TRPM8 inhibitors for use in the prevention or treatment of joint damage, joint degeneration and / or joint inflammation caused by osteoarthritis

Abstract

The invention relates to TRPM8 inhibitors for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

Description

[0001] TRPM8 INHIBITORS FOR USE IN THE PREVENTION OR TREATMENT OF

[0002] JOINT DAMAGE, JOINT DEGENERATION AND / OR JOINT INFLAMMATION CAUSED BY OSTEOARTHRITIS

[0003] TECHNICAL FIELD

[0004] The invention relates to TRPM8 inhibitors for use in the treatment of osteoarthritis. In detail, the invention relates to TRPM8 inhibitors for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis. The invention is also directed to TRPM8 inhibitors for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0005] BACKGROUND OF THE INVENTION

[0006] Osteoarthritis (OA) is a chronic, commonly age-related degenerative disease of the joint tissue, including articular cartilage, subchondral bone, and synovium. The damage of the joint tissue results in pain and in decreased function of the affected joint (Mintarjo JA, et al., Cureus. 2023 Jun 26;15(6):e40966). Beyond aging, other OA risk factors include being overweight and different types of injuries or diseases, such as infection, autoimmune processes, degenerative processes, and trauma. Its occurrence is estimated at 22.9% in persons over 40 years of age in 2020 (Cui A, et al., EClinicalMedicine 2020; 29-30: 100587).

[0007] The knee is a frequent site for OA (Uivaraseanu B, et al. Exp Ther Med. 2022;23:328; Hamood R, et al., J Clin Med. 2021 ;10:4282; Oo WM et al., Ther Adv Musculoskelet Dis. 2022 May 20; 14: 1759720X221090297). Knee osteoarthritis (KOA) can cause joint pain, muscle weakness, physical disability, and decreased quality of life. Nearly half of the cases of OA are KOA, and its prevalence increases with age and degree of obesity.

[0008] Despite the enormous impact of OA in patients, the treatment of OA is currently focused on symptomatic improvement only, especially in the management of pain (Bannuru RR et al., Osteoarthritis Cartilage 2019; 27: 1578-1589) and is thus mostly palliative. The pharmacologic treatment is primarily performed with analgesics, NSAIDs and opioids (Hochberg MC. Osteoarthritis Cartilage 2012; 20(12):1465-1469; Hochberg MC et al., Arthritis Care Res. (Hoboken) 2012; 64(4):465-474; Jordan KM, et al., Ann Rheum Dis 2003; 62(12):1145-1155). When the pharmacologic treatment is not effective at controlling the symptoms, surgery is required to replace the damaged joint (Bajpayee AG, et al., Osteoarthritis Cartilage 2016; 24(1 ):71 -81 ; Han Y, et al., Pain Med 2019; 20(7):1418-1429; Jansen MP, et al., Cartilage 2021 ; 12(2):181 -191 ). Unfortunately, surgery is often a temporary solution, and revision surgeries need to be performed as the time passes (Rodriguez-Merchan, Arch Bone Jt Surg. 2023; 11 (1 ): 11 -22).

[0009] Currently, no effective disease-modifying osteoarthritis drugs (DMOADs), i.e. , drugs able to delay or reverse the progression of the structural damage of the joint, have been approved by regulatory bodies (Oo WM et al., Drug Des Devel Ther 2021 ; 15: 2921-2945; Rodriguez-Merchan, Arch Bone Jt Surg. 2023; 11 (1 ): 11 -22). The clinical trials published so far have produced disappointing outcomes, given that the medications have only been effective in the short term or have shown no efficacy (Chevalier X, et al., Nat Rev Rheumatol. 2013; 9(7):400-410; Rodriguez-Merchan, Arch Bone Jt Surg. 2023; 11 (1 ): 1 1 -22).

[0010] It is therefore felt the need to develop new therapies that not only provide symptomatic relief from pain but also are able to prevent, delay, block or reverse the progression of structural damage and degeneration of the joint, and associated tissues, caused by osteoarthritis.

[0011] Transient Receptor Potential (TRP) channels are one of the largest groups of ion channels and, based on their sequence homology, are classified into 6 sub-families (TRPV, TRPM, TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selective channels activated by several physical (such as temperature, osmolarity and mechanical stimuli) and chemical stimuli. TRPM8, which was cloned in 2002, is a non-selective cation channel of the TRP family expressed on a subpopulation of somatic sensory nerves on dorsal root ganglion and trigeminal ganglia that causes sensory nerve excitation. It is activated by mild cold temperatures and synthetic cool-mimetic compounds such as menthol, eucalyptol and icilin (McKemy D.D. et al., Nature (2002) 416, 52-58; Peier A.M. et al. Cell (2002) 108, 705-715). Like several other TRP channels, TRPM8 is also gated by voltage (Nilius B. et al., J. Physiol. (2005) 567, 35-44). The voltage dependence of TRPM8 is characterized by a strong outward rectification at depolarized transmembrane potential and a rapid and potential-dependent closure at negative membrane potentials. Cooling agents and menthol application shifts the activation curve towards more negative potentials, increasing the possibility for the opening of the channel and boosting inward currents at physiological membrane potentials. Other endogenous factors, such as phospholipase A2 products (Vanden Abeele F. et al., J. Biol.Chem. (2006) 281 , 40174-40182), endocannabinoids (De Petrocellis L. et al., Exp.Cell. Res. (2007) 313, 1911 -1920) and PIP2 (Rohacs T. et al., Nat. Neurosci. (2005) 8, 626-634) also participate in channel regulation.

[0012] There is a lot of direct and indirect evidence of a pivotal role of TRPM8 channel activity in diseases such as itch, irritable bowel diseases, cold induced and / or exacerbated respiratory disorders, ischemia, neurodegeneration, psychiatric disorders, stroke, urological disorders, dry eye syndrome and epiphora.

[0013] Over the last few years, several classes of non-peptide TRPM8 antagonists have been disclosed. WO 2006 / 040136, WO 2007 / 017092, WO 2007 / 017093, WO 2007 / 017094, and WO 2007 / 080109 describe benzyloxy derivatives as TRPM8 antagonists for the treatment of urological disorders; WO 2007 / 134107 describes phosphorous-bearing compounds as TRPM8 antagonists for the treatment of TRPM8-related disorders; WO 2009 / 012430 describes sulfonamides for the treatment of diseases associated with TRPM8; WO 2010 / 103381 describes the use of spirocyclic piperidine derivatives as TRPM8 modulators in prevention or treatment of TRPM8-related disorders or diseases; WO 2010 / 125831 describes sulfamoyl benzoic acid derivatives as modulators of the TRPM8 receptor and their use in the treatment of inflammatory, pain and urological disorders; and WO 2013 / 092711 describes 2-aryl oxazole and thiazole derivatives as TRPM8 receptor modulators and their use in prevention, reduction of the risk of, amelioration and / or treatment of urological - related disorders. Nonetheless, a relevant side effect of TRPM8 inhibitors which limits their clinical applicability is represented by the lowering of body temperature which is induced by these molecules (Bautista D.M. et al., Nature (2007) 448, 204-208; Knowlton W.M. et al., PLoS ONE (2011 ) 6, e25894; Almeida M.C. et al., J. Neurosci. (2012) 32, 2086-2099; Gavva N.R. et al., Mol. Pain. (2012) 8, 36).

[0014] The present invention is aimed at providing an effective therapeutic management of osteoarthritis, including prevention or treatment of joint damage, joint degeneration and joint inflammation caused by osteoarthritis.

[0015] SUMMARY OF THE INVENTION

[0016] The invention is directed to a TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0017] The invention is also directed to a TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0018] The invention is also directed to a pharmaceutical composition comprising a TRPM8 inhibitor and at least one pharmaceutically acceptable excipient or carrier for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0019] The invention is also directed to a pharmaceutical composition comprising a TRPM8 inhibitor and at least one pharmaceutically acceptable excipient or carrier for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0020] The invention is also directed to a method of preventing or treating joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject, which comprises administering an effective amount of one or more TRPM8 inhibitors to a subject in need thereof.

[0021] The invention is also directed to a method of preventing or treating joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis, which comprises administering an effective amount of one or more TRPM8 inhibitors to a subject in need thereof.

[0022] The invention is also directed to the use of a TRPM8 inhibitor in the manufacture of a medicament for the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0023] The invention is also directed to the use of a TRPM8 inhibitor in the manufacture of a medicament for the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0024] BRIEF DESCRIPTION OF FIGURES

[0025] Figure 1 shows in panel A) the effect of DFL23693 on gross pathology of knee of monosodium iodoacetate (MIA)-induced osteoarthritis. Data indicates Mean ± SEM. One-way ANOVA followed by Sidak's multiple comparisons test, n=6- 14. ###p<0.001 Vs NaTve / Saline (Intra-articular) + Vehicle;

[0026] *p<0.05,***p<0.001 Vs MIA + Vehicle / MIA + Placebo; and in panel B) representative images of morphology of tibial articular cartilage during MIA induced osteoarthritic changes in rat knee joint.

[0027] Figure 2 shows the effect of DFL23693 on tibial histopathological grades of knee during monosodium iodoacetate (MIA)-induced osteoarthritis. Data indicates Mean ± SEM. One-way ANOVA followed by Sidak's multiple comparisons test, n=6-14. ###p<0.001 Vs NaTve / Saline (Intra-articular) + Vehicle;**p<0.01 Vs MIA + Placebo.

[0028] Figure 3 shows the effect of DFL23693 on tibial cartilage inflammation score of knee in the monosodium iodoacetate (MIA)-induced osteoarthritis. Data indicates Mean ± SEM. One-way ANOVA followed by Sidak's multiple comparisons test, n=6-14. ###p<0.001 Vs NaTve / Saline (Intra-articular) + vehicle;*p<0.05 Vs MIA + Placebo.

[0029] Figure 4 shows the effect of DFL23693 on tibial cartilage proteoglycan score of knee during monosodium iodoacetate (MIA)-induced osteoarthritis. Data indicates Mean ± SEM. One-way ANOVA followed by Sidak's multiple comparisons test, n=6-14. ###p<0.001 Vs NaTve / Saline (Intra-articular) + vehicle;*p<0.05 Vs MIA + Placebo.

[0030] Figure 5 shows the effect of DFL23693 on rectal temperature of monosodium iodoacetate (MIA)-induced osteoarthritic pain on days 3 (panel A), 7 (panel B), 14 (panel C), 21 (panel D) and 28 (panel E). Data indicates Mean ± SEM. Two- way ANOVA followed by Dunnett's multiple comparisons test, n=7-14.

[0031] Figure 6 shows the effect of oral administration of DFL23693 and PF- 05105679 on the OARSI score in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below.

[0032] Figure 7 shows the effect of oral administration of DFL23693 and PF- 05105679 on the percentage of eroded cartilage in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below. Figure 8 shows the effect of oral administration of DFL23693 and PF- 05105679 on the percentage of inflammatory infiltrate in the subchondral bone in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below.

[0033] Figure 9 shows the effect of oral administration of DFL23693 and PF- 05105679 on the percentage of TRAP+ surface in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below.

[0034] Figure 10 shows the effect of oral administration of DFL23693 and PF- 05105679 on the percentage of COL10A surface in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below.

[0035] Figure 11 shows the effect of oral administration of DFL23693 in COMP in the monosodium iodoacetate (MIA)-induced osteoarthritis as described in Example 2 below.

[0036] Figure 12 shows the mean concentration of IL1 b in the supernatants of M1 macrophages treated as described in Example 3 below.

[0037] Figure 13 shows the mean concentration of CCL2 in the supernatants of M1 macrophages treated as described in Example 3 below.

[0038] Figure 14 shows the mean concentration of TNFa in the supernatants of M1 macrophages treated as described in Example 3 below.

[0039] Figure 15 shows the mean concentration of IL-6 in the supernatants of M1 macrophages treated as described in Example 3 below.

[0040] Figure 16 shows the mean concentration of IL-8 in the supernatants of M1 macrophages treated as described in Example 3 below.

[0041] Figure 17 shows the mean concentration of osteopontin (OPN) in the supernatants of osteoblasts of Donor 1 treated as described in Example 4 below.

[0042] Figure 18 shows the mean concentration of osteopontin (OPN) in the supernatants of osteoblasts of Donor 2 treated as described in Example 4 below.

[0043] Figure 19 shows the Alizarin Red S (ARS) staining performed on osteoblasts of Donor 1 and Donor 2 treated as described in Example 4 below.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] It has been surprisingly found that inhibitors of TRPM8 are effective in the prevention and treatment of pain and joint damage, joint degeneration and joint inflammation in subjects with osteoarthritis.

[0046] Accordingly, the invention is directed to a TRPM8 inhibitor for use in the treatment of osteoarthritis in a subject. Furthermore, the invention is directed to a TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0047] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage caused by osteoarthritis in a subject. According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint degeneration caused by osteoarthritis in a subject.

[0048] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint inflammation caused by osteoarthritis in a subject.

[0049] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage and joint degeneration caused by osteoarthritis in a subject.

[0050] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage and joint inflammation caused by osteoarthritis in a subject.

[0051] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0052] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage, joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0053] The invention is also directed to a TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0054] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage in a subject with osteoarthritis.

[0055] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint degeneration in a subject with osteoarthritis. According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint inflammation in a subject with osteoarthritis.

[0056] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage and joint degeneration in a subject with osteoarthritis.

[0057] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage and joint inflammation in a subject with osteoarthritis.

[0058] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint degeneration and joint inflammation in a subject with osteoarthritis.

[0059] According to a preferred embodiment, said TRPM8 inhibitor is for use in the prevention or treatment of joint damage, joint degeneration and joint inflammation in a subject with osteoarthritis.

[0060] The term “prevention” as used herein refers to the inhibition of onset of the disorder being treated or to the delay in the onset of the disorder being treated. The delay in the onset of the disorder being treated is measured relative to the time of onset of the disorder observed in a subject affected by osteoarthritis of comparable severity not receiving the TRPM8 inhibitor for use according to the present invention.

[0061] Thus, according to a preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject. According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage or joint degeneration or joint inflammation caused by osteoarthritis in a subject.

[0062] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage caused by osteoarthritis in a subject.

[0063] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint degeneration caused by osteoarthritis in a subject.

[0064] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint inflammation caused by osteoarthritis in a subject.

[0065] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint degeneration and joint inflammation caused by osteoarthritis in a subject. According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint degeneration caused by osteoarthritis in a subject.

[0066] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint inflammation caused by osteoarthritis in a subject.

[0067] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0068] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis. According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage or joint degeneration or joint inflammation in a subject with osteoarthritis.

[0069] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage in a subject with osteoarthritis.

[0070] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint degeneration in a subject with osteoarthritis.

[0071] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint inflammation in a subject with osteoarthritis.

[0072] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint degeneration and joint inflammation in a subject with osteoarthritis.

[0073] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint degeneration in a subject with osteoarthritis.

[0074] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and joint inflammation in a subject with osteoarthritis.

[0075] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint degeneration and joint inflammation in a subject with osteoarthritis.

[0076] The term “treatment” as used herein refers to the mitigation, amelioration, inhibition of the progression or slowing of the progression of the disorder being treated or of one or more of the symptoms associated thereof, notwithstanding the fact that the patient may still be afflicted with the underlying disorder. The slowing of the progression of the disorder being treated or of one or more of the symptoms associated thereof is measured relative to the progression of the disorder being treated or of one or more of the symptoms associated thereof observed in a subject affected by osteoarthritis of comparable severity not receiving the TRPM8 inhibitor for use according to the present invention.

[0077] Thus, according to a preferred embodiment, said TRPM8 inhibitor is for use in i) the inhibition or slowing of the progression of joint damage and / or joint degeneration and / or joint inflammation or ii) the reduction of the entity of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0078] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage or joint degeneration or joint inflammation caused by osteoarthritis in a subject.

[0079] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0080] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage caused by osteoarthritis in a subject.

[0081] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint degeneration caused by osteoarthritis in a subject.

[0082] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint inflammation caused by osteoarthritis in a subject.

[0083] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint degeneration and joint inflammation caused by osteoarthritis in a subject. According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint degeneration caused by osteoarthritis in a subject.

[0084] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint inflammation caused by osteoarthritis in a subject.

[0085] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0086] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage or joint degeneration or joint inflammation caused by osteoarthritis in a subject.

[0087] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage caused by osteoarthritis in a subject.

[0088] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint degeneration caused by osteoarthritis in a subject.

[0089] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint inflammation caused by osteoarthritis in a subject.

