WO2017021002A1

WO2017021002A1 - Use of sigma receptor ligands in dyslipidemia

Info

Publication number: WO2017021002A1
Application number: PCT/EP2016/001322
Authority: WO
Inventors: Antonio GUZMAN-CANO; Jose-Miguel Vela-Hernandez; Manuel Merlos-Roca
Original assignee: Laboratorios del Dr Esteve SA
Current assignee: Esteve Pharmaceuticals SA
Priority date: 2015-07-31
Filing date: 2016-07-29
Publication date: 2017-02-09
Anticipated expiration: 2018-01-31
Also published as: EP3328365A1

Abstract

The invention relates to compounds of general formula (I) having pharmacological activity towards the sigma receptor, for use in the treatment prevention of dyslipidemia.

Description

USE OF SIGMA RECEPTOR LIGANDS IN DYSLIPIDEMIA

FIELD OF THE INVENTION

The present invention relates to the use of sigma receptor ligands, and more particularly to some pyrazole derivatives, to pharmaceutical compositions comprising them, and to their use for increasing the HDL-C and/or decreasing triglycerides plasma levels in the prevention and treatment of atherosclerotic cardiovascular disease (ACVD). BACKGROUND OF THE INVENTION

Despite considerable improvements in medical care over the past 25 years, cardiovascular disease (CVD) remarks a major public health challenge, being one of the leading causes of death in the world. Among other, cardiovascular disease or disorder includes but not limits to coronary heart disease, stroke, high blood pressure, dyslipidemia, congestive heart failure and peripheral vascular disease.

Cholesterol, in both free and esterified forms, and triglycerides are the two main lipids in plasma. They are transported in lipoproteins, pseudomicellar lipid-protein complexes, in which the main apolipoproteins (apo B- 100/48, apo A-I, apo A-II, apo E and apo Cs) are integral components. Apo A-I and apo A-II are components of HDL (High Density Lipoprotein) and the apo A-I/A-II lipoprotein classes are closely inter-related via several metabolic pathways.

In dyslipidaemic patients with cardiometabolic risk, increased free fatty acid flux may represent a significant abnormality driving increased hepatic assembly and secretion of VLDL, IDL and/or LDL particles. Although other mechanisms are also implicated, low plasma levels of HDL-apo A-I are associated with its increased fractional removal.

The complexity of HDL metabolism is clearly relevant when strategies to raise HDL-C (High Density Lipoprotein-Cholesterol) are reviewed; indeed HDL-C concentration is at most an indirect marker of the anti-atherogenic activities that are associated with this lipoprotein. Current statin therapy alone, in addition to best standards of care, is unable to completely normalize CV risk associated with atherogenic dyslipidemia. Higher doses may partially correct residual dyslipidemia, but can also increase the risk of side effects, especially myopathy and liver enzymes. Addition of other pharmacological treatments (as ezetimibe, bile acid resins, niacin, or fibrates) to statin therapy has either have an increase in adverse events risks (myopathy, hepatotoxicity, gastro-intestinal side effects, gout, cholesterol gallstones, triglycerides raise, etc.) and/or modest effects on triglycerides and HDL-C levels

Evidence is supportive of therapeutic approaches aimed at concomitantly lowering TRL (Triglycerides) and raising HDL-C to reduce cardio vascular (CV) risk. HDL-C raising, per se, may represent a key determinant of the clinical benefits associated with lipid-modifying therapy (Chapman,M.J. et al.; Eur. Heart J. Access published April 29, 2011; pages 1-23).

Even current best treatment including lifestyle intervention and pharmacotherapy aimed at lowering plasma concentrations of Low Density Lipoprotein Cholesterol (LDL-C), reducing high blood pressure, controlling diabetes, and preventing thrombotic events; cardiovascular risk is a major health issue, and there is still room for improving ACVD in people at risk. There is still a need for new therapies regarding the prevention and treatment of cardiovascular diseases, especially regarding the ones related to atherogenic dyslipidemia.

We have found one family of pyrazol derivatives which are particularly selective inhibitors of the sigma receptor.

This family presents a pyrazol group which is characterized by the substitution at position 3 by an alkoxy group directly bounded to nitrogen. These compounds have been described in WO 2006/021462.

The sigma (σ) receptor is a cell surface and endoplasmic reticulum receptor expressed in the central nervous system (CNS) among other tissues. From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma receptor ligand rimcazole clinically shows effects in the treatment of psychosis (Hanner, M. et al. Proc. Natl. Acad. ScL, 1996, 93:8072-8077; Snyder, S.H., Largent, B.L. J. Neuropsychiatry 1989, 1 , 7). The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol.

The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-l) site, and has micromolar affinity for the sigma (σ-2) site. Haloperidol has similar affinities for both subtypes. Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them. Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci. , 1992, 13:85-86). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.

It was surprisingly found that the sigma-receptor ligands of the invention are effective for the prevention or the treatment of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidaemia, by increasing the HDL-C plasma levels and/or reducing the triglycerides plasma levels.

Therefore, the present invention provides sigma-receptor ligands, its pharmaceutical compositions and methods of using such compositions that are effective in the treatment or prevention of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia, because its HDL-C plasma levels increase and/or triglycerides plasma levels decrease. SUMMARY OF THE INVENTION

In one aspect the invention is directed to a compound binding to the sigma-receptor for use in the treatment or prevention of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia.

