AND METABOLIC SYNDROME

FIELD OF THE INVENTION

The present invention relates to the use of sigma receptor ligands, and more particularly to some pyrazole derivatives, and to the use of pharmaceutical compositions comprising them for the treatment of diabetes.

BACKGROUND OF THE INVENTION

Diabetes is a metabolic disorder caused by interaction of genetic, environmental, immunological, as well as life-style factors. In 2004, according to the World Health Organization (WHO), more than 150 million people worldwide suffer from diabetes. Its incidence is increasing rapidly and it is estimated that by the year 2025 this number will double. According to the American Diabetes Association (ADA; http://www.diabetes.org/home.jsp) has identified four major categories of diabetes including:

Type 1 diabetes mellitus: The body's fails to produce insulin

Type 2 diabetes mellitus: Results from insulin resistance, combined with relative insulin deficiency

Gestational diabetes: Occurs during pregnancy. Impaired glucose tolerance (i.e. prediabetes): When a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes.

In the pathological course of diabetes often, further complications may arise such as peripheral vascular disease, diabetic neuropathy, diabetic foot problems, diabetic retinopathy and nephropathy. One of the most common complications of diabetes is peripheral neuropathy. Globally it affects about 20-30 million people, and with the increase in obesity rates and the prevalence of type 2 diabetes, this could double by 2025 (Said, 2007).

In the development of diabetes a series of pathogenic processes are involved, ranging from the autoimmune destruction of the β cells of the pancreas to faults that cause resistance to insulin action. The basis of the anomalies in the metabolism of carbohydrates, lipids and proteins in the diabetes is the deficient action of this hormone in target tissues. Often coexist in the same patient deficiency of insulin secretion and the defect in the action thereof; therefore, one cannot determine which is the main cause of hyperglycemia (American Diabetes Association, 2013). Hyperglycemia induces macrovascular disorders (myocardial infarction, stroke and peripheral vascular disease) and microvascular impairment causes damage to specific cell groups such as vascular endothelial cells in the retina, mesangial in the renal glomerulus, neuronal axons and cells Schwann in the peripheral nerves, causing retinopathy, nephropathy and neuropathy respectively (Mendez et al., 2014). Furthermore autonomic neuropathy, involving both the sympathetic and parasympathetic nervous system, causes gastrointestinal symptoms, urogenital, cardiovascular and sexual dysfunction (American Diabetes Association, 2013).

In its initial phase, type 2 diabetes is asymptomatic and can be diagnosed after a long time. In this period, the disease could be demonstrated by measuring the fasting blood glucose test or performing a tolerance to it, because hyperglycemia develops gradually. In these early stages, although not show severe symptoms typical of the disease can develop macro and microvascular complications (American Diabetes Association, 2013).

Type-2 diabetes is usually associated with metabolic syndrome (MS); comprising abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia or decreased HDL cholesterol bound to. Although its specific etiology is unknown, there are probably many different causes; most of these patients are obese or have a higher percentage of fat in the abdominal region which causes insulin resistance. Risk factors include age, obesity and physical inactivity; It is also more common in women with history of gestational diabetes and people with hypertension or dyslipidemia (Federation, 2014,Roberts et al., 2013).

The treatment of metabolic syndrome is of great importance in medicine. The metabolic syndrome is a widespread disease, particularly in the United States and Europe. Based on survey data from 1988 to 1994 and 2000 census data, the American Centre for Disease Control and Prevention estimates that 47 million people in the US have metabolic syndrome. There is currently a world-wide need for treatment of this syndrome as it is identified as heightening the risk of cardiovascular mortality. Consequently, it is an object of the present invention to provide medicaments, which are suitable for the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes. Another object of the present invention is to provide medicaments suitable for the treatment of diabetes, and more particularly type-2 diabetes. Another object of the present invention is to provide medicaments suitable for controlling the diabetes-associated glycaemia by decreasing the blood glucose levels. Another object of the present invention is to provide medicaments suitable as diabetes adjuvant therapy. Another object of the present invention is to provide medicaments suitable for the treatment of hyperglycemia. 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. Sci., 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-1 ) 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.

The presence of sigma-1 receptor (o1 R) in rat pancreas by using the o1 R radiotracer 18F-FTC-146 has been described (James et al., 2014). Although some non-selective sigma receptor ligands are known to promote insulin release from isolated rat islets (Chan and Morgan, 1998), the pathophysiological relevance of o1 R in the pancreatic function or in the control of glycaemia has not yet been established. We found one family of pyrazole derivatives which are particularly selective inhibitors of the sigma-1 receptor.