[0090] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage, joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0091] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage and joint degeneration caused by osteoarthritis in a subject.

[0092] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage and joint inflammation caused by osteoarthritis in a subject.

[0093] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0094] According to a further preferred embodiment, said TRPM8 inhibitor is for use in i) the inhibition or slowing of progression of joint damage and / or joint degeneration and / or joint inflammation or ii) the reduction of the entity of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0095] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage or joint degeneration or joint inflammation in a subject with osteoarthritis.

[0096] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage in a subject with osteoarthritis.

[0097] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint degeneration in a subject with osteoarthritis.

[0098] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint inflammation in a subject with osteoarthritis.

[0099] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint degeneration and joint inflammation in a subject with osteoarthritis.

[0100] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint degeneration in a subject with osteoarthritis.

[0101] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint damage and joint inflammation in a subject with osteoarthritis.

[0102] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the inhibition or slowing of the progression of joint degeneration and joint inflammation in a subject with osteoarthritis.

[0103] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage or joint degeneration or joint inflammation in a subject with osteoarthritis.

[0104] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage in a subject with osteoarthritis.

[0105] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint degeneration in a subject with osteoarthritis.

[0106] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint inflammation in a subject with osteoarthritis.

[0107] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage, joint degeneration and joint inflammation in a subject with osteoarthritis.

[0108] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage and joint degeneration in a subject with osteoarthritis.

[0109] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint damage and joint inflammation in a subject with osteoarthritis.

[0110] According to a further preferred embodiment, said TRPM8 inhibitor is for use in the reduction of the entity of joint degeneration and joint inflammation in a subject with osteoarthritis.

[0111] The effect of the TRPM8 inhibitor for use according to the invention on the joint damage and / or joint degeneration and / or joint inflammation results in preservation or improvement of the functionality of the joints, and inhibition or treatment of symptoms such as stiffness and loss of mobility.

[0112] Thus, the invention is also directed to a TRPM8 inhibitor for use in the prevention or treatment of stiffness and loss of mobility caused by osteoarthritis in a subject.

[0113] Furthermore, the invention is also directed to a TRPM8 inhibitor for use in the prevention or treatment of stiffness and loss of mobility in a subject with osteoarthritis.

[0114] Preferably, said TRPM8 inhibitor is for use in i) the inhibition of onset or in the delay in the onset of stiffness and loss of mobility, or ii) the inhibition or slowing of the progression of stiffness and loss of mobility, or iii) the reduction of the entity of stiffness and loss of mobility caused by osteoarthritis in a subject.

[0115] Preferably, said TRPM8 inhibitor is for use in i) the inhibition of onset or in the delay in of the onset of stiffness and loss of mobility, or ii) the inhibition or slowing of the progression of stiffness and loss of mobility, or iii) the reduction of the entity of stiffness and loss of mobility in a subject with osteoarthritis.

[0116] The delay in the onset of stiffness and loss of mobility is measured relative to the time of onset of stiffness and loss of mobility in a subject affected by osteoarthritis of comparable severity not receiving the TRPM8 inhibitor for use according to the present invention.

[0117] The slowing of the progression of stiffness and loss of mobility is measured relative to the rate of progression of stiffness and loss of mobility in a subject affected by osteoarthritis of comparable seventy not receiving the TRPM8 inhibitor for use according to the present invention.

[0118] The present invention is also directed to a TRPM8 inhibitor for use in the prevention or treatment of osteoarthritic pain in a subject.

[0119] According to a preferred embodiment, said TRPM8 inhibitor is for use in reducing the entity of osteoarthritic pain in a subject.

[0120] According to a preferred embodiment, said TRPM8 inhibitor is for use in delaying the onset of pain in a subject affected by osteoarthritis. The delay in the onset of pain is measured relative to the time of onset of pain in a subject affected by osteoarthritis of comparable seventy not receiving the TRPM8 inhibitor for use according to the present invention.

[0121] According to a preferred embodiment, said TRPM8 inhibitor is for use in slowing the progression of osteoarthritic pain in a subject.

[0122] The slowing of the progression of osteoarthritic pain in the subject is measured relative to the progression of osteoarthritic pain observed in a subject affected by osteoarthritis of comparable severity not receiving the TRPM8 inhibitor for use according to the present invention

[0123] According to a preferred embodiment, said subject is a human subject.

[0124] According to a preferred embodiment, said subject is selected after a clinical evaluation of the affected joint by means of an imaging technique, preferably by means of radiography or Magnetic Resonance Imaging (MRI).

[0125] According to a preferred embodiment, said subject is at least 25 years old, preferably at least 40 years old, more preferably at least 50 years old.

[0126] According to a preferred embodiment, said subject has confirmation of osteoarthritis based on the clinical and radiological criteria of American College of Rheumatology Criteria for OA, preferably as disclosed in any of the following papers: Altman, Seminars in Arthritis and Rheumatism, Volume 20, Issue 6, Supplement 2, 1991 , pages 40-47; Altman R. et al., Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986 Aug;29(8):1039-49; Altman R. et al., Arthritis Rheum. 1991 May;34(5):505-14.

[0127] According to a preferred embodiment, said subject has a Kellgren-Lawrence (K-L) Grade 1 , 2 or 3, more preferably 2 or 3, based on an imaging technique, preferably based on Magnetic Resonance Imaging (MRI) or radiography.

[0128] Preferably, said Kellgren-Lawrence (K-L) Grade is measured as disclosed in Liu, et al., Neural Processing Letters, Volume 54, pages 5199-5224, (2022). According to a preferred embodiment, said joint damage is joint cartilage damage.

[0129] According to a preferred embodiment, said joint degeneration is joint cartilage degeneration.

[0130] According to a preferred embodiment, said joint damage is joint bone damage. According to a preferred embodiment, said joint degeneration is joint bone degeneration.

[0131] According to a preferred embodiment, said joint damage is joint cartilage damage and joint bone damage.

[0132] According to a preferred embodiment, said joint degeneration is joint cartilage degeneration and joint bone degeneration.

[0133] Preferably, said joint bone damage is subchondral bone damage.

[0134] Preferably, said joint bone degeneration is subchondral bone degeneration.

[0135] According to a preferred embodiment, said joint damage and / or said joint degeneration includes the formation of osteophytes.

[0136] Thus, according to this embodiment, said TRPM8 inhibitor is for use in: i) the inhibition or slowing of the formation of osteophytes, ii) the inhibition or slowing of the progression of the formation of osteophytes, or iii) the reduction of the number and / or size of osteophytes caused by osteoarthritis in a subject. Preferably, according to this embodiment, said TRPM8 inhibitor is for use in: i) the inhibition or slowing of the formation of osteophytes, ii) the inhibition or slowing of the progression of the formation of osteophytes, or iii) the reduction of the number and / or size of osteophytes in a subject with osteoarthritis.

[0137] According to a preferred embodiment, also in combination with any of the above embodiments, said osteoarthritis is selected from hand osteoarthritis, knee osteoarthritis, hip osteoarthritis, osteoarthritis of the lower back, osteoarthritis of the spine, ankle osteoarthritis, elbow osteoarthritis, osteoarthritis of the fingers, foot osteoarthritis, shoulder osteoarthritis, wrist osteoarthritis, first metatarsophalangeal (MTP) joint osteoarthritis, sacroiliac (SI) joint arthritis and cervical osteoarthritis. According to the most preferred embodiment, said osteoarthritis is selected from knee osteoarthritis and hand osteoarthritis, preferably it is knee osteoarthritis.

[0138] According to a preferred embodiment, said prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation is evaluated as change from baseline of one or more of the following:

[0139] - change in ultrasound scores,

[0140] - change in the cartilage thickness as assessed by an imaging technique, preferably by standardized Magnetic Resonance Imaging (MRI),

[0141] - change in cartilage structure and morphology, preferably based on Magnetic Resonance Imaging (MRI) assessment of cartilage volume and composition,

[0142] - change in cartilage volume, preferably calculated based on quantitative MRI (qMRI),

[0143] - change in cartilage T2 relaxation time, preferably assessed by the Double Echo Steady State (DESS) Magnetic Resonance Imaging (MRI) for the same regions of interest as for cartilage morphometry

[0144] - change in concentration of cartilage degradation fragments in blood plasma, preferably Aggrecan fragment neoepitope (ARGS), preferably as assessed by ELISA assay,

[0145] - change in Medial Joint Space Width (mJSW), preferably as assessed by an imaging technique, more preferably by radiography or Magnetic Resonance Imaging (MRI),

[0146] - change in Minimal Joint Space Width (mJSW), preferably as assessed by an imaging technique, more preferably by X-ray or Magnetic Resonance Imaging (MRI),

[0147] - change in joint space narrowing, preferably based on x-ray assessment,

[0148] - changes in joint synovitis / effusion volume, preferably calculated based on an imaging technique, preferably based on Magnetic Resonance Imaging (MRI),

[0149] - change in inflammatory activity compared to baseline, preferably based on Magnetic Resonance Imaging (MRI) assessment of synovitis, - structural changes in subchondral bone,

[0150] - change in subchondral bone marrow lesions (BML) area and volume, preferably calculated based on an imaging technique, preferably based on Magnetic Resonance Imaging (MRI),

[0151] - change in bone mineral density (BMD), preferably as assessed by quantitative computed tomography (qCT) or dual-energy X-ray absorptiometry (DXA),

[0152] - change in bone shape, preferably evaluated based on an imaging technique, preferably based on Magnetic Resonance Imaging (MRI),

[0153] - change in serum bone biomarker N-terminal propeptide of procollagen type I (PINP),

[0154] - change in serum bone biomarker [3-C-terminal telopeptide (|3-CTX),

[0155] - change in blood levels of biomarker C-telopeptide of crosslinked collagen type I (CTX-I),

[0156] - change in urine levels of biomarker C-telopeptide of crosslinked collagen type II (CTX-II),

[0157] - change in serum cartilage biomarker cartilage oligomeric matrix protein (COMP).

[0158] According to a preferred embodiment, said osteoarthritis is knee osteoarthritis, and said prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation can be evaluated as change from baseline of one or more of the following:

[0159] - change in the number of areas with worsening in cartilage thickness using the MRI Osteoarthritis Knee Scores (MOAKS), wherein said MOAKS is preferably calculated as disclosed in D. J. Hunter et al., Osteoarthritis and Cartilage, Volume 19, Issue 8, pp. 990-1002, August 2011 ,

[0160] - change in osteophytes formation, preferably as assessed by an imaging technique, e.g. x-ray or Magnetic Resonance Imaging (MRI),

[0161] - change in osteophytes score in each location according to size using MOAKS,

[0162] - change in meniscal morphology features using MOAKS,

[0163] - change in whole knee effusion using MOAKS,

[0164] - change in infra-patellar fat pad synovitis (Hoffa’s synovitis) using MOAKS ,

[0165] - change in MRI MOAKS Semi-quantitative measures, - structural changes in subchondral bone, preferably as assessed by change in MRI-based B-score.

[0166] The above changes are measured relative to the same parameter observed in the same subject before treatment with the TRPM8 inhibitor for use according to the present invention or in another subject affected by osteoarthritis of comparable severity not receiving the TRPM8 inhibitor for use according to the present invention.

[0167] The term “TRPM8 inhibitor” in accordance with the present invention means any compound able to inhibit the biological activity of TRPM8.

[0168] Methods and tests for determining the inhibition of the biological activity of TRPM8 and for classifying a compound as “TRPM8 inhibitor” are known in the art and are described, for example, in Sui et al., Fitoterapia 145 (2020) 104631 , and Chodon et al. BMC Cancer 2010, 10:212, which discloses the techniques used to analyze the expression of TRPM8 channels that can be implemented to analyze the ability of a compound to inhibit TRPM8 by inhibiting its expression.

[0169] According to a preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the invention is an antibody, preferably selected from ACC-049, ab235890, ab314169 and NBP1 -97311.

[0170] According to an alternative preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the invention is a small molecule. The term “small molecule” refers to an organic compound having a molecular weight of 900 Daltons or lower.

[0171] According to a preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the invention is a TRPM8 antagonist.

[0172] To date, several TRPM8 antagonists, such as small molecules, peptides and antibodies, have been disclosed, some of which are currently undergoing clinical trials (Gonzalez-Muniz, R. et al., Int. J. Mol. Sci. 2019, 20(11 ), 2618; Izquierdo, C. et al., Int. J. Mol. Sci. 2021 , 22(16), 8502).

[0173] According to a preferred embodiment, also in combination with any of the above embodiments, the TRPM8 antagonist for use according to the present invention is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0174] R is selected from H, Br, CN, NO2, SO2NH2, SO2NHR' and SO2N(R')2, where R' is selected from linear or branched C1-C4 alkyl;

[0175] X is selected from F, Cl, C1-C3 alkyl, NH2 and OH;

[0176] Y is selected from 0, CH2, NH and SO2;

[0177] R1 and R2, independently one from the other, are selected from H, F and linear or branched C1-C4 alkyl;

[0178] R3 and R4, independently one from the other, are selected from H and linear or branched C1-C4 alkyl;

[0179] Z is selected from NR6 and R6R7N+, where R6 and R7 independently one from the other, are selected from H and linear or branched C1-C4 alkyl;

[0180] R5 is a residue selected from H and linear or branched C1-C4 alkyl;

[0181] Het is a heteroaryl group selected from a substituted or not substituted pyrrolyl, a substituted or not substituted N-methylpyrrolyl, a substituted or not substituted thiophenyl, a substituted or not substituted furyl and a substituted or not substituted pyridinyl, and preferably it is a substituted or not substituted pyrrol-2-yl, a substituted or not substituted N- methylpyrrol-2-yl, a substituted or not substituted thiophen-2-yl, a substituted or not substituted fur-2-yl, a substituted or not substituted pyridin-2-y I.

[0182] According to preferred embodiments of the invention, also in combination one with the other, in the above compounds, independently one from the other: R is preferably selected from H, Br and CN, and even more preferably from H and CN;

[0183] X is preferably selected from F, Cl and C1-C3 alkyl, more preferably from F, Cl and C2H5, even more preferably from F and Cl;

[0184] Y is preferably selected from -0-, CH2, NH and SO2, and, more preferably, from CH2, 0 and SO2;

[0185] R1 and R2, independently one from the other, are preferably selected from H, F and CH3, more preferably from H and CH3;

[0186] R3 and R4, independently one from the other, are preferably selected from H and CH3;

[0187] Z is preferably selected from NR6 and R6R7N+where R6 and R7, independently one from the other, are selected from H and CH3; more preferably it is NH;

[0188] R5 is preferably selected from H and CH3 and, more preferably it is H.

[0189] According to a further preferred embodiment of the invention, also in combination with all the above embodiments, when Het is a substituted pyrrolyl, a substituted N-methylpyrrolyl, a substituted thiophenyl or a substituted furyl, it is preferably substituted with one or more substituents selected from F, Cl, CH3, NH2 and OH, and more preferably from F, Cl and CH3, even more preferably from Cl and CH3. Preferably, said substituent is in position 5.

