Uses of NMN for the Prevention and / or Treatment of Pain and Corresponding Compositions

Abstract

The present invention relates to nicotinamide mononucleotide, its pharmaceutically acceptable precursors, its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts for use in the prevention and / or treatment of pain, in particular nociceptive pain, and the invention also relates to compositions containing them.

Description

[Technical Field]

[0001] The present invention relates to the use of nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of pain, particularly nociceptive pain. The present invention also relates to a composition comprising NMN, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of pain, particularly nociceptive pain. [Background technology]

[0002] Pain can be both a symptom and a disease. Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with or resembling actual or potential tissue damage" (see definition at the following link, updated December 14, 2017): https: / / www.iasp-pain.org / Education / Content.aspx?ItemNumber=1698&navItemNumber=576#Pai). Pain is information processed by the nervous system.

[0003] The nervous system of mammals, such as humans, has two main parts: -The central nervous system consists of the brain (cerebellum), brainstem, cerebellum and spinal cord. The role of the central nervous system is to receive, register and interpret signals coming from the peripheral nervous system. -The peripheral nervous system consists of the cranial and spinal nerves attached to the central nervous system and their corresponding terminals. The role of the peripheral nervous system is to (i) transmit information received by peripheral sensitivity and pain receptors to the central nervous system, and (ii) transmit commands sent by the central nervous system, especially to muscles.

[0004] Pain is a complex phenomenon and can therefore be classified in various ways. There are three main categories of pain: nociceptive pain, neuropathic pain, and central pain (also known as central sensitization).

[0005] Nociceptive pain or peripheral pain is caused by the activation of nociceptors. Nociceptors are receptors located at the end of nerve fibers. In the case of nociceptive pain, the nervous system is not affected. Nociceptive pain can be induced by various different stimuli, such as mechanical stimuli, heat stimuli, chemical stimuli, inflammatory diseases or infectious diseases. An example of nociceptive pain that can be mentioned is the pain caused by burning skin.

[0006] Neuropathic pain is caused by lesions to the nerves of the peripheral nervous system. An example that may be mentioned is diabetic neuropathic pain.

[0007] Central pain results from a disruption in the processing of pain by the central nervous system. Examples that may be mentioned include fibromyalgia or phantom limb pain.

[0008] In contrast, migraine is a different pain category from these three aforementioned categories and therefore currently constitutes a separate category.

[0009] It should also be clarified that these pain categories are not mutually exclusive, and patients may experience a variety of different types of pain simultaneously. Indeed, in cases of major injury, cancer, or infectious disease, the lesion may involve both the tissues and nerves present within the organ.

[0010] Nociceptive pain generally responds readily to conventional analgesic treatment. The World Health Organization classifies analgesics into three categories based on their efficacy: Substances that help to reduce pain are classified as analgesics.

[0011] Level I analgesics are intended to treat mild to moderate pain and include aspirin, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, and tenoxicam. NSAIDs are so named to distinguish them from steroidal anti-inflammatory drugs, or corticosteroids, which are derived from cortisol, a hormone released during the stress response. Examples of corticosteroids include betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, and triamcinolone.

[0012] Level II analgesics are intended to treat moderate or severe pain, or pain for which Level I analgesics provide inadequate relief, and include codeine, dihydrocodeine, and tramadol, alone or in combination with aspirin or paracetamol.

[0013] Level III analgesics are intended to treat severe pain that is resistant to other analgesics and include morphine and other opiate derivatives such as buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone and pethidine.

[0014] However, none of these treatments are without harmful side effects. For example, the use of NSAIDs can cause various adverse effects, such as bleeding, asthma, kidney problems, and, more frequently, stomach problems and ulcers. Paracetamol can lead to liver toxicity. Aspirin thins the blood and attacks the stomach. Corticosteroids lead to corticosteroid dependence, which leads to weight gain, weakened immune defenses, weakened bones, and reduced effectiveness. Codeine, dihydrocodeine, and tramadol induce various adverse effects, the most common of which are nausea, vomiting, constipation, drowsiness, and drug dependence. As for morphine and opium derivatives, they induce significant adverse effects, particularly a high risk of physical and psychological dependence. Furthermore, morphine overdose can block respiratory muscles and prove fatal.

[0015] Finally, certain patients may develop allergies to conventional pain medications. Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, there is a need to develop new compositions for the treatment and / or prevention of pain that help alleviate the shortcomings of prior art analgesics. [Means for solving the problem]

[0017] These objectives are achieved thanks to nicotinamide mononucleotide (NMN) and compositions comprising it for use in the prevention and / or treatment of pain.

[0018] The present invention relates to nicotinamide mononucleotide (NMN), a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of pain.

[0019] Advantageously, NMN is used in an amount comprised between 0.01 mg / kg / day and 1000 mg / kg / day, preferably between 1 mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, and even more preferably between 10 mg / kg / day and 20 mg / kg / day.

[0020] In one embodiment, the NMN derivative is alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted as NMN-H), a compound of formula (I): [ka] or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable crystal thereof, -X is selected from among O, CH2, S, Se, CHF, CF2 and C=CH2; R1 is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl, and OR; wherein R is selected from H and (C1-C8) alkyl; R2, R3, R4 and R5 are independently H, halogen, azide, cyano, hydroxyl, (C1-C 12 ) alkyl, (C1-C 12 ) thioalkyl, (C1-C 12 ) heteroalkyl, (C1-C 12 ) haloalkyl and OR; wherein R is selected from H, (C1-C 12 ) alkyl, C(O)(C1-C 12 ) alkyl, C(O)NH(C1-C 12 ) alkyl, C(O)O(C1-C 12 ) alkyl, C(O) aryl, C(O)(C1-C 12 ) alkylaryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 ) alkylaryl and C(O)CHR AA NH2;AA is a side chain selected from proteinogenic amino acids; R6 is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl, and OR; wherein R is selected from H and (C1-C8) alkyl; -R7 is H, P(O)R9R 10 , and P(S)R9R 10 wherein: -R9 and R 10 are independently OH, OR 11 , NHR 13 , N.R. 13 R 14 , (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C 10 ) cycloalkyl, (C5-C 12 )aryl, (C1-C8)alkylaryl, (C1-C8)arylalkyl, (C1-C8)heteroalkyl, (C1-C8)heterocycloalkyl, heteroaryl, and NHCHR A R A´ C(O)R 12 wherein: -R 11 is (C1~C 10 ) Alkyl, (C3-C 10 ) cycloalkyl, (C5-C 18 ) aryl, (C1-C 10 ) Alkylaryl, substituted (C5-C 12 ) aryl, (C1-C 10 ) heteroalkyl, (C3-C 10 ) heterocycloalkyl, (C1-C 10 ) haloalkyl, heteroaryl, -(CH2) n C(O)(C1~C 15 ) alkyl, -(CH2) n OC(O)(C1~C 15 ) alkyl, -(CH2) n OC(O)O(C1~C 15 ) alkyl, -(CH2) n SC(O)(C1~C 15) alkyl, -(CH2) n C(O)O(C1~C 15 ) alkyl, and -(CH2) n C(O)O(C1~C 15 ) alkylaryl (wherein n is an integer selected from 1 to 8), P(O)(OH)OP(O)(OH); halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R 11a )2, C1-C6 acylamino, -COR 11b , -OCOR 11b ;NHSO2(C1-C6 alkyl), -SO2N(R 11a )2SO2(wherein, R 11a are each independently selected from H and (C1-C6) alkyl; 11b is selected from among OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; -R 12 H, C1~C 10 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 Haloalkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 18 Aryl, C1-C4 alkylaryl, and C5-C 12 heteroaryl; said aryl or heteroaryl group is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; and -R A and R A´ are independently H, (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) thioalkyl, (C1-C 10 ) hydroxyl alkyl, (C1-C 10 ) alkylaryl, and (C5-C12 ) Aryl, (C3-C 10 ) heterocycloalkyl, heteroaryl, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, a side chain selected from among proteinogenic or non-proteinogenic amino acids; the aryl group is selected from hydroxyl, (C1-C 10 ) optionally substituted with a group selected from alkyl, (C6-C1)alkoxy, halogen, nitro, and cyano; or -R9 and R 10 together with the phosphorus atom to which they are attached, form -R9-R 10 - represents -CH2-CH2-CHR-, forming a 6-membered ring; where R is selected from H, a (C5-C6)aryl group and a (C5-C6)heteroaryl group, said aryl or heteroaryl group being optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano; or R9 and R 10 together with the phosphorus atom to which they are attached, form -R9-R 10 - represents -O-CH2-CH2-CHR-O-, forming a 6-membered ring; wherein R is selected from H, a (C5-C6)aryl group, and a (C5-C6)heteroaryl group, said aryl group or heteroaryl group being optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, and cyano; -R8 is H, OR, NHR 13 , N.R. 13 R 14 , NH-NHR 13 , SH, CN, N3 and halogen; 13 and R 14 is H, (C1-C8) alkyl, (C1-C8) alkylaryl and -CR B R C -C(O)-OR D wherein R B and R Care independently a hydrogen atom, a (C1-C6) alkyl, a (C1-C6) alkoxy, a benzyl, an indolyl, or an imidazolyl; the (C1-C6) alkyl and the (C1-C6) alkoxy may be optionally substituted independently of one another by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl groups, and the benzyl group is optionally substituted by one or more halogen or hydroxyl groups; or R B and R C together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group optionally substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl; R D is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl; -Y is selected from among CH, CH2, C(CH3)2 and CCH3; - [ka] represents a single or double bond along Y; - [ka] is the alpha or beta anomer depending on the position of R1; or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof); or Formula (II): [ka] or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof, wherein -X'1 and X'2 are independently selected from O, CH2, S, Se, CHF, CF2, and C=CH2; R'1 and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR, where R is selected from H and C1-C8 alkyl; -R´2, R´3, R´4, R´5, R´9, R´ 10 , R´ 11 , R´ 12 H, halogen, azide, cyano, hydroxyl, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Heteroalkyl, C1-C 12 haloalkyl and OR; wherein R is H, C1-C 12 Alkyl, C(O)(C1-C 12 ) alkyl, C(O)NH(C1-C 12 ) alkyl, C(O)O(C1-C 12 ) alkyl, C(O) aryl, C(O)(C1-C 12 ) aryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 ) alkylaryl or C(O)CHR AA NH groups; AA is a side chain selected from proteinogenic amino acids; R'6 and R'8 are independently selected from H, azido, cyano, C1-C8 alkyl, and OR, where R is selected from H and C1-C8 alkyl; -R´7 and R´ 14 are independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N3, and halogen; wherein R and R' are independently selected from H and (C1-C8) alkylaryl; -Y'1 and Y'2 are independently selected from CH, CH2, C(CH3)2 or CCH3; -M' is selected from H or a suitable counterion; - [ka] represents a single or double bond depending on Y'1 and Y'2; - [ka] is R´1 and R´ 13 represents the alpha or beta anomer depending on the position of and combinations thereof.