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

SUMMARY OF THE INVENTION

It has been surprisingly found that the sigma-receptor ligands of the invention are effective for the treatment of diabetes.

It has been surprisingly found that the sigma-receptor ligands of the invention are effective for the treatment of diabetes, in particular controlling the associated glycaemia by decreasing the blood glucose levels.

It has been also surprisingly found that the sigma-receptor ligands of the invention can be used as adjuvant therapy in the diabetes treatment.

It has been also surprisingly found that the sigma-receptor ligands of the invention are effective to treat metabolic syndrome, and more particularly the diabetes associated metabolic syndrome.

It has been also surprisingly found that the sigma-receptor ligands of the invention are effective to treat hyperglycemia.

According to the present invention, the term "diabetes" preferably refers to type-2 diabetes.

Therefore, in one aspect, the invention is directed to a compound binding to the sigma- receptor for use in the treatment of diabetes.

In a preferred embodiment, the invention is directed to a compound binding to the sigma-receptor according to general formula (I) for use in the treatment of diabetes:

(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 arylalkyi, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR ₈ , -C(0)OR ₈ , -C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , - N=CR ₈ R ₉ , and halogen;

R ₂ 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 arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR ₈ , -C(0)OR ₈ , -C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, - OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -N R ₈ R ₉ , -N R ₈ C(0)R ₉ , -N0 ₂ , -N=CR ₈ R ₉ , and halogen;

R ₃ and R ₄ 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 arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR ₈ , -C(0)OR ₈ , - C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , -N=CR ₈ R ₉ , and halogen, or together they form an optionally substituted fused ring system; R ₅ and R ₆ 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, -COR ₈ , -C(0)OR ₈ , -

C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , -N=CR ₈ R ₉ , 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;

R ₈ and R ₉ 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 another aspect, the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use in controlling the diabetes- associated glycaemia by decreasing the blood glucose levels.

In another aspect, the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use to treat metabolic syndrome, preferably metabolic syndrome associated with diabetes.

In another aspect, the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use as adjuvant therapy in the diabetes treatment.

In another aspect, the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use to treat hyperglycemia.

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

In another aspect, the invention is directed to the use in controlling the diabetes- associated glycaemia by decreasing the blood glucose levels of a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

In another aspect, the invention is directed to the use to treat metabolic syndrome, in particular the diabetes associated metabolic syndrome, of a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

In another aspect, the invention is directed to the use as adjuvant therapy in the diabetes treatment of a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

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

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.

Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above. Another aspect of the invention is a method of treatment of a patient suffering from diabetes by controlling the diabetes-associated glycaemia by decreasing the blood glucose levels, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.

Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above as adjuvant therapy. Another aspect of the invention is a method of treatment of a patient suffering from metabolic syndrome, in particular diabetes-associated metabolic syndrome, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above. Another aspect of the invention is a method of treatment of a patient suffering from hyperglycemia, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.

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

These aspects and preferred embodiments thereof are additionally also defined hereinafter in the detailed description and in the claims.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : Evolution of the glycaemia and body weight gain in ZDF treated with saline or with Example 1 and LEAN rats. Lines represent the mean ± SEM of the glucose levels on weeks 7, 10, 13, 14 and 15.

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 of diabetes, and more particularly type-2 diabetes. Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes. Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in controlling the diabetes-associated glycaemia by decreasing the blood glucose levels. Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use as diabetes adjuvant therapy. Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in the treatment of hyperglycemia. 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 o1 -receptor performed as described (DeHaven-Hudkins et al., Eur J Pharmacol,'\ 992, 227, 371 ) or binding assays for o2-receptor as described (Radesca et al., J Med Chem, 1991 , 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 ³ [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 ^"7 M 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 ³ [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 one aspect the compound binding to the sigma-receptor, preferably to the sigma-1 receptor subtype, is used in the treatment of diabetes and more particularly type-2 diabetes. In another aspect the compound binding to the sigma-receptor, preferably to the sigma-1 receptor subtype, is used in the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes. In another aspect the compound binding to the sigma- receptor, preferably to the sigma-1 receptor subtype, is used in controlling the diabetes-associated glycaemia by decreasing the blood glucose levels. In another aspect the compound binding to the sigma-receptor, preferably to the sigma-1 receptor subtype, is used as diabetes adjuvant therapy. In another aspect the compound binding to the sigma-receptor, preferably to the sigma-1 receptor subtype, is used in the treatment of hyperglycemia.