In a preferred embodiment of the use as defined above the compound increases HDL-C plasma levels and/or decreases triglycerides plasma levels.

In a preferred embodiment of the use as defined above the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist.

In a preferred embodiment of the use as defined above the compound is selected from selective Sigma neutral antagonist receptor ligands.

In a preferred embodiment of the use as defined above the compound binds selectively to the sigma- 1 receptor subtype.

In a preferred embodiment of the use as defined above the compound is a compound according to formula I:

(I)

wherein

Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)ORg, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)_t-R₈, -NR₈R₉, -NR₈C(0)R₉, - N0₂, - N=CR₈R₉, and halogen;

R₂ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)_t-R₈, -NR₈R₉, - NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen;

R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0),-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together they form an optionally substituted fused ring system;

R5 and R are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)_t-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8; t is 1,2 or 3;

Rs and R9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

In a preferred embodiment of the use as defined above the compound is 4- { 2- [5 -methyl- 1- (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}morpholine or one of its pharmaceutically acceptable salts or hydrates for use in the treatment or prevention of dyslipidemia. Preferably, this is 4-{2-[5-methyl-l -(naphthalen-2-yl)-lH-pyrazol-3- yloxy]ethyl}morpholine hydrochloride and/or the compound is administered to a woman, and/or is administered at a dosage of between 300 and 500 mg/day.

In another aspect the invention is directed to a pharmaceutical composition comprising a compound as defined above, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

The above mentioned preferences and embodiments can be combined to give further preferred compounds or uses.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : Total Cholesterol plasma determination in a 4 weeks (4w) toxicity study in monkeys.

Figure 2: HDL-C fraction plasma determination in a 4w toxicity study in monkeys.

Figure 3: LDL-C fraction plasma determination in a 4w toxicity study in monkeys.

Figure 4: HDL-C/LDL-C ratio plasma determination in a 4w toxicity study in monkeys. Figure 5: Total Cholesterol plasma determination in a 13 weeks (13w) toxicity study monkeys.

Figure 6: HDL-C fraction plasma determination in a 13w toxicity study in monkeys. Figure 7: LDL-C fraction plasma determination in a 13w toxicity study in monkeys. Figure 8: HDL-C/LDL-C ratio plasma determination in a 13w toxicity study in monkeys.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention is directed to a compound binding to the sigma-receptor for use in the treatment or prevention atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia.

The term "cardiovascular disease" herein refers to any disease or disorder of the heart or blood vessels (/. e. arteries and veins) or any symptom thereof. Non-limiting examples of cardio vascular related diseases or disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidaemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction and other cardio vascular events.

The term "treatment and/or prevention of dyslipidemia" refers to any kind of effect of the compounds of the invention regarding the increase of HDL-C plasma levels and/or the decrease of triglycerides plasma levels as defined above.

The term "compound binding to the sigma receptor" refers to any compound that binds with high affinity to the sigma-receptor, preferably to the sigma- 1 receptor subtype.

The expression "binding with high affinity to the sigma receptor" refers to compounds of the invention that can replace a ligand in competitive binding assays, preferably in competitive radioligand-binding assays as exemplary described in WO2006/021462, e.g. in binding assays for the σΐ -receptor performed as described (DeHaven-Hudkins et al., Eur J Pharmacol, 1992, 227, 371) or binding assays for o2-receptor as described (Radesca et al., J Med Chem,\ 99\ , 34, 3058).Preferably, binding of the compounds of the invention, with respect to binding to the sigma- 1 receptor subtype, is measured by competing with the binding of [H]-(+)-pentazocine, e.g. in radioligand-assays as described in the art (e.g. in DeHaven-Hudkins et al., 1992). Preferably, compounds of the invention when assayed at a concentration of 10^"7M yield at least 25%, more preferably at least 45%, even more preferably at least 65%, yet even more preferably at least 75%, most preferably at least 85% binding to the sigma- 1 receptor in [H]-(+)-pentazocine radioligand-assays as defined above. The expression "binding selectively to the Sigma receptor" refers to compounds of the invention that shows nanomolar affinity for its target while showing either a percentage of inhibition less than 50% when tested at 1 micromolar in a panel of other non-specific targets or when there is one hundred times less affinity or functional activity for those non- specific targets.

Thus, in a preferred embodiment the compound binding to the sigma-receptor is used in the treatment or prevention of an atherosclerotic cardiovascular disease. In a more preferred embodiment the invention is directed to the use of the compound binding to the sigma-receptor in the treatment or prevention of dyslipidemia.

In a still more preferred embodiment the compound binding to the sigma-receptor is used for increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels.

In a preferred embodiment of the compound for use in the treatment or prevention of an atherosclerotic cardiovascular disease or of dyslipidemia according to the invention, the HDL-C plasma levels are increased and/or the triglycerides plasma levels are decreased by the use of the compound.

In another more preferred embodiment the compound binding to the sigma-receptor is used for increasing the HDL-C plasma levels.

In another more preferred embodiment the compound binding to the sigma-receptor is used for decreasing the triglycerides plasma levels.

In a preferred embodiment the compound binding to the sigma-receptor is used in the treatment of an atherosclerotic cardiovascular disease. In a preferred embodiment the compound binding to the sigma-receptor is used in the treatment of dyslipidaemia. In a preferred embodiment the compound binding to the sigma-receptor is used in the prevention of an atherosclerotic cardiovascular disease.