[0190] Preferred compounds of formula (I) for use according to the present invention are listed in the following:

[0191] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanaminium chloride; 2-[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]ethanaminium chloride;

[0192] N-[(5-chlorofuran-2-yl)methyl]-2-[(1 -chloronaphthalen-2-yl)oxy]ethanaminium; 2-[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2- yl)methyl]ethanaminium;

[0193] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanaminium;

[0194] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanaminium;

[0195] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-[(1 -methyl-1 H-pyrrol-2- yl)methyl]ethanaminium;

[0196] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-2-methylpropan-2- amine;

[0197] 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-[(5-methylfuran-2- yl)methyl]propan-2- amine;

[0198] N-[(5-chlorofuran-2-yl)methyl]-1 -[(1 -chloronaphthalen-2-yl)oxy]-2- methylpropan-2- amine;

[0199] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]-2- methylpropan-2- amine; 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-(thiophen-2-ylmethyl)propan-2- amin;

[0200] 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-(pyridin-2-ylmethyl)propan-2- amine;

[0201] 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-[(1 -methyl-1 H-pyrrol-2- yl)methyl]propan-2-amine;

[0202] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)propan-1 -amine;

[0203] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]propan-1 - amine;

[0204] N-[(5-chlorofuran-2-yl)methyl]-2-[(1 -chloronaphthalen-2-yl)oxy]propan-1 - amine;

[0205] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]propan-1 - amine;

[0206] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)propan-1 -amine;

[0207] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)propan-2-amine;

[0208] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]propan-2- amine;

[0209] N-[(5-chlorofuran-2-yl)methyl]-1 -[(1 -chloronaphthalen-2-yl)oxy]propan-2- amine;

[0210] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-[(5-chlorothiophen-2-yl)methyl]propan-2- amine;

[0211] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)propan-2 -amine;

[0212] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-(furan-2-ylmethyl)ethanamine;

[0213] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-[(5-methylfuran-2- yl)methyl]ethanamine;

[0214] N-[(5-chlorofuran-2-yl)methyl]-2-[(1 -chloronaphthalen-2- yl)sulfonyl]ethanamine;

[0215] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-[(5-chlorothiophen-2- yl)methyl]ethanamine;

[0216] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-(thiophen-2-ylmethyl)ethanamine;

[0217] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-(pyridin-2-ylmethyl)ethanamine;

[0218] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-[(1 -methyl-1 H-pyrrol-2- yl)methyl]ethanamine;

[0219] 3-(1 -chloronaphthalen-2-yl)-N-(furan-2-ylmethyl)propan-1 -amine; 3-(1 -chloronaphthalen-2-yl)-N-[(5-methylfuran-2-yl)methyl]propan-1 -amine;

[0220] N-[(5-chlorofuran-2-yl)methyl]-3-(1 -chloronaphthalen-2-yl)propan-1 -amine;

[0221] 3-(1 -chloronaphthalen-2-yl)-N-[(5-chlorothiophen-2-yl)methyl]propan-1 - amine;

[0222] 3-(1 -chloronaphthalen-2-yl)-N-(thiophen-2-ylmethyl)propan-1 -amine;

[0223] 3-(1 -chloronaphthalen-2-yl)-N-(pyridin-2-ylmethyl)propan-1 -amine;

[0224] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N-methylethanamine;

[0225] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N,N- dimethylethanaminium iodide;

[0226] N-{2-[(1 -chloronaphthalen-2-yl)oxy]ethyl}-1 -(5-methylfuran-2-yl)ethanamine;

[0227] N-(1 -chloronaphthalen-2-yl)-N'-(furan-2-ylmethyl)ethane-1 ,2-diamine;

[0228] N-(l-chloronaphthalen-2-yl)-N'-[(5-methylfuran-2-yl)methyl]ethane-1 ,2- diamine;

[0229] N-[(5-chloromran-2-yl)methyl]-N'-(l-chloronaphthalen-2-yl)ethane-1 ,2- diamine;

[0230] N-(1 -chloronaphthalen-2-yl)-N'-[(5-chlorothiophen-2-yl)methyl]ethane-1 ,2- diamine;

[0231] N-(1 -chloronaphthalen-2-yl)-N'-(thiophen-2-ylmethyl)ethane-1 ,2-diamine;

[0232] N-(1 -chloronaphthalen-2-yl)-N'-(pyridin-2-ylmethyl)ethane-1 ,2-diamine;

[0233] N-(1 -chloronaphthalen-2-yl)-N'-[(1 -methyl-1 H-pyrrol-2-yl)methyl]ethane-1 ,2- diamine;

[0234] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine;

[0235] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-[(5-methylfuran-2-yl)methyl]ethanamine;

[0236] N-[(5-chlorofuran-2-yl)methyl]-2-[(1 -fluoronaphthalen-2-yl)oxy]ethanamine;

[0237] N-[(5-chlorothiophen-2-yl)methyl]-2-[(1 -fluoronaphthalen-2- yl)oxy]ethanamine;

[0238] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanamine;

[0239] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanamine;

[0240] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-[(1 -methyl-1 H-pyrrol-2- yl)methyl]ethanamine;

[0241] 5-chloro-6-{2-[(pyridin-2-ylmethyl)amino]ethoxy}naphthalene-2 -carbonitrile; 5-chloro-6-{2-[(furan-2-ylmethyl)amino]ethoxy}naphthalene-2 -carbonitrile;

[0242] 5-chloro-6-(2-{[(5-methylfuran-2-yl)methyl]amino}ethoxy)naphthalene-2- carbonitrile; 5-chloro-6-(2-{[(5-chlorofuran-2-yl)methyl]amino}ethoxy)naphthalene-2- carbonitrile;

[0243] 5-chloro-6-(2-{[(5-chlorothiophen-2-yl)methyl]amino}ethoxy)naphthalene-2- carbonitrile;

[0244] 5-chloro-6-{2-[(thiophen-2-ylmethyl)amino]ethoxy}naphthalene-2-carbonitrile;

[0245] 2-[(1 -ethylnaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine;

[0246] 2,2-difluoro-2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine; and

[0247] 2-[(6-bromo-1 -fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine.

[0248] Particularly preferred compounds of formula (I) for use according to the present invention are:

[0249] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanaminium chloride; 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanaminium;

[0250] 2-[(1 -chloronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanaminium;

[0251] 1 -[(1 -chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-2-methylpropan-2- amine;

[0252] 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-(pyridin-2-ylmethyl)propan-2- amine;

[0253] 1 -[(1 -chloronaphthalen-2-yl)oxy]-2-methyl-N-[(1 -methyl-1 H-pyrrol-2- yl)methyl]propan-2-amine;

[0254] 2-[(1 -chloronaphthalen-2-yl)sulfonyl]-N-(furan-2-ylmethyl)ethanamine;

[0255] 3-(1 -chloronaphthalen-2-yl)-N-(furan-2-ylmethyl)propan-1 -amine;

[0256] 3-(1 -chloronaphthalen-2-yl)-N-[(5-methylfuran-2-yl)methyl]propan-1 -amine; N-[(5-chlorofuran-2-yl)methyl]-3-(1 -chloronaphthalen-2-yl)propan-1 -amine; 3-(1 -chloronaphthalen-2-yl)-N-[(5-chlorothiophen-2-yl)methyl]propan-1 - amine;

[0257] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine;

[0258] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(thiophen-2-ylmethyl)ethanamine;

[0259] 2-[(1 -fluoronaphthalen-2-yl)oxy]-N-(pyridin-2-ylmethyl)ethanamine;

[0260] 5-chloro-6-{2-[(pyridin-2-ylmethyl)amino]ethoxy}naphthalene-2 -carbonitrile; and

[0261] 5-chloro-6-{2-[(thiophen-2-ylmethyl)amino]ethoxy}naphthalene-2-carbonitrile. Compounds of formula (I) are disclosed in W02012 / 101244A1 , which also discloses their methods of synthesis and their inhibitory activity towards TRPM8.

[0262] According to a preferred embodiment, also in combination with any of the above embodiments, said TRPM8 antagonist for use according to the present invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein

[0263] X is selected from S and 0;

[0264] R1 is selected from the group consisting of:

[0265] -0R5 wherein R5 is selected from H; C1-C4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (halo)benzyl, (trifluoromethyl)benzoyl, N- benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C1-C3 alkyl group, (C1-C3 alkoxy)methyl, C1-C3 alkanoyl and CH2CH2NHR6, wherein R6 is selected from H and (furan-2-yl)methyl; and

[0266] -NHR7 wherein R7 is selected from H, tert-butoxycarbonyl, C1-C3 alkanoyl, (4- trifluoromethyl)benzoyl, N-phenylaminoacarbonyl, CH2R8, wherein R8 is selected from phenyl, benzo[d][1 ,3] dioxole, pyridin-3-yl, (pyrrolid in-1 -yl) methyl, -CH2NHR9 wherein R9 is selected from H, C1-C3 alkyl and cycloalkyl; R2 is selected from the group consisting of

[0267] -COOR10 wherein R10 is selected from H, C1-C3 alkyl and cyclohexyl, optionally substituted with at least one C1-C3 alkyl group;

[0268] -OH; -CONH2; CN; -tetrazol-5-yl, 1 -(Ci-C3alkyl)tetrazol-5-yl, 2-(CI-C3alkyl)tetrazol-5-yl, 5-(CI -C3 alkyl)1 ,2,4 triazol-3-y I, 5-(CI -C3 alkyl)1 ,2,4- oxadiazol-3yl, 5-(CI -C3 alkyl) 1 ,3,4-oxadiazol-2-yl;

[0269] R3 is selected from F and H,

[0270] R4 is selected from H; CH3; halogen; dimethylamino; pyridin-4yl; phenyl; 2- or 4- (halo)phenyl; 2- or 4- (trifluoromethyl)phenyl; 2- and / or 4-halobenzyloxy.

[0271] According to a preferred embodiment, in said compounds of formula (II), R5 may be selected from H, C1-C4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (chloro)benzyl, (trifluoromethyl)benzoyl, N- benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C1-C3 alkyl group, (methoxy)methyl, propanoyl and CH2CH2NHR6 wherein R6 is as above.

[0272] Particularly preferred among compounds of formula (II) are compounds wherein R5 is selected from H, methyl, isobutyl, trifluoromethanesulfonyl, benzyl, 4-(trifluoromethyl)benzyl, (chloro)benzyl, 4-(trifluoromethyl)benzoyl, N-benzylcarbamoyl, 2-isopropyl-5-methylcyclohexyloxyacetoyl,

[0273] (methoxy)methyl, propanoyl and CH2CH2NHR6 wherein R6 is as above. According to a further preferred embodiment, also in combination with any of the preceding embodiment, in said compounds of formula (II) R7 may be selected from H, tert-butoxycarbonyl, acetyl, 4-(trifluoromethyl)benzoyl, N- phenylaminoacarbonyl, CH2R8, wherein R8 is selected from phenyl, benzo[d][1 ,3] dioxole, pyridin-3-yl, (pyrrolidin-1 -yl)methyl, -CH2NHR9 wherein R9 is selected from H, C1-C3 alkyl and cyclopentyl.

[0274] According to a further preferred embodiment, also in combination with any one of the preceding embodiments, in said compounds of formula (II) R10 may be selected from H, C1-C3 alkyl and 2-isopropyl-5-cyclohexyl.

[0275] According to a further preferred embodiment, also in combination with any one of the preceding embodiments, in said compounds of formula (II) R4 may be selected from H, CH3, F, Cl, dimethylamino, preferably in position para, pyridin-4yl, phenyl, 2-F-phenyl, 2-trifluoromethylphenyl and 2- or 4- halobenzyloxy, wherein said halo is preferably F or Cl.

[0276] According to a further preferred embodiment, in said compounds of formula (II)

[0277] X is selected from S and 0;

[0278] R1 is selected from the group consisting of:

[0279] -0R5 wherein R5 is selected from H, C1-C4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (chloro)benzyl, (trifluoromethyl)benzoyl, N- benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C1-C3 alkyl group, (methoxy)methyl, propanoyl and -CH2CH2NHR6, wherein R6 is selected from H and (furan-2-yl)methyl

[0280] -NHR7 wherein R7 is selected from H, tert-butoxycarbonyl, acetyl, (4- trifluoromethyl)benzoyl, N-phenylaminocarbonyl, CH2R8, wherein R8 is selected from phenyl, benzo[d][1 ,3] dioxole, pyridin -3-y I, (pyrrolidin-1 - yl)methyl, -CH2NHR9 wherein R9 is selected from H, C1-C3 alkyl and cyclopentyl

[0281] R2 is selected from the group consisting of:

[0282] -COOR10 wherein R10 is selected from H, C1-C3 alkyl and 2-isopropyl-5- methylcyclohexyloxycarbonyl,

[0283] -OH; -CONH2; CN; tetrazol-5-yl or 1 -(Ci-C3 alkyl)tetrazol-5-yl; 2-(CI-C3 alkyl)tetrazol-5-yl; 5-( C1-C3 alkyl)1 ,2,4 triazol-3-yl;- 5-(CI -C3 alkyl) 1 ,2,4- oxadiazol-3yl; -5-(CI -C3 alkyl) 1 ,3,4-oxadiazol-2-yl;

[0284] R3 is selected from F and H,

[0285] R4 is selected from H, F, Cl, dimethylamino, preferably in position para, pyridin-4yl, phenyl, 2-F-phenyl, 2-trifluoromethylphenyl, 2- and / or 4-F- benzyloxy.

[0286] Particularly preferred compounds of formula (II) for use according to the invention are compounds of formula (II) wherein R1 is selected from:

[0287] -OR5, wherein R5 is selected from H, benzyl, (chloro)benzyl, (trifluoromethyl)benzoyl, CH2-CH2NH2; and

[0288] -NHCH2CH2R9 wherein R9 is selected from H and C1-C3 alkyl.

[0289] Particularly preferred are also compounds of formula (II) wherein R2 is selected from COOR10 wherein R10 is selected from H and C1-C3 alkyl. Particularly preferred are also compounds of formula (II) wherein R3 is H.

[0290] Particularly preferred among the above compounds are those compounds of formula (II) wherein: R1 is selected from:

[0291] OR5, wherein R5 is selected from H, benzyl, (chloro)benzyl, (trifluoromethyl)benzoyl; and CH2-CH2NH2; and

[0292] NHCH2CH2R9 wherein R9 is selected from C1-C3 alkyl and H;

[0293] R2 is COOR10 wherein R10 is selected from H, C1-C3 alkyl R3 is H.

[0294] According to a preferred embodiment, also in combination with any preceding embodiment, when X is S, in the above compounds of formula (II) when R1 is OH and R2 is COOH, R4 is different from Cl in meta position on the aromatic ring.

[0295] According to another preferred embodiment, also in combination with any preceding embodiment, when R1 is OH and R2 is COOH or COOEt, R3 and R4 are not H at the same time.

[0296] According to a further preferred embodiment, also in combination with any preceding embodiments, in said compounds of formula (II) when R3 is F, R3 is in position ortho of the aromatic ring and R4 is F in position para of the aromatic ring, and when R3 is H, R4 is in position para or meta on the aromatic ring.

[0297] According to a further preferred embodiment, the compound of formula (II) for use according to the present invention is selected from: 2-(4-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid; 4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid; 2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid;

[0298] 2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid; methyl 4-hydroxy-2-phenyl-1 ,3-thiazole-5-carboxylate; methyl 2-(2,4-difluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-(pyridin-4-yl)-1 ,3-thiazole-5-carboxylate; ethyl 2-[4-(dimethylamino)phenyl]-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-[2'-(trifluoromethyl)biphenyl-3-yl]-1 ,3-thiazole-5- carboxylate; ethyl 2-(2'-fluorobiphenyl-3-yl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-[2'-(trifluoromethyl)biphenyl-4-yl]-1 ,3-thiazole-5- carboxylate; ethyl 2-(2'-fluorobiphenyl-4-yl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-{4-[(2-fluorobenzyl)oxy]phenyl}-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-fluorophenyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 4-methoxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-methylphenyl)-4-(2-methylpropoxy)-1 ,3-thiazole-5-carboxylate; ethyl 4-(benzyloxy)-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(3-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 4-(2-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)acetoyloxy)-2-(4- methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(benzylcarbamoyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-(2-aminoethoxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{2-[(furan-2-ylmethyl)amino]ethoxy}-1 ,3-thiazole-5- carboxylate;

[0299] 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;

[0300] 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylic acid;

[0301] 4-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0302] 4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0303] 4-(benzyloxy)-2-phenyl-1 ,3-thiazole-5-carboxylic acid;

[0304] 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0305] 4-[(2-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylic acid;

[0306] 4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid; 4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0307] 4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0308] 4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;

[0309] 4-[(2-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid;

[0310] 2-phenyl-4-{[4-(trifluoromethyl)benzyl]oxy}-1 ,3-thiazole-5-carboxylic acid;

[0311] 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzyl]oxy}-1 ,3-thiazole-5-carboxylic acid;

[0312] 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5-carboxylic acid;

[0313] 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylic acid;

[0314] 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylic acid;

[0315] 4-methoxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;

[0316] 2-(4-methylphenyl)-4-(2-methylpropoxy)-1 ,3-thiazole-5-carboxylic acid; ethyl 4-[(tert-butoxycarbonyl)amino]-2-(4-fluorophenyl)-1 ,3-thiazole-5- carboxylate; ethyl 4-amino-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylate hydrochloride; ethyl 4-(acetylamino)-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-methylphenyl)-4-[(phenylcarbamoyl)amino]-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(methylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(propylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-[2'-(trifluoromethyl)biphenyl-4-yl]-1 ,3- thiazole-5-carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-[2'-(trifluoromethyl)biphenyl-3-yl]-1 ,3- thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(cyclopentylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-phenyl-4-{[2-(pyrrolidin-1 -yl)ethyl]amino}-1 ,3-thiazole-5-carboxylate; ethyl 4-(benzylamino)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(1 ,3-benzodioxol-5-ylmethyl)amino]-2-(3-fluorophenyl)-1 ,3-thiazole-5- carboxylate; ethyl 2-(3-fluorophenyl)-4-[(pyridin-3-ylmethyl)amino]-1 ,3-thiazole-5- carboxylate; 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;