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, -COR ₈ , -C(0)OR ₈ ,

-C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , - N=CR ₈ R ₉ , and halogen;

R ₂ 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 ₈ , -C(0)OR ₈ , -C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, - OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -N R ₈ R ₉ , -N R ₈ C(0)R ₉ , -N0 ₂ , -N=CR ₈ R ₉ , and halogen;

R ₃ and R ₄ 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 arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR ₈ , -C(0)OR ₈ , - C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , -N=CR ₈ R ₉ , and halogen, or together they form an optionally substituted fused ring system;

R ₅ and R ₆ 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 arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR ₈ , -C(0)OR ₈ , - C(0)NR ₈ R ₉ , -CH=NR ₈ , -CN, -OR ₈ , -OC(0)R ₈ , -S(0) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C(0)R ₉ , - N0 ₂ , -N=CR ₈ R ₉ , 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;

R ₈ and R ₉ 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 R-i selected from H, -COR ₈ , 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 R-i is hydrogen.

In a preferred embodiment of the use as defined above the compound is characterized in that R ₂ is H or alkyl, preferably methyl or H. In a preferred embodiment of the use as defined above the compound is characterized in that R ₃ and R ₄ 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 R ₃ and R ₄ 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 R ₃ and R ₄ 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 R ₅ and R ₆ , together, form a morpholin-4-yl group.

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

[1 ] 4-{2-(1 -(3,4-Dichlorophenyl)-5-methyl-1 H pyrazol-3-yloxy)ethyl} morpholine, [2] 2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]-N,N-diethylethanamine hydrochloride,

[3] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride, [4] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole hydrochloride,

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

[6] 1 -{2-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}-1 H-imidazole,

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

[8] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}-4- methylpiperazine,

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

[10] 1 -(4-(2-(1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy)ethyl)piperazin-1 - yl)ethanone,

[1 1] 4-{2-[1 -(4-Methoxyphenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

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

[13] 1 -(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole,

[14] 1 -[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-[1 -(3,4-Dichlorophenyl)-5-phenyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[17] 1 -(3,4-Dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1 -yl)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-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}morpholine hydrochloride,

[23] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1 -yl)butoxy]-1 H-pyrazole,

[24] 1 -{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-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] 1 -{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-1 H-imidazole,

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

[28] 1 -{4-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-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- 1 H-indol-4(5H)-one,

[30] 2-{4-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-1 ,2,3,4- tetrahydroisoquinoline,

[31 ] 4-{2-[1 -(3,4-dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[32] 2-[1 -(3,4-Dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]-N,N- diethylethanamine,

[33] 1 -(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

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

[35] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-isopropyl-1 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-yloxy]ethyl}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-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]ethyl}morpholine,

[45] 2-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]-N,N- diethylethanamine hydrochloride,

[46] 1 -(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

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

[48] 1 -{2-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]ethyl}piperidine,

[49] 4-{4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]butyl}morpholine

hydrochloride,

[50] (2S,6R)-4-{4-[1 -(3,4-dichlorophenyl)-1 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] 1 -(3,4-Dichlorophenyl)-3-[4-(pyrrolidin-1 -yl)butoxy]-1 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-dichlorophenyl)-1 H-pyrazol-3-yloxy]-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)-1 H-pyrazol-4- yl]ethanone oxalate,

[58] 1 -{1 -(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazol-4- yl}ethanone oxalate,

[59] 1 -{1 -(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1 -yl)ethoxy]-1 H-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-1 -(naphthalen-2-yl)-1 H-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-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof. In a still more preferred embodiment of the use as defined above the compound is 4-{2- [5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or solvates or a prodrug thereof.

"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.

"Cycloalkyi" 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 cycloalkyi radical may 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 quaternized ; 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-NH ₂ , -NHRa or -NRaRb, optionally quaternized, 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 fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a Ci _-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 ¹³ C- or ¹⁴ C-enriched carbon or ¹⁵ 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, Ν,Ν-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 general 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 encompass all such forms.

As used herein, the terms "treat", "treating" and "treatment" include the eradication, removal, reversion, alleviation, modification, or control of diabetes, metabolic syndrome, hyperglycemia and/or its related symptoms. In some embodiments, the invention relates to the treatment of diabetes-associated glycaemia by decreasing the blood glucose levels.

Another aspect of this invention relates to a method of treating diabetes, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a compound of general formula (I) as above defined or a pharmaceutical composition thereof.

Another aspect of the invention is a method of treatment of a patient suffering from diabetes by controlling the diabetes-associated glycaemia by decreasing the blood glucose levels, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.

Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above, as adjuvant therapy.

Another aspect of the invention is a method of treatment of a patient suffering from metabolic syndrome, in particular diabetes-associated metabolic syndrome, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.

Another aspect of the invention is a method of treatment of a patient suffering from hyperglycemia, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.

In another aspect, the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of diabetes. In another aspect, the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for controlling the diabetes-associated glycaemia by decreasing the blood glucose levels.

