Dimeric compounds

Details Dimeric compounds Dimeric compounds

2001-02-16

2002-10-29

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S311000, C514S314000, C546S153000, C546S157000

Reexamination Certificate

active

06472408

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to dimeric compounds comprising two 5-amino-5,6,7,8-tetrahydroquinoline fragments joined together by a divalent linking group, processes for their preparation, intermediates for their preparation, pharmaceutical compositions containing such dimeric compounds and the use of such compounds as cholinesterase inhibitors and in the treatment of neurodegenerative diseases, such as Alzheimer's Disease and myasthenia gravis.
2. Description of Related Art
Huperzine A is a selective and potent reversible acetylcholinesterase (AChE) inhibitor isolated from the club moss
Huperzia serrata
which shows considerable promise for the palliative treatment of Alzheimer's Disease.
Total syntheses of the racemate and asymmetric syntheses of huperzine A have been reported (see for instance, Xia, Y.; Kozikowski, A. P;
J. Am. Chem. Soc
. 1989, 111, 4116-4117; Qian, L.; Ji, R.;
Tetrahedron Lett
. 1989, 30, 2089-2090; Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y-P.; Miller, J. H.; McKinney, M.;
J. Am. Chem. Soc
. 1991, 113, 4695-4696; Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S.;
Tetrahedron
1998, 54, 5471-5484; and He, X.-C.; Wang, B.; Bai, D.;
Tetrahedron Lett
. 1998, 39, 411-414. However, these-syntheses require a minimum of 12 steps.
Enormous effort has also been directed towards the development of more easily synthesised analogues which might prove to. be. more potent than huperzine A. More than 100 such analogues have been disclosed in the scientific and patent literature. For instance, U.S. Pat. No. 5,929,084 discloses huperzine A derivatives in which the hydrogen atom at the 1-position in huperzine A is optionally replaced by a C
1-5
alkyl, pyridoyl or C
1-5
alkoxy-substituted benzoyl group and the amino group at the 5-position in huperzine A is replaced by a group —N(R″)YR where Y is a carbonyl group, R″ is a hydrogen atom or a C
1-5
alkyl group, or R″ and Y together form a group ═CH, and R is a C
1-5
alkyl or an optionally substituted phenyl, benzyl, naphthyl or pyridyl group. U.S. Pat. No. 5,547,960 discloses huperzine A derivatives which are mono- or disubstituted at the 10-position. Substitution at other positions of the huperzine A molecule is also contemplated in U.S. Pat. No. 5,547,960 but no examples of any such compounds are provided. However, to date, the only huperzine A analogues which have shown superior potency relative to the natural product feature the judicious addition of one or two methyl groups at the 10-position. In this respect, the compounds of formula A above in which R is methyl and R′ is hydrogen and both R and R′ are methyl are 8- and 1.4-fold more potent than huperzine A respectively. However, the syntheses of these compounds are longer than that of the natural product.
Removal of the three carbon bridge (C-6 to C-8) from huperzine A has also been explored (see, for instance Kozikowski, A. P.; Miller, C. P.; Yamada, F.; Pang, Y-P.; Miller, J. H.; McKinney, M.; Ball, R. G.;
J. Med. Chem
. 1991, 34, 3399-3402; Bai. D.;
Pure
&
Appl. Chem
. 1993, 65, 1103-1112; and Fink. D. M.; Bores, G. M.; Effland, R. C.; Huger, F. P.; Kurys, B. E.; Rush, D. K.; Selk, D. E.;
J. Med. Chem
. 1995, 38, 3645-3651). However, in general, these derivatives are very weak AChE inhibitors (IC
50
generally >100,000 nM). Similarly, U.S. Pat. No. 5,110,815 discloses certain 5-amino-5,6,7,8-tetrahydroquinolines which are said to inhibit AChE and relieve memory dysfunction. However, the compounds disclosed are very weak AChE inhibitors (IC
50
values in the range of 3.1 to 9.6 &mgr;M).
Another AChE inhibitor which has been approved for use in the US for the palliative treatment of Alzheimer's Disease is 9-amino-1,2,3,4-tetrahydroacridine, also known as THA or tacrine. However, tacrine is a weaker AChE inhibitor than huperzine A and the use of tacrine is currently limited by its peripheral toxicity.