[0317] 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;

[0318] 4-[(2-aminoethyl)amino]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid; sodium 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5- carboxylate; sodium 4-(4-chlorobenzyloxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(4-chlorobenzyloxy)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate;

[0319] (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-(benzyloxy)-2-(4- methylphenyl)-1 ,3-thiazole-5-carboxylate;

[0320] (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-hydroxy-2-(4-methylphenyl)- 1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxylate;

[0321] 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxylic acid;

[0322] 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxamide;

[0323] 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carbonitrile;

[0324] 2-(4-chlorophenyl)-5-(1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol;

[0325] 2-(4-chlorophenyl)-5-(1 -methyl-1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol;

[0326] 2-(3-fluorophenyl)-5-(1 -methyl-1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol;

[0327] 2-(4-chlorophenyl)-5-(5-methyl-4H-1 ,2 ,4-triazol-3-yl)-1 ,3-thiazol-4-ol;

[0328] 2-(3-fluorophenyl)-5-(5-methyl-4H-1 ,2 ,4-triazol-3-yl)-1 ,3-thiazol-4-ol;

[0329] 2-(4-chlorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-4-ol; 2-(3-fluorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-4-ol;

[0330] 3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazol-5-yl}-5-methyl-1 ,2,4- oxadiazole;

[0331] 2-(4-chlorophenyl)-5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3-thiazol-4-ol;

[0332] 2-(3-fluorophenyl)-5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3-thiazol-4-ol; ethyl 4-hydroxy-2-phenyl-1 ,3-oxazole-5-carboxylate; ethyl 2-(3-fluorophenyl)-4-hydroxy-1 ,3-oxazole-5-carboxylate; ethyl 4-hydroxy-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylate; ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-oxazole-5-carboxylate;

[0333] 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-oxazole-5-carboxylic acid;

[0334] 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazole-5-carboxylic acid;

[0335] 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylic acid;

[0336] 2-(3-fluorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-oxazol-4-ol;

[0337] 3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazol-5-yl}-5-methyl-1 ,2,4- oxadiazole; ethyl 2-(3-fluorophenyl)-5-hydroxy-1 ,3-thiazole-4-carboxylate; and

[0338] 2-(3-fluorophenyl)-5-(2-ethyl-2H-tetrazol-5-yl)-1 ,3-thiazol-4-ol, also known as DFL23448.

[0339] Compounds of formula (II) are disclosed in WO2013 / 092711A1 , which also discloses their method of synthesis and their inhibitory activity towards TRPM8.

[0340] According to a further preferred embodiment, also in combination with any of the above embodiments, said TRPM8 antagonist for use according to the invention is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein

[0341] X is oxygen, sulphur, NH, NOH, or NOMe;

[0342] R is a group selected from aryl and heteroaryl, optionally substituted by one or more substituents selected from

[0343] - hydrogen,

[0344] - halogen,

[0345] - CF3,

[0346] - linear or branched Ci-Ce alkyl,

[0347] - OR5 and

[0348] - NR6R7, wherein R5, R6 and R7 are independently hydrogen or linear or branched Ci-Ce alkyl;

[0349] R1 is a group selected from

[0350] - linear or branched Ci-Ce alkyl,

[0351] - (CH2)m-OR2, wherein m is an integer between 1 and 3 and R2 is selected from hydrogen and linear C1-C3 alkyl,

[0352] - C3-C6 cycloalkyl, and

[0353] - N(R3)OR4, wherein R3 and R4 are independently hydrogen or linear or branched C1-C3 alkyl.

[0354] According to a first preferred embodiment in said compounds of formula (III) R1 is selected from:

[0355] - linear or branched Ci-Ce alkyl,

[0356] - (CH2)m-OR2 wherein m is 1 and R2 is linear C1-C3 alkyl,

[0357] - C3-C6 cycloalkyl, or

[0358] N(R3)OR4, wherein R3 and R4 are as defined above.

[0359] Particularly preferred compounds according to this embodiment are compounds of formula (III) wherein R1 is linear or branched Ci-Ce alkyl,

[0360] - (CH2)m-OR2 wherein m is 1 and R2 is CH3,

[0361] - cyclopropyl,

[0362] - or

[0363] - N(R3)OR4, wherein R3 and R4 are independently C1-C3 alkyl, preferably CH3. According to a second preferred embodiment, also in combination with the preceding embodiment, in the above compounds of formula (III), R1 is not methyl. Particularly preferred compounds according of this embodiment are compounds wherein R1 is selected from the group consisting of ethyl, isopropyl, isobutyl, CH2OCH3, cyclopropyl and N(CH3)OCH3.

[0364] According to a third preferred embodiment, also in combination with the first embodiment mentioned above, R1 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, CH2OCH3, cyclopropyl and N(CH3)OCH3.

[0365] According to a further preferred embodiment, also in combination with the first and third embodiment mentioned above, in the above compounds of formula (III) when R1 is methyl, R is not selected from 3-pyridyl, 4-chlorophenyl, 4- trifluoromethylphenyl, 3-tiophenyl, 3-thiazolyl-(2-methyl), phenyl, thiazole, 2-4- difluorophenyl, 4-methoxyphenyl and 2-methylthiazole.

[0366] According to another preferred embodiment, also in combination with any of the preceding embodiments, X is oxygen.

[0367] According to a further preferred embodiment, also in combination with any of the preceding embodiments, said aryl is phenyl and said heteroaryl is a 5- or 6- membered heteroaryl containing from 1 to 3 heteroatoms selected from N, 0 and S. Preferably, said 5- or 6- membered heteroaryl is selected from the group consisting of thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxazolyl and pyridinyl.

[0368] According to a further preferred embodiment, also in combination with any of the preceding embodiments, in said compounds of formula (III), wherein R is aryl, the aryl is optionally substituted with a group selected from:

[0369] - halogen, preferably selected from Br and F;

[0370] - linear or branched C1-C3 alkyl, preferably CH3;

[0371] -OR5 and NR6R7, wherein R5, R6 and R7 are independently hydrogen or linear C1-C3 alkyl.

[0372] Preferred identities of OR5 and NR6R7 are OH, NH2 and NHCH3, respectively.

[0373] According to a further preferred embodiment, also in combination with any of the preceding embodiments, in said compounds of formula (III), wherein R is heteroaryl, this is optionally substituted with linear or branched Ci-Ce alkyl, preferably with CH3.

[0374] Particularly preferred compounds of formula (III) for use according to the present invention are those wherein R is selected from the group consisting of 3- fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylaminophenyl, 4- methylaminophenyl, thiophen-2yl, furan-2yl, pyrrol-2yl, 1 H-imidazol-5yl, 1 -methyl- imidazol-5yl, pyrazol-4yl, 1 ,2,4-oxadiazol-3yl, 1 ,2-oxazol-5yl, pyridin-2yl, pyridin- 3yl and pyridin-4yl.

[0375] Particularly preferred compounds of formula (III) for use according to the invention are selected from:

[0376] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one; sodium 2-(3-fluorophenyl)-5-propanoyl-1 ,3-thiazol-4-olate, also known as DFL23693;

[0377] 2-(3-fluorophenyl)-4-hydroxy-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;

[0378] 1-(2-(3-fluorophenyl)-4-hydroxythiazol-5-yl)ethenone;

[0379] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-2-methylpropan-1 -one; 4-hydroxy-N-methoxy-N-methyl-2-(thiophen-2-yl)-1 ,3-thiazole-5-carboxamide;

[0380] 1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0381] 4-hydroxy-N-methoxy-N-methyl-2-(2-methylphenyl)-1 ,3-thiazole-5-carboxamide;

[0382] 1 -[4-hydroxy-2-(2-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0383] 2-(2-bromophenyl)-4-hydroxy-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;

[0384] 1 -[2-(2-bromophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0385] 4-hydroxy-2-(2-hydroxyphenyl)-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;

[0386] 1 -[2-(2-hydroxyphenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0387] 1 -[2-(3-bromophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0388] 1 -[2-(furan-2-yl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0389] 1 -[4-hydroxy-2-(1 H-pyrrol-2-y l)-1 ,3-thiazol-5-yl]propan-1 -one;

[0390] 1 -[4-hydroxy-2-(1 -methyl-1 H-pyrrol-2-y l)-1 ,3-thiazol-5-yl]propan-1 -one;

[0391] 1 -[4-hydroxy-2-(1 -methyl-1 H-imidazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0392] 1 -[4-hydroxy-2-(1 H-imidazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0393] 1 -[4-hydroxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0394] 1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]butan-1 -one;

[0395] 1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]-3-methylbutan-1 -one;

[0396] 1 -[4-hydroxy-2-(1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0397] 1 -[4-hydroxy-2-(1 ,2-oxazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0398] 1 -[4-hydroxy-2-(pyridin-3-yl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0399] 1 -[4-hydroxy-2-(pyridin-4-yl)-1 ,3-thiazol-5-yl]propan-1 -one; 1 -[4-hydroxy-2-(pyrid in-2-y l)-1 ,3-thiazol-5-yl]propan-1 -one;

[0400] 1 -[4-hydroxy-2-(3-hydroxyphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0401] 1 -[4-hydroxy-2-(4-hydroxyphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0402] 1 -[4-hydroxy-2-(3-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0403] 1 -[4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;

[0404] 1 -[2-(3-aminophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0405] 1 -[2-(4-aminophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0406] 1 -{4-hydroxy-2-[3-(methylamino)phenyl]-1 ,3-thiazol-5-yl}propan-1 -one;

[0407] 1 -{4-hydroxy-2-[4-(methylamino)phenyl]-1 ,3-thiazol-5-yl}propan-1 -one;

[0408] 1 -[2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;

[0409] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]butan-1 -one;

[0410] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-3-methylbutan-1 -one;

[0411] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-2-methoxyethanone;

[0412] 1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propane-1 -thione;

[0413] 2-(3-fluorophenyl)-4-hydroxy- / V-methoxy- / \ / -methyl-1 ,3-thiazole-5-carbothioamide;

[0414] 2-(3-fluorophenyl)-5-[(1 E)-N-methoxypropanimidoyl]-1 ,3-thiazol-4-ol;

[0415] 2-(3-fluorophenyl)-5-propanimidoyl-1 ,3-thiazol-4-ol; and

[0416] 2-(3-fluorophenyl)-5-[(1 E)-N-hydroxypropanimidoyl]-1 ,3-thiazol-4-ol.

[0417] Compounds of formula (III) are disclosed in WO2015 / 197640A1 , which also discloses their method of synthesis and their inhibitory activity towards TRPM8.

[0418] According to a further preferred embodiment, also in combination with any of the above embodiments, said TRPM8 antagonist for use according to the present invention is a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R1is an unsubstituted or substituted 5, 6 or 7-membered, aliphatic or aromatic heterocycle group containing 1 , 2, 3 or 4 heteroatoms selected from N, 0 and S; R2is selected from hydrogen, C1-C2 alkyl, F, Cl and OH.

[0419] The term “substituted” herein refers to mono- or poly-substitution by a named (or undefined) substituent to the extent that such a single or multiple substitution is chemically allowed.

[0420] Preferably, said 5, 6 or 7-membered, aliphatic or aromatic heterocycle is unsubstituted or substituted with one or more groups independently selected from C1-C3 alkyl or cycloalkyl, Cl and F. Preferably, said C1-C3 alkyl is methyl.

[0421] According to a preferred embodiment the heterocycle is substituted with R3and R4that taken together can form a saturated cyclic moiety, preferably cyclobutane, cyclopentane or cyclohexane.

[0422] According to a preferred embodiment the heterocycle is unsubstituted.

[0423] Preferably, R1is selected from the group consisting of oxazolidinyl, oxolanyl, pyrrolidinyl, oxazinanyl, morpholinyl, piperidinyl, methylpyrrolidinyl, pyrrolyl, methylpyrrolyl, furanyl, thiophenyl, pyridinyl, imidazolyl, pyrazolyl, oxadiazolyl and oxazolyl.

[0424] More preferably, R1is selected from the group consisting of 1 ,2-oxazolidin-2-yl, 1 ,3-oxazolidin-3-yl, oxolan-2-yl, pyrrolidin-1 -yl, 1 ,2-oxazinan-2-yl, 1 ,3-oxazinan-3- yl, morpholin-4-yl, piperidin-1 -yl, pyrrolidin-2-yl, 1 -methylpyrrolidin-2-yl, 1 H-pyrrol- 2-yl, 1 -methyl-1 H-pyrrol-2-yl, furan-2-yl, thiophen-2-yl, 1 H-pyrrol-1 -yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 H-imidazol-1 -yl and 1 H-pyrazol-1 -yl.

[0425] Preferably, R2is F or OH.

[0426] More preferably, R2is 3-F or 2-OH

[0427] In an embodiment according to the invention,

[0428] R1is oxazolidinyl and R2is F or OH.

[0429] In another embodiment according to the invention,

[0430] R1is oxolanyl and R2is F or OH.

[0431] In another embodiment according to the invention,

[0432] R1is pyrrolidinyl and R2is F or OH.

[0433] In another embodiment according to the invention,

[0434] R1is oxazinanyl and R2is F or OH.

[0435] In another embodiment according to the invention,

[0436] R1is morpholinyl and R2is F or OH. In another embodiment according to the invention, R1is piperidinyl and R2is F or OH.

[0437] In another embodiment according to the invention, R1is methylpyrrolidinyl and R2is F or OH.

[0438] In another embodiment according to the invention, R1is pyrrolyl and R2is F or OH.

[0439] In another embodiment according to the invention, R1is methylpyrrolyl and R2is F or OH.

[0440] In another embodiment according to the invention, R1is furanyl and R2is F or OH.

[0441] In another embodiment according to the invention, R1is thiophenyl and R2is F or OH.

[0442] In another embodiment according to the invention, R1is pyridinyl and R2is F or OH.

[0443] In another embodiment according to the invention, R1is imidazolyl and R2is F or OH.

[0444] In another embodiment according to the invention, R1is pyrazolyl and R2is F or OH.

[0445] Preferred compounds of formula (IV) for use according to the invention are selected from:

[0446] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23877, or the sodium salt thereof, also known as DFL24072; [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23880, or the sodium salt thereof, also known as DFL24080; [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,3-oxazolidin-3-yl)methanone; [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,3-oxazolidin-3-yl)methanone; [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](oxolan-2-yl)methanone;

[0447] [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](oxolan-2-yl)methanone; [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyrrolidin-1 -yl)methanone;

[0448] [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,2-oxazinan-2-yl)methanone;

[0449] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazinan-2-yl)methanone; [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,3-oxazinan-3-yl)methanone; [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,3-oxazinan-3-yl)methanone; [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](morpholin-4-yl)methanone; [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](morpholin-4-yl)methanone;

[0450] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](piperidin-1-yl)methanone;

[0451] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyrrolidin-2-yl)methanone;

[0452] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1-methylpyrrolidin-2-yl)methanone;

[0453] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 H-pyrrol-2-yl)methanone;

[0454] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 -methyl-1 H-pyrrol-2- yl)methanone;

[0455] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](furan-2-yl)methanone;

[0456] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](thiophen-2-yl)methanone;

[0457] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-pyrrol-1 -yl)methanone;

[0458] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-2-yl)methanone;

[0459] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-3-yl)methanone;

[0460] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-4-yl)methanone;

[0461] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-imidazol-1 -yl)methanone;

[0462] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-pyrazol-1 -yl)methanone;

[0463] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazepan-2-yl)methanone;

[0464] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](5-oxa-6-azaspiro[2.4]heptan-6- yl)methanone;

[0465] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](5-methyl-1 ,2-oxazolidin-2- yl)methanone;

[0466] [2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](hexahydro-2H- cyclopenta[d][1 ,2]oxazol-2-yl)methanone;

[0467] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-1 , 2, 3-triazol-1 -yl)methanone; and

[0468] [2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 -methyl-1 H-tetrazol-5- yl)methanone.

[0469] Compounds of formula (IV) are disclosed in WO2017 / 108632A1 , which also discloses their method of synthesis and their inhibitory activity towards TRPM8.

