ITPD20070209A1 - ANALOGUES OF THE OMOCISTEINE - Google Patents

Description

"ANALOGS OF HOMOCYSTEINE"

DESCRIPTION

The present invention generally relates to the pharmacological field and, more particularly, relates to a new class of homocysteine analogous compounds. Further, the invention relates to the use of this class of compounds for the preparation of a drug for the treatment of a pathology linked to the action of homocysteine.

Homocysteine is a sulphured amino acid whose production in the body occurs through the demethylation of methionine. Normally, homocysteine levels are regulated so as to be kept below 13-15 μΜ, especially by means of methionine remethylation processes, in a reaction that requires the presence of folate and vitamin B12 and the synthesis of cysteine, during which 1 <1> homocysteine is condensed with serine. However, the plasma values of homocysteine can increase in case of metabolic dysfunctions or following pharmacological therapies: for example, in subjects treated with L-DOPA there is a marked increase in the piasmatic value of homocysteine, as the metabolism of L- Piasmatic DOPA of homocysteine, as the metabolism of L-DOPA leads to the formation of the sulfur amino acid.

It has been observed that an elevated level of homocysteine in the plasma, a condition known as hyperhomocysteinemia, is a common risk factor for vascular diseases, such as stroke and myocardial infarction, but also for many cancers, such as glioblastoma. Furthermore, a link has been suggested between hyperhomocysteinemia and diseases such as spina bifida, meningocele, autism, depression, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease.

Experimental data acquired over time have shown that the pathological action of homocysteine is linked to the formation of oxygen free radicals through a mechanism of self-oxidation. Furthermore, homocysteine also possesses a more specific action, involving precise molecular targets.

In fact, it has been demonstrated that homocysteine exerts a negative allosteric action on D2 receptors, the receptors involved, for example, in the treatment of Parkinson's disease and schizophrenia (Agnati et al., J. Proteome Res., Vol. 5, pages 3077-3083, 2006). Homocysteine binds to D2 receptors at a different allosteric site than the active site; this allosteric site consists of a region rich in Arginine, with which 1 <1> homocysteine is able to establish a bond by means of electrostatic interactions. As demonstrated by Agnati et al., The interaction between D2 receptors and homocysteine leads to a reduction in signal transmission mediated by the D2 receptor pathway. over time, of L-DOPA therapy on patients with Parkinson's disease: the administration of L-DOPA leads to an increase in homocysteine levels and, while L-DOPA activates the D2 receptors, 1 <1> homocysteine tends to exert a negative action on the same receptors, therefore an increasing quantity of L-DOPA must be administered to counteract the inhibiting effects of homocysteine.

The action of homocysteine on NMDA receptors is carried out in a similar way, by means of the binding of the sulfur amino acid at the level of an allosteric site on the NMDA receptor. (Lipton et al., Proc. Nati. Acad. Sci. U.S.A., Vol. 94, pages 5923-5928, 1997) The effects of this interaction are characterized in the form of a positive allosteric action, with a consequent overstimulation of NMDA receptors , as a result of which there is a high release of calcium ions, whose massive influx into the cells triggers apoptotic phenomena (neurotoxicity).

Further experimental evidence indicates that homocysteine has a specific action in the development of Alzheimer's disease: circular dichroism studies have shown that homocysteine interacts with the beta-amyloid peptide 40 and 42 (Αβ40 and Αβ42), favoring its acquisition of the "β-sheet" conformation, the first step in the formation of amyloid aggregates and toxic compounds that have pathogenetic significance in Alzheimer's disease.

As regards the development of tumor forms, in particular glioblastoma, it has been discovered that homocysteine can act at the level of the p53 protein, a genetic dysfunction of which is often at the basis of tumor forms, both by controlling cellular expression and favoring a conformational alteration in it, with cascading effects on cell survival and / or replication.

By virtue of the involvement of homocysteine in the pathologies listed above, for example through the ability to modulate specific receptors, this compound is potentially useful in the field of pharmacological therapies. However, as mentioned, plasma homocysteine levels above 13-15 μΜ are characterized by toxic effects, partly due to the formation of oxygen radicals during the self-oxidation of homocysteine itself and partly due to neurotoxicity phenomena, induced for example by the overstimulation of NMDA receptors.

There is therefore a need to provide homocysteine analogues, which are able to exert therapeutic effects, also through the modulation of the activity of the naturally target receptors of homocysteine, but which are nevertheless devoid of the characteristic contraindications of homocysteine, such as neurotoxicity. and ability to form free radicals.

The main purpose of this invention is therefore to provide a compound analogous to homocysteine, capable of acting on the same molecular targets as homocysteine, without however exhibiting its contraindications.