[0021] In a first preferred embodiment, the pharmaceutically acceptable derivative is a compound having formula (I).

[0022] In one variation of the first embodiment, X represents oxygen.

[0023] In one variation of the first embodiment, R1 and R6 each independently represent hydrogen.

[0024] In one variant of the first embodiment, R2, R3, R4 and R5 each independently represent hydrogen or OH.

[0025] In one variant of the first embodiment, Y represents CH.

[0026] In one variant of the first embodiment, Y represents CH2.

[0027] In one variant of the first embodiment, R7 represents hydrogen.

[0028] In one variant of the first embodiment, R7 represents P(O)(OH)2.

[0029] In one variation of the first embodiment, X represents oxygen; and / or R1 and R6 each independently represent hydrogen; and / or R2, R3, R4 and R5 each independently represent hydrogen, or R2, R3, R4 and R5 independently represent OH; and / or Y represents CH or CH; and / or R7 is P(O)R9R 10 wherein R9 and R 10 OH, OR 11 , NHR 13 , N.R. 13 R 14 , C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C5-C 12 Aryl, C1-C8 arylalkyl, C1-C8 alkylaryl, C1-C8 heteroalkyl, C1-C8 heterocycloalkyl, heteroaryl, and NHCR A R A´ C(O)R 12 are independently selected from

[0030] In one particularly preferred variant of the first embodiment, the compound of the invention is selected from among the compounds having formulae IA to IH.

[0031] [Table 1]

[0032] In a second preferred embodiment, the pharmaceutically acceptable derivative is a compound having formula (II).

[0033] In one variation of the second embodiment, X'1 and X'2 each independently represent oxygen.

[0034] In one variation of the second embodiment, R'7 and R'14 each independently represent NH2.

[0035] In one variation of the second embodiment, R'1 and / or R'13 each independently represent hydrogen.

[0036] In one variation of the second embodiment, R'6 and / or R'8 each independently represent hydrogen.

[0037] In one variation of the second embodiment, R'2, R'3, R'4, R'5, R'9, R'10, R'11, and R'12 each independently represent hydrogen.

[0038] In one variation of the second embodiment, R'2, R'3, R'4, R'5, R'9, R'10, and R'11 each independently represent OH.

[0039] In one variation of the second embodiment, Y'1 and Y'2 each independently represent CH.

[0040] In one variation of the second embodiment, Y'1 and Y'2 each independently represent CH2.

[0041] In one variant of the second embodiment, the compound according to the invention is selected from among compounds having formulae II-A to II-F.

[0042] [Table 2]

[0043] In one variation of the first preferred embodiment, the pharmaceutically acceptable derivative is alpha-NMN, which has the formula:

[0044] [ka]

[0045] In a fourth preferred embodiment, the pharmaceutically acceptable derivative is NMN-H.

[0046] [ka]

[0047] Advantageously, the pharmaceutically acceptable precursor is nicotinamide riboside (denoted NR):

[0048] [ka] or dihydronicotinamide riboside (written as -NR-H) having the formula: [ka]

[0049] Advantageously, nicotinamide mononucleotide (NMN), its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt may be administered via various routes: oral, ocular, sublingual, parenteral, transdermal, vaginal, epidural, intravesical, rectal, or inhalation.

[0050] Preferably, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt is administered via oral or parenteral routes.

[0051] Advantageously, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt is used for the treatment and / or prevention of pain in a mammal, preferably a human.

[0052] In a preferred embodiment, the pain is nociceptive pain.

[0053] In a preferred embodiment, the pain is not neuropathic pain.

[0054] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used to reduce allodynia.

[0055] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used to reduce hyperalgesia.

[0056] Advantageously, the pain is visceral pain.

[0057] Advantageously, the pain is pain of the urogenital (or genitourinary) system.

[0058] Advantageously, the pain is pain caused by a urinary tract infection.

[0059] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used in combination with at least one other therapeutic agent.

[0060] Advantageously, the at least one additional therapeutic agent is selected from among antibiotics, antifungals, antivirals, and combinations thereof.

[0061] Advantageously, at least one therapeutic agent is an analgesic.

[0062] Advantageously, the analgesic is selected from among paracetamol, aspirin, non-steroidal anti-inflammatory drugs, cortisone derivatives, and combinations thereof.

[0063] Advantageously, the non-steroidal anti-inflammatory drug is selected from among ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam, and combinations thereof.

[0064] Advantageously, the cortisone derivative is chosen from among betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone, and combinations thereof.

[0065] Advantageously, the analgesic is chosen from codeine, dihydrocodeine, tramadol, and combinations thereof.

[0066] Advantageously, the analgesic is selected from morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and combinations thereof.

[0067] The present invention also relates to a composition comprising nicotinamide mononucleotide, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for its use in the prevention and / or treatment of pain as described above.

[0068] Advantageously, the composition according to the invention is in the form of a tablet, capsule, sachet, granule, soft capsule, lozenge, lyophilisate, suspension, gel, syrup, solution, water / oil emulsion, oil / water emulsion, oil, cream, milk, spray, ointment, ampoule, suppository, eye drops, vaginal suppository, vaginal capsule, liquid for inhalation, dry powder inhaler, pressurised metered dose inhaler.

[0069] Preferably, the compositions according to the invention are in the form of gastro-resistant capsules or sublingual tablets.

[0070] Advantageously, the composition according to the invention is a pharmaceutical composition.

[0071] Advantageously, the composition according to the invention is a dietary supplement.

[0072] The present invention also relates to a composition comprising nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient, and at least one additional therapeutic agent for its use in the prevention and / or treatment of pain as described above.

[0073] definition In the present invention, the following terms have the following meanings:

[0074] Unless otherwise specified, the nomenclature of substituents not explicitly defined in this invention is obtained by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment.

[0075] "Alkyl," by itself or as part of another substituent, refers to a hydrocarbyl group having the formula CH, where n is a number equal to or greater than 1. Generally, alkyl groups of the present invention contain 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 2 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as indicated herein. Alkyl suitable for the purpose of implementing the present invention can be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl; pentyl and its isomers, such as n-pentyl and iso-pentyl; and hexyl and its isomers, such as n-hexyl and iso-hexyl; heptyl and its isomers (e.g., n-heptyl, iso-heptyl); octyl and its isomers (e.g., n-octyl, iso-octyl); nonyl and its isomers (e.g., n-nonyl, iso-nonyl); decyl and its isomers (e.g., n-decyl, iso-decyl); undecyl and its isomers; dodecyl and its isomers. Preferably, the alkyl group can be selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.Saturated and branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl The alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl. Cx-Cy-alkyl refers to an alkyl group containing x to y carbon atoms.

[0076] The suffix "ene" ("alkylene"), when used in conjunction with an alkyl group, indicates that the alkyl group, as defined herein, has two single bonds as its points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.

[0077] The term "alkenyl," as used herein, refers to an unsaturated hydrocarbyl group containing one or more carbon-carbon double bonds, which may be straight-chain or branched. Suitable alkenyl groups contain 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and other similar groups.

[0078]

[0067] The term "alkynyl," as used herein, refers to a class of monovalent unsaturated hydrocarbyl groups, in which the unsaturation results from the presence of one or more carbon-carbon triple bonds. Alkynyl groups generally and preferably have the same number of carbon atoms as described herein above for alkenyl groups. Without limitation, some examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, and the like.

[0079] "Alkoxy" refers to an alkyl group, as defined herein above, that is bonded to another moiety via an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and the like. An alkoxy group may be optionally substituted with one or more substituents. The alkoxy group contained in the compound of the present invention may be optionally substituted with a solubilizing group.

[0080] "Aryl," as used herein, refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked, generally containing 5 to 18 atoms, preferably 5 to 12 atoms, and more preferably 6 to 10 atoms, wherein at least one of the rings is aromatic. The aromatic ring may optionally contain one or two additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Examples of aryl include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl; 4-, 5-, 6- or 7-indenyl; 1-, 2-, 3-, 4-, or 5-acenaphthylenyl; 3-, 4-, or 5-acenaphthenyl; 1- or 2-pentalenyl; 4- or 5-indanyl; 5-, 6-, 7-, or 8-tetrahydronaphthyl; 1,2,3,4-tetrahydronaphthyl; 1,4-dihydronaphthyl; and 1-, 2-, 3-, 4-, or 5-pyrenyl.

[0081] When at least one carbon atom in an aryl group is replaced with a heteroatom, the resulting ring is referred to herein as a "heteroaryl" ring.

[0082] "Alkylaryl" refers to an aryl group substituted with an alkyl group.

[0083] "Amino acid" refers to an alpha-aminocarboxylic acid, ie, a molecule containing a carboxylic acid functional group and an amino functional group in the alpha position of the carboxylic acid group, eg, a proteinogenic or non-proteinogenic amino acid.

[0084] "Proteinogenic amino acid" refers to an amino acid that is incorporated into protein during translation of messenger RNA by ribosomes in vivo, i.e., alanine (ALA), arginine (ARG), asparagine (ASN), aspartate (ASP), cysteine ​​(CYS), glutamate (glutamic acid) (GLU), glutamine (GLN), glycine (GLY), histidine (HIS), isoleucine (ILE), leucine (LEU), lysine (LYS), methionine (MET), phenylalanine (PHE), proline (PRO), pyrrolysine (PYL), selenocysteine ​​(SEL), serine (SER), threonine (THR), tryptophan (TRP), tyrosine (TYR), or valine (VAL).

[0085] "Non-proteinogenic amino acid," as used herein, refers to an amino acid that is not naturally encoded or found in the genetic code of an organism. Some non-limiting examples of non-proteinogenic amino acids are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, δ-aminolevulinic acid, β-alanine, cystathionine, γ-aminobutyric acid, dihydroxyphenylalanine (DOPA), 5-hydroxytryptophan, D-serine, ibotenic acid, α-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine, and D-glutamate.

[0086] The term "cycloalkyl," as used herein, refers to a cyclic alkyl group having one or two ring structures, i.e., a monovalent saturated or unsaturated hydrocarbyl group. The term "cycloalkyl" includes monocyclic and bicyclic hydrocarbyl groups. Cycloalkyl groups may contain three or more carbon atoms in the ring, and generally, according to the present invention, contain 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, with cyclopropyl being particularly preferred.

[0087] The term "pharmaceutically acceptable excipient" refers to an inert carrier or support substance used as a vehicle or diluent in which an active ingredient is formulated and / or administered and which does not cause adverse allergic or other reactions when administered to animals, preferably humans. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, absorption delaying agents, and other similar ingredients. For human administration, formulations must meet specific standards of sterility, general safety, and purity as required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Within the meaning of the present invention, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients and all pharmaceutically acceptable carriers, diluents, and / or adjuvants.