[0470] According to a further preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the present invention is selected from:

[0471] 6-[[[(S)-(3-Fluoro-2-pyridinyl)[3-fluoro-4- (trifluoromethoxy)phenyl]methyl]amino]carbonyl]-3-pyridinecarboxylic acid, also known as AMG-333 (IC50 of 0.2 nM); (1 R)-N-(4-Fluorophenyl)-3,4-dihydro-1 -[4-(trifluoromethyl)phenyl]-2(1 H)- isoquinolinecarboxamide, also known as AMG-8788 (IC50 of 63.2 nM); 4-[(4-cyclopropylisoquinolin-3-yl)-[[4- (trifluoromethoxy)phenyl]methyl]sulfamoyl]benzoic acid, also known as elismetrep;

[0472] RQ-00434739, also known as XG-2002;

[0473] CC-002;

[0474] (1 R)-3,4-Dihydro-N-[(1 S)-2,2 ,2-trif luoro-1 -methylethyl]-1 -[4-

[0475] (trifluoromethyl)phenyl]-2(1 H)-isoquinolinecarboxamide, also known as AMG- 9678 (IC50 of 31.2 nM);

[0476] N,N-Bis(phenylmethyl)-L-tryptophan methyl ester, also known as TRPM8 antagonist 2 (IC50 of 0.2 nM);

[0477] [4-Hydroxy-2-(2-hydroxyphenyl)-5-thiazolyl]-2-isoxazolidinylmethanone, also known as TRPM8 antagonist 3 (IC50 of 11 nM);

[0478] 3-[[[(1 R)-1 -(4-Fluorophenyl)ethyl](3-quinolinylcarbonyl)amino]methyl]benzoic acid, also known as PF-05105679 (IC50 of 103 nM);

[0479] 4-[[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl][[4- (trifluoromethoxy)phenyl]methyl]amino]sulfonyl]benzoic acid, also known as RQ-00203078 (IC50 of 5.3 nM);

[0480] 3-[7-(Trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1 H-benzimidazol-2-yl]-1 - oxa-2-azaspiro[4.5]dec-2-ene, also known as TC-l-2014 (IC50 of 3 nM);

[0481] 4-[[(4-Cyclopropyl-3-isoquinolinyl)[[4-

[0482] (trifluoromethoxy)phenyl]methyl]amino]sulfonyl]benzoic acid, also known as MT-8554;

[0483] N-(2-aminoethyl)-N-[[3-methoxy-4-(phenylmethoxy)phenyl]methyl]-2- thiophenecarboxamide monohydrochloride, also known as M8-B;

[0484] (8R)-5,8-Dihydro-N-[(1 S)-2,2 ,2-trif luoro-1 -methylethyl]-8-[4-

[0485] (trifluoromethyl)phenyl]-1 ,7-naphthyridine-7(6H)-carboxamide, also known as AMG-2850.

[0486] According to a particularly preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the present invention is selected from:

[0487] 2-(3-fluorophenyl)-5-(2-ethyl-2H-tetrazol-5-yl)-1 ,3-thiazol-4-ol, also known as DFL23448; sodium 2-(3-fluorophenyl)-5-propanoyl-1 ,3-thiazol-4-olate, also known as

[0488] DFL23693;

[0489] 2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23877, or the sodium salt thereof, also known as DFL24072; and [4-hydroxy-2-(2-hydroxyphenyl)-1 , 3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23880, or the sodium salt thereof, also known as DFL24080. According to a particularly preferred embodiment, the TRPM8 inhibitor for use according to the present invention is selected from the compounds in the following table:

[0490] According to a particularly preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the present invention is sodium 2-(3-fluorophenyl)-5-propanoyl-1 ,3-thiazol~4- olate, also known as DFL23693.

[0491] The TRPM8 inhibitor for use according to the present invention may form stable pharmaceutically acceptable acid or base salts with a pharmaceutically acceptable organic or inorganic acid or base, and in such cases administration of the TRPM8 inhibitor as a salt may be appropriate. Examples of acid addition salts may include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2- hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate.

[0492] Examples of base addition salts may include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non-toxic physiologically acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product. The salts may be formed by conventional means, such as by reacting the free form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, such as for example water or ethanol, which is removed under vacuum or by freeze drying.

[0493] Certain TRPM8 inhibitor compounds for use according to the present invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of those compounds unless otherwise specified.

[0494] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e. , the R and S configurations for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers.

[0495] Particular optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another method involves synthesis of covalent diastereomers by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolysed to deliver the enantiomerically pure compound. Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

[0496] According to a preferred embodiment, also in combination with any of the above embodiments, the TRPM8 inhibitor for use according to the present invention is administered by intra-articular injection (also known as joint injection) to the subject.

[0497] Preferably, the TRPM8 inhibitor for use according to the present invention is administered by intra-articular injection to the subject in form of a solution, which may be a liquid solution or a viscous solution.

[0498] Preferably, the TRPM8 inhibitor for use according to the present invention is administered by intra-articular injection to the subject in form of a solution which comprises a TRPM8 inhibitor, as above defined, and one or more of the following components: polyethylene glycol (PEG), also known as polyethylene oxide (PEG), from 800,000 to 1 ,000,000 molecular weight (MW), preferably at an amount between 0.1 % and 2% w / V; carboxymethyl cellulose (CMC) from 700,000 to 1 ,000,000 molecular weight (MW), preferably at an amount between 0.1 % and 1.0 % w / V; polyvinylpyrrolidone (PVP) from 360 to 370 kDA, preferably at an amount between 0.1 % and 0.5 % w / V.

[0499] More preferably, the TRPM8 inhibitor for use according to the present invention is administered by intra-articular injection to the subject in form of a solution which comprises a TRPM8 inhibitor, as above defined, and one or more of the following components:

[0500] 0.25 % w / V polyethylene glycol (PEG), also known as polyethylene oxide (PEG), 1 ,000,000 MW, 0.2 % w / V carboxymethyl cellulose (CMC) 700,000 MW,

[0501] 0.2 % w / V polyvinylpyrrolidone (PVP) 365 kDA.

[0502] Preferably, the concentration of said TRPM8 inhibitor in said solution is between 50 pM and 600 pM, more preferably between 100 pM and 500 pM, even more preferably said concentration is selected from 100 pM and 500 pM. According to a preferred embodiment, also in combination with any of the above embodiments, said TRPM8 inhibitor is DFL23693.

[0503] According to a further preferred embodiment, the TRPM8 inhibitor for use according to the present invention is administered orally to the subject.

[0504] Preferably, according to this embodiment, the TRPM8 inhibitor for use according to the present invention is administered orally to the subject in form of a solution, which may be a liquid solution or a viscous solution.

[0505] Alternatively, the TRPM8 inhibitor for use according to the present invention may be administered orally to the subject in form of a solid dosage form, preferably a capsule or a tablet.

[0506] Preferably, the TRPM8 inhibitor for use according to the present invention is administered orally to the subject in form of a solution which comprises a TRPM8 inhibitor, as above defined, and the following components:

[0507] 10% v / v [SOLUTOL HS-15 / N-methyl pirrolidone 2:1 (W / V)] + 90% v / v Phosphate Buffer Solution 25 mM.

[0508] SOLUTOL HS-15 is also known as Polyethylene Glycol 12-hydroxystearate. Preferably, said TRPM8 inhibitor is DFL23693.

[0509] The average daily dose of the TRPM8 inhibitor depends on several factors such as the severity of the disease, the condition, age, sex and weight of the patient. The dose will vary generally from 1 to 1000 mg of the TRPM8 inhibitor per day, optionally divided into multiple administrations.

[0510] As will be discussed in the experimental section, the present inventors have shown that oral and intra-articular administrations of a TRPM8 inhibitor using an animal model of MIA-induced osteoarthritis result in a decrease in gross pathological score of the knee joint when compared to the vehicle-treated group (oral administration) and placebo-treated group (intra-articular administration). Also, the group of animals which was treated with the highest dose tested via intra-articular injection showed a significant decrease in tibial histopathological grades, tibial inflammation scores and tibial proteoglycan scores when compared with the placebo-treated group. Collectively, these results show that the TRPM8 inhibitor preserved the cartilage and the bone of the joint from the damage and degeneration induced by the disease.

[0511] Unless otherwise indicated, each embodiment disclosed above is intended to be disclosed also in combination with any of the other embodiments disclosed above, to the extent technically compatible.

[0512] The invention is also directed to a pharmaceutical composition comprising a TRPM8 inhibitor, as defined above, and at least one pharmaceutically acceptable excipient or carrier for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0513] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage or joint degeneration or joint inflammation caused by osteoarthritis in a subject.

[0514] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0515] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint degeneration caused by osteoarthritis in a subject.

[0516] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint inflammation caused by osteoarthritis in a subject.

[0517] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint degeneration and joint inflammation caused by osteoarthritis in a subject.

[0518] The invention is also directed to a pharmaceutical composition comprising a TRPM8 inhibitor, as defined above, and at least one pharmaceutically acceptable excipient or carrier for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0519] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage or joint degeneration or joint inflammation in a subject with osteoarthritis. According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint degeneration and joint inflammation in a subject with osteoarthritis.

[0520] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint degeneration in a subject with osteoarthritis.

[0521] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint damage and joint inflammation in a subject with osteoarthritis.

[0522] According to a preferred embodiment, said pharmaceutical composition is for use in the prevention or treatment of joint degeneration and joint inflammation in a subject with osteoarthritis.

[0523] As used herein, the term “pharmaceutically acceptable excipient or carrier” includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, surfactant, synthetic polymer, film-forming agents, plasticizers, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0524] Some examples of materials which can serve as pharmaceutically acceptable excipient include, but are not limited to, sugars such as lactose, glucose and sucrose; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatine; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; pharmaceutical carriers such us poly(vinylpyrrolidone), chitosan, polyethylene glycol; surfactants such us polyoxyethylene sorbitan monooleate, poly(vinyl alcohol), polyoxyethylene sorbitan, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate, poly(vinylpyrrolidone), polyethylene glycol lauryl ether, ethoxylated hydrogenated castor oil; suspending agents such us gum arabic, alginic acid, pectin, polyoxyethylene sorbitan monolaurate, guar gum, sodium alginate, a-Tocopheryl polyethylene glycol succinate, carrageenan, maltitol, gum tragacanth, pullulan; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; sterilized water; Ringer's solution; buffered saline; dextrose solution; maltodextrin solution; ethyl alcohol; and phosphate buffer solutions; organic solvents as N-methyl pyrrolidone, ethanol.

[0525] Further, the composition of the present invention may be suitably formulated using appropriate methods known in the art or by the method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton Pa.

[0526] According to a preferred embodiment, the pharmaceutical composition for use according to the present invention is suitable for oral administration. Preferably, according to this embodiment, said pharmaceutical composition for use according to the present invention is a solution, which may be a liquid solution or a viscous solution. Preferably, said solution comprises a TRPM8 inhibitor, as above defined, and the following components: 10% v / v [SOLUTOL HS-15 I N-methyl pirrolidone 2:1 (W / V)] + 90% v / v Phosphate Buffer Solution 25 mM. Preferably, said TRPM8 inhibitor is DFL23693.

[0527] Alternatively, according to this embodiment, said pharmaceutical composition for use according to the present invention is a solid dosage form, preferably a capsule or a tablet.

[0528] According to a further preferred embodiment, the pharmaceutical composition for use according to the present invention is suitable for intra-articular injection. Preferably, according to this embodiment, said pharmaceutical composition for use according to the present invention is a solution, which may be a liquid solution or a viscous solution. Preferably, said solution comprises a TRPM8 inhibitor, as above defined, and one or more of the following components: polyethylene glycol (PEG), also known as polyethylene oxide (PEG), from 800,000 to 1 ,000,000 molecular weight (MW), preferably at an amount between 0.1 % and 2% w / V; carboxymethyl cellulose (CMC) from 700,000 to 1 ,000,000 molecular weight (MW), preferably at an amount between 0.1 % and 1.0 % w / V; polyvinylpyrrolidone (PVP) from 360 to 370 kDA, preferably at an amount between 0.1 % and 0.5 % w / V.

[0529] More preferably, said solution comprises a TRPM8 inhibitor, as above defined, and one or more of the following components:

[0530] 0.25 % w / V polyethylene glycol (PEG), also known as polyethylene oxide (PEG), 1 ,000,000 MW,

[0531] 0.2 % w / V carboxymethyl cellulose (CMC) 700,000 MW,

[0532] 0.2 % w / V polyvinylpyrrolidone (PVP) 365 kDA.

[0533] Preferably, the concentration of said TRPM8 inhibitor in said solution is between 50 pM and 600 pM, more preferably between 100 pM and 500 pM, even more preferably said concentration is selected from 100 pM and 500 pM. Preferably, said TRPM8 inhibitor is DFL23693.

[0534] A “therapeutically effective amount” according to the present invention means an amount sufficient to achieve treatment of the disease.

[0535] A “prophylactically effective amount” according to the present invention means an amount sufficient to achieve prevention of the disease.

[0536] Determination of the therapeutically or prophylactically effective amounts is well within the capability of those skilled in the art based upon the achievement of a desired effect. An effective amount will depend on factors including, but not limited to, the weight of a subject and / or the degree of the disease or unwanted condition from which a subject suffers.

[0537] Unless otherwise indicated, each embodiment disclosed above is intended to be disclosed also in combination with any of the other embodiments disclosed above, to the extent technically compatible.

[0538] The invention also relates to the use of a TRPM8 inhibitor, as above defined, in the manufacture of a medicament for the prevention and / or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

[0539] The invention further relates to the use of a TRPM8 inhibitor, as above defined, in the manufacture of a medicament for the prevention and / or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

[0540] The invention is also directed to a method of preventing and / or treating joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject, which comprises administering an effective amount of one or more TRPM8 inhibitors, as above defined, to a subject in need thereof. The invention is also directed to a method of preventing and / or treating joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis, which comprises administering an effective amount of one or more TRPM8 inhibitors, as above defined, to a subject in need thereof. According to a preferred embodiment, said method comprises the steps of i) selecting a subject to be treated after a clinical evaluation of the affected joint by means of an imaging technique, preferably by means of radiography, and ii) administering an effective amount of one or more TRPM8 inhibitors, as above defined, to said subject. The invention is further illustrated by the following examples, which do not limit the scope of the invention as defined in the claims.

[0541] EXPERIMENTAL SECTION

[0542] EXAMPLE 1

[0543] A study was designed to evaluate the effect of administration of the TRPM8 inhibitor DFL23693 in monosodium iodoacetate (MIA) induced osteoarthritis in male Sprague Dawley (SD) rats. The rats were divided into 8 groups as summarized in the following table: Two to three rats per cage were housed in standard polysulfone cages with stainless steel top grill having access for pelleted food and polycarbonate drinking water bottle with stainless steel sipper tubes. Rats were provided with clean & sterilized com cob as bedding. Animals’ post-MIA administration was maintained in soft bedding.

[0544] Certified rodent diet was provided ad libitum. Water was available ad libitum.

[0545] Periodic analysis of the water was performed, and the results will be archived at the test facility. Environmental controls for the animal room were set to maintain a temperature of 22 to 25°C, humidity of 30-70% RH, and a 12-h light / 12-h dark cycle.

[0546] The preparation protocol for the DFL23693 formulation, dose of 30 mpk, was carried out following the instructions in the table below:

[0547] The following dose volumes were used for the different groups: - The dose volume of Tramadol, 30 mpk to be administered via oral route to group 5 was 6 mL / kg.

[0548] - The dose volume of DFL23693, 100 pM or 500 pM to be administered via intra-articular injection to groups 7 & 8 was 0.05 mL / knee.

[0549] - The dose volume of DFL23693, 30 mpk to be administered via oral route to group 6 was 10 mL / kg.

[0550] - The dose volume placebo to be administered via intra-articular injection to group 3 was 0.05 mL / knee.

[0551] For induction of osteoarthritis, rats were anesthetized with isoflurane and given a single intra-articular injection of 3 mg mono-iodoacetate (MIA, Sigma) through the infrapatellar ligament of the right knee (Bove, S. E., et al., 2003, Osteoarthritis and cartilage, 11 (11 ), 821 -830; Combe R, et al., Neurosci Lett. 2004; 370(2-3):236-40). MIA was dissolved in saline and administered in a volume of 50 pL by using 1 mL BD syringe with 26-gauge, 0.5-inch needle. To ensure uniform distribution, the knee joint was flexed 5 times, and the rats were recovered.

[0552] Groups 1 to 8 received their respective treatments on days 3, 7, 14, 21 and 28 post-MIA injection.

[0553] - Group 1 , naive (p.o.)