A further object of the invention is to provide a use of the homocysteine analogue compound of the invention for the preparation of a drug for the treatment of a pathology selected from the group consisting of spina bifida, meningocele, autism, depression, schizophrenia, a extrapyramidal disease, a neurodegenerative disease, a form of dementia, a memory deficit, a motor deficit, Huntington's disease, a tumor form and cardiocerebrovascular disease.

This and other purposes which will appear better later, are achieved by a compound selected from the group of compounds having formula:

m which:

R1 and R2 are independently of each other hydrogen, -alkyl-SH, -CO-alkyl, - (CH2) „- X1, - (CH2) n-Z, -COH or -CS-alkyl;

R3 and R4 are independently of each other hydrogen, alkyl, alkenyl, alkynyl, alkyl halide, - (CH2) n-X! Or - (CH2) n-Z;

R5 is -OH, -O-alkyl, -O-alkyl halide, -SH, -S-alkyl or -N (R6) (R7);

R6 and R7 are independently of each other, hydrogen, alkyl, alkenyl, alkynyl or alkyl halide;

Xx is hydrogen, alkyl, alkenyl, alkynyl, alkyl halide or - (CH2) p-;

X2 is hydrogen, alkyl, alkenyl, alkynyl, alkyl halide, - (CHa) p- o - (CH2) n-Xi;

when Χχ or X2 are not hydrogen, Zx and Z2 are independent of each other hydrogen, -SH, -OH, -SeH, -TeH, -0-P03H2, -0-S03H or form a ring with RI, R2, R3 or R4 wherein Zx or Z2 are -0-, -S-, -Se- or -Te-;

m is 0, X or 2;

n and l, 2 or 3;

p is 0, 1, 2, or 3.

In the context of the present description and the claims presented herein, the following terms have the meaning that will be set forth below.

The term "alkyl" identifies a linear or branched hydrocarbon chain, containing at least one carbon atom. Non-limiting examples of an alkyl are represented by a functional group selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylbutyl, 3-methylhexyl, 3,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl-n-heptyl, noctyl, n-nonyl and n-decyl.

The term "alkenyl" identifies a linear or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Non-limiting examples of an alkenyl are represented by a functional group selected from ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1- heptenyl and 3-decenyl.

The term "alkynyl" identifies a linear or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of an alkynyl are represented by a functional group selected from acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentinyl and 1-butynyl.

The term "alkyl halide" identifies an alkyl group as defined above, in which at least one atom is replaced by a halogen, namely -Cl, -Br, -I or -F. Non-limiting examples of an alkyl halide are represented by a functional group selected from chloromethyl, 2 -fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.

The term "-CO-alkyl" identifies an alkyl group as previously defined, in which a carbon atom of the chain is bonded to a carbonyl group (-CO-). Non-limiting examples of a -CO-alkyl are represented by a functional group selected from -CO-methyl, -CO-ethyl and -CO-propyl.

The term "-CS-alkyl" identifies an alkyl group as previously defined, in which a carbon atom of the chain is bonded to a -CS- group, where the sulfur atom and the carbon atom are joined by a carbon-sulfur double bond. Non-limiting examples of a -CS-alkyl are represented by a functional group selected from -CS-methyl, -CS-ethyl and -CS-propyl. The term "-O-alkyl" identifies an alkyl group as defined above, in which a carbon atom of the chain is bonded to an oxygen atom. Non-limiting examples of a -0-alkyl are represented by a functional group selected from -0-methyl, -0-ethyl and -0-propyl.

The term "-0-alkyl halide" identifies an alkyl halide group as defined above, in which a carbon atom of the chain is bonded to an oxygen atom. Non-limiting examples of a -0-alkyl halide are represented by a functional group selected from 0-chloromethyl, -0-2-fluoroethyl, -0-trifluoromethyl, -0-pentafluoroethyl and -0-2-chloro-3-fluoropentyl.

The term "-S-alkyl" identifies an alkyl group as defined above, in which a carbon atom of the chain is bonded to a sulfur atom. Non-limiting examples of a -S-alkyl are represented by a functional group selected from -S-methyl, -S-ethyl and -S-propyl.

The term "alkyl-SH" identifies an alkyl group as defined above, in which a carbon atom of the chain is bonded to a thiol group (-SH). Non-limiting examples of an SH-alkyl are represented by a functional group selected from methyl-thiol, ethyl-thiol and propyl-thiol.

For example, the homocysteine analog compound can be selected from the group of compounds comprising:

or

In another aspect, this invention consists in the use of the compound of formula (I), (II) or (III) analogue of homocysteine described herein for the preparation of a drug for the treatment of a pathology selected from the group consisting of from spina bifida, meningocele, autism, depression, schizophrenia, an extrapyramidal disease, a neurodegenerative disease, a form of dementia, a memory deficit, a motor deficit, Huntington's disease, a tumor form and cardiocerebrovascular disease.