[0088] "Halogen" or "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

[0089] "Haloalkyl", alone or in combination, refers to an alkyl group having the meaning as defined herein above, in which one or more hydrogen atoms are replaced by halogen as defined herein above. Examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and similar groups. "Cx-Cy-haloalkyl" and "Cx-Cy-alkyl" refer to alkyl groups containing x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

[0090] "Heteroalkyl" refers to an alkyl group as defined herein above, in which one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen, and sulfur atoms. In heteroalkyl groups, heteroatoms are bonded only to carbon atoms along the alkyl chain, i.e., each heteroatom is separated from all other heteroatoms by at least one carbon atom. However, nitrogen and sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized. Heteroalkyl is bonded to another group or molecule only by carbon atoms, i.e., the bonded atom is not selected from the heteroatoms contained in the heteroalkyl group.

[0091] The term "heteroaryl," as used herein, alone or as part of another group, refers, but is not limited to, an aromatic ring of 5 to 12 carbon atoms or a ring system containing one or two fused or covalently linked rings, generally containing 5 or 6 atoms, at least one of which is aromatic, wherein one or more carbon atoms in one or more of the rings are replaced by oxygen, nitrogen, and / or sulfur atoms, and wherein the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. These rings may be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl ring.Some examples of such heteroaryls include, but are not limited to, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl. , indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzisothiazolyl Examples include benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0092] When at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resulting ring is referred to herein as a "heterocycloalkyl" or "heterocyclyl."

[0093] The terms "heterocyclyl," "heterocycloalkyl," or "heterocyclo," as used herein by themselves or as part of another group, refer to a fully saturated or partially unsaturated (e.g., 3- to 7-membered monocyclic group, 7- to 11-membered bicyclic group, or a total of 3 to 10 ring atoms) non-aromatic cyclic group having at least one heteroatom in at least one ring containing carbon atoms. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms; the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Any carbon atom of a heterocyclic group may be substituted with oxo (e.g., piperidone, pyrrolidinone). A heterocyclic group may be attached to any heteroatom or carbon atom in the ring or ring system, valence permitting. The rings of a polycyclic heterocycle may be fused, bridged, and / or bonded / linked by one or more spiro atoms.Exemplary heterocyclic groups include, but are not limited to, the following groups: oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5 ... Oximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

[0094] The term "precursor," as used herein, also refers to a pharmacologically acceptable derivative, e.g., an ester, of a compound having formula (I) or (II), the in vivo biotransformation product of which is an active drug. Precursors are characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Precursors suitable for the purposes of the present invention include, in particular, carboxylic acid esters, particularly alkyl esters, aryl esters, acyloxyalkyl esters, and carboxylic acid esters of dioxolenes; ascorbic acid esters.

[0095] "Pharmaceutically acceptable" refers to a substance that has been approved or potentially approved by a regulatory agency for use in animals, more preferably humans, or that is listed in a recognized pharmacopoeia. It can refer to a substance that is not biologically or otherwise undesirable, i.e., the substance can be administered to an individual without causing adverse biological effects or adverse interactions with one of the components of the composition in which it is contained. Preferably, a "pharmaceutically acceptable" salt or excipient refers to any salt or any excipient approved by the European Pharmacopoeia (written as "Ph.Eur.") and the United States Pharmacopoeia (called "United States Pharmacopeia (USP)" in English).

[0096] The term "active ingredient" refers to a molecule or substance that, when administered to a subject, slows or stops the progression, severity, or worsening of one or more symptoms of a disease or condition; alleviates the symptoms of a disease or condition; or cures a disease or condition. According to one of these embodiments, the therapeutic component is a natural or synthetic small molecule. According to another embodiment, the therapeutic component is a biological molecule, such as, for example, an oligonucleotide, small interfering RNA (siRNA), microRNA (miRNA), DNA fragment, aptamer, antibody, etc. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts of these salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples which may be cited include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, iodine ... Examples of suitable base salts include hydroxybenzoates, ... Preferred pharmaceutically acceptable salts are hydrochloride / chloride, bromide / hydrobromide, bisulfate / sulfate, nitrate, citrate and acetate salts.

[0097] Pharmaceutically acceptable salts may be prepared by one or more of the following methods: i. by reacting the compound with the desired acid; ii. By reacting the compound with a desired base; iii. by removing an acid- or base-labile protecting group from a suitable precursor of the compound under basic or acidic conditions using the desired acid, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam; or iv. By converting one salt of the compound to another by reacting the initial salt with a suitable acid or by using a suitable ion exchange column.

[0098] All of these reactions are generally carried out in solution. The salt can be precipitated from the solution and recovered by filtration or by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0099] The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

[0100] The term "substituent" or "substituted" indicates that a hydrogen radical on a compound or group may be replaced by any desired group that is substantially stable under the reaction conditions, either in unprotected form or when protected by a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl as described above; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amide; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be fused or non-fused monocyclic or polycyclic; or heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), which may be fused or non-fused monocyclic or polycyclic; aryl or heteroaryl (e.g., aryl, heteroaryl ... aryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); fused or non-fused monocyclic or polycyclic (e.g., aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl and benzofuranyl; amino (primary, secondary, or tertiary); COCH; CONH; OCHCONH; NH; SONH; OCHF; FC; OCF, which may be optionally substituted with a fused ring bridge or structure, such as —OCHO—. These substituents may be optionally further substituted with a substituent selected from this group.In certain instances, the term "substituent" or the adjective "substituted" refers to any group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR. 11 R 12 , -NR 13 C(O)R 14 , halo, -OR 13 , cyano, nitro, haloalkoxy, -C(O)R 13 , -NR 11 R 12 , -SR 13 , -C(O)OR´ 13 , -OC(O)R 13 , -NR 13 C(O)NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 13 C(O)OR 14 , -S(O)rR13, -NR 13 S(O)rR 14 , -OS(O)rR 14 , S(O)rNR 11 R 12 , -O, -S, and -NR 13 where r is 1 or 2; R 11 and R 12 is, for each occurrence, independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 11 and R 12 together with the nitrogen to which they are attached, are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R 13 and R 14is, for each occurrence, independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain variations, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0101] The term "administration" or variations of this term (e.g., "administering") refers to providing an active ingredient, whether alone or as part of a pharmaceutically acceptable composition, to a recipient patient in connection with the treatment or prevention of a condition, symptom, or disease.

[0102] The terms "treat," "cure," and "treatment," as used herein, are intended to include the alleviation, alleviation, or elimination of a condition, or disease and / or its associated symptoms.

[0103] The terms "prevent," "hinder," and "prevention," as used herein, refer to methods that serve the purpose of delaying or hindering or preventing the onset of a condition, or disease and / or its associated symptoms; preventing a patient from contracting a condition or disease; or reducing a patient's risk of contracting a given disease or condition.

[0104] Asymmetric carbon bonds are represented herein by solid triangles [ka] , dotted triangle [ka] , or zigzag lines [ka] It can be expressed using: DETAILED DESCRIPTION OF THE INVENTION

[0105] Detailed Description of the Invention The subject of the present invention relates to nicotinamide mononucleotide (NMN), its pharmaceutically acceptable precursors, its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts for use in the prevention and / or treatment of pain.

[0106] The subject of the present invention also relates to a composition comprising nicotinamide mononucleotide (NMN), a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for its use in the prevention and / or treatment of pain as described above.

[0107] Nicotinamide adenine dinucleotide (NAD) is a coenzyme present in all living cells. NAD exists within cells as either the oxidized form NAD+ or the reduced form NADH. NAD's role is as an electron carrier involved in metabolic redox reactions. Furthermore, NAD is involved in several cellular processes, such as adenosine diphosphate (ADP) ribosylation, which is involved in post-translational modification of proteins.

[0108] NAD can be synthesized de novo by cells from amino acids such as tryptophan or aspartate. However, such synthesis is limited because the primary pathway for NAD synthesis is the salvage pathway, whereby cells, and primarily the cell nucleus, recycle compounds to regenerate NAD from precursors. Precursors of NAD include niacin, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide.

[0109] NMN is one of the compounds that enables the synthesis of NAD through the salvage pathway and has the formula:

[0110] [ka]

[0111] The present inventors have demonstrated that the use of NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention makes it possible to obtain an effect on pain comparable to that of commonly used pharmaceuticals for treating pain. More precisely, the use of NMN according to the present invention and the composition according to the present invention provides a means for reducing the intensity of pain generated in response to pain stimuli, and therefore provides the ability to prevent pain. The use of NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention is also effective in treating existing pain.

[0112] Furthermore, the use of NMN, a molecule naturally occurring in the body, has many advantages.In particular, the NMN and compositions of the present invention are well tolerated by patients.The use of NMN and compositions of the present invention does not actually induce allergies in patients.Furthermore, the use of NMN and compositions of the present invention does not induce harmful side effects, such as ulcers, liver toxicity, anticoagulation, drowsiness, nausea and vomiting, which are frequently encountered with conventional analgesics.

[0113] Furthermore, unlike analgesics containing morphine or opium derivatives, NMN does not induce physical or psychological dependence. Therefore, the use of NMN and the composition according to the present invention to prevent and / or treat pain is safe for patients.

[0114] Therefore, NMN and compositions according to the present invention can be used by children and adults.NMN is actually well tolerated by children.In the context of the present invention, a patient is considered to be a child if he / she is under 16 years old, and considered to be an adult if he / she is 16 years old or older.

[0115] In a preferred embodiment, NMN is in the form of a zwitterion. The term "zwitterion" is generally understood to refer to a molecular species with charges of opposite sign located on non-adjacent atoms of the molecule.

[0116] Pharmaceutically acceptable excipients may be selected from among fillers, lubricants, flavoring agents, coloring agents, emulsifiers, compression agents, diluents, preservatives, gelling agents, plasticizers, surfactants, or combinations thereof. Those skilled in the art will know to determine the excipients to choose based on the galenic form they will have chosen.

[0117] In the context of the present invention, an "excipient" refers to any substance other than NMN that is in a composition and has no therapeutic effect. An excipient does not chemically interact with NMN or any other additional therapeutic agent.

[0118] The NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention can be administered in a therapeutically effective amount. In the context of the present invention, the therapeutically effective amount indicates that the composition is administered to a patient in an appropriate amount sufficient to achieve the desired therapeutic effect, in this case, the alleviation of pain sensation.