[0554] - Group 2, rats received saline, in. articular + vehicle (p.o.,)

[0555] - Group 3, animals received MIA + placebo (in-articular.,)

[0556] - Group 4, animals received MIA + vehicle (p.o.,)

[0557] - Group 5, animals received MIA + Tramadol - 30 mg / kg (p.o.,)

[0558] - Group 6, animals received MIA + DFL23693 - 30 mg / kg (p.o.,)

[0559] - Group 7, animals received MIA + DFL23693 - 100 pM (in-articular.,)

[0560] - Group 8, animals received MIA + DFL23693 - 500 pM (in-articular.,)

[0561] The body temperature was assessed delicately inserting a lubricated thermocouple probe 40 mm into each rat’s rectum. The rat was positioned with all four paws on a smooth surface, gently secured by a hand over the back and the tail was lifted for the insertion of the thermocouple probe, which was left in the rectum for 40 seconds to ensure temperature stabilization. The body temperature was recorded at baseline, 0, 0.5, 3, and 7h post-test item on days 3, 7, 14, 21 and 28 post-MIA injection or on the day of dosing.

[0562] For the scoring of the knee lesion, rats were euthanized by exposure to a slowly rising concentration of CO2 on day 28 post-MIA administration. The right knee was removed and dissected, and the tibia was fixed in a 10% formalin neutral-buffered solution. The observation and scoring of knees were conducted in accordance with the method in a previous report. Briefly, the degree of lesion on the surface of the tibial head was scored on a scale of 0-4 in a blinded manner as follows: 0 = normal appearance, 1 = rough surface, 2 = moderate lesion of cartilage surface, 3 = sever lesion of subchondral bone, 4 = appearance of osteophyte formation with sever lesion of subchondral bone (Ishikawa, G., et al., 2015, Osteoarthritis and cartilage, 23(6), 925-932). Histologic analysis (microscopic): Rats were euthanized by exposure to a solely rising concentration of CO2 on day 28 post-MIA administration. The right knee was removed and dissected, and the tibia was fixed in a 10% formalin neutral-buffered solution and subsequently decalcified with formic acid. Samples were dehydrated in an ethanol series and embedded in paraffin. Sections were stained with hematoxylin-eosin (H&E staining).

[0563] Scoring: To assess the degree of synovial inflammation a relative scoring system was used. OARSI Histopathology Grading Scale: Grade 0: Surface Intact, Cartilage morphology intact. Grade 1 : Surface Intact, Grade 2: Surface Discontinuity, Grade 3: Vertical Fissures (clefts), Grade 4: Erosion, Grade 5: Denudation and Grade 6: Deformation. Inflammation Grading: Each joint was scored on a scale of 0-4 as follows: 0 = no inflammation, 1 = minimal, 2 = mild, 3 = moderate and 4 = severe / marked by a veterinary pathologist. A subsequent tissue section of 5-7 pM was stained with safranin O-fast green. Proteoglycan content was scored in safranin O-fast green stained slides on a scale of 0-4 where 0 = no loss of proteoglycan staining relative to a normal control, 1 = minimal loss, 2 = mild loss, 3 = moderate loss and 4 = total loss of proteoglycan staining. A veterinarian pathologist has been performing the histological assessment in a blind manner (Bove, S. E., et al., 2003, Osteoarthritis and cartilage, 11 (1 1 ), 821-830; Pritzker, K. P., et al., 2006, Osteoarthritis and cartilage, 14(1 ), 13-29).

[0564] Statistical Analysis

[0565] The data were presented as Mean ± SEM. For single variable data, one-way ANOVA was conducted followed by Sidak's multiple comparisons test. For data involving two variables, two-way ANOVA was performed followed by Dunnett's multiple comparisons test. Statistical analyses were carried out using GraphPad Prism v10.2.2.

[0566] Effect of DFL23693 on gross pathology of knee of monosodium iodoacetate (MIA)-induced osteoarthritic pain

[0567] The results of the evaluation of gross pathology score are shown in Figure 1 . DFL23693 30 mpk group exhibited a significant decrease in gross pathological score when compared with MIA + Vehicle group (Figure 1A).

[0568] DFL23693 100 pM & 500 pM treated group showed significant decrease in gross pathological score in comparison to MIA + Placebo group (Figure 1A).

[0569] This is evident from the images reported in panel B of Figure 1 , which shows that the animals treated with DFL23693 had a healthier structure of the bone and of the cartilage of the knee, with less osteophyte formation, when compared with animals treated with tramadol, used as reference drug, and animals treated with placebo or vehicle.

[0570] The above results show that both oral and intra-articular administration of the TRPM8 inhibitor DFL23693 are effective in preserving the structure of the joint - specifically, both cartilage and bone - from the damage and degeneration induced by osteoarthritis.

[0571] Effect of DFL23693 on histopathology scores of monosodium iodoacetate (MIA) -induced osteoarthritic pain.

[0572] MIA + Vehicle and MIA + Placebo exhibited a significant increase in tibial histopathological grades, tibial inflammation scores and tibial proteoglycan scores when compared with Naive group.

[0573] DFL23693 500 pM treated group showed significant decrease in tibial histopathological grades, tibial inflammation scores and tibial proteoglycan scores when compared with MIA + Placebo group.

[0574] The results are shown in Figure 2, 3 and 4.

[0575] Collectively, the above-discussed results show that the TRPM8 inhibitor preserved the cartilage and the bone of the joint from the damage, inflammation and degeneration induced by the OA disease model.

[0576] Effect of DFL23693 on rectal temperature of monosodium iodoacetate (MIA)- induced osteoarthritic pain

[0577] No significant difference in rectal temperature was found in saline (IA) + vehicle group in comparison to naive group except day 21 at 3h (p<0.001 ). Also, as can be seen in Figure 5, no significant difference in rectal temperature on experiment days was found for all the tested formulation when compared with MIA + Vehicle group (oral formulation) or MIA + Placebo group (intraarticular formulations).

[0578] Despite a clear demonstration of pharmacological activity, both in terms of an effect against joint inflammation, articular cartilage destruction and the adverse events seen, DFL23693 had no effect on core body temperature. Collectively, these data demonstrate a clear advantage of this compound during preclinical studies, strengthening its progress to the clinical phases, particularly considering the negative effect of DFL23693 on modulating the body temperature of animals.

[0579] EXAMPLE 2

[0580] A further study was designed to evaluate the effect of oral administration of the TRPM8 inhibitors DFL23693 and PF-05105678 in the same animal model (monosodium iodoacetate MIA induced osteoarthritis in male Sprague Dawley rats) disclosed in Example 1 . The rats were divided into the following groups:

[0581] • Naive (n=3), corresponding to healthy rats not receiving MIA injection or any treatment.

[0582] • MIA + Vehicle (n=5), corresponding to MIA rats treated with daily oral administration of vehicle (Polyethylene glycol 400 (PEG 400) (20% v / v) + D-a-Tocopheryl polyethylene glycol 1000 succinate (TPGS) (10% v / v) + 1 % w / v Kollidon VA 64 in pH 7.4 phosphate buffer (70% v / v)) from day 3 to day 28 post-MIA injection.

[0583] • MIA + DFL23693 30 mpk OD (n=5), corresponding to MIA rats treated with daily oral administration of 30 mg / kg of DFL23693 from day 3 to day 28 post-MIA injection.

[0584] • MIA + DFL23693 60 mpk OD (n=5), corresponding to MIA rats treated with daily oral administration of 60 mg / kg of DFL23693 from day 3 to day 28 post-MIA injection.

[0585] • MIA + DFL23693 60 mpk BID (n=5), corresponding to MIA rats treated with two daily oral administrations of 60 mg / kg of DFL23693 from day 3 to day 28 post-MIA injection. The two administrations carried out in each day were carried out 6 hours apart.

[0586] • MIA + PF-05105678 20 mpk BID (n=4), corresponding to MIA rats treated with two daily oral administrations of 20 mg / kg of PF-05105678 from day 3 to day 28 post-MIA injection. The two administrations carried out in each day were carried out 6 hours apart

[0587] The preparation protocol for the DFL23693 formulation, dose of 30 mpk, was carried out following the instructions in the table below:

[0588] The preparation protocol for the DFL23693 formulation, dose of 60 mpk, was carried out following the instructions in the table below:

[0589] PF-05105678 was acquired from BOC Science (catalogue and CAS number 1398583-3131 -7, batch: B25S05161 ) and administered in form of a solution using Polyethylene glycol 400 (PEG 400) (20% v / v) + D-a-Tocopheryl polyethylene glycol 1000 succinate (TPGS)(10% v / v) + 1 % w / v Kollidon VA 64 in pH 7.4 phosphate buffer (70% v / v) as vehicle and the compound at the concentration of 2 mg / mL.

[0590] The following dose volumes were used for the different groups:

[0591] - The dose volume of DFL23693, 30 mpk to be administered via oral route was 10 mL / kg.

[0592] - The dose volume of DFL23693, 60 mpk to be administered via oral route was

[0593] 10 mL / kg.

[0594] - The dose volume of PF-05105678, 20 mpk to be administered via oral route was 10 mL / kg.

[0595] Rats were euthanized by exposure to a slowly rising concentration of CO2 on day 29 post-MIA administration. The right knee was removed and dissected, and the tibia was fixed in a 10% formalin neutral -buffered solution and subsequently decalcified with formic acid. Samples were dehydrated in an ethanol series and embedded in paraffin. Serum samples were obtained at the sacrifice from animals of each group.

[0596] The following analyses were carried out in order to assess the diseasemodifying potential of the inhibition of TRPM8: OARSI scoring, cartilage erosion quantification, evaluation of inflammatory infiltration (CD45+ staining), TRAP quantification and COL10A quantification, as well as COMP quantification in serum, as described below.

[0597] OARSI scoring

[0598] The OARSI scoring was carried out as follows. One series of sections was stained with Safranin 0 and light green for morphological evaluation and scored, using the OARSI scoring method based on the grading and the staging of cartilage lesion (Pritzker KP et al. Osteoarthritis Cartilage 2006; 14: 13-29). For each joint an OA knee grade and an OA knee stage were calculated representing the average grade and stage score for both femur and tibia. Finaly for each samples an OA knee score was calculated by multiplying both OA knee grade and OA knee stage.

[0599] The OARSI (Osteoarthritis Research Society International) histopathology scoring system is used to assess the severity of osteoarthritic changes in cartilage and subchondral bone, with higher scores indicating more extensive cartilage erosion, structural disruption, and osteophyte formation; thus, an increasing OARSI score reflects disease progression, while a decrease or stabilization suggests attenuation or repair of joint degeneration (Pritzker KP et al. Osteoarthritis Cartilage 2006; 14: 13-29).

[0600] As can be seen in Figure 6, an increased Increase OARSI score of the knee was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0601] All the groups treated with the TRPM8 inhibitors DFL23693 and PF-05105679 showed reduced OARSI scores of the knee compared to the MIA + vehicle group. This effect was particularly evident for the group treated with a single administration of DFL23693 and for the group treated with PF-05105679. These results confirm that the oral administration of TRPM8 inhibitors is able to counteract, attenuate and repair joint degeneration caused by osteoarthritis. Cartilage erosion quantification

[0602] The cartilage erosion quantification was carried out as follows. Using Visiopharm imaging software, articular cartilage from Safranin O / light green stained sections, was automatically detected. An eroded cartilage percentage was calculated as follows: [(area of eroded+ area damaged cartilage) / total cartilage area]xl00.

[0603] In osteoarthritis, cartilage erosion is a hallmark feature of disease progression, resulting from the combined effects of chondrocyte hypertrophy, extracellular matrix degradation, and catabolic enzyme activity, which together compromise the structural integrity and function of the articular cartilage (Yasuda T., Mod Rheumatol 16, 197-205 (2006).

[0604] As can be seen in Figure 7, an increase in the percentage of eroded cartilage was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0605] All the groups treated with the TRPM8 inhibitors DFL23693 and PF-05105679 showed reduced percentages of cartilage erosion compared to the MIA + vehicle group. This effect was particularly evident for the group treated with a single administration of DFL23693 and for the group treated with PF- 05105679. These results confirm that the oral administration of TRPM8 inhibitors is able to preserve the functional integrity and function of the joint cartilage.

[0606] Evaluation of inflammatory infiltration (CD45+ staining)

[0607] The evaluation of inflammatory infiltration was carried out as follows. Immunohistochemistry analysis was performed on 4pm thick sections which were deparaffinized prior to antigen retrieval (proteinase K or trypsin) in an automated stainer (Bond Rx, Leica). Then, the sections were incubated 1 hour with the primary antibody against CD45 (ab10558, Abeam, 1 :50). After incubation with the primary antibody, the appropriate secondary antibody for each primary antibody (Bond refine polymer detection kit, DS9800, Leica) was applied for 8 min and peroxidase activity was determined using the same kit (DS9800, Leica). Synovial tissue was automatically detected by Visiopharm imaging software. In the synovial tissue, CD45 positive surface was quantified and normalized to the total synovial surface. In the subchondral bone, the area of inflammatory infiltrates was automatically quantified and normalized to the total epiphysis area. The subchondral bone inflammatory infiltrates were then used to quantify the percentage of CD45 positive area in that region.

[0608] In osteoarthritis, subchondral bone often exhibits an inflammatory infiltrate characterized by CD45-positive immune cells, reflecting activation of local inflammatory pathways that contribute to osteochondral disruption and disease progression (Guillem-Llobat, P. et al., Int. J. Mol. Sci. 2024, 25, 1710.

[0609] As can be seen in Figure 8, an increase in subchondral bone infiltration of inflammatory cells was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0610] All the groups treated with the TRPM8 inhibitors DFL23693 and PF-05105679 showed reduced subchondral bone infiltration of inflammatory cells and reduced CD45+ cells contained in the subchondral bone infiltrate compared to the MIA + vehicle group. These results confirm that the oral administration of TRPM8 inhibitors is able reduce osteochondral disruption and disease progression occurring in osteoarthritis.

[0611] TRAP quantification

[0612] The quantification of Tartrate-resistant acid phosphatase (TRAP) was carried out as follows. Immunohistochemistry analysis was performed on 4pm thick sections which were deparaffinized prior to antigen retrieval (proteinase K or trypsin) in an automated stainer (Bond Rx, Leica). Then, the sections were incubated 1 hour with the primary antibody against TRAP (ab185716, Abeam, 1 :600). After incubation with the primary antibody, the appropriate secondary antibody for each primary antibody (Bond refine polymer detection kit, DS9800, Leica) was applied for 8 min and peroxidase activity was determined using the same kit (DS9800, Leica). TRAP positive area was automatically detected and normalized by the total epiphysis area by Visiopharm imaging software.

[0613] TRAP, an enzyme characteristic of activated osteoclasts, plays an important role in osteoarthritis progression because it reflects increased bone resorption activity and contributes to degenerative changes at the osteochondral junction (Logar DB et al., J Bone Miner Metab. 2007;25(4):219-25). As can be seen in Figure 9, an increase in TRAP+ staining was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0614] All the groups treated with the TRPM8 inhibitors DFL23693 and PF-05105679 showed reduced TRAP+ staining compared to the MIA + vehicle group. These results confirm that the oral administration of TRPM8 inhibitors is able to counteract the bone resorption and the degenerative changes at the osteochondral junction occurring in osteoarthritis.

[0615] COL1 QA quantification

[0616] The quantification of COL10A1 was carried out as follows. Immunohistochemistry analysis was performed on 4pm thick sections which were deparaffinized prior to antigen retrieval (proteinase K or trypsin) in an automated stainer (Bond Rx, Leica). Then, the sections were incubated 1 hour with the primary antibody against Collagen X (14-9771 -82, Thermofisher, 1 :50). After incubation with the primary antibody, the appropriate secondary antibody for each primary antibody (Bond refine polymer detection kit, DS9800, Leica) was applied for 8 min and peroxidase activity was determined using the same kit (DS9800, Leica). Articular cartilage was automatically segmented and Collagen type X positive area was quantified. Collagen type X staining area was reported to the total cartilage area.

[0617] Type X collagen (encoded by COL10A1 ) is a hallmark of chondrocyte hypertrophy, a pathological process that accelerates cartilage breakdown (Rim YA et al., Int J Mol Sci. 2020 Mar 29;21 (7):2358).

[0618] As can be seen in Figure 10, an increase in COL10A+ staining was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0619] All the groups treated with the TRPM8 inhibitors DFL23693 and PF-05105679 showed reduced COL10+ staining compared to the MIA + vehicle group. These results confirm that the oral administration of TRPM8 inhibitors is able to counteract the cartilage breakdown occurring in osteoarthritis.