In another aspect, the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for diabetes adjuvant therapy.

In another aspect, the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of metabolic syndrome, in particular diabetes-associated metabolic syndrome.

In another aspect, the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of hyperglycemia.

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 the use as defined above of 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 microcrystalline 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 general formula (I) of the invention the compounds, optionally in the form of a pharmaceutical composition, are administered once daily.

In a preferred embodiment of the use of the compounds of the invention, the sigma ligand of general formula (I) is administered as a daily dose of from to 100 mg to 600 mg per day. Even more preferably, the sigma ligand of general formula (I) is administered as a daily dose of from 200 mg to 400 mg per day.

The compounds and compositions of this invention may be used to provide with other drugs 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.

Advantageously, the other drugs are selected among the known drugs currently used in the treatment of diabetes, especially type-2 diabetes.

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-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl} 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 HCI, 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).

¹ H-NMR (DMSO-d6) 6 ppm: 10,85 (bs, 1 H), 7,95 (m, 4H), 7,7 (dd, J=2,2, 8,8 Hz,1 H), 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

Materials and methods

Animals

Six weeks old male ZDF rats or their respective control (age-matched lean nondiabetic

Zucker rats, LEAN) were obtained from Charles River Laboratories (Research Models, Barcelona, Spain). The animals were housed in a certified animal care facility, in cages (2-3 animals) and maintained in environmentally controlled conditions (temperature 20 °C, humidity 60%) with a 12-h light/dark cycle until they reached 15 weeks of life. Animals were maintained on Purina 5008 (16.7 kcal% fat) diet and sterile tap water, chow and water being available ad libitum through all the experimental period.

In this model for non-insulin-dependent diabetes mellitus, hyperglycemia and insulin resistance begins to develop at, approximately, 7 weeks of age and glucose levels typically reach a plateau (more than 300 mg/dl) by 15-16 weeks of age (Peterson et al., 1990).

All experimental protocols were approved by the Ethical Committee of the Universidad Rey Juan Carlos and performed in strict accordance with the EC regulation for care and use of experimental animals (2010/63/EU). Glycaemia

Non-fasting blood glucose levels were daily measured in the morning (9 h) using a glucose strip tester (Glucocard sensor, Arkray, Inc. Kyoto Japan), throughout the experimental period (weeks 7, 10, 13, 14 and 15).

Experimental protocol After one week of adaptation (week 7 of life) non fasting blood glucose levels were monitored on LEAN and ZDF rats for the first time in order to facilitate the detection of the development of diabetes and neuropathies.

Behavioral tests were repeated at the end of the week 13 of life and then, ZDF rats were randomly assigned to two separated groups to be treated with a single dose of Example 1 (64 mg/kg i.p, 0.5 ml, n=8) or with the same volume of saline solution (n=7), LEAN rats group (n=7) was treated with saline.

Sub-chronic treatment was started 24 hours after this first administration. Rats received two daily intraperitoneal injections for 14 days (weeks 14 and 15) of compound Example 1 (25 mg/kg) or saline solution. Glycaemia was monitored throughout all the experimental period.

Example 2: Glycaemia in ZDF rats treated with Example-1

Animals were habituated to the corresponding test environments two days before the experiment by leaving them daily inside the recording device for ten minutes. The ZDF rats showed a mean blood glucose concentration of 88.1 ±5.1 , 329.3±26.0, and 413.6±22.6 mg/dl, on week 7, 10 and 13, respectively, being the difference of week 10 and 13 vs week 7 values statistically significant (p<0.001 ).

The LEAN mean blood glucose concentration was of 64.8±1 .4, 60.6±1 .3, and 69.9±2.6 mg/dl, on week 7, 10 and 13, respectively. These values were significantly different from those recorded in both saline- and Example 1 -treated ZDF rats (p<0.001 ).

Non-fasting blood glucose levels in ZDF rats were slight but significantly (p<0.01 ) decreased from the first administration of Example 1 in comparison with values recorded in saline treated ZDF animals (Figure 1 ). A one way ANOVA followed by Bonferroni post hoc test was used for statistical analysis of glycaemia differences between saline and Exaple 1 ZDF treated rats (**p<0.01 ). A two way ANOVA followed by Bonferroni post hoc test was used when comparing body weight among the three groups (+ p<0.05; ++ p<0.01 ; +++ p<0.001 vs LEAN) (N=7-8). In summary, in the results obtained in example 2 the compound of example 1 shows a significant reduction in the glycaemia.

Thus, the compound of Example 1 and the other compounds of general formula (I) will be useful to treat diabetes, metabolic syndrome, hyperglycemia, etc.