[0119] In one embodiment, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt is administered in an amount of 0.01 mg / kg / day to 1000 mg / kg / day, preferably 1 mg / kg / day to 100 mg / kg / day, more preferably 5 mg / kg / day to 50 mg / kg / day, and even more preferably 10 mg / kg / day to 20 mg / kg / day. Those skilled in the art can adapt the administered dose of NMN depending on the patient's age and weight, as well as the intensity of the pain being treated.

[0120] Suitable dosage levels may be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dose may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 milligram to 1000 milligrams of active ingredient, particularly 1.0 milligram, 5.0 milligram, 10.0 milligram, 15.0 milligram, 20.0 milligram, 25.0 milligram, 50.0 milligram, 75.0 milligram, 100.0 milligram, 150.0 milligram, 200.0 milligram, 250.0 milligram, 300.0 milligram, 400.0 milligram, 500.0 milligram, 600.0 milligram, 750.0 milligram, 800.0 milligram, 900.0 milligram and 1000.0 milligram active ingredient, for dosage adjustment based on the symptoms of the patient to be treated. For example, the dosage can be comprised between 100 mg / day and 5000 mg / day, preferably between 500 mg / day and 1000 mg / day. The compound may be administered on a schedule of 1 to 4 times daily, preferably 1, 2, or 3 times daily, preferably 3 times daily. The duration of treatment is up to and determined by the physician. It may range from 1 day to 1 year or more, preferably 1 week to 3 months, more preferably 2 weeks to 6 weeks. However, it should be understood that the specific dose level and frequency, as well as the duration for a given patient, may vary and depend on a variety of factors, particularly the potency of the action of the particular compound used, the metabolic stability and duration of action of the compound, the subject's age, weight, general health, sex, diet, mode and time of administration, excretion rate, pharmaceutical combination, and the host being treated.

[0121] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt may be administered at a daily dose of 10 mg / kg, with a minimum of 50 mg / day and a maximum of 1000 mg / day.

[0122] There are various pain scales for assessing pain, based on the age of the patient and their cognitive status, which are well known to those skilled in the art. These include: - Self-assessment (self-report) by the patient, either an adult or a child aged 4-6 years (school-age) who is able to communicate the intensity or characteristics of pain; - Peer-rated, i.e., caregiver-rated pain in adults who are unable to communicate (elderly, intensive care patients, people with multiple disabilities, etc.) or children under 4 years of age.

[0123] Self-report pain scales in children include, among others, the vertical visual analogue (VAS) scale, the numerical value (NS) scale, the facial pain scale, the poker chips scale, and a body diagram on which the child localizes the pain.

[0124] Peer-rated scales for acute pain in children include the Neonatal Facial Coding System (NFCS), the Neonatal Infant Pain Scale (NIPS), an observation-based scale of facial expression, leg and arm movements, crying, and consolability (i.e., "Face, Legs, Activity, Cry, Consolability" or FLACC), a comfort scale (or "comfort behavior" scale), the Premature Infant Pain Profile (or PIPP), the Children's Hospital of Eastern Ontario Pain Scale (or CHEOPS), and the French Pediatric Pain Scale, ENVENDOL (Evaluation Enfant Douleur). Other-rated scales for chronic pain in children include the French Neonatal Pain and Discomfort Scale EDIN (Evaluation de Douleur et d´Inconfort du Nouveau-ne), the objective pain scale, the Amiel-Tison system with reverse scoring, the Gustave-Roussy Pediatric Pain Scale (Douleur Enfant Gustave-Roussy-DEGR), the French Pediatric Pain Other-Rating Scale HEDEN (Hetero Evaluation de la Douleur de l´Enfant), and the Saint-Antoine Pain Questionnaire (Questionnaire de la Douleur de Saint-Antoine-QDSA).

[0125] Self-rating (self-report) scales for adults include the vertical visual analogue scale, the numerical rating scale (NRS), and the verbal rating scale (VRS). Other-rating scales for adults include the Algoplus test, the Doloplus test, and the Behavioral Pain Assessment Scale for the Elderly (ECPA). Finally, there is a specific test for the assessment of neuropathic pain: the DN4 test (Douleur Neuropathique 4 Questions).

[0126] The NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention can be administered once a day or multiple times a day. In particular, the NMN and the composition according to the present invention can be administered 1 to 12 times a day, preferably 3 to 10 times a day, and more preferably 5 to 8 times a day.

[0127] The dose administered and the frequency of administration will depend, inter alia, on the intensity of the pain experienced by the patient.

[0128] use According to the present invention, the NMN according to the present invention, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and composition are used to prevent and / or treat pain.In one embodiment, the pain is not neuropathic pain.Preferably, the pain is nociceptive pain.

[0129] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and compositions according to the present invention are particularly used to reduce pain sensitivity.In one embodiment, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and compositions comprising the same are used to reduce allodynia.In the context of the present invention, allodynia is pain felt in response to stimuli that do not normally cause pain.In other words, in the context of allodynia, the patient's pain tolerance threshold is reduced.Therefore, the use of NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and compositions comprising the same according to the present invention can restore the patient's normal pain tolerance threshold and eliminate or at least alleviate the phenomenon of allodynia.A variety of different techniques well known to those skilled in the art can be used to evaluate allodynia in humans. Allodynia in humans can be measured, for example, by stimulation with different filaments (the von Frey test principle) on wounds (postoperative surfaces), after intradermal injection of capsaicin, or after application of heat to the skin. Allodynia can also be measured using questionnaires in which patients indicate their pain scores, for example, after immersing the hand in ice, after applying heat to an area at a given temperature for a given time, or after applying defined pressure to different areas (arm, knee, perineum, anus, etc.). Another possible approach to assessment is to stimulate an area with a stimulus known to be non-pain-inducing and then assess the pain felt by the patient using a questionnaire.

[0130] In one embodiment, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention are used to alleviate hyperalgesia. In the context of the present invention, hyperalgesia is defined as pain that worsens in response to pain-inducing stimuli.

[0131] In one embodiment, the pain is visceral pain. In the context of the present invention, visceral pain is caused by activation of nociceptors in the organs of the chest, abdomen, and pelvis. Such pain may include, in particular, a feeling of distension, a cut, a burn, and a combination thereof. "Distension" refers to any symptom such as stretching, cramping, pulling, pressure or squeezing, and twisting. Visceral pain may be caused, in particular, by sudden traction on the mesentery, stretching of the serosal membrane, compression of the viscera causing secondary distension, or distension of hollow organs such as the stomach or intestines. From a clinical perspective, visceral pain may be caused by inflammation, infection, disruption of normal mechanical processes such as gastrointestinal motility disorders, tumors, and ischemia.

[0132] In one embodiment, visceral pain is pain felt within the female or male urogenital tract. The urogenital (or genitourinary) system includes the kidneys, ureters, bladder, urethra, female reproductive system, male reproductive system, ovaries, and testes.

[0133] Such pain may particularly indicate interstitial cystitis. Interstitial cystitis or painful bladder syndrome is an inflammatory disease of the bladder characterized by abnormal urinary urgency (urgent and / or frequent need to urinate) and significant pain in the lower abdomen and bladder, the specific site of pain being the urethra (the tube that carries urine from the bladder to the outside of the body) or vagina in women, sometimes accompanied by difficulty in urination. The severity of symptoms varies from person to person. Pain may also be due to inflammation of the urogenital tract that is not caused by bacteria, fungi, or viruses. For example, pain may be caused by non-microbial cystitis.

[0134] In one embodiment, the visceral pain is pain caused by urinary tract infection.Urinary tract infection can be caused by bacterial, fungal, or viral infection, or a combination thereof.Urinary tract infection can affect multiple organs of the genitourinary system, such as the kidneys, ureters, bladder, urethra, and prostate.This often manifests as pain with or without a burning sensation when urinating.Urinary tract infection can be cystitis, urethritis, pyelonephritis, prostatitis, or a combination thereof.

[0135] Cystitis is the most common form of urinary tract infection. It is an inflammation of the bladder. Cystitis can be caused by the overgrowth of intestinal bacteria, such as Escherichia coli, which is often found around the anus. In women, the bacteria travel from the anal area through the urinary tract to the bladder, causing local inflammation. In men, cystitis is often caused by bacterial infections, such as chlamydia or gonorrhea. Cystitis can also be caused by fungal infections, such as Candida albicans.

[0136] Urethritis refers to inflammation of the urethra, the tube that connects the bladder to the urinary tract. In men, given that the prostate is located near the urethra, inflammation can also affect the prostate, in which case the condition corresponds to prostatitis.

[0137] Pyelonephritis refers to inflammation of the renal pelvis, the cavity that collects urine in the kidney. It is often caused by a bacterial infection, especially poorly treated cystitis. In this case, bacteria can travel up the ureter and infect the kidney.

[0138] In one preferred embodiment, NMN according to the present invention, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition are used to treat or prevent pain caused by cystitis.Therefore, NMN according to the present invention, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition provide a means of treating pain caused by urinary tract infection.

[0139] Mode of administration and galenical forms NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and compositions according to the present invention can be administered via various routes: oral, ocular, inhalation, sublingual, intravenous, intraarterial, intramuscular, subcutaneous, transdermal, vaginal, epidural, topical, intravesical, or rectal. Preferably, NMN and compositions according to the present invention are administered via the oral route.

[0140] The compositions according to the invention may be in the form of tablets, capsules, sachets, granules, soft capsules, lyophilisates, lozenges, suspensions, gels, syrups, solutions, water / oil emulsions, oil / water emulsions, oils, creams, milks, sprays, ointments, ampoules, suppositories, eye drops, vaginal suppositories, vaginal capsules, liquids for inhalation, dry powder inhalers, pressurised metered dose inhalers. Preferably, the compositions according to the invention are in the form of gastroresistant capsules or sublingual tablets.

[0141] The term "gastroresistant" refers to a galenical form that does not dissolve in the stomach. Such galenical forms are designed to have a delayed release, i.e., a coating or coating composition that is resistant to the acidic pH of the stomach (pH < 2) so that they can dissolve in the intestine. The gastroresistant properties are determined according to tests established by the European Pharmacopoeia. Briefly, the gastroresistant properties of capsules are measured in a disintegration apparatus using 0.1 M hydrochloric acid at 37°C as the disintegration medium. This medium mimics the physicochemical conditions of the stomach. The capsules are incubated in this medium for 1 hour. They should not show any signs of disintegration or cracking that could lead to the loss of their contents. The capsules are then incubated for 1 hour at 37°C in a phosphate buffer solution with a pH of 6.8, which mimics the conditions of the intestinal environment according to the European Pharmacopoeia recommendations. The capsules should completely disintegrate in less than 1 hour.

[0142] The term "sublingual tablet" is understood to mean a galenical form that is placed under the tongue in order for the active ingredient to be absorbed by the sublingual mucosa, in particular by the sublingual veins and arteries.