[0620] COMP quantification

[0621] The quantification of cartilage oligomeric matrix protein (COMP) was carried out as follows. Rat COMP ELISA kit (Cat# E-EL-R0159 by Elabscience) was used to measure the total amount of COMP in the serum of rats MIA model. The samples were 100-fold diluted in the assay buffer provided by the kit and loaded on pre-coated plates in accordance with the manufacturer's protocol. The optical density was measured immediately using the pre-heated microplate reader set to 450 nm. The concentration of each analyte was determined by extrapolating the absorbance values from the standard curve using 4PL analysis.

[0622] In osteoarthritis, elevated serum COMP — a non-collagenous cartilage matrix glycoprotein — reflects increased cartilage matrix turnover and degradation and has been repeatedly associated with radiographic severity and clinical progression; thus, higher COMP levels in serum can serve as a biomarker of greater joint damage and disease severity (Clark AG et al., Arthritis Rheum. 1999 Nov;42(11 ):2356-64; Bi X., J Orthop Surg Res. 2018 Oct 19; 13(1 ):262). As can be seen in Figure 1 1 , an increase in COMP serum levels was observed in MIA + vehicle group compared to Naive group, indicative of osteoarthritic changes induced by the MIA injection.

[0623] Animals treated with the TRPM8 inhibitors DFL23693 at 60 mg / kg BID showed reduced COMP serum levels compared to the MIA + vehicle group. These results confirm that the oral administration of TRPM8 inhibitors is able to decrease cartilage matrix degradation and turnover and attenuate joint tissue damage.

[0624] EXAMPLE 3

[0625] In osteoarthritis, activation of macrophages in the synovium and subchondral bone drives the local inflammatory milieu through the release of pro- inflammatory cytokines such as IL-1 (3, TNF-a, IL-6, IL-8, and chemokines like CCL2, which promote cartilage degradation, osteoclast activation, and overall disease progression; thus, elevated levels of these mediators reflect heightened joint inflammation and tissue damage (Bondeson, J. et al., Arthritis Res Ther 8, R187 (2006); Chen Y et al., Am J Transl Res. 2020 Jan 15;12(1 ):261 -268).

[0626] The present inventors thus carried out in vitro experiments to evaluate the effect of several TRPM8 inhibitors on the release of inflammatory cytokines and chemokines from M1 (pro-inflammatory) macrophages.

[0627] Peripheral blood mononuclear cells (PBMCs) acquired from D.I.D. (Diagnostic International Distribution, code 70025) were plated in 12-well plates (3x106 cells / wel I) in MEMa medium (Sigma-Aldrich cat. n. M4526) supplemented with FBS 10%, Pe / Strep 1X and added with macrophage colony stimulating factor (M-CSF Thermofisher, cat. n. H6916) 50 ng / ml for 6 days in order to differentiate them into MO macrophages. The cells were then polarized to M1 macrophages by challenging them with 100 ng / ml Lipopolysaccharides (LPS) from Escherichia coli 055: B5 (Sigma-Aldrich, cat. n. L2880) plus 20ng / ml IFNg (Merck Millipore, cat. n. IF005) for 24 hours with and without the addition of TRPM8 inhibitors. The following TRPM8 inhibitors were used: DFL23693, PF-05105679, AMG333 (Biotechne, code 6874), TC-l-2014 (Biotechne, code 5410). All the TRPM8 inhibitors were used at the concentration of 30 pM. Untreated M0 macrophages were used as control.

[0628] After 24 hours of M1 polarization, the supernatants were collected and the levels of IL-6, IL-1 b, TNFa, CCL2 and IL-8 were determined as follows. Samples were diluted 5000-fold for the detection of IL8, and 500-fold for all the other analytes using the sample diluent provided by the cartridge (SPCKE- PS-10336 by Protein Simple). This latter was filled according to manufacturer’s instructions and run in the Ella ™ Automated ELISA instrument (Protein Simple).

[0629] As can be seen from figures 12 to 16, after 24 hours of challenge, while the treatment of macrophages with 100ng / mL LPS + 20ng / ml IFNg without TRPM8 inhibitors resulted in a marked induction of the secretion of IL1 b, CCL2, TNFa, IL-6 and IL-8, the addition of any of the above mentioned TRPM8 inhibitors resulted in a decreased release of all these cytokines from the macrophages. This is representative of the efficacy of TRPM8 inhibitors in reducing the release of cytokines from the macrophages and, consequently, in counteracting the processes of cartilage degradation, osteoclast activation and overall disease progression occurring in osteoarthritis.

[0630] EXAMPLE 4

[0631] The present inventors carried out in vitro experiments to assess the effect of various TRPM8 inhibitors on matrix mineralization and osteogenic gene expression under inflammatory conditions.

[0632] Specifically, Human Bone Marrow-derived Stromal Cells (hBMSC - cod. C-12974 by Merck) from 2 different donors were cultured and maintained in MEMa medium (Sigma-Aldrich cat. n. M4526) supplemented with FBS 10%, Pe / Strep 1X (basal medium). For the osteogenic capacity evaluation, cells were plated in 12-well plate until confluence («90%). Cells were then cultured in osteogenic conditions in basal medium supplemented with 50 pM ascorbic acid (Sigma-Aldrich cat. n. A8960), 10 mM [3-glycerophosphate (Sigma-Aldrich cat. n. G9422) and 100 nM dexamethasone (Sigma-Aldrich cat. n. D4902) (Osteogenic Medium, OM), for 7 days. Then medium was replaced with OM without dexamethasone and cells were treated with TNFa (Proteintech cat. n. 16831276) 20 ng / ml alone or in combination with the different TRPM8 inhibitors (DFL23693, PF-05105679, AMG333, RQ00203078 (Biotechne, cod. n. 5388), TC-l-2014) all at the concentration of 30 pM for the subsequent 21 days. A further week was included during the experiments. Control samples were not treated with TNFa, but with vehicle only. The OM and treatments were replaced every 48 hours. The following parameters were evaluated: mean concentration of osteopontin (OPN) and Alizarin Red S (ARS) staining.

[0633] Osteopontin evaluation

[0634] The mean concentration of osteopontin (OPN) was evaluated in the supernatant of the cells as follows. Cell supernatants were 2-fold diluted and OPN content was evaluated using a Quantikine ELISA kit (cod. DOST00 by Biotechne) following the manufacturer’s instructions. The optical density was measured using the EnVision microplate reader (by Perkin Elmer) set to 450 nm, after correction on 540 nm, and the quantification was calculated using a four- parameter logistic (4-PL) curve-fit with the standard curve.

[0635] Osteopontin (OPN) is a multifunctional matricellular protein that can support osteochondral repair by promoting osteoblast activity, matrix mineralization, and tissue remodeling; in the context of osteoarthritis, appropriate OPN expression may contribute to the restoration of bone-cartilage homeostasis (Luo W. et al., Genes Dis. 2022 Sep 1 ; 10(4): 1714-1725).

[0636] As can be seen in Figure 17 (Donor 1 ) and 18 (Donor 2), treatment of osteoblasts with 20 ng / ml TNFa induced a slight reduction in OPN at day 21 . All the tested TRPM8 inhibitors induced an increase in OPN secretion over TNFa challenge. This is indicative of the potential of TRPM8 inhibitors in the restoration of bone-cartilage homeostasis in osteoarthritis.

[0637] Alizarin Red S (ARS) staining

[0638] At the end of the differentiation, cells were fixed in cold 70% Ethanol for 1 hour at room temperature, washed twice with double distilled water and then stained for the evaluation of calcium deposits by Alizarin Red S (ARS, Sigma-Aldrich cat. n. A5533) staining solution (2% w / v, pH 4.1 -4.3) for 30 min at room temperature. Then samples were washed 3 times with double distilled water and ARS-stained cultures were photographed using an inverted Leica DMi1 microscope. ARS quantification was conducted by dye extraction with 10% acetic acid for 15 min, then the extracted solution was centrifuged at 2,000 rpm for 10 minutes to pellet the debris and the supernatants were used for reading absorbance at A405 nm.

[0639] Alizarin Red S (ARS) staining is commonly used to assess mineralized matrix deposition by osteoblasts in vitro, with the intensity and area of staining reflecting the extent of osteogenic differentiation and extracellular matrix mineralization; thus, increased ARS staining indicates enhanced osteoblast activity and bone-forming potential (Zainal Ariffin SH et al., PeerJ. 2024 Jul 25; 12:e17790.)

[0640] As can be seen in Figure 19, after 28 days, treatment of osteoblast with 20ng / ml TNFa induced a slight reduction on bone matrix mineralization, while all the tested TRPM8 inhibitors restored this functionality upon TNFa challenge. This is indicative of the efficacy of TRPM8 inhibitors in enhancing osteoblast activity and, consequently, bone forming potential in osteoarthritis. EXAMPLE 5

[0641] A study was designed to evaluate the effect of administration of the TRPM8 inhibitor DFL23693 on tactile allodynia and cold allodynia in a monosodium iodoacetate (MIA) induced osteoarthritis in male Sprague Dawley (SD) rats, following the same experimental setting disclosed in Example 1 above. Tactile allodynia

[0642] To assess the mechanical sensitivity, tactile allodynia was measured using calibrated von Frey filaments and the Dixon up-down procedure (Dixon, 1965). On days 3, 7, 14, 21 and 28 post-MIA injection, the baseline tactile allodynia on the plantar surface of the ipsilateral hind limb was tested. The 50% paw withdrawal threshold (50% PWT) was calculated as previously described (Chaplan et al., 1994). Rats injected with MIA scoring < 5g on the 50% PWT were considered allodynic and included in further testing. Subsequently, rats were randomly assigned to different groups, as mentioned in Example 1 .

[0643] The results are shown in the following tables.

[0644]

[0645] Data indicates Mean ± SEM. Two-way ANOVA followed by Dunnett's multiple comparisons test, #p<0.05, ##p<0.01 and ###p<0.001 Vs NaTve / Saline (Intra- articular)+vehicle; *p<0.05, **p<0.01 and ***p<0.001 Vs MIA+Vehicle / MIA+Placebo

[0646] Conclusions:

[0647] • At days 3, 7, 14, 21 , and 28, both the MIA+Placebo and MIA+Vehicle groups exhibited a significant reduction (p<0.05 on day 7 and p<0.001 ) in paw withdrawal threshold when compared to the Naive group across all time points.

[0648] • MIA+Tramadol 30 mpk treated group demonstrated a significant increase (p<0.05, p<0.01 and p<0.001 ) in paw withdrawal threshold on days 3, 7, 14, 21 and 28 across time points spanning from 1 h to 6h when compared with MIA+ Placebo and MIA+ Vehicle group except on Day 14 & 28 (6th hour).

[0649] • DFL23693 100 pM and 500 pM treated groups showed a significant increase (p<0.05, p<0.01 and p<0.001 ) in paw withdrawal threshold across time points from 1 to 6 hours on days 3, 7, 14, 21 , and 28 in comparison to MIA+Placebo group except DFL23693 100 pM at 1 st hour on day 3.

[0650] • The DFL23693 30 mpk treated group demonstrated a significant increase (p<0.01 and p<0.001 ) in paw withdrawal threshold from hours 1 to 6 on days 3, 7, 14, 21 , and 28, in comparison to the MIA+Vehicle group. However, there was no significant difference during the first hour of day 3.

[0651] Cold allodynia

[0652] Cold allodynia was evaluated by applying 100 pL of acetone on to the plantar surface of the rat’s paw positioned on a wire mesh, avoiding direct skin contact (Choi et al., 1994). The rat’s response to acetone was observed for 2 minutes and the duration or number of nocifensive responses (quick / prolonged withdrawal, or stamp of the paw, or repeated flinching or licking of the paw) were recorded with stopwatch. The process was repeated 3 times on the hind paw, with a 5 minutes interval between acetone applications.

[0653] The results are shown in the following tables.

[0654]

[0655]

[0656] Data indicates Mean ± SEM. Two-way ANOVA followed by Dunnett's multiple comparisons test. #p<0.05, ##p<0.01 and ###p<0.001 Vs NaTve / Saline (Intra- articular)+vehicle; *p<0.05, **p<0.01 and ***p<0.001 Vs MIA+Vehicle / MIA+Placebo

[0657] Conclusions:

[0658] • At days 3, 7, 14, 21 , and 28, both the MIA+Placebo and MIA+Vehicle groups exhibited a notable increase (p<0.01 and p<0.001 ) in nocifensive response when compared to the Naive group across all time points. • MIA+Tramadol 30 mpk treated group demonstrated a significant decrease (p<0.05, p<0.01 and p<0.001 ) in nocifensive response on days 3, 7, 14, 21 and 28 across time points spanning from 1 h to 6h when compared with MIA+ Placebo and MIA+ Vehicle group except on Day 3,

[0659] 7 & 14 (6th hour when compared with MIA+Placebo).

[0660] • DFL23693 100 pM and 500 pM treated groups showed a significant decrease (p<0.05, p<0.01 and p<0.001 ) in nocifensive response across time points from 1 to 6 hours on days 7, 14, 21 , and 28 in comparison to MIA+Placebo group. On day 3, DFL23693 100 pM and 500 pM showed significant decrease in nocifensive response at 1 h and 1 h to 2h, respectively.

[0661] • The DFL23693 30 mpk treated group demonstrated a significant increase (p<0.05, p<0.01 and p<0.001 ) in paw withdrawal threshold from hours 1 to 6 on days 7, 14, 21 , and 28, in comparison to the MIA+Vehicle group. Whereas, there was no significant difference on day 3.

Claims

1. CLAIMS1. A TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation caused by osteoarthritis in a subject.

2. A TRPM8 inhibitor for use in the prevention or treatment of joint damage and / or joint degeneration and / or joint inflammation in a subject with osteoarthritis.

3. A TRPM8 inhibitor for use according to claim 1 or claim 2, wherein said TRMP8 inhibitor is for use in the inhibition of onset or in the delay in the onset of joint damage and / or joint degeneration and / or joint inflammation.

4. A TRPM8 inhibitor for use according to claim 1 or claim 2, wherein said TRPM8 inhibitor is for use in the inhibition or slowing of progression of joint damage and / or joint degeneration and / or joint inflammation.

5. A TRPM8 inhibitor for use according to claim 1 or claim 2, wherein said TRPM8 inhibitor is for use in the reduction of entity of joint damage and / or joint degeneration and / or joint inflammation.

6. A TRPM8 inhibitor for use according to any one of the preceding claims, wherein said TRPM8 inhibitor is for use in i) the inhibition of onset or in the delay in the onset of stiffness and loss of mobility, or ii) the inhibition or slowing of the progression of stiffness and loss of mobility, or iii) the reduction of the entity of stiffness and loss of mobility.

7. A TRPM8 inhibitor for use according to any one of the preceding claims, wherein said joint damage or degeneration is selected from joint cartilage damage or degeneration, joint bone damage or degeneration, joint cartilage and joint bone damage or degeneration, subchondral bone damage or degeneration.

8. A TRPM8 inhibitor for use according to any one of the preceding claims, wherein said osteoarthritis is selected from hand osteoarthritis, knee osteoarthritis, hip osteoarthritis, osteoarthritis of the lower back, osteoarthritis of the spine, ankle osteoarthritis, elbow osteoarthritis, osteoarthritis of the fingers, foot osteoarthritis, shoulder osteoarthritis, wrist osteoarthritis, first metatarsophalangeal (MTP) joint osteoarthritis, sacroiliac (SI) joint arthritis and cervical osteoarthritis.

9. A TRPM8 inhibitor for use according to any one of the preceding claims, wherein said TRPM8 inhibitor is an antibody selected from ACC-049, ab235890, ab314169 and NBP1 -97311.