The compound of the invention can be used for the treatment of a pathology in which a role for homocysteine has been determined, whether due to the induction of oxygen radicals, modulation of the activity of a receptor, such as for example dopaminergic D2 receptors or NMDA glutamate receptors, or following the direct interaction of homocysteine with specific protein complexes, such as p53 protein or a beta-amyloid peptide.

In particular, the compound of the invention can be used to prepare a drug for the treatment of a pathology that falls into the group consisting of spina bifida, meningocele, autism, depression, schizophrenia, an extrapyramidal disease, a neurodegenerative disease, a form of dementia , a memory deficit, a motor deficit, Huntington's disease, a form of cancer and cardiocerebrovascular disease.

In a preferred embodiment, the treated cardiocerebrovascular disease can be, for example, stroke or myocardial infarction, while the tumor form can be, for example, glioblastoma.

In another preferred embodiment, the treated pathology is an extrapyramidal disease, in particular it can be Parkinson's disease. In a further preferred embodiment, the treated pathology is a neurodegenerative disease, which can be, for example, Alzheimer's disease.

Typically, the disease can be treated by administering the compound of the invention, either alone or in combination with another active ingredient, for example, as part of a therapeutic regimen.

In a preferred embodiment, the invention consists in the use of the compound of formula (I), (II) or (III) for the preparation of a drug for the treatment of a neurodegenerative disease, in particular Alzheimer's disease, by joint administration with a drug that acts on NMDA receptors. Such a drug can be, for example, memantine. As regards the doses of these drugs to be used during combined therapy, "patient titration" can be carried out, establishing the minimum threshold dose, ie the minimum effective dose to significantly reduce symptoms, according to the judgment of the patient. doctor and patient, and then use a dose of drug that acts on NMDA receptors just below this threshold.

In another preferred embodiment, the invention consists in the use of the compound of formula (I), (II) or (III) for the preparation of a drug for the treatment of Parkinson's disease, by means of joint administration with a drug for the treatment of Parkinson's disease. This drug can be selected from the group consisting of L-DOPA, an analogue of L-DOPA, a dopaminergic agonist, amantadine, selegiline and an acetylcholine antagonist. Preferably the dopaminergic agonist is bromocriptine. The acetylcholine antagonist can for example be selected from the group consisting of benztropine, diperidene and trihexyphenidyl. As regards the doses of these drugs to be used during combined therapy, "patient titration" can be carried out, establishing the minimum threshold dose, ie the minimum effective dose to significantly reduce symptoms, according to the judgment of the patient. doctor and patient, and then use a dose of anti-Parkinson's drug just below this threshold.

In a further preferred embodiment, the invention consists in the use of the compound of formula (I), (II) or (III) for the preparation of a drug for the treatment of schizophrenia, through joint administration with a neuroleptic. Preferably, this drug can be selected from the group consisting of a phenothiazine, a butyrophenone and a benzamide. For example, phenothiazine can be flupentixol. Typically a butyrophenone used for the treatment of schizophrenia can be haloperidol. Finally, an example of benzamide useful for combined treatment is sulpiride. As regards the doses of neuroleptics to be used during the combined therapy, it is possible to proceed with the "titration of the patient", establishing the minimum threshold dose, ie the minimum effective dose to significantly reduce symptoms, according to the doctor's judgment. and the patient, to then use a dose of neuroleptic just below this threshold.

In a further preferred embodiment, the invention consists in the use of the compound of formula (I), (II) or (III) for the preparation of a drug for the treatment of a memory deficit, by means of joint administration with a cholinergic drug. Typically, the cholinergic drug can be selected from the group consisting of an angiotensin converting enzyme inhibitor, an alternative drug, an atypical neuroleptic, and an aceticolinesterase inhibitor. An alternative drug, which can be a homeopathic product, is for example ginseng or a derivative of vitis vinifera. Typically the atypical neuroleptic can be selected from the group consisting of amisulpiride and clozapine. Examples of an aceticolinesterase inhibitor useful in combination therapy are donezepil, rivastigmine or galantamine.

Without wishing to be bound to any particular theory, it is believed that the therapeutic action of the compound of the invention is due to its characteristics as an analogue of homocysteine, thanks to which it can interact with the molecular targets characteristic of the sulfur amino acid, without however present the contraindications of homocysteine.

For example, since the activity of dopaminergic D2 receptors is linked to pathologies such as Parkinson's disease and schizophrenia, the compound of the invention can be used for the treatment of these pathologies, thanks to its ability to act as a modulator of dopaminergic receptors. D2.