[0143] The compositions according to the invention may also be in galenical forms designed to have immediate release, which serve to allow rapid absorption of the nicotinamide adenine dinucleotide (NAD) precursor and thus a reduced onset of action. Immediate release galenical forms include in particular dispersible tablets, orodispersible tablets, effervescent tablets and oral lyophilisates.

[0144] The compositions according to the invention may also be in galenical forms designed for slow (decelerated) release. Dissolution and absorption of the NAD precursor occurs in the intestine, thereby limiting the degradation of the active ingredient, which is sensitive to stomach irritation or acidic pH. These are mainly gastroresistant forms, i.e., tablets or granules coated with a polymer film that is insoluble in acidic media but permeable to water in alkaline media or lipid media that are degraded by intestinal lipase.

[0145] The compositions according to the invention may also be in galenical forms designed for sequential and sustained release. To ensure that an effective plasma concentration is maintained in the patient's body for a longer period of time, sequential release (release at precise time intervals) and sustained release (continuous release of the active ingredient until depletion) galenical forms facilitate the release of the active ingredient over time. Such galenical forms provide a means of relieving the patient's pain over a longer period of time and spreading out the dosage of the medicine.

[0146] The appropriate mode of administration and galenical form will be determined by one skilled in the art based on the anatomical location of the pain to be treated and relevant patient information. In this regard, reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0147] The compositions of the present invention can be formulated using suitable support materials or carriers, excipients, and diluents for these formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, water (sterile), methylcellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils, and mineral oils, or suitable mixtures thereof. The formulations may optionally contain other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, extenders, fillers, preservatives, sweeteners, flavoring agents, flow regulators, release agents, etc. The compositions can also be formulated to allow rapid, sustained, or slow (decelerated) release of the active compound or compounds contained therein.

[0148] The compositions according to the invention are preferably in unit dose form and may be packaged in any suitable manner, for example in a box, blister pack, vial, bottle, sachet, ampule, or any other suitable support or container suitable for single-dose or multi-dose packaging (which may be suitably labelled), and optionally include one or more package inserts containing relevant information and / or instructions for use of the product.

[0149] Therapeutic Combinations Advantageously, the NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, and the composition according to the present invention are used in combination with at least one additional therapeutic agent. In one embodiment, the composition according to the present invention comprises NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, a pharmaceutically acceptable excipient, and at least one additional therapeutic agent.

[0150] Advantageously, the at least one additional therapeutic agent is selected from antibiotics, antifungals, antivirals, and combinations thereof. Therefore, the use of NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, or a composition according to the present invention can alleviate nociceptive pain associated with bacterial infection, fungal infection, viral infection, or a combination thereof. For example, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, or a composition according to the present invention can be used in combination with antibiotics. Such a combination can prove useful for topical application, for example, in throat lozenges, which can reduce the microbial load in bacterial angina and relieve pain associated with local inflammation. NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt, or a composition according to the present invention can also be used in combination with antifungals. Such a combination can prove useful, for example, in the treatment or prevention of urinary tract, vaginal, dermatomycosis, etc.

[0151] In one embodiment, the antibiotic may be selected from among beta-lactams, cyclins, macrolides, related macrolides, quinolones, fluoroquinolones, quinolines, aminoglycosides, fusidic acid, lincosamides, phenicols, polymyxins, sulfonamides (whether or not related to trimethoprim), antilepers, fosfomycin, mupirocin, nitrofurantoin, nitrofurans, nitroimidazoles, oxazolidinones, glycopeptides, lipopeptides, polymyxins, and antituberculosis drugs.

[0152] In one embodiment, the antifungal agent may be selected from among amphotericin B, flucytosine, azole derivatives, terbinafine, selenium sulfide, triclocarban, nystatin, griseofulvin, amorolfine, salicylic acid, ciclopiroxolamine, amorolfine, tolphanate, and combinations thereof.

[0153] The antifungal azole derivative may in particular be selected from among bifonazole, clotrimazole, econazole, fenticonazole, fluconazole, isoconazole, itroconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, voriconazole, and combinations thereof.

[0154] The antiviral agent may in particular be selected from among antagonists of the CCR5 receptor (CC chemokine receptor type 5), systemic antivirals, phosphate derivatives, integrase inhibitors, fusion inhibitors, neuraminidase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, nucleosides and nucleotides excluding reverse transcriptase inhibitors, and combinations thereof.

[0155] In one embodiment, the composition according to the present invention also comprises at least one analgesic, which may belong to the WHO classification of Level I, Level II, Level III analgesics, or a combination thereof.

[0156] In one embodiment, the Level I analgesic is selected from among paracetamol, aspirin, nonsteroidal anti-inflammatory drugs, cortisone derivatives, and combinations thereof.

[0157] The nonsteroidal anti-inflammatory drug may be selected from among ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam, and combinations thereof.

[0158] The cortisone derivative may be selected from among betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone.

[0159] Level II analgesics may be selected from codeine, dihydrocodeine, tramadol, and combinations thereof.

[0160] Level III analgesics may be selected from among morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine, and combinations thereof.

[0161] In the context of the present invention, an "excipient" refers to any substance other than NMN that is in a composition and has no therapeutic effect. An excipient does not chemically interact with NMN or any other additional therapeutic agent.

[0162] The excipients may be selected from among fillers, lubricants, flavoring agents, coloring agents, emulsifiers, compression agents, diluents, preservatives, gelling agents, plasticizers, surfactants, or combinations thereof. Those skilled in the art will know to determine the excipients to choose based on the galenic form they will have chosen.

[0163] The composition according to the invention may be a pharmaceutical composition, in which case the excipient is a pharmaceutically acceptable excipient as defined herein above.

[0164] The composition according to the invention may be a dietary supplement.

[0165] NMN derivatives and precursors According to the present invention, NMN derivatives include alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (referred to as NMN-H), and the compound represented by formula (I):

[0166] [ka] or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable crystal thereof (wherein -X is selected from among O, CH2, S, Se, CHF, CF2 and C=CH2; R1 is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl, and OR; wherein R is selected from H and (C1-C8) alkyl; R2, R3, R4 and R5 are independently H, halogen, azide, cyano, hydroxyl, (C1-C 12 ) alkyl, (C1-C 12 ) thioalkyl, (C1-C 12 ) heteroalkyl, (C1-C 12 ) haloalkyl and OR; wherein R is selected from H, (C1-C 12 ) alkyl, C(O)(C1-C 12 ) alkyl, C(O)NH(C1-C 12 ) alkyl, C(O)O(C1-C 12 ) alkyl, C(O) aryl, C(O)(C1-C 12 ) alkylaryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 ) alkylaryl and C(O)CHR AA NH2; AA is a side chain selected from proteinogenic amino acids; R6 is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl, and OR; wherein R is selected from H and (C1-C8) alkyl; -R7 is H, P(O)R9R 10 , and P(S)R9R 10 wherein: -R9 and R 10 are independently OH, OR 11 , NHR 13 , N.R. 13 R14 , (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C 10 ) cycloalkyl, (C5-C 12 )aryl, (C1-C8)alkylaryl, (C1-C8)arylalkyl, (C1-C8)heteroalkyl, (C1-C8)heterocycloalkyl, heteroaryl, and NHCHR A R A´ C(O)R 12 wherein: -R 11 is (C1~C 10 ) Alkyl, (C3-C 10 ) cycloalkyl, (C5-C 18 ) aryl, (C1-C 10 ) Alkylaryl, substituted (C5-C 12 ) aryl, (C1-C 10 ) heteroalkyl, (C3-C 10 ) heterocycloalkyl, (C1-C 10 ) haloalkyl, heteroaryl, -(CH2) n C(O)(C1~C 15 ) alkyl, -(CH2) n OC(O)(C1~C 15 ) alkyl, -(CH2) n OC(O)O(C1~C 15 ) alkyl, -(CH2) n SC(O)(C1~C 15 ) alkyl, -(CH2) n C(O)O(C1~C 15 ) alkyl, and -(CH2) n C(O)O(C1~C 15 ) alkylaryl (wherein n is an integer selected from 1 to 8), P(O)(OH)OP(O)(OH); halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R 11a )2, C1-C6 acylamino, -COR 11b , -OCOR 11b ;NHSO2(C1-C6 alkyl), -SO2N(R 11a )2SO2(wherein, R 11aare each independently selected from H and (C1-C6) alkyl; 11b is selected from among OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; -R 12 H, C1~C 10 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 Haloalkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 18 Aryl, C1-C4 alkylaryl, and C5-C 12 heteroaryl; the aryl or heteroaryl group is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and cyano; and -R A and R A´ are independently H, (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) thioalkyl, (C1-C 10 ) hydroxyl alkyl, (C1-C 10 ) alkylaryl, and (C5-C 12 ) Aryl, (C3-C 10 ) heterocycloalkyl, heteroaryl, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, a side chain selected from among proteinogenic or non-proteinogenic amino acids; the aryl group is selected from hydroxyl, (C1-C 10 ) optionally substituted with a group selected from alkyl, (C6-C1)alkoxy, halogen, nitro, and cyano; or -R9 and R 10together with the phosphorus atom to which they are attached, form -R9-R 10 - represents -CH2-CH2-CHR-, forming a 6-membered ring; where R is selected from H, a (C5-C6)aryl group and a (C5-C6)heteroaryl group, said aryl or heteroaryl group being optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano; or R9 and R 10 together with the phosphorus atom to which they are attached, form -R9-R 10 - represents -O-CH2-CH2-CHR-O-, forming a 6-membered ring; wherein R is selected from H, a (C5-C6)aryl group, and a (C5-C6)heteroaryl group, said aryl group or heteroaryl group being optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, and cyano; -R8 is H, OR, NHR 13 , N.R. 13 R 14 , NH-NHR 13 , SH, CN, N3 and halogen; 13 and R 14 is H, (C1-C8) alkyl, (C1-C8) alkylaryl and -CR B R C -C(O)-OR D wherein R B and R C are independently a hydrogen atom, a (C1-C6) alkyl, a (C1-C6) alkoxy, a benzyl, an indolyl, or an imidazolyl; the (C1-C6) alkyl and the (C1-C6) alkoxy may be optionally substituted independently of one another by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl groups, and the benzyl group is optionally substituted by one or more halogen or hydroxyl groups; or R B and R Ctogether with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group optionally substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl; R D is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl; -Y is selected from among CH, CH2, C(CH3)2 and CCH3; - [ka] represents a single or double bond along Y; - [ka] is the alpha or beta anomer depending on the position of R1; or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof); or Formula (II): [ka] or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof, wherein -X'1 and X'2 are independently selected from O, CH2, S, Se, CHF, CF2, and C=CH2; -R´1 and R´ 13 is independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR, where R is selected from H and C1-C8 alkyl; -R´2, R´3, R´4, R´5, R´9, R´ 10 , R´ 11 , R´ 12H, halogen, azide, cyano, hydroxyl, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Heteroalkyl, C1-C 12 haloalkyl and OR; wherein R is H, C1-C 12 Alkyl, C(O)(C1-C 12 ) alkyl, C(O)NH(C1-C 12 ) alkyl, C(O)O(C1-C 12 ) alkyl, C(O) aryl, C(O)(C1-C 12 ) aryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 ) alkylaryl or C(O)CHR AA NH groups; AA is a side chain selected from proteinogenic amino acids; R'6 and R'8 are independently selected from H, azido, cyano, C1-C8 alkyl, and OR, where R is selected from H and C1-C8 alkyl; -R´7 and R´ 14 are independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N3, and halogen; wherein R and R' are independently selected from H and (C1-C8) alkylaryl; -Y'1 and Y'2 are independently selected from CH, CH2, C(CH3)2 or CCH3; -M' is selected from H or a suitable counterion; - [ka] represents a single or double bond depending on Y'1 and Y'2; - [ka] is R´1 and R´13 represents the alpha or beta anomer depending on the position of and combinations thereof.