In a preferred embodiment the compound binding to the sigma-receptor is used in the prevention of dyslipidemia.

In a preferred embodiment of the use according to the present invention, the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist.

In a preferred embodiment of the use as defined above the compound binds to the sigma- 1 receptor subtype.

(I) wherein

Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈R₉, -NR₈C(0)R₉, - N0₂, - N=CR₈R₉, and halogen;

R₂ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR , -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈R₉, - NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen;

R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together they form an optionally substituted fused ring system;

R5 and R6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8; t is 1 ,2 or 3;

R₈ and R9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

In a preferred embodiment of the use as defined above the compound is characterized in that Ri selected from H, -COR₈, or substituted or unsubstituted alkyl, preferably it is selected from H, methyl or acetyl. In a preferred embodiment of the use as defined above the compound is characterized in that Ri is hydrogen.

In a preferred embodiment of the use as defined above the compound is characterized in that R₂ is H or alkyl, preferably methyl or H.

In a preferred embodiment of the use as defined above the compound is characterized in that R₃ and R₄ are situated in the meta and para positions of the phenyl group.

In a preferred embodiment of the use as defined above the compound is characterized in that R₃ and R4 are independently selected from halogen, or substituted or unsubstituted alkyl, more preferably selected from halogen or haloalkyl.

In an especially preferred embodiment of the use as defined above the compound is characterized in that both R₃ and R4 together with the phenyl group form an optionally substituted fused ring system. More preferably, said fused ring system is selected from a substituted or unsubstituted fused aryl group and a substituted or unsubstituted aromatic or partially aromatic fused heterocyclyl group. Said fused ring system preferably contains two rings and/or from 9 to about 18 ring atoms, more preferably 9 or 10 ring atoms. Even more preferably, the fused ring system is naphthyl, especially a 2-naphthyl ring system, substituted or unsubstituted.

In a preferred embodiment of the use as defined above the compound is characterized in that n is selected from 2, 3, 4, more preferably n is 2.

In a preferred embodiment of the use as defined above the compound is characterized in that R₅ and R , together, form a morpholin-4-yl group.

In a preferred variant of the invention the sigma ligand of general formula (I) is selected from:

[I] 4-{2-(l -(3,4-Dichlorophenyl)-5-methyl-lH pyrazol-3-yloxy)ethyl} morpholine, [2] 2- [ 1 -(3 ,4-Dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy] -Ν,Ν-diethy lethanamine hydrochloride,

[3] l-(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-l-yl)ethoxy]-lH-pyrazole hydrochloride,

[4] l-(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-l-yl)propoxy]-lH-pyrazole hydrochloride,

[5] 1 - { 2-[ 1 -(3 ,4-Dichlorophenyl)-5-methyl- 1 H-pyrazol-3-yloxy]ethyl } piperidine, [6] l -{2-[l -(3,4-dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]ethyl}-lH-imidazole, [7] 3-{ l -[2-(l-(3 ,4-Dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy)ethyl]piperidin-4- yl}-3H-imidazo[4,5-b]pyridine,

[8] l -{2-[l -(3,4-Dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]ethyl}-4- methylpiperazine,

[9] Ethyl 4-{2-[l -(3 ,4-dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy] ethyl } piperazine carboxylate,

[10] l -(4-(2-( l -(3,4-dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy)ethyl)piperazin- l - yl)ethanone,

[I I ] 4-{2-[l -(4-Methoxyphenyl)-5-methyl-lH-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[12] 1 -(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin- 1 -yl)ethoxy]- 1 H-pyrazole,

[13] l -(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-l -yl)propoxy]-l H-pyrazole,

[ 14] I -[2-( 1 -(4-Methoxyphenyl)-5-methyl- 1 H-pyrazol-3-yloxy)ethyl]piperidine, [15] 1 - {2-[ 1 -(4-Methoxyphenyl)-5-methyl- 1 H-pyrazol-3-yloxy]ethyl} - 1 H-imidazole, [16] 4-{2-[l-(3,4-Dichlorophenyl)-5-phenyl-lH-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[17] 1 -(3 ,4-Dichlorophenyl)-5 -phenyl-3 - [2-(pyrrolidin- 1 -y l)ethoxy] - 1 H-pyrazole hydrochloride,

[18] 1 -(3 ,4-Dichlorophenyl)-5 -phenyl-3 - [3 -(pyrrolidin- 1 -yl)propoxy] - 1 H-pyrazole, [19] 1 - { 2- [ 1 -(3 ,4-Dichlorophenyl)-5 -phenyl- 1 H-pyrazol-3 -yloxy] ethyl } piperidine, [20] 1 - { 2- [ 1 -(3 ,4-Dichlorophenyl)-5-phenyl- 1 H-pyrazol-3 -yloxy]ethyl } - 1 H-imidazole hydrochloride,

[21] 2- { 2- [ 1 -(3 ,4-dichlorophenyl)-5 -phenyl- 1 H-pyrazol-3 -yloxy]ethyl } - 1 ,2,3 ,4- tetrahydroisoquinoline hydrochloride,

[22] 4-{4-[l-(3,4-Dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]butyl}morpholine hydrochloride,

[23] l-(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-l-yl)butoxy]-lH-pyrazole, [24] l-{4-[l-(3,4-Dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]butyl}piperidine hydrochloride,

