
14
and R
15
, independently of each other, denote C
1-6
alkyl and R
2
to R
10
, R
12
, R
13
, R
16
to R
18
, X and Y have the above meanings, or in which
R
3
denotes A, R
11
denotes OH or C
1-6
alkoxy, R
14
and R
15
, independently of each other, denote C
1-6
alkyl, and R
1
, R
2
, R
4
to R
10
, R
12
, R
13
, R
16
to R
18
, X and Y have the above meanings, or in which
R
5
denotes A, R
11
denotes OH or C
1-6
alkoxy, R
14
and R
15
, independently of each other, denote C
1-6
alkyl, and R
1
to R
4
, R
6
to R
10
, R
12
, R
13
, R
16
to R
18
, X and Y have the above meanings.
Other preferred compounds comprise the following:
rac-cis-[3-dimethylaminomethyl-2-(3-methoxyphenyl)]-1,2,3,4-tetahydro-acridin-2-ol hydrochloride;
rac-cis-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)]-1,2,3,4tetrahydro-acridin-3-ol hydrochloride;
[3-dimethylaminomethyl-2-(3-hydroxy-phenyl)]-3,4-diydro-acridin-1-enehydrochloride;
rac-trans-[3-dimethylaminomethyl-2-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol hydrochloride;
rac-cis-[3-dimethylaminomethyl-2-(3-hydroxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol hydrochloride;
[1-(3-methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
[3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
[3-dimethylaminomethyl-2-(3-methoxy-phenyl)]-3,4-dihydro-acridin-1-enehydrochloride;
rac-trans-[1-(3-methoxy-phenyl)-1,2,3,4-tetrrhydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
rac-cis-[1-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
rac-trans-[3-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
rac-cis-[3-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamine hydrochloride;
[3-(2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)]-phenol hydrochloride;
[3-(2-dimethylaminomethyl-1,2-dihydro-acridin-3-yl 1-phenol;
rac-trans-[3-(2-dimethylaminomethyl-1,2,3,4-tetra-hydro-acridin-3-yl)]-phenol;
rac-trans-[3-(2-dimethylaminomethyl-1,2,3,4-tetra-hydro-acridin-1-yl)]-phenol hydrochloride;
rac-cis-[2-dimethylaminomethyl-1-(3-methoxy-phenyl)]-3,3-dimethyl-1,2,3,4tetrahydro-acridin-1-ol hydrochloride; and
3-(2-dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-acridin-1-yl)-phenol hydrochloride.
In the context of the present invention, the expression “C
1-6
alkyl” means straight chain or branched hydrocarbons comprising 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl isopropyl, n-butyl, sec-butyl, tert-butyl, neopentyl and n-hexyl.
In the context of the present invention, the expression “C
1-6
alkoxy” means straight chain or branched hydrocarbons comprising 1 to 6 carbon atoms, such as those defined above, which are bonded via an oxygen atom.
In the context of the present invention, the expression “C
3-7
cycloalkyl” means saturated cyclic hydrocarbons comprising 3 to 7 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
In the context of the present invention, the expression “aryl” means phenyl groups which are unsubstituted or which are singly- or multiply-substituted with OH, F, Cl, CF
3
, C
1-6
alkyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
2-6
alkylene, heterocyclyl or phenyl. This expression can also denote naphthyl.
In the context of the present invention, the expression “heterocyclyl” means 5- or 6-membered saturated or unsaturated heterocyclic compounds,

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