[0167] In a first preferred embodiment, the pharmaceutically acceptable derivative is a compound having formula (I).

[0168] In one variation of the first embodiment, X represents oxygen.

[0169] In one variation of the first embodiment, R1 and R6 each independently represent hydrogen.

[0170] In one variant of the first embodiment, R2, R3, R4 and R5 each independently represent hydrogen or OH.

[0171] In one variant of the first embodiment, Y represents CH.

[0172] In one variant of the first embodiment, Y represents CH2.

[0173] In one variant of the first embodiment, R7 represents hydrogen.

[0174] In one variant of the first embodiment, R7 represents P(O)(OH)2.

[0175] In one variation of the first embodiment, the compound of the invention is selected from among compounds having formulae IA-IH.

[0176]

number

[0177] In one preferred variation of the first preferred embodiment, the pharmaceutically acceptable derivative is alpha-NMN, which has the formula:

[0178] [ka]

[0179] In a second preferred embodiment, the pharmaceutically acceptable derivative is a compound having formula (II).

[0180] In one variation of the second embodiment, X'1 and X'2 each independently represent oxygen.

[0181] In one variation of the second embodiment, R'7 and R'14 each independently represent NH2.

[0182] In one variation of the second embodiment, R'1 and / or R'13 each independently represent hydrogen.

[0183] In one variation of the second embodiment, R'6 and / or R'8 each independently represent hydrogen.

[0184] In one variation of the second embodiment, R'2, R'3, R'4, R'5, R'9, R'10, R'11, and R'12 each independently represent hydrogen.

[0185] In one variation of the second embodiment, R'2, R'3, R'4, R'5, R'9, R'10, R'11 and R'12 each independently represent OH.

[0186] In one variation of the second embodiment, Y'1 and Y'2 each independently represent CH.

[0187] In one variation of the second embodiment, Y'1 and Y'2 each independently represent CH2.

[0188] In one variant of the second embodiment, the compound according to the invention is selected from among compounds having formulae II-A to II-F.

[0189]

number

[0190] In a fourth preferred embodiment, the pharmaceutically acceptable derivative is NMN-H.

[0191] [ka]

[0192] Advantageously, the pharmaceutically acceptable precursor is nicotinamide riboside (denoted NR):

[0193] [ka] or the expression: [ka] or a combination thereof. Preferably, the precursor is nicotinamide riboside (NR).

[0194] Preferably, the NMN derivative is dihydronicotinamide mononucleotide (NMN-H) and / or alpha-NMN. Compound preparation method for preparing compounds having formula (I) and (II)

[0195] The derivatives having formula (I) or formula (II) may be prepared according to any method known to those skilled in the art.

[0196] Compound preparation method for preparing a compound having formula (I)

[0197] The derivatives having formula (I) can be prepared according to the methods described in International Patent Application WO2017 / 024255A1.

[0198] In particular, derivatives having formula (I) and alpha-NMN can be prepared according to the methods described below.

[0199] In particular, compounds having formula (I) disclosed herein can be prepared from substrates A to E as described below. It should be understood by those skilled in the art that these reaction schemes are not intended to be limiting in any way, and modifications thereof can be made without departing from the spirit and scope of the present invention.

[0200] According to one embodiment, the present invention relates to a compound preparation process for preparing a compound having formula (I) as defined above.

[0201] The method comprises, in a first step, monophosphorylating a compound having formula (A) in the presence of phosphoryl chloride and a trialkyl phosphate, thereby producing a phosphorodichloridate having formula (B):

[0202] [ka] In the formula, X, R1, R2, R3, R4, R5, R6, R8, Y, [ka] is as defined herein above for compounds having formula (I).

[0203] In a second step, the phosphorodichloridate having the formula (B) is hydrolyzed, thereby producing a phosphate having the formula (C),

[0204] [ka] In the formula, X, R1, R2, R3, R4, R5, R6, R8, Y, [ka] is as defined herein above for compounds having formula (I).

[0205] According to one embodiment, compounds having formula (A) are synthesized by a variety of methods known to those skilled in the art.

[0206] According to one embodiment, a compound having formula (A) is synthesized by reacting a pentose having formula (D) with a nitrogen derivative having formula (E), where R, R2, R3, R4, R5, R6, R7, Y are as defined herein above for compounds having formula I, thereby producing a compound having formula (A-1), which is then selectively deprotected to obtain a compound having formula (A).

[0207] [ka] In the formula, X, R1, R2, R3, R4, R5, R6, R8, Y, [ka] is as defined herein above for compounds having formula (I).

[0208] According to one embodiment, R is a suitable protecting group known to those skilled in the art. In one embodiment, the protecting group is selected from triarylmethyl and / or silyl. Some examples of triarylmethyl include, but are not limited to, trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4"-trimethoxytrityl groups. Some examples of silyl groups include, but are not limited to, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-isopropylsilyloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0209] According to one embodiment, any hydroxyl groups attached to the pentose are protected by a suitable protecting group known to those skilled in the art.

[0210] The selection and exchange of protecting groups is well within the knowledge and expertise of one skilled in the art. Protecting groups can also be removed using methods well known to those skilled in the art, such as using an acid (e.g., an inorganic or organic acid), a base, or a fluoride source.

[0211] In one preferred embodiment, a nitrogen derivative having formula (E) is coupled to a pentose having formula (D) by reaction in the presence of a Lewis acid to produce a compound having formula (A-1). Some non-limiting examples of Lewis acids include trimethylsilyl trifluoromethanesulfonate (TMSOTf), BF3.OEt2, TiCl4, and FeCl3.

[0212] In one embodiment, the method of the present invention also further comprises a reduction step of reducing a compound having formula (A) by various methods well known to those skilled in the art, thereby producing a compound having formula (A'), wherein CH, R, R, R, R, R, R, R, R, Y, [ka] is as defined herein above for compounds having formula (I).

[0213] In one particular embodiment, the present invention relates to a compound preparation method for preparing compounds having formula IA, IC, IE, IG.

[0214] In the first step, nicotinamide having formula E is coupled to ribose tetraacetic acid having formula D by a coupling reaction in the presence of a Lewis acid, thereby producing a compound having formula A-1.

[0215] [ka]

[0216] In the second step, ammonia treatment of the compound having formula A-1 is carried out, thereby producing a compound having formula IA.

[0217] [ka]

[0218] In the third step, monophosphorylation of the compound having formula IA in the presence of phosphoryl chloride and a trialkyl phosphate produces the phosphorodichloridate having formula IA'.

[0219] [ka]

[0220] In the fourth step, the phosphorodichloridate having formula B is hydrolyzed, thereby producing a compound having formula IC.

[0221] [ka]

[0222] In one embodiment, a reduction step is performed in which a compound having formula IA is reduced to produce a compound having formula IE.

[0223] The compound having formula IE is then monophosphorylated and hydrolyzed as described in the fourth step to produce the compound having formula IG.

[0224] According to one embodiment, the compound having formula (I) is selected from compounds IA to IH in the table below.

[0225]

number

[0226] In one preferred embodiment, the compound of the present invention is a compound having formula IA, IC, IE, and IG in the table above, or a pharmaceutically acceptable salt and / or solvate thereof. In an even more preferred embodiment, the compound is a compound having formula IC or ID, or a pharmaceutically acceptable salt and / or solvate thereof.

[0227] Method for preparing derivatives having formula (II)

[0228] In particular, compounds having formula II presented herein can be prepared from substrates X-XIII as described below: It should be understood by those skilled in the art that these diagrams are not intended to be limiting in any way and that variations therein in detail can be made without departing from the spirit and scope of the invention.

[0229] According to one embodiment, the present invention relates to a compound preparation process for preparing a compound having formula I above.

[0230] The method comprises first monophosphorylating a compound having formula X in the presence of phosphoryl chloride in a trialkyl phosphate to obtain the compound phosphorodichloridate XI;

[0231] [ka] In the formula, X´1, R´1, R´2, R´3, R´4, R´5, R´6, R´7, Y´1, [ka] is as defined above.

[0232] In a second step, hydrolysis of the phosphorodichloridate XI obtained in the first step gives the phosphate compound having formula XII.

[0233] [ka] In the formula, X´1, R´1, R´2, R´3, R´4, R´5, R´6, R´7, Y´1, M´, [ka] is as defined above.

[0234] The phosphate compound having formula XII obtained in the second step is then reacted with a phosphorodichloridate compound having formula XIII obtained as described in the first step to obtain a compound having formula II as described herein;

[0235] [ka] In the formula, X´2, R´8, R´9, R´ 10 , R´ 11 , R´ 12 , R´ 13 , R´ 14 , Y´2, [ka] is as described herein for Formula II.

[0236] According to one embodiment, the method comprises the steps of: Y'1 and Y'2 are identical and each represent CH2; and X'1, X'2, R'1, R'2, R'3, R'4, R'5, R'6, R'7, R'8, R'9, R' 10 , R´ 11 , R´ 12 , R´ 13 , R´ 14 , Y'1, Y'2, and [ka] The method further comprises a reduction step of reducing the compound having formula II using various methods known to those skilled in the art to obtain a compound having formula II, wherein:

[0237] According to one variation, R is a suitable protecting group known to those skilled in the art. Triarylmethyl and / or silyl groups are examples of suitable protecting groups. Some examples of triarylmethyl include, but are not limited to, trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4"-trimethoxytrityl. Some examples of silyl groups include, but are not limited to, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-isopropylsilyloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0238] According to one representative example, any hydroxyl groups attached to the pentose ring are protected by a suitable protecting group known to those skilled in the art.