Various compounds have been synthesised which contain tacrine moieties in the search for further efficacious AChE inhibitors. For instance, U.S. Pat. No. 5,783,584 discloses certain alkylene-linked bis-tacrine compounds which are much more potent and much more selective for AChE inhibition than monomeric tacrine. However, despite the increased anti-AChE potency of these bis-tacrine compounds, the very presence of two tacrine moieties in such molecules is likely to cause some significant residual toxicity.
U.S. Pat. No. 5,886,007 discloses tacrine derivatives in which the amino group at the 9-position is substituted by an aralkyl group. These compounds also inhibit AChE but are generally less active than monomeric tacrine and 100- to 15000-fold less active than the compounds of U.S. Pat. No. 5,783,584.
Similarly, Carlier, P. R.; Du, D-M.; Han,Y.;Lin, J.; Pang, Y-P.;
Bioorg. Med. Chem. Lett
. 1999, 9, 2335-2338, discloses tacrine derivatives in which the amino group at the 9-position is attached to a 5-amino-5,6,7,8-tetrahydro-2(1H)-quinolone moiety by an alkylene chain. However, whilst these compounds are stronger inhibitors of AChE than monomeric tacrine, they are not as potent as the compounds of U.S. Pat. No. 5,783,584. Moreover, like the compounds of U.S. Pat. No. 5,886,007, these compounds still contain one tacrine moiety and are therefore likely to exhibit toxicity problems.
DETAILED DESCRIPTION OF THE INVENTION
It has now been surprisingly discovered that dimeric compounds containing two 5-amino-5,6,7,8-tetrahydroquinoline or similar moieties joined together by a divalent linking group exhibit high potency as cholinesterase, especially AChE, inhibitors despite the fact that the activity of the constituent 5-amino-5,6,7,8-tetrahydroquinoline or similar monomers is extremely low. Indeed, the optimum dimers are twice as potent as huperzine A. Moreover, such dimeric compounds do not contain any toxic tacrine moieties and can be synthesised in just nine steps from commercially available starting materials.
According to the present invention there is therefore provided a dimeric compound comprising two fragments, which may be the same or different, joined together by a divalent linking group, each fragment having a nucleus of the general formula
which may be substituted or unsubstituted, in which Q represents the number of carbon atoms necessary to form a 5,6 or 7-membered ring;
R
1
represents a hydrogen atom or an optionally substituted alkyl group;
—W—X— represents a group
—N(R
2
)—C(O)— or N═C(OR
3
)—, where R
2
represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl or aralkyl group, and R
3
represents a hydrogen atom or an optionally substituted alkyl or aralkyl group; or a salt thereof.
Suitable salts include acid addition salts and these may be formed by reaction of a suitable compound of formula I with a suitable acid, such as an o organic acid or a mineral acid, which is pharmaceutically acceptable. Pharmaceutically acceptable acid addition salts formed by reaction with a mineral acid are particularly preferred, especially salts formed by reaction with hydrochloric or hydrobromic acid. However, pharmaceutically acceptable acid addition salts formed by reaction with an organic acid are also preferred. Suitable organic acids include monobasic carboxylic acids, such as ethanoic and propanoic acid, dibasic carboxylic acids, such as maleic, tartaric, fumaric and oxalic acids, and tribasic carboxylic acids, such as carboxysuccinic and citric acid. Salts formed by reaction with tartaric, fumaric or oxalic acid are also preferred.
Any alkyl, alkenyl or alkynyl group, unless otherwise specified, may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl and butyl. When an alkyl moiety forms part of another group, for example the alkyl moiety of an aralkyl group, it is preferred that it contains up to 6, especially up to 4, carbon atoms. Preferred alkyl moieties in this respect are methyl and ethyl.
An aryl group may

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