[25] 1 - {4-[ 1 -(3 ,4-Dichlorophenyl)-5-methyl- 1 H-pyrazol-3-yloxy]butyl } -4- methylpiperazine dihydrochloride,

[26] l-{4-[l-(3 ,4-Dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy]buty 1 } - 1 H- imidazole,

[27] 4-[ 1 -(3,4-Dichlorophenyl)-5-methyl- 1 H-pyrazol-3-yloxy]-N,N-diethylbutan- 1 - amine,

[28] l-{4-[l-(3,4-dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]butyl}-4- phenylpiperidine hydrochloride,

[29] 1 - {4-[ 1 -(3 ,4-dichlorophenyl)-5-methyl- 1 H-pyrazol-3-yloxy]butyl} -6,7-dihydro- lH-indol-4(5H)-one,

[30] 2-{4-[l-(3,4-dichlorophenyl)-5-methyl-lH-pyrazol-3-yloxy]butyl}-l ,2,3,4- tetrahydroisoquinoline,

[31 ] 4-{2-[l-(3,4-dichlorophenyl)-5-isopropyl- lH-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[32] 2-[l -(3,4-Dichlorophenyl)-5-isopropyl-lH-pyrazol-3-yloxy]-N,N- diethylethanamine, [33] l -(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-l-yl)ethoxy]-l H-pyrazole hydrochloride,

[34] 1 -(3 ,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin- 1 -yl)propoxy]- 1 H-pyrazole hydrochloride,

[35] l-{2-[l-(3,4-Dichlorophenyl)-5-isopropyl-l H-pyrazol-3-yloxy]ethyl}piperidine, [36] 2- { 2- [ 1 -(3 ,4-dichlorophenyl)-5 -isopropyl- 1 H-pyrazol-3 -yloxy] ethyl } - 1 ,2,3 ,4- tetrahydroisoqui-noline hydrochloride,

[37] 4- { 2- [ 1 -(3 ,4-dichlorophenyl)- 1 H-pyrazol-3 -yloxy] ethyl } morpholine,

[38] 2- [ 1 -(3 ,4-dichlorophenyl)- 1 H-pyrazol-3 -yloxy] N,N-diethylethanamine,

[39] 1 -(3 ,4-dichlorophenyl)-3 - [2-(pyrrolidin- 1 -yl)ethoxy] - 1 H-pyrazole,

[40] 1 - {2- [ 1 -(3 ,4-dichlorophenyl)- 1 H-pyrazol-3 -yloxyjethyl } piperidine,

[41] 1 -(3 ,4-dichlorophenyl)-3 - [3 -(pyrrolidin- 1 -yl)propoxy] - 1 H-pyrazole,

[42] 1 - { 2- [ 1 -(3 ,4-Dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy]ethyl } piperazine dihydrochloride,

[43 ] 1 - {2- [ 1 -(3 ,4-Dichlorophenyl)-5 -methyl- 1 H-pyrazol-3 -yloxy]ethyl } pyrrolidin-3 - amine,

[44] 4-{2-[l-(3,4-Dichlorophenyl)-4,5-dimethyl-lH-pyrazol-3- yloxy]ethyl}morpholine,

[45] 2-[l -(3,4-Dichlorophenyl)-4,5-dimethyl-l H-pyrazol-3-yloxy]-N,N- diethylethanamine hydrochloride,

[46] l-(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-l-yl)ethoxy]-lH-pyrazole hydrochloride,

[47] 1 -(3,4-Dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-l -yl)propoxy]-l H-pyrazole hydrochloride,

[48] l-{2-[l -(3,4-Dichlorophenyl)-4,5-dimethyl-lH-pyrazol-3-yloxy]ethyl}piperidine, [49] 4-{4-[l -(3,4-dichlorophenyl)-lH-pyrazol-3-yloxy]butyl}morpholine

hydrochloride,

[50] (2S,6R)-4-{4-[l -(3,4-dichlorophenyl)-l H-pyrazol-3-yloxy]butyl}-2,6- dimethylmorpholine hydrochloride,

[51 ] 1 -{4-[ 1 -(3,4-Dichlorophenyl)- 1 H-pyrazol-3 -yloxy]butyl} piperidine

hydrochloride,

[52] ] -(3,4-Dichlorophenyl)-3-[4-(pynOlidin-l -yl)butoxy]-l H-pyrazole hydrochloride, [53] 4-[ 1 -(3,4-dichlorophenyl)- 1 H-pyrazol-3-yloxy]-N,N-diethylbutan- 1 -amine oxalate,

[54] N-benzyl-4- [ 1 -(3 ,4-dichloropheny 1)- 1 H-pyrazol-3 -y loxy] -N-methylbutan- 1 - amine oxalate,

[55] 4- [ 1 -(3 ,4-dichlorophenyl)- 1 H-pyrazol-3 -yloxy] -N-(2-methoxyethyl)-N- methylbutan-1 -amine oxalate,

[56] 4- { 4- [ 1 -(3 ,4-dichlorophenyl)- 1 H-pyrazol-3 -yloxy] butyl } thiomorpholine oxalate, [57] 1 -[1 -(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-lH-pyrazol-4- yl]ethanone oxalate,

[58] l-{ l-(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-l-yl)ethoxy]-lH-pyrazol-4- yl}ethanone oxalate,