[0239] The selection and exchange of protecting groups is well within the knowledge and expertise of one of ordinary skill in the art. Any protecting group can also be removed using methods known in the art, for example, using an acid (e.g., an inorganic or organic acid), a base, or a fluoride source.

[0240] According to one preferred embodiment, a nitrogen compound having formula XV is added to pentose XIV by a coupling reaction in the presence of a Lewis acid to give a compound having formula X-1. Some non-limiting examples of suitable Lewis acids include trimethylsilyl trifluoromethanesulfonate (TMSOTf), BF3.OEt2, TiCl4, and FeCl3.

[0241] According to one particular embodiment, the present invention provides a compound having formula VIII

[0242] [ka] or a pharmaceutically acceptable salt and / or solvate thereof.

[0243] In the first step, nicotinamide having formula XV is added to ribose tetraacetic acid XIV by a coupling reaction in the presence of a Lewis acid to give a compound having formula X-1.

[0244] [ka]

[0245] In the second step, treatment of the compound having formula X-1 with ammonia gives the compound having formula X.

[0246] [ka]

[0247] In the third step, monophosphorylation of the compound having formula X in the presence of phosphoryl chloride in trialkyl phosphate gives the compound phosphorodichloridate XI.

[0248] [ka]

[0249] In the fourth step, the phosphorodichloridate compound XI obtained in the third step is partially hydrolyzed to obtain the phosphate compound having formula XII.

[0250] [ka]

[0251] In the fifth step, the phosphate compound having formula XII obtained in the fourth step is then reacted with the phosphorodichloridate compound having formula XI obtained as described in the third step to obtain a compound having formula VIII.

[0252] According to another particular embodiment, the present invention provides a compound having formula IX

[0253] [ka] or a pharmaceutically acceptable salt and / or solvate thereof.

[0254] According to one variant, the compound of formula IX is obtained from a compound of formula VIII previously synthesized as described above.

[0255] In this embodiment, a compound having formula IX is obtained by reducing a compound having formula VIII using a suitable reducing agent known to one skilled in the art to obtain a compound having formula IX.

[0256] According to one embodiment, preferred compounds of the present invention are compounds II-A to II-F listed in Table 2.

[0257]

number

[0258] [Figure 1] 1 is a graph showing the nociceptive score and nociceptive threshold induced by administration of cyclophosphamide in rats relative to vehicle-treated animals. [Figure 2] 1 is a graph showing the time course of nociceptive scores and nociceptive thresholds 2 hours and 4 hours after administration of cyclophosphamide in rats compared with vehicle. [Figure 3] FIG. 1 shows nociceptive thresholds in cyclophosphamide-treated animals administered vehicle, NMN, or ibuprofen at T0, T=2 hours, or T=4 hours after cyclophosphamide administration. [Figure 4] FIG. 1 shows nociceptive scores in cyclophosphamide-treated animals administered vehicle, NMN, or ibuprofen at T0, T=2 hours, or T=4 hours after cyclophosphamide administration. [Figure 5A] Graph showing baseline nociceptive thresholds for each experimental group. [Figure 5B] Graph showing baseline nociceptive scores for all experimental groups. [Figure 6A]FIG. 1 is a graph showing nociceptive thresholds for the effects of NMN, Compound A, and Compound B on CYP-induced allodynia at 2 hours. [Figure 6B] FIG. 1 is a graph showing nociceptive thresholds for the effects of NMN, Compound A, and Compound B on CYP-induced allodynia at 4 hours. [Figure 7A] FIG. 1 is a graph showing the effect of NMN on visceral pain induced by CYP at 2 hours (nociceptive score). [Figure 7B] FIG. 1 is a graph showing the effect of NMN on visceral pain induced by CYP at 4 hours (nociceptive score). [Figure 8A] FIG. 1 is a graph showing the effect of Compound A on CYP-induced visceral pain at 2 hours (nociceptive score). [Figure 8B] FIG. 1 is a graph showing the effect of Compound A on CYP-induced visceral pain at 4 hours (nociceptive score). [Figure 9A] FIG. 1 is a graph showing the effect of Compound B on CYP-induced visceral pain at 2 hours (nociceptive score). [Figure 9B] FIG. 1 is a graph showing the effect of Compound B on CYP-induced visceral pain at 2 hours (nociceptive score). [Example]

[0259] In the remainder of this specification, the described examples are intended as illustrations of the present invention and are not intended to limit its scope in any way.

[0260] Example 1

[0261] The effectiveness of the use of NMN according to the present invention was evaluated in rats in a nociceptive pain model. More precisely, the model used is a visceral pain model. The administration of cyclophosphamide (CYP) serves as a means to simulate cystitis in rats.

[0262] The positive control was ibuprofen, a nonsteroidal anti-inflammatory drug frequently prescribed to relieve nociceptive pain. The negative control was the carrier for NMN and ibuprofen, i.e., distilled water.

[0263] For this study, 7-week-old female Sprague-Dawley rats were divided into three groups, each consisting of six rats: - a control group given 5 ml of distilled water (vehicle); - a group treated with 500 mg / kg NMN; and - Group treated with 300 mg / kg ibuprofen.

[0264] NMN is in the form of a zwitterion.

[0265] After 24 hours of adaptation, a test to measure each animal's pain tolerance threshold was performed using von Frey filaments before the start of the study. This measurement, before any exposure to painful stimuli, allowed us to obtain a baseline pain tolerance threshold level in the animals and served as a negative control.

[0266] Von Frey filaments are used as a device to measure skin touch sensitivity. The use of von Frey filaments allows for testing allodynia and hyperalgesia in rodents. Briefly, each filament corresponds to a given force. The filaments are applied in increasing order to the animal's skin. Rodents actually have a withdrawal reflex when unexpected contact occurs. The withdrawal in response to force exerted on the rodent indicates the animal's threshold for pain tolerance. The use of von Frey filaments is commonly practiced for measuring pain in rodents (Deuis JR, Dvorakova LS, and Vetter I (2017) Methods Used to Evaluate Pain Behaviors in Rodents. Front. Mol. Neurosci. 10:284).

[0267] In this study, eight filaments were used, each applied three times to the animal's abdomen near the bladder in an increasing order of force: 1 g, 2 g, 4 g, 6 g, 8 g, 10 g, 15 g, and 26 g. The animal's response was assessed as follows: - Score 0: No response - Score 1: Abdominal contraction - Score 2: Animal stamping or change of position - Score 3: Twitching, or curving or rounding of the abdomen, or licking of the area stimulated by the von Frey filaments.

[0268] For each rat, the results are expressed as follows: - Nociceptive threshold: the first force level at which a response is observed from the animal (response score ≥ 1). This represents the lowest threshold of pain tolerance for measuring allodynia. - Nociceptive score: percentage of maximum response for each filament, which indicates the overall pain response.

[0269] Each group of animals was given either a carrier, 500 mg / kg NMN, or 300 mg / kg ibuprofen administered orally. After administration of the test compound (carrier, NMN, or ibuprofen), cyclophosphamide was injected intraperitoneally into each rat. Cyclophosphamide induces strong inflammation in the bladder, simulating the pain induced by urinary tract infections such as cystitis.

[0270] To measure the animal's pain response, repeat the test with von Frey filaments 2 hours after the injection of cyclophosphamide and then 4 hours later.

[0271] The results were analyzed by one-way analysis of variance (i.e., one-way ANOVA) test supplemented by Dunnett's test or two-way ANOVA analysis. For statistical significance, * means p<0.05, ** means p<0.01, and *** means p<0.001 compared to the vehicle-treated group.

[0272] As can be seen in Figure 1A, administration of cyclophosphamide elicits a response from the rat immediately after application of the first filament at a force of 1 g. However, responses from the animals prior to exposure indicate that the animals show no response to pain up to 10 g prior to administration of cyclophosphamide. Thus, injection of cyclophosphamide lowers the allodynia threshold. This result is supported by Figure 1B, which shows that administration of cyclophosphamide lowers the pain tolerance threshold from 10 g to 3 g. In other words, the allodynia threshold is significantly lowered by injection of cyclophosphamide into rats. Therefore, animals treated with cyclophosphamide are more sensitive to pain.

[0273] Figures 2A and 2B show that the allodynia threshold continues to decrease, with animals exhibiting lower pain tolerance 4 hours after injection of cyclophosphamide compared to 2 hours after injection.

[0274] Figure 1A also shows that animals experience greater pain with equal force, thus, cyclophosphamide injection induces hyperalgesia. Figure 2B shows that this effect persists over time, with pain scores measured in treated rats 4 hours later being higher than pain scores from measurements taken 2 hours after injection.

[0275] Thus, injection of cyclophosphamide induces, on the one hand, a decrease in allodynia and an increase in hyperalgesia in treated animals, an effect that becomes more pronounced over time.

[0276] Figures 3 and 4 show the effect of administration of NMN and ibuprofen on pain threshold and score in rats treated with cyclophosphamide.

[0277] As shown in Figures 3A, 3B, and 3C, administration of NMN significantly increases the threshold for nociceptive pain responses at T0, T=2 hours, and T=4 hours after injection. In a predictable manner, ibuprofen also significantly increases the threshold for pain tolerance in cyclophosphamide-treated rats at T0, T=2 hours, and T=4 hours after injection. These results indicate that administration of NMN reduces allodynia.

[0278] As shown in Figure 4A, NMN, ibuprofen, and vehicle show similar curves of nociceptive scores at TO, the time of cyclophosphamide injection. This demonstrates that animals do not develop pain in response to administration of NMN or ibuprofen. Meanwhile, Figures 4B and 4C show that administration of NMN, like ibuprofen, serves as a means to reduce nociceptive scores 2 and 4 hours after administration of cyclophosphamide.

[0279] Therefore, administration of NMN and compositions containing it makes it possible to significantly reduce allodynia and hyperalgesia in a manner similar to ibuprofen.

[0280] Example 2

[0281] Synthesis of Compounds of the Invention

[0282] material and method

[0283] All reagents were obtained from commercial suppliers and used without further purification. Thin-layer chromatography was performed on TLC silica gel 60 F254 plastic sheets (layer thickness 0.2 mm) from Merck. Column chromatographic purification was performed on silica gel 60 (70-230 mesh ASTM, Merck). Melting points were determined uncorrected on a digital device (Electrothermal IA 8103) or on a WME-type Kofler heating bench (Wagner & Munz). 1 H,19 F and 13 The structures of all compounds were confirmed by C nuclear magnetic resonance (NMR) and infrared (IR) spectra. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer. NMR spectra were recorded on a BRUKER AC300 or 400 spectrometer using CDCl3, CD3CN, D2O, or DMSO-d6 as solvents. 1 300 or 400 MHz for the H spectrum, 13 75 or 100 MHz for the C spectrum, 19 F spectra were recorded at 282 or 377 MHz. Chemical shifts (δ) were (i) 1 For H, CHCl3 (δ 7.27), (ii) 13 For C, indirectly using CDCl3 (δ 77.2), (iii) 19 Signals were expressed in parts per million relative to F directly using CFCl (internal standard) (δ0). Chemical shifts are given in ppm, and peak multiplicities are expressed as follows: s, singlet; br, s, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; quint, quintet; m, multiplet. High-resolution mass spectra (HRMS) were obtained from the "Service central d´analyse de Solaize" (French National Center for Scientific Research (Solaize)) and recorded on a Waters spectrometer using electrospray ionization time-of-flight (ESI-TOF) mass spectrometry.

