Compounds and their therapeutic use

Details Compounds and their therapeutic use Compounds and their therapeutic use

2002-12-20

2004-06-08

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S448000, C549S070000, C549S073000

Reexamination Certificate

active

06747057

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention is enclosed within the pharmaceutical research and industry field. In particular, it is centred on the identification of previously described or new chemical compounds useful in the treatment of any pathology related to the phosphorylating activity of the enzyme GSK-3 as, for instance, Alzheimer's Disease, AD.
BACKGROUND OF THE INVENTION
The progressive ageing of the world population brings on the undesired consequence of an increase in the incidence of senile dementia, The most widely spread of this dementia is AD, which affects near 50% of the population aged 85 years or more and, as longevity increases, this rate will also increase unless the strategies to prevent or arrest the neurocdegenerative processes become successful.
There are several biochemical processes affected in AD patients. The treatment of these pathologies would be a correct approach to diminish the damage caused by the disease but, up to now, the only drugs commercialised are some agents that improve cholinergic neurotransmission. Although temporarily, they alleviate the cognoscitive and memory failures associated to AD, At present, most of the research is mainly focused on the search of new agents useful in the treatment of two other pathologies, senile plaques and neurofibrillary tangles, which constitute the major histological lesions observed in AD brains and are also associated with the cholinergic neurotransmission [“Modulation of &bgr;-amyloid precursor protein processing and tau phosphorylation by acetylcholine receptors” Hellström-Lindahl, E.;
Eur. J. Pharmacology
2000, 393, 255-2633].
The object of this invention is precisely related to the discovery of new products which are able to interfere the developing of neurofibrillary tangles. These tangles are formed by paired helical filaments whose main component is an intracellular, polar, quite hydrosoluble, microtubule-associated phosphoprotein protein named tau which appears abnormally phosphorylated. In normal cells, tau is essential for the integrity and stability of the neuronal cytoskeleton but its biological activity appears regulated by the degree of phosphorylation: normal brain tau contains 2-3 moles phosphate/mole protein while AD abnormally hyperphosphorylated tau contains 5-9 moles phosphate/mole protein [“Brain microtubule associated proteins: Modifications and disease” (Kosic, K. and Avila, J. Eds.) Chap. 7: “Tau phosphatases” Iqbal, K. et al. Harwood Academic Publishers, New York, pp. 95-111 (1997)]. Pathological tau presents a diminished capacity to stabilise microtubules, bringing on the corresponding neuronal degeneration, and aggregates into the filaments that form the tangles.
Hyperphosphorylation of tau and progress of AD relation is well demonstrated. Thus, selective inhibitors of the enzymes (kinases) that catalyse the abnormal phosphorylation of tau could become very useful therapeutic agents in the treatment of AD. In fact, the search for these inhibitors is an outstanding field of current pharmaceutical research [“Tau protein as a therapeutic target in Alzheimer's disease and other neurodegenerative diseases” Larner, A. J.;
Expert Opinion on Therapeutic Patents
1999, 9, 1359-1370].
Neither the whole tau hyperphosphorylation process nor all the kinases involved in it are completely known, but it is clear that GSK-3 is an in vivo kinase in brain and that it plays a central role in the pathological process. The discovery of non-toxic GSK-3 inhibitors would be very important, both from the scientific and industrial points of view, because, until now, the lithium cation is the only agent that have proved to inhibit GSK-3 but in therapeutically unacceptable high concentrations. A comprehensive review on this subject may be found in “Inhibition of tau phosphorylation: a new therapeutic strategy for the treatment of Alzheimer's disease and other neurodegenerative disorders” Castro, A.; Martinez, A.;
Expert Opinion on Therapeutic Patents
2000, 10, 1519-1527. It has also been observed that insulin inactivates GSK-3 and that non-dependent insulin diabetes mellitus is related to the activation of the enzyme, so, there is the possibility that GSK-3 inhibitors could became new useful agents in the treatment of that kind of diabetes.
Research conducted by the present applicants has recently shown that a new family of aromatic and heteroaromatic ketones exhibit GSK-3 inhibitor activity at a micromolar or lower concentration level, thus leading to the completion of the present invention.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides compounds of general formula I:
wherein:
X represents —CH═CH—, —CH═CR—, —CR═CR—, —CO—, —O—, —NH—, —NR—, —S—, —SO—, —SO
2
—, —CH═N—, —CR═N—, —CH═N(O)—, —CR═N(O)— or any other atom or group of atoms capable of forming a 5- or 6-membered heterocyclic ring;
Y
1
, Y
2
and Y
3
independently represent hydrogen or halogen;
R
1
, R
2
and R
3
are independently represent hydrogen, halogen, hydrocarbyl (—R), hydroxyl (—OH), hydrocarbyloxy (—O—R), mercapto (—SH), hydrocarbylthio (—S—R), hydrocarbylsulfinyl (—SO—R), hydrocarbylsulfonyl (—SO
2
—R), nitro (—NO
2
), amino (—NH
2
), hydrocarbylamino (—NHR), bis(hydrocarbyl)amino (—NR
2
), hydrocarbylcarbonylamino (—NH—CO—R), cyano (—CN), carbamoyl (—CONH
2
), hydrocarbylcarbamoyl (—CONHR), bis(hydrocarbyl)carbamoyl (—CONR
2
), carboxyl (—CO
2
H), hydrocarbyloxycarbonyl (—CO
2
R), formyl (—CHO), hydrocarbylcarbonyl (—COR), hydrocarbylcarbonyloxy (—OCOR), optionally substituted heteroaryl or optionally substituted heterocyclic;
the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be substituted by one or more substituents, selected from those defined above in relation to R
1
, R
2
and R
3
.
As described below, the compounds of formula (I) are inhibitors of kinases in general and of GSK-3 in particular, and are therefore useful as possible therapeutic agents.
Therefore, in a second aspect, the invention provides the use of a compound of formula (I) as a medicament, in particular in the manufacture of a medicament for the treatment including prophylaxis of diseases mediated by the activation of GSK-3.
In a third aspect, the invention provides a method of treating a mammal, notably a human, affected by a disease mediated by the activation of GSK-3, which comprises administering to the affected individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition thereof.
In further aspects, the present invention provides a pharmaceutical preparation which contain as active ingredient a compound or compounds of the invention, as well as a process for the preparation of such a pharmaceutical.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In the compounds of formula (I), the hydrocarbyl group R and the hydrocarbyl component of the other groups is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl. These are defined in more detail below.
In the definitions used in the present application, alkyl groups may be straight or branched chain groups and preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.
Preferred alkenyl and alkynyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more pr

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