[59] l-{ l-(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-l-yl)ethoxy]-lH-pyrazol-4- yl}ethanone oxalate,

[60] 1 - { 1 -(3 ,4-dichlorophenyl)-3 - [2-(diethylamino)ethoxy] -5 -methyl- 1 H-pyrazol-4- yl}ethanone oxalate,

[61 ] 4- {2- [5 -Methyl- 1 -(naphthalen-2-yl)- 1 H-pyrazol-3 -yloxy] ethyl }morpholine,

[62] N,N-Diethyl-2-[5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethanamine, [63 ] 1 - { 2- [5 -Methyl- 1 -(naphthalen-2-yl)- 1 H-pyrazol-3 -yloxy] ethyl } piperidine hydrochloride,

[64] 5 -Methyl- 1 -(naphthalen-2-yl)-3 - [2-(pyrrolidin- 1 -yl)ethoxy] - 1 H-pyrazole hydrochloride, their salts, different alternative pharmaceutically acceptable salts, solvates or prodrugs.

In a more preferred embodiment of the use as defined above the compound is 4-{2-[5- methyl-l -(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof. In a more preferred embodiment of the use as defined above the compound is 4-{2-[5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3- yloxy]ethyl}morpholine or its pharmaceutically acceptable salts or solvates.

In a still more preferred embodiment of the use as defined above the compound is 4-{2-[5- methyl- 1 -(naphthalen-2-y 1)- 1 H-pyrazol-3 -yloxy]ethyl } morpholine hydrochloride or solvates or a prodrug thereof. In a still more preferred embodiment of the use as defined above the compound is 4-{2-[5-methyl-l-(naphthalen-2-yl)-l H-pyrazol-3- yloxy]ethyl}morpholine hydrochloride or solvates thereof.

One of the most preferred embodiments of the invention [EMBODIMENT X] refers to 4- {2-[5-methyl-l -(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}mo holine or one of its pharmaceutically acceptable salts or hydrates for use in the treatment or prevention of dyslipidemia.

A preferred embodiment of EMBODIMENT X refers to 4-{2-[5-methyl-l-(naphthalen-2- yl)-lH-pyrazol-3-yloxy]ethyl}morpholine hydrochloride for use in the treatment or prevention of dyslipidemia.

A preferred embodiment of all embodiments mentioned before including EMBODIMENT X is an embodiment,

a) wherein the compound is administered to a mammal of female gender, preferably is administered to a woman and/or

b) wherein the compound is administered by oral administration, and/or

c) wherein the compound is administered one, two, three or four times per day, preferably once or twice per day, more preferably once per day, and/or

d) wherein the compound is administered daily for at least 4 weeks, preferably for at least 6 weeks, more preferably for at least 13 weeks, and/or

e) wherein the compound is administered at a dosage of 10 to 125 mg/kg/day, or is administered at a dosage of 300 to 500 mg/day.

Regarding the above feature a) "wherein the compound is administered to a mammal of female gender", this includes administration of the compound to all mammals of female gender thus especially to female humans including babies of the age of 0 to 2 years, girls of the age of 2 to 18 years and women at the age of over 18 years. Preferably the compound is administered to a woman at the age of over 18 years. Regarding the above feature b) "wherein the compound is administered by oral administration", this includes administration of the compound in tablet form, in form of a capsule, in form of a powder from a sachet or in form of a fluid comprising the compound. Preferably the compound is administered in form of a tablet or capsule. Regarding the above feature c) "wherein the compound is administered one, two, three or four times per day", this includes administration of the compound in any fitting pharmaceutical formulation for 1- 4 times per day thus within 24 hours. Preferably the compound is administered once or twice per day, or only once per day. It is also preferred if at least one of the applications of the compound is done in the morning.

Regarding the above feature d) "wherein the compound is administered daily for at least 4 weeks", this includes daily administration of the compound in any fitting pharmaceutical formulation and optionally more than once per day as long as the administration is done for a period of time exceeding or equal to 4 weeks. In other preferred options the administration is done for a period of time exceeding or equal to 6 or 13 weeks.

Regarding the above feature e) "wherein the compound is administered at a dosage of 10 to 125 mg/kg/day", this includes administration at any dosage within this dosage range. Other preferred dosage ranges include administration at a dosage of 30 to 125 mg/kg/day or at a dosage of 80 and 125 mg/kg/day. It could also include selected dosages selected from 10, 20, 30, 80, 100 or 125 mg/kg/day, preferably selected from 80, 100 or 125 mg/kg/day. In a parallel regime - preferably used in humans, especially in women - the compound is administered at a dosage of 1 to 10 mg/kg/day, preferably at 2 to 8 mg/kg/day, most preferably at 3 to 7 mg/kg/day. Or - again used preferably in humans, especially in women - the compound is administered at a dosage of 250 to 750 mg/day, preferably at a dosage of 300 to 500 mg/day, or more preferably at a dosage of 300 to 500 mg/day or most preferably at a dosage of 400 mg/day.

An even more preferred embodiment of all embodiments mentioned before including EMBODIMENT X is an embodiment, wherein the compound is administered daily for at least 4 weeks to a woman at a dosage of 80 and 125 mg/kg/day. Preferably the compound is administered by oral administration once or twice per day.