[0284] protocol

[0285] Step 1: Synthesis of compounds having formula X-1

[0286] A compound of formula XIV (1.0 equivalent) is dissolved in dichloromethane. Nicotinamide of formula XV (1.50 equivalents) and TMSOTf (1.55 equivalents) are added at ambient temperature. The reaction mixture is heated under reflux and stirred until the reaction is complete. The mixture is cooled to ambient temperature and filtered. The filtrate is concentrated to dryness to obtain crude nicotinamide riboside tetraacetic acid of formula X-1.

[0287] Step 2: Synthesis of compounds having formula X

[0288] The crude NR tetraacetate having the formula X-1 is dissolved in methanol and cooled to -10°C. Following this, 4.6 M ammonia in methanol (3.0 equivalents) is added at -10°C, and the mixture is stirred at this temperature until the reaction is complete. Dowex HCR (H + ) is added until a pH of 6-7 is reached. The reaction mixture is heated to 0°C and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in acetonitrile and concentrated to dry the solids. The residue is dissolved in acetonitrile to obtain a solution of crude nicotinamide riboside triflate having formula X.

[0289] Step 3: Synthesis of Compounds Having Formula XI

[0290] A solution of crude nicotinamide riboside triflate in acetonitrile is diluted with trimethyl phosphate (10.0 equivalents). The acetonitrile is distilled under vacuum and the mixture is cooled to -10°C. Phosphorus oxychloride (4.0 equivalents) is added at -10°C, and the mixture is stirred at -10°C until the reaction is complete.

[0291] Steps 4 and 5: Synthesis of Compounds Having Formula IA

[0292] The mixture is hydrolyzed by adding a 50 / 50 mixture of acetonitrile and water, followed by the addition of methyl tert-butyl ether (or tert-butyl methyl ether). The mixture is filtered and the solid is dissolved in water. The aqueous solution is neutralized by adding sodium bicarbonate and extracted with dichloromethane. The aqueous layer is concentrated to dryness to obtain a crude mixture of NMN and di-NMN having the formula IA.

[0293] Isolation of di-NMN having formula IA:

[0294] NMN having the formula IA and di-NMN are separated by purification on Dowex 50wx8 with elution with water. The fractions containing di-NMN are concentrated and the solid is dried. The residue is purified by column chromatography on silica gel (isopropanol / water gradient). The pure fractions are combined and concentrated. The residue is lyophilized to give di-NMN as a beige solid.

[0295] Biological data

[0296] The purpose of this study was to evaluate the effects of oral administration of 500 mg / kg of nicotinamide mononucleotide (NMN), alpha-NMN (Compound A) and Compound IA (Compound B), on visceral pain responses in a model of acute cystitis induced by cyclophosphamide (CYP) in female Sprague-Dawley rats.

[0297] material and method

[0298] Animals: Sprague-Dawley female rats aged from birth to 7 weeks

[0299] Pharmacological treatment: -NMN: 500mg / kg -Alpha-NMN: 500mg / kg -Compound IA: 500mg / kg -Carrier: Distilled water -Route of administration: per os[po] (oral administration), 5ml / kg -Dosage frequency: D0, once 15 minutes before intraperitoneal injection (ip) of CYP.

[0300] CYP-induced acute cystitis: CYP was injected by intraperitoneal injection at 150 mg / kg in saline with a final volume of 5 ml / kg.

[0301] Mechanical stimulation using von Frey filaments

[0302] Rats were placed in individual Plexiglas boxes with metal mesh floors and allowed to adapt to the chamber for at least 30 min before the start of any test. Eight von Frey filaments were used at increasing force levels: 1, 2, 4, 6, 8, 10, 15, and 26 g. Each calibrated filament was applied three times to the lower abdomen near the bladder.

[0303] Assessment of nociceptive behavior for each application - Score 0 = no response Score 1 = abdominal contractions - Score 2 = Stamping or change in position Score 3 = wheezing or whining, or abdominal curvature, or licking at the site stimulated with the von Frey filament

[0304] For each rat, the results were expressed as follows: - Nociceptive threshold: the first von Frey force level at which a stimulus is perceived as painful (a score of ≥ 1 is obtained) ⇒ lowered threshold = allodynia - Nociceptive score: % of maximum response to each filament (total for 3 combined applications = 9) ⇒ total response to pain

[0305] Experimental groups (6 rats per group): Group 1: Vehicle (5ml / kg) + CYP -Group 2: NMN (500mg / kg)+CYP -Group 3: Compound A (500mg / kg)+CYP -Group 4: Compound B (500mg / kg)+CYP

[0306] result

[0307] Baseline nociceptive parameters for all experimental groups (before CYP injection): The results show that the baseline nociceptive responses were similar among all of the experimental groups (before CYP injection) (Figures 5A and 5B).

[0308] Visceral pain induced by CYP at 2 and 4 hours after injection (compared to baseline values ​​in the vehicle-treated group): The results show that, compared to the baseline response, CYP (150 mg / kg, i.p.) induced a significant decrease in the nociceptive threshold (Figure 2A) and a significant increase in the nociceptive score (Figure 2B) at the two time points.

[0309] Effect of NMN, Compound A and Compound B on CYP-induced allodynia (nociceptive threshold): Results show the following compared to vehicle: -NMN (500 mg / kg, po) produced a small increase in nociceptive threshold at +2 hours (Fig. 6A) and +4 hours (Fig. 6B), with the effect just above statistical significance at +4 hours (p=0.063). Compound A (500 mg / kg, po) increased the nociceptive threshold at +2 hours (FIG. 6A) and +4 hours (significant at +4 hours) (FIG. 6B). Compound B (500 mg / kg, po) produced a significant increase in the nociceptive threshold only at +4 hours (FIG. 6B) and did not induce any effect at +2 hours (FIG. 6A).

[0310] Effect of NMN, Compound A and Compound B on CYP-induced visceral pain (nociceptive score): Results show the following compared to vehicle (Figures 7, 8 and 9): -NMN (500 mg / kg, po) produced a significant decrease in nociceptive scores at +2 hours (Figure 7A) and +4 hours (Figure 7B). - Compound A (500 mg / kg, po) produced a decrease in nociceptive scores at +2 h (Fig. 8A) and +4 h (Fig. 8B), which only achieved statistical significance at +4 h. Compound B (500 mg / kg, po) produced a significant decrease in the nociceptive score at +4 hours (FIG. 9B) (no effect was observed at +2 hours (FIG. 9A)).

[0311] Summary of results

[0312] Baseline nociceptive responses were similar in all experimental groups (before injection of CYP).

[0313] Compared to baseline responses, the effects of CYP (150 mg / kg, ip) at 2 and 4 hours were characterized by the following: -A significant decrease in the nociceptive threshold at +2 and +4 hours; - Significant increase in nociceptive scores at +2 and +4 hours.

[0314] Compared to vehicle, in CYP-injected rats, the effects of NMN (500 mg / kg, po) resulted in: - A small increase in nociceptive threshold at +2 and +4 hours, with the effect just above statistical significance at +4 hours (p=0.063) - Significant reduction in nociceptive scores at +2 and +4 hours.

[0315] Compared to vehicle, the effects of Compound A (500 mg / kg, po) in rats injected with CYP were characterized by: - an increase in the nociceptive threshold at +2 and +4 hours, an effect that reached significance only at +4 hours; - A decrease in nociceptive scores at +2 and +4 hours, which only achieved statistical significance at +4 hours.

[0316] Compared to vehicle, in CYP-injected rats, the effects of Compound B (500 mg / kg, po) resulted in: - a significant increase in the nociceptive threshold at +4 hours (no effect was observed at +2 hours); - A significant reduction in nociceptive scores at +4 hours (no effect was observed at +2 hours).

[0317] conclusion

[0318] A single intraperitoneal injection of CYP (150 mg / kg) induced visceral pain at 2 and 4 hours after injection, with a more pronounced effect at +4 hours.

[0319] A single oral treatment of NMN (500 mg / kg) attenuated CYP-induced visceral pain at two time points, with a higher level of significance at +4 hours.

[0320] Administration of alpha-NMN (Compound A) reduced CYP-induced visceral pain at +2 and +4 hours, but the effect only reached significance at +4 hours.

[0321] In CYP-injected rats, oral treatment with Compound IA (Compound B) had no beneficial effect at +2 hours, but showed significant antinociceptive activity at later time points (i.e., +4 hours).

[0322] Thus, the inventors have demonstrated that the use of NMN and its pharmaceutically acceptable derivatives, such as alpha NMN and compound IA, according to the present invention, and compositions comprising them, provides the ability to reduce nociceptive pain, more specifically visceral pain induced by cystitis.

[0323] Thus, the use of NMN and its pharmaceutically acceptable derivatives, such as alpha NMN and Compound IA, according to the present invention, and compositions comprising them, provides the ability to treat and prevent pain, particularly nociceptive pain.

Claims

1. 1. A composition for use in the prevention and / or treatment of pain comprising nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, The NMN derivative is dihydronicotinamide mononucleotide (represented as NMN-H), or a compound selected from the following 1-A to 1-F, or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable crystal thereof; 【Transformation 7】 or The following II-A to II-F 【Transformation 8】 or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof; and combinations thereof, wherein the pain is nociceptive visceral pain and is not neuropathic pain.

2. 2. A composition for its use in the prevention and / or treatment of pain according to claim 1, for increasing the pain tolerance threshold.

3. 3. A composition for its use in the prevention and / or treatment of pain according to claim 1 or 2, for alleviating pain that worsens in response to pain-inducing stimuli.

4. 4. A composition for its use in the prevention and / or treatment of pain according to any one of claims 1 to 3, wherein the pain is pain caused by a urinary tract infection.

5. 5. A composition for its use in the prevention and / or treatment of pain according to any one of claims 1 to 4, further comprising at least one other therapeutic agent.

6. 6. The composition for its use in the prevention and / or treatment of pain according to claim 5, wherein the at least one other therapeutic agent is selected from among antibiotics, antifungals, antivirals, and combinations thereof.

7. 7. The composition for its use in the prevention and / or treatment of pain according to claim 5 or 6, wherein said at least one therapeutic agent is an analgesic.

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