10. A TRPM8 inhibitor for use according to any one of claims 1 to 8, wherein said TRPM8 inhibitor is selected from: a compound of formula (I):or a pharmaceutically acceptable salt thereof, whereinR is selected from H, Br, CN, NO2, SO2NH2, SO2NHR' and SO2N(R')2, where R' is selected from linear or branched C1-C4 alkyl;X is selected from F, Cl, C1-C3 alkyl, NH2 and OH;Y is selected from 0, CH2, NH and SO2;R1 and R2, independently one from the other, are selected from H, F and linear or branched C1-C4 alkyl;R3 and R4, independently one from the other, are selected from H and linear or branched C1-C4 alkyl;Z is selected from NR6 and R6R7N+, where R6 and R7 independently one from the other, are selected from H and linear or branched C1-C4 alkyl;R5 is a residue selected from H and linear or branched C1-C4 alkyl;Het is a heteroaryl group selected from a substituted or not substituted pyrrolyl, a substituted or not substituted N- methylpyrrolyl, a substituted or not substituted thiophenyl, a substituted or not substituted furyl and a substituted or not substituted pyridiny I, and preferably it is a substituted or not substituted pyrrol-2-yl, a substituted or not substituted N- methylpyrrol-2-yl, a substituted or not substituted thiophen-2-yl, a substituted or not substituted fur-2-yl, a substituted or not substituted pyridin-2-y I; a compound of formula (II):or a pharmaceutically acceptable salt thereof, whereinX is selected from S and 0;R1 is selected from the group consisting of:-0R5 wherein R5 is selected from H; C1-C4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (halo)benzyl, (trifluoromethyl)benzoyl, N- benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C1-C3 alkyl group, (C1-C3 alkoxy)methyl, C1-C3 alkanoyl and CH2CH2NHR6, wherein R6 is selected from H and (furan-2-yl)methyl; and-NHR7 wherein R7 is selected from H, tert-butoxycarbonyl, C1-C3 alkanoyl, (4- trifluoromethyl)benzoyl, N-phenylaminoacarbonyl, CH2R8, wherein R8 is selected from phenyl, benzo[d][1 ,3] dioxole, pyridin-3-yl, (pyrrolid in-1 -yl) methyl, -CH2NHR9 wherein R9 is selected from H, C1-C3 alkyl and cycloalkyl; R2 is selected from the group consisting of-COOR10 wherein R10 is selected from H, C1-C3 alkyl and cyclohexyl, optionally substituted with at least one C1-C3 alkyl group;-OH; -CONH2; CN; -tetrazol-5-yl, 1 -(Ci-C3alkyl)tetrazol-5-yl, 2-(CI-C3alkyl)tetrazol-5-yl, 5-(CI -C3 alkyl)1 ,2,4 triazol-3-y I, 5-(CI -C3 alkyl)1 ,2,4- oxadiazol-3yl, 5-(CI -C3 alkyl) 1 ,3,4-oxadiazol-2-yl;R3 is selected from F and H,R4 is selected from H; CH3; halogen; dimethylamino; pyridin-4yl; phenyl; 2- or 4- (halo)phenyl; 2- or 4- (trifluoromethyl)phenyl; 2- and / or 4-halobenzyloxy; a compound of formula (III):or a pharmaceutically acceptable salt thereof, whereinX is oxygen, sulphur, NH, NOH, or NOMe;R is a group selected from aryl and heteroaryl, optionally substituted by one or more substituents selected from- hydrogen,- halogen,- CF3,- linear or branched Ci-Ce alkyl,- OR5 and- NR6R7, wherein R5, R6 and R7 are independently hydrogen or linear or branched Ci-Ce alkyl;R1 is a group selected from- linear or branched Ci-Ce alkyl,- (CH2)m-OR2, wherein m is an integer between 1 and 3 and R2 is selected from hydrogen and linear C1-C3 alkyl,- C3-C6 cycloalkyl, and- N(R3)OR4, wherein R3 and R4 are independently hydrogen or linear or branched C1-C3 alkyl; a compound of formula (IV):or a pharmaceutically acceptable salt thereof, whereinR1is an unsubstituted or substituted 5, 6 or 7-membered, aliphatic or aromatic heterocycle group containing 1 , 2, 3 or 4 heteroatoms selected from N, 0 and S;R2is selected from hydrogen, C1-C2 alkyl, F, Cl and OH;6-[[[(S)-(3-Fluoro-2-pyridinyl)[3-fluoro-4- (trifluoromethoxy)phenyl]methyl]amino]carbonyl]-3-pyridinecarboxylic acid, also known as AMG-333;(1 R)-N-(4-Fluorophenyl)-3,4-dihydro-1 -[4-(trifluoromethyl)phenyl]-2(1 H)- isoquinolinecarboxamide, also known as AMG-8788;4-[(4-cyclopropylisoquinolin-3-yl)-[[4- (trifluoromethoxy)phenyl]methyl]sulfamoyl]benzoic acid, also known as elismetrep;RQ-00434739, also known as XG-2002;CC-002;(1 R)-3,4-Dihydro-N-[(1 S)-2,2 ,2-trif luoro-1 -methylethyl]-1 -[4-(trifluoromethyl)phenyl]-2(1 H)-isoquinolinecarboxamide, also known as AMG- 9678;N,N-Bis(phenylmethyl)-L-tryptophan methyl ester, also known as TRPM8 antagonist 2;[4-Hydroxy-2-(2-hydroxyphenyl)-5-thiazolyl]-2-isoxazolidinylmethanone, also known as TRPM8 antagonist 3;3-[[[(1 R)-1 -(4-Fluorophenyl)ethyl](3-quinolinylcarbonyl)amino]methyl]benzoic acid, also known as PF-05105679;4-[[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl][[4- (trifluoromethoxy)phenyl]methyl]amino]sulfonyl]benzoic acid, also known as RQ-00203078;3-[7-(Trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1 H-benzimidazol-2-yl]-1 - oxa-2-azaspiro[4.5]dec-2-ene, also known as TC-l-2014;4-[[(4-Cyclopropyl-3-isoquinolinyl)[[4- (trifluoromethoxy)phenyl]methyl]amino]sulfonyl]benzoic acid, also known as MT-8554;N-(2-aminoethyl)-N-[[3-methoxy-4-(phenylmethoxy)phenyl]methyl]-2- thiophenecarboxamide monohydrochloride, also known as M8-B;(8R)-5,8-Dihydro-N-[(1 S)-2,2 ,2-trif luoro-1 -methylethyl]-8-[4-(trifluoromethyl)phenyl]-1 ,7-naphthyridine-7(6H)-carboxamide, also known as AMG-2850.11 . A TRPM8 inhibitor for use according to claim 10, wherein said compound of formula (II) is selected from:2-(4-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid;4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid;2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylic acid; methyl 4-hydroxy-2-phenyl-1 ,3-thiazole-5-carboxylate; methyl 2-(2,4-difluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-(pyridin-4-yl)-1 ,3-thiazole-5-carboxylate; ethyl 2-[4-(dimethylamino)phenyl]-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-chlorophenyl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-[2'-(trifluoromethyl)biphenyl-3-yl]-1 ,3-thiazole-5- carboxylate; ethyl 2-(2'-fluorobiphenyl-3-yl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 4-hydroxy-2-[2'-(trifluoromethyl)biphenyl-4-yl]-1 ,3-thiazole-5- carboxylate; ethyl 2-(2'-fluorobiphenyl-4-yl)-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-{4-[(2-fluorobenzyl)oxy]phenyl}-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-4-hydroxy-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-fluorophenyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 4-methoxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-methylphenyl)-4-(2-methylpropoxy)-1 ,3-thiazole-5-carboxylate; ethyl 4-(benzyloxy)-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(3-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate;ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5-carboxylate; ethyl 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylate; ethyl 4-(2-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)acetoyloxy)-2-(4- methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(benzylcarbamoyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-(2-aminoethoxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{2-[(furan-2-ylmethyl)amino]ethoxy}-1 ,3-thiazole-5- carboxylate;4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylic acid;4-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-(benzyloxy)-2-phenyl-1 ,3-thiazole-5-carboxylic acid;4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-phenyl-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;4-[(2-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid;2-phenyl-4-{[4-(trifluoromethyl)benzyl]oxy}-1 ,3-thiazole-5-carboxylic acid;2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzyl]oxy}-1 ,3-thiazole-5-carboxylicacid;2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5-carboxylic acid;2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylic acid;2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-thiazole-5- carboxylic acid;4-methoxy-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid;2-(4-methylphenyl)-4-(2-methylpropoxy)-1 ,3-thiazole-5-carboxylic acid; ethyl 4-[(tert-butoxycarbonyl)amino]-2-(4-fluorophenyl)-1 ,3-thiazole-5- carboxylate; ethyl 4-amino-2-(4-fluorophenyl)-1 ,3-thiazole-5-carboxylate hydrochloride; ethyl 4-(acetylamino)-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-methylphenyl)-4-[(phenylcarbamoyl)amino]-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(methylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(propylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1 ,3-thiazole-5- carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-[2'-(trifluoromethyl)biphenyl-4-yl]-1 ,3- thiazole-5-carboxylate; ethyl 4-[(2-aminoethyl)amino]-2-[2'-(trifluoromethyl)biphenyl-3-yl]-1 ,3- thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-{[2-(cyclopentylamino)ethyl]amino}-1 ,3-thiazole-5- carboxylate; ethyl 2-phenyl-4-{[2-(pyrrolidin-1 -yl)ethyl]amino}-1 ,3-thiazole-5-carboxylate; ethyl 4-(benzylamino)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; ethyl 4-[(1 ,3-benzodioxol-5-ylmethyl)amino]-2-(3-fluorophenyl)-1 ,3-thiazole-5- carboxylate;ethyl 2-(3-fluorophenyl)-4-[(pyridin-3-ylmethyl)amino]-1 ,3-thiazole-5- carboxylate; 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid; 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylic acid; 4-[(2-aminoethyl)amino]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylic acid; sodium 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-thiazole-5- carboxylate; sodium 4-(4-chlorobenzyloxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(4-chlorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(4-methylphenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(2-chlorobenzyloxy)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; sodium 4-(4-chlorobenzyloxy)-2-(3-fluorophenyl)-1 ,3-thiazole-5-carboxylate; (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-(benzyloxy)-2-(4- methylphenyl)-1 ,3-thiazole-5-carboxylate; (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-hydroxy-2-(4-methylphenyl)- 1 ,3-thiazole-5-carboxylate; ethyl 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxylate; 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxylic acid; 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carboxamide; 2-(4-chlorophenyl)-4-(methoxymethoxy)-1 ,3-thiazole-5-carbonitrile; 2-(4-chlorophenyl)-5-(1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol; 2-(4-chlorophenyl)-5-(1 -methyl-1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol; 2-(3-fluorophenyl)-5-(1 -methyl-1 H-tetrazol-5-yl)-1 ,3-thiazol-4-ol; 2-(4-chlorophenyl)-5-(5-methyl-4H-1 ,2 ,4-triazol-3-yl)-1 ,3-thiazol-4-ol; 2-(3-fluorophenyl)-5-(5-methyl-4H-1 ,2 ,4-triazol-3-yl)-1 ,3-thiazol-4-ol; 2-(4-chlorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-4-ol;2-(3-fluorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-4-ol;3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-thiazol-5-yl}-5-methyl-1 ,2,4- oxadiazole;2-(4-chlorophenyl)-5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3-thiazol-4-ol; 2-(3-fluorophenyl)-5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 ,3-thiazol-4-ol; ethyl 4-hydroxy-2-phenyl-1 ,3-oxazole-5-carboxylate;ethyl 2-(3-fluorophenyl)-4-hydroxy-1 ,3-oxazole-5-carboxylate; ethyl 4-hydroxy-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazole-5-carboxylate; ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylate; ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1 ,3-oxazole-5-carboxylate;4-[(4-chlorobenzyl)oxy]-2-phenyl-1 ,3-oxazole-5-carboxylic acid;4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazole-5-carboxylic acid;4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1 ,3-oxazole-5-carboxylic acid;2-(3-fluorophenyl)-5-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,3-oxazol-4-ol;3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1 ,3-oxazol-5-yl}-5-methyl-1 ,2,4- oxadiazole; ethyl 2-(3-fluorophenyl)-5-hydroxy-1 ,3-thiazole-4-carboxylate; and 2-(3-fluorophenyl)-5-(2-ethyl-2H-tetrazol-5-yl)-1 ,3-thiazol-4-ol, also known as DFL23448.

12. A TRPM8 inhibitor for use according to claim 10, wherein said compound of formula (III) is selected from:1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one; sodium 2-(3-fluorophenyl)-5-propanoyl-1 ,3-thiazol-4-olate, also known as DFL23693;2-(3-fluorophenyl)-4-hydroxy-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;1-(2-(3-fluorophenyl)-4-hydroxythiazol-5-yl)ethenone;1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-2-methylpropan-1 -one;4-hydroxy-N-methoxy-N-methyl-2-(thiophen-2-yl)-1 ,3-thiazole-5-carboxamide;1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]propan-1 -one;4-hydroxy-N-methoxy-N-methyl-2-(2-methylphenyl)-1 ,3-thiazole-5-carboxamide;1 -[4-hydroxy-2-(2-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;2-(2-bromophenyl)-4-hydroxy-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;1 -[2-(2-bromophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;4-hydroxy-2-(2-hydroxyphenyl)-N-methoxy-N-methyl-1 ,3-thiazole-5-carboxamide;1 -[2-(2-hydroxyphenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -[2-(3-bromophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -[2-(furan-2-yl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(1 H-pyrrol-2-y l)-1 ,3-thiazol-5-yl]propan-1 -one;801 -[4-hydroxy-2-(1 -methyl-1 H-pyrrol-2-y l)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(1 -methyl-1 H-imidazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(1 H-imidazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(1 -methyl-1 H-pyrazol-4-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]butan-1 -one;1 -[4-hydroxy-2-(thiophen-2-yl)-1 ,3-thiazol-5-yl]-3-methylbutan-1 -one;1 -[4-hydroxy-2-(1 ,2,4-oxadiazol-3-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(1 ,2-oxazol-5-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(pyridin-3-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(pyridin-4-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(pyridin-2-yl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(3-hydroxyphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(4-hydroxyphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(3-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[4-hydroxy-2-(4-methylphenyl)-1 ,3-thiazol-5-yl]propan-1 -one;1 -[2-(3-aminophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -[2-(4-aminophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -{4-hydroxy-2-[3-(methylamino)phenyl]-1 ,3-thiazol-5-yl}propan-1 -one;1 -{4-hydroxy-2-[4-(methylamino)phenyl]-1 ,3-thiazol-5-yl}propan-1 -one;1 -[2-(4-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propan-1 -one;1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]butan-1 -one;1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-3-methylbutan-1 -one;1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]-2-methoxyethanone;1 -[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl]propane-1 -thione;2-(3-fluorophenyl)-4-hydroxy- / V-methoxy- / \ / -methyl-1 ,3-thiazole-5-carbothioamide;2-(3-fluorophenyl)-5-[(1 E)-N-methoxypropanimidoyl]-1 ,3-thiazol-4-ol;2-(3-fluorophenyl)-5-propanimidoyl-1 ,3-thiazol-4-ol; and2-(3-fluorophenyl)-5-[(1 E)-N-hydroxypropanimidoyl]-1 ,3-thiazol-4-ol.

13. A TRPM8 inhibitor for use according to claim 10, wherein said compound of formula (IV) is selected from:[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23877, or the sodium salt thereof, also known as DFL24072; [4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,2-oxazolidin-2-yl)methanone, also known as DFL23880, or the sodium salt thereof, also known as DFL24080;81[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,3-oxazolidin-3-yl)methanone;[4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,3-oxazolidin-3-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](oxolan-2-yl)methanone;[4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](oxolan-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyrrolidin-1-yl)methanone;[4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,2-oxazinan-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazinan-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,3-oxazinan-3-yl)methanone;[4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](1 ,3-oxazinan-3-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](morpholin-4-yl)methanone;[4-hydroxy-2-(2-hydroxyphenyl)-1 ,3-thiazol-5-yl](morpholin-4-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](piperidin-1-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyrrolidin-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1-methylpyrrolidin-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 H-pyrrol-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 -methyl-1 H-pyrrol-2- yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](furan-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](thiophen-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-pyrrol-1 -yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-3-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](pyridin-4-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-imidazol-1 -yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-pyrazol-1 -yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](1 ,2-oxazepan-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](5-oxa-6-azaspiro[2.4]heptan-6- yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](5-methyl-1 ,2-oxazolidin-2- yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 ,3-thiazol-5-yl](hexahydro-2H- cyclopenta[d][1 ,2]oxazol-2-yl)methanone;[2-(3-fluorophenyl)-4-hydroxy-1 , 3-thiazol-5-y l]( 1 H-1 , 2, 3-triazol-1 -yl)methanone; and82[2-(3-fluorophenyl)-4-hydroxy-1 , 3-th iazol-5-y l]( 1 -methyl-1 H-tetrazol-5- yl)methanone.

14. The TRPM8 inhibitor for use according to any one of the preceding claims, wherein said TRPM8 inhibitor is administered by intra-articular injection to the subject.

15. The TRPM8 inhibitor for use according to any one of claims 1 -13, wherein said TRPM8 inhibitor is administered orally to the subject.

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