An even more preferred EMBODIMENT X is an embodiment, wherein 4-{2-[5-methyl-l - (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}morpholine or one of its pharmaceutically acceptable salts or hydrates is for use in the treatment or prevention of dyslipidemia, wherein the compound is the hydrochloride salt and/or the compound is administered daily for at least 4 weeks and/or is administered to a woman and/or is administered at a dosage of 80 and 125 mg/kg/day. Preferably the compound is administered by oral administration and/or is administered once or twice per day.

A most preferred embodiment (also of EMBODIMENT X) is an embodiment, wherein 4- {2-[5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}morpholine or one of its pharmaceutically acceptable salts or hydrates is for use in the treatment or prevention of dyslipidemia, wherein the compound is administered to a woman. Preferably, the compound is administered orally once per day at a dosage of 400 mg.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i- propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl it corresponds to an "arylalkyl or aralkyl" radical, such as benzyl and phenethyl. "Alkenyl" refers to an alkyl radical having at least two carbon atoms and having one or more unsaturated bonds.

"Cycloalkyl" refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. The cycloalkyl radicalmay be optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

"Aryl" refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.

"Heterocyclyl" refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8 -membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms. It may be aromatic or not aromatic. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quatemized ; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.

"Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc. "Amino" refers to a radical of the formula-NH₂, -NHRa or -NRaRb, optionally quatemized, wherein Ra and Rb is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.

"Halo" or "hal" refers to bromo, chloro, iodo or fluoro.

"Fused ring system" refers to a polycyclic ring system that contains fused rings. Typically, the fused ring system contains 2 or 3 rings and/or up to 18 ring atoms. As defined above, cycloalkyl radicals, aryl radicals and heterocyclyl radicals may form fused ring systems. Thus, fused ring system may be aromatic, partially aromatic or not aromatic and may contain heteroatoms. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the system. Examples of fused ring systems are, but are not limited to, adamantyl, naphthyl (e.g. 2-naphthyl), indenyl, fenanthryl, anthracyl, pyrenyl, benzimidazole, benzothiazole, etc.

Unless otherwise stated specifically in the specification, all the groups may be optionally substituted, if applicable. References herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fiuoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a C_1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms ; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³C- or ^l4C- enriched carbon or ^{l 5}N-enriched nitrogen are within the scope of this invention.

The term "pharmaceutically acceptable salts, solvates, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.

For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- toluenesulphonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.

Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery" Taylor & Francis (april 2002).

The compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.

The compounds of general formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

The compounds of the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

The compounds of formula (I) and their salts or solvates can be prepared as disclosed in the previous application WO2006/021462.

The obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form, including such crystalline form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms. Another aspect of this invention relates to a method of treating or preventing an atherosclerotic cardiovascular disease, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of treating or preventing a dyslipidemia, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of increasing the HDL-C plasma levels which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of decreasing the triglycerides plasma levels, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. A preferred embodiment relates to the method of treating of an atherosclerotic cardiovascular disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.

A more preferred embodiment relates to the method of treating of dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.

A preferred embodiment relates to the method of preventing an atherosclerotic cardiovascular disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.

A more preferred embodiment relates to the method of preventing dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.

One of the most preferred embodiments of the invention refers to method of treating or preventing dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of 4-{2-[5-methyl-l -(naphthalen-2-yl)- lH-pyrazol-3-yloxy] ethyl }morpholine or one of its pharmaceutically acceptable salts or hydrates. In a preferred embodiment of this method the compound is 4-{2-[5-methyl-l - (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}morpholine hydrochloride for use in the treatment or prevention of dyslipidemia.

A preferred embodiment of the method of treating or preventing dyslipidemia described above is an embodiment,

• wherein the compound is administered to a mammal of female gender, preferably is administered to a woman and/or • wherein the compound is administered by oral administration, and/or

• wherein the compound is administered one, two, three or four times per day, preferably once or twice per day, more preferably once per day, and/or

• wherein the compound is administered daily for at least 4 weeks, preferably for at least 6 weeks, more preferably for at least 13 weeks, and/or

• wherein the compound is administered at a dosage of 10 to 125 mg/kg/day, preferably at a dosage of 30 to 125 mg/kg/day, more preferably at a dosage of 80 and 125 mg/kg/day or at a dosage selected from 10, 20, 30, 80, 100 or 125 mg/kg/day, preferably at a dosage selected from 80, 100 or 125 mg/kg/day, or · wherein the compound is administered at a dosage of 1 to 10 mg/kg/day, preferably at a dosage of 3 to 7 mg/kg/day or at a dosage from 250 to 750 mg/day, preferably at a dosage from 300 to 500 mg/day or at a dosage of 400 mg/day.

An even more preferred embodiment of the method of treating or preventing dyslipidemia described above is an embodiment, wherein the compound is administered daily for at least 4 weeks to a woman either at a dosage of 80 and 125 mg/kg/day or at a dosage of 400 mg/day. Preferably the compound is administered by oral administration once or twice per day. In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for the treatment or prevention of an atherosclerotic cardiovascular disease.

In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for the treatment or prevention of dyslipidemia.

In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels.

In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for increasing the HDL-C plasma levels. In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for decreasing the triglycerides plasma levels.

A preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the treatment of an atherosclerotic cardiovascular disease.

A more preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the treatment of dyslipidemia. A preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the prevention of an atherosclerotic cardiovascular disease.