The activity of NMDA glutamate receptors is linked to various physiological processes, including also the mechanisms of learning and memory, therefore the use of the compound of the invention can help in the treatment of pathologies dependent on dysfunctions in signal transduction mediated by NMDA receptors, such as memory deficits, without however stimulating the neurotoxic effects of homocysteine.

In the field of the treatment of Parkinson's disease, a treatment with a drug prepared starting from the compound of the invention can be accompanied at a later time by the administration of a drug for the treatment of Parkinson's disease, with the further advantage of being able to use reduced doses of these compounds. It is thus possible to avoid the side effects due for example to the repeated administration of L-DOPA or dopamine agonists.

Similarly, in the treatment of schizophrenia, a treatment with a drug prepared starting from the compound of the invention can be accompanied at a later time by the administration of a neuroleptic, which can be used in reduced therapeutic doses, to avoid the induction of effects in patients. collateral.

Also in the treatment of memory deficits a treatment with a drug prepared starting from the compound of the invention can be assisted by the administration of another drug, typically a cholinergic drug.

Claims (26)

CLAIMS 1.A compound selected from the group consisting of the compounds of formula: from ) , or (III) m which R1 and R2 are independently of each other hydrogen, alkyl-SH, -CO-alkyl, - (CH2) n-X1, - {CH2) n-Z, -COH or -CS-alkyl; R3 and R4 are independently of each other hydrogen, alkyl, alkenyl, alkynyl, alkyl halide, - (CH2) n-Xi or - (CH2) n-Z; R5 is -OH, -O-alkyl, -O-alkyl halide, -SH, -S-alkyl or -N (R6) (R7); R6 and R7 are independently of each other, hydrogen, alkyl, alkenyl, alkynyl or alkyl halide; X2 is hydrogen, alkyl, alkenyl, alkynyl, alkyl halide or - (CH2) P-; X2 is hydrogen, alkyl, alkenyl, alkynyl, alkyl halide, - (CH2) P- O - (CH2) n-Xi; when Xi or X2 are not hydrogen, Zi and Z2 are independent of each other hydrogen, -SH, -OH, -SeH, -TeH, -0-P03H2, -0-S03H or form a ring with RI, R2, R3 or R4 where Zi or Z2 are -0-, -S-, -Se- or -Te-; m is 0, 1 or 2; n and l, 2 or 3; p is 0, 1, 2, or 3. 2. The compound according to claim 1 selected from the group consisting of the compounds of formula: or 3. Use of the compound according to claim 1 for the preparation of a drug for the treatment of a pathology selected from the group of spina bifida, meningocele, autism, depression, schizophrenia, an extrapyramidal disease, a neurodegenerative disease, a form of dementia, a memory impairment, a motor deficit, Huntington's disease, a form of cancer or cardiocerebrovascular disease. The use according to claim 3 wherein the cardiocerebrovascular disease is stroke or myocardial infarction. The use according to claim 3 wherein the tumor form is glioblastoma. The use according to claim 3 wherein the pathology is a neurodegenerative disease The use according to claim 6, wherein the neurodegenerative disease is Alzheimer's disease. The use according to claim 6 or 7 in combination with a drug acting on NMDA receptors. The use according to claim 8 wherein the drug acting on NMDA receptors is memantine. The use according to claim 3 wherein the extrapyramidal disease is Parkinson's disease. The use according to claim 10 in combination with a drug for the treatment of Parkinson's disease. The use according to claim 11 wherein the drug for the treatment of Parkinson's disease is selected from the group consisting of L-DOPA, an L-DOPA analogue, a dopaminergic agonist, amantadine, selegiline and an acetylcholine antagonist . The use according to claim 12 wherein the dopaminergic agonist is bromocriptine. The use according to claim 12 wherein the aceticoline antagonist is selected from the group consisting of benztropine, diperidene and trihexyphenidyl. The use according to claim 3 wherein the pathology is schizophrenia. The use according to claim 15 in combination with a neuroleptic. The use according to claim 16 wherein the neuroleptic is selected from the group consisting of a phenothiazine, a butyrophenone and a benzamide. The use according to claim 17 wherein the phenothiazine is flupentixol. The use according to claim 17 wherein the butyrophenone is haloperidol. The use according to claim 17 wherein the benzamide is sulpiride. The use according to claim 3 wherein the pathology is a memory deficit. The use according to claim 21 in combination with a cholinergic drug. The use according to claim 22 wherein the cholinergic drug is selected from the group consisting of an angiotensin converting enzyme inhibitor, an alternative drug, an atypical neuroleptic and an aceticolinesterase inhibitor. The use according to claim 23 wherein the alternative drug is selected from the group consisting of ginseng and a derivative of vitis vinifera. The use according to claim 23 wherein the atypical neuroleptic is selected from the group consisting of amisulpiride and clozapine. The use according to claim 23 wherein the aceticholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine and galantamine.