A more preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the prevention of dyslipidemia.

The present invention further provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.

In another aspect the invention is thus directed to a pharmaceutical composition comprising a compound as defined above, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration. In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or macrocrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts. Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated. Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.

In a preferred embodiment of the use of the compounds of the invention the compounds, optionally in the form of a pharmaceutical composition, are administered once daily. The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.

The following examples are given only as further illustration of the invention; they should not be taken as a definition of the limits of the invention.

EXAMPLES

Example 1

Synthesis of 4-{2-[5-Methyl-l-(naphthalen-2-yl)-lH-pyrazoI-3- yloxyjethyl} morpholine (compound 63) and its hydrochloride salt

Compound 63 Example 1

Compound 63 can be prepared as disclosed in the previous application WO2006/021462 (Compound 63 is example 61 in WO2006/021462). Its hydrochloride can be obtained according the following procedure:

Compound 63 (6,39 g) was dissolved in ethanol saturated with HCl, the mixture was stirred then for some minutes and evaporated to dryness. The residue was crystallized from isopropanol. The mother liquors from the first crystallization afforded a second crystallization by concentrating. Both crystallizations taken together yielded 5.24 g (63 %) of the corresponding hydrochloride salt (m.p. = 197-199 °C).

1H-NMR (DMSO-d6) 6 ppm: 10,85 (bs, 1H), 7,95 (m, 4H), 7,7 (dd, J=2,2, 8,8 Ηζ,ΙΗ), 7,55 (m, 2H), 5,9 (s, 1 H), 4,55 (m, 2H), 3,95 (m, 2H), 3,75 (m, 2H), 3,55-3,4 (m, 4H), 3,2 (m, 2H), 2,35 (s, 3H).

HPLC purity: 99.8%.

Pharmacological data

Example 2: Total Cholesterol, HDL-C and LDL-C plasma determination in a 4-weeks toxicity study with Example 1. In a 4-week toxicity study in monkeys, Example 1 was administered by oral route (gavage) to three groups of 3 males and 3 females each, at doses of 20, 80 and 125 mg/kg/day. A fourth group received the vehicle (water) acting as control group. Additionally, 2 males and 2 females were initially assigned to the control and high-dose groups to be subjected to a 2-weeks recovery period after the end of treatment. On week 4 of treatment, after overnight food deprivation, blood samples were obtained from all animals and collected into tubes containing lithium heparin as anticoagulant. All tubes were agitated mechanically for at least five minutes and the sample subsequently centrifuged at 2000 g for 10 minutes in order to separate the plasma. After separation, the plasma was examined using a Roche P Modular Analyser in respect of: Total Cholesterol (Figure 1), HDL-C and LDL-C.

Example 1 treatment produced increases in the total plasma cholesterol, which were due to increases in the HDL-C fraction, mainly in females (Figure 2). On the contrary, LDL-C fraction was reduced in both males and females (Figure 3). Overall, HDL-C/LDL-C ratio dose-dependently increased in both sexes after 4w Example 1 treatment (Figure 4).

An increase in the HDL-C/LDL-C ratio, that is 'good cholesterol' vs 'bad cholesterol', implies a beneficial effect regarding the cardiovascular risk.

Example 3: Total Cholesterol, HDL-C and LDL-C plasma determination in a 13- weeks toxicity study with Example 1.

In a 13 -week study in monkeys, Example 1 was administered by oral route (gavage) to three groups of 3 males and 3 females each, at doses of 10, 30 and 100 mg/kg/day. A fourth group received the vehicle (water) acting as a control group. Additionally, 2 males and 2 females were assigned to the control and high dose groups to be subjected to a 4- week recovery period after the end of treatment. On weeks 6 and 13 of treatment, after overnight food deprivation, blood samples were obtained from all animals and collected into tubes containing lithium heparin as anticoagulant. All tubes were agitated mechanically for at least five minutes and the sample subsequently centrifuged at 2000 g for 10 minutes in order to separate the plasma. After separation, the plasma was examined using a Roche P Modular Analyser in respect of: Total Cholesterol, HDL-C and LDL-C. In accordance with the 4 wk toxicity study, 13-wk treatment with Example 1 produced a dose-dependent increase in the total plasma cholesterol (Figure 5), which was more evident in males. This increase in total cholesterol was due to the increase in the HDL-C fraction in both males and females (Figure 6), whereas LDL-C fraction was actually reduced, mainly in females (Figure 7). A dose-dependent increase in the HDL-C/LDL-C ratio was observed in both sexes after 13 wk of treatment with Example 1 , which was more evident in females (Figure 8). Overall, the results in the 13w study confirmed those found in the 4w study, indicating a sustained beneficial effect in plasma lipoprotein profile after Example 1 treatment.

Example 4: Clinical data

The results obtained in animal tests (see Example 2 and 3 and associated figures) were corroborated through the same parameters measurement in different clinical studies done by the Example 1, as can be seen in Table 1.

There were 3 Clinical Studies (A, B and C).

In Study A 87 patients completed the study with 41 receiving the compound Example 1 and 46 receiving placebo. Example 1 was administered at 400 mg in capsules for 28 days orally once daily.

In Study B 163 patients completed the study with 85 receiving the compound Example 1 and 78 receiving placebo. Example 1 was administered at 400 mg in capsules for 28 days orally once daily in the morning before food intake.

In Study C 13 patients completed the study with 4 receiving the compound Example 1 and 9 receiving placebo. Example 1 was administered at 400 mg for 28 days orally once daily in the morning.

In the clinical studies performed, complete laboratory tests (including haematology, clinical chemistry, coagulation, urinalysis) were done at screening visit and Day 28 (plus follow up tests if necessary) according to standard defined protocols.

The following laboratory safety parameters were measured: Category Laboratory Parameter

Haematology Haemoglobin, red blood cells count, haematocrit, white blood cells (WBC) count and differential WBC, mean cell volume (MCV), mean corpuscular haemoglobin (MCH), MCH concentration (MCHC) and platelets count,

Clinical Chemistry Sodium, potassium, AST, ALT, GGT, total bilirubin, bilirubin direct/bilirrubin conjugated (to be performed in case of abnormal total bilirubin value) creatinine, total proteins, glucose, urea/BUN, fasting lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides)

Coagulation Prothrombin time and activated partial thromboplastin time (APTT)

Urinalysis Dipstick determination of pH, protein, glucose, leukocytes, nitrites, ketones, blood. If the results of the dipstick are abnormal, a biochemistry urinalysis +/- a microbiology analysis will be performed if needed.

Urine pregnancy test, urinalysis and coagulation parameters were performed locally at the local laboratory at each investigational site.

A validated central laboratory processed and provides results for the haematology and biochemistry clinical laboratory tests.

For the parameters disclosed in Table 1 the blood samples treatment was as following:

immediately after blood collection, invert the serum Vacutainer 6-8 times and let the

sample coagulate in upright position for 30 min (max. 60 min) at room temperature,

protected from light. Then centrifuge the sample for 10 min at 1300 g/room temperature.

Afterwards, transfer the clear supernatant into a serum tube using a disposable pipette. The serum tube was examined and the parameters determined by photometry using an Advia-Siemens Healthcare instrument.

Table 1

(*)PBO stands for Placebo; SCR stands for screening visit

Also, the 4-wk treatment of human volunteers with Example 1 produced in all studies A, B, and C a reduction of the triglycerides (table 1). This effect was in all cases more pronounced than the effect seen in placebo. Finally, changes on LDL-C were more variable among these three studies (when a decreasing effect in LDL-C was observed, this was only seen with Example 1 but no with placebo) and ranged from:

• Study A: 15% decrease with Example 1 (placebo only 1 % decrease)

• Study B: 1% increase with Example 1 (placebo 1 % increase, as well)

• Study C: 4% decrease with Example 1 (placebo 1 % increase) Overall, the results in the clinical trial confirmed those found in the 4wk and 13wk toxicity study, indicating a sustained beneficial effect in plasma lipoprotein profile after Example 1 treatment.

Claims

1. A compound binding to the sigma-receptor for use in the treatment or prevention of an atherosclerotic cardiovascular disease (ACVD).

2. The compound according to claim 1 for use in the treatment or prevention of dyslipidemia.

3. The compound for use according to claim 1 or 2, wherein the HDL-C plasma levels are increased and/or the triglycerides plasma levels are decreased by the use of the compound.

4. The compound for use according to claims 1 to 3, wherein the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist.

5. The compound for use according to claims 1 to 4, wherein the compound binds to the sigma- 1 receptor subtype. 6. The compound for use according to claims 1 to 5, wherein the compound is a compound according to formula I:

(I)

wherein

R₂ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR , -C(0)OR , -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈R₉, - NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen;

R3 and R₄ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together they form an optionally substituted fused ring system;

R5 and R6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5,

6, 7 or 8; t is 1 ,2 or 3;

Rg and R9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

7. The compound for use according to claim 6, wherein the compound is characterized in that Ri is hydrogen.

8. The compound for use according to claims 6 or 7, wherein the compound is characterized in that R₂ is H or alkyl, preferably methyl or H.

9. The compound for use according to claims 6 to 8, wherein the compound is characterized in that R₃ and together with the phenyl forms a naphthyl group.

10. The compound for use according to claims 6 to 9, wherein the compound is characterized in that n is selected from 2, 3, 4, more preferably n is 2.

1 1. The compound for use according to claims 6 to 10, wherein the compound is characterized in that R5 and R₆, together, form a morpholine-4-yl group.

12. The compound for use according to claims 1 to 1 1 , wherein the compound is selected from 4-{2-[5-Methyl-l -(naphthalen-2-yl)- l H-pyrazol-3- yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof and 4-{2-[5-Methyl- l -(naphthalen-2-yl)-l H-pyrazol-3- yloxy]ethyl}morpholine hydrochloride or solvates or a prodrug thereof.

13. The compound for use according to claims 1 to 12, wherein the compound is 4-{2- [5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl}moφholine or one of its pharmaceutically acceptable salts or hydrates for use in the treatment or prevention of dyslipidemia, wherein the compound is administered to a woman.

14. The compound for use according to claims 1 to 13,

• wherein the compound is administered to a mammal of female gender, preferably is administered to a woman and/or

• wherein the compound is administered by oral administration, and/or

• wherein the compound is administered at a dosage of 10 to 125 mg/kg/day, or is administered at a dosage of 300 to 500 mg/day.

15. Pharmaceutical composition comprising a compound for the use according to claims 1 to 14, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle.