Use of NMN for preventing and / or treating pain and corresponding compositions

Abstract

The present invention relates to nicotinamide mononucleotide, a pharmaceutically acceptable precursor, a pharmaceutically acceptable derivative or a pharmaceutically acceptable salt thereof for preventing and / or treating pain, especially nociceptive pain; the present invention also relates to a composition comprising the same.

Description

Field of the Invention

[0001] The present invention relates to nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing pain, in particular nociceptive pain. The present invention also relates to a composition comprising NMN, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing pain, in particular nociceptive pain. Background Art

[0002] Pain can be both a symptom and a disease. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with or resembling actual or potential tissue damage" (see the definition in the following link in the updated version of 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:

[0004] -The central nervous system is made up of the brain (brain), brainstem, cerebellum, and spinal cord. The central nervous system receives, registers, and interprets signals from the peripheral nervous system; and

[0005] -The peripheral nervous system consists of cranial and spinal nerves that are connected to the central nervous system and their corresponding terminals. The function of the peripheral nervous system is to (i) transmit information received by peripheral sensitive and pain receptors to the central nervous system and (ii) specifically transmit the instructions sent by the central nervous system to the muscles.

[0006] Pain is a complex phenomenon and can therefore be classified in different ways. There are three main categories of pain: nociceptive pain, neuropathic pain and central pain (also called central sensitization).

[0007] Nociceptive pain or peripheral pain is caused by the activation of nociceptors. Nociceptors are receptors located at the ends of nerve fibers. In the case of nociceptive pain, the nervous system is not affected. Nociceptive pain can be caused by a variety of different stimuli such as mechanical, thermal, chemical, inflammatory or infectious diseases. An example of nociceptive pain that can be cited is the pain due to a burn on the skin.

[0008] Neuropathic pain is caused by damage to the nerves of the peripheral nervous system. An example that can be cited is diabetic neuropathic pain.

[0009] Central pain is due to disruptions in pain processing in the central nervous system. Examples that can be cited include fibromyalgia or phantom limb pain.

[0010] In contrast, migraine is a type of pain that is distinct from any of the three above categories, so it is currently a separate category.

[0011] It should also be clarified that these categories of pain are not mutually exclusive and that patients may experience a variety of different categories of pain at the same time. In fact, if a major injury, cancer, or infectious disease occurs, the pathology may extend to the tissues and nerves present in the organs.

[0012] Nociceptive pain is often very responsive to conventional analgesic treatments. The World Health Organization classifies analgesics into three categories based on their effectiveness. Substances used to relieve pain are classified as analgesics.

[0013] Class I analgesics are used 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, and fenvalerate. NSAIDs include acetaminophen, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, and tenoxicam. NSAIDs are called nonsteroidal anti-inflammatory drugs to distinguish them from steroidal anti-inflammatory drugs or corticosteroids, which are derived from cortisol, one of the hormones released during stress. As examples of corticosteroids, mention may be made of betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone.

[0014] Class II analgesics are used to treat moderate or severe pain, or pain that is not adequately relieved by Class I analgesics; they include codeine, dihydrocodeine, and tramadol, used alone or in combination with aspirin or paracetamol.

[0015] Schedule III analgesics are used to treat severe pain that is resistant to other analgesics and include morphine and other opium derivatives such as buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, and pethidine.

[0016] However, not all of these treatments are free of adverse side effects. For example, the use of NSAIDs may cause various adverse reactions, such as bleeding, asthma, kidney problems, and more commonly, stomach diseases and ulcers. Paracetamol may cause liver toxicity. Aspirin thins the blood and attacks the stomach. Corticosteroids can cause weight gain, weakened immune defenses, weak bones, and corticosteroid dependence, which reduces their effectiveness. Codeine, dihydrocodeine, and tramadol can cause various adverse reactions, the most common of which are nausea, vomiting, constipation, drowsiness, and drug dependence. As for morphine and opium derivatives, they can cause serious adverse reactions, especially a high risk of physical and psychological dependence. In addition, an overdose of morphine can block the respiratory muscles and can be fatal.

[0017] Finally, some patients may develop allergies to conventional analgesics.

[0018] Therefore, there is a need to develop novel compositions for the treatment and / or prevention of pain that alleviate the disadvantages of prior art analgesics. SUMMARY OF THE INVENTION

[0020] These objectives are achieved thanks to nicotinamide mononucleotide (NMN) and compositions comprising the same for use in preventing and / or treating pain.

[0021] 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 preventing and / or treating pain.

[0022] Advantageously, the amount of NMN used includes 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 more preferably 10 mg / kg / day to 20 mg / kg / day.

[0023] In one embodiment, the NMN derivative is selected from: α-nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted as NMN-H), a compound having formula (I) or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable crystal thereof:

[0024] [Formula 1]

[0025]

[0026] in:

[0027] -X is selected from: O, CH2, S, Se, CHF, CF2 and C=CH2;

[0028] -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;

[0029] - R2, R3, R4 and R5 are independently selected from the group consisting of: H, halogen, azido, 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; R AA is a side chain selected from proteinogenic amino acids;

[0030] -R6 is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)alkylthio, (C1-C8)heteroalkyl and OR; wherein R is selected from H and (C1-C8)alkyl;

[0031] -R7 is selected from H, P(O)R9R 10 and P(S)R9R 10 ;in,

[0032] -R9 and R 10 Independently selected from: OH, OR 11 、NHR 13 NR 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 ;in:

[0033] -R11 Selected from the following group: (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)2; halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R 11a )2, C1-C6 acylamino, -COR 11b 、-O COR 11b ; NHSO2(C1-C6 alkyl), -SO2N(R 11a )2SO2; wherein each R 11a are independently selected from: H and (C1-C6) alkyl, and R 11b Independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2;

[0034] -R 12 Selected from H, C1-C 10 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 Haloalkyl, C 3- C 10 Cycloalkyl, C 3- C 10 Heterocycloalkyl, C5-C 18 Aryl, C1-C4 alkylaryl and C5-C 12Heteroaryl; wherein the aryl or heteroaryl is optionally substituted by one or two groups selected from the group consisting of halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; and

[0035] -R A and R A' Independently selected from: H, (C 1- C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) alkynyl, (C 3- C 10 )cycloalkyl, (C1-C 10 ) thioalkyl, (C 1- C 10 ) hydroxyalkyl, (C1-C 10 ) alkylaryl and (C5-C 12 ) aryl, (C 3- C 10 )heterocycloalkyl, heteroaryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from proteinogenic amino acids or non-proteinogenic amino acids; wherein the aryl group is optionally substituted by a group selected from the group consisting of hydroxyl, (C1-C 10 )alkyl, (C6-C1)alkoxy, halogen, nitro and cyano; or

[0036] -R9 and R 10 Together with the phosphorus atom to which it is attached, it forms a 6-membered ring, wherein –R9-R 10 - represents -CH2-CH2-CHR-; wherein R is selected from: H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano; or

[0037] R9 and R 10 Together with the phosphorus atom to which it is attached, it forms a 6-membered ring, wherein –R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from: H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0038] -R8 is selected from H, OR, NHR 13 NR 13 R 14 NH-NHR 13 , SH, CN, N3 and halogen; among which R13 and R 14 are independently selected from: H, (C1-C8)alkyl, (C1-C8)alkylaryl, and -CR B R C -C(O)-OR D , where R B and R C R is independently a hydrogen atom, a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a benzyl group, an indolyl group, or an imidazolyl group; wherein the (C1-C6) alkyl group and the (C1-C6) alkoxy group may be optionally and independently substituted with one or more of the following: a halogen, an amino group, an acylamino group, a guanidino group, a hydroxyl group, a thiol group, or a carboxyl group, and the benzyl group is optionally substituted with one or more halogen or hydroxyl groups; or B and R C Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group optionally substituted with one or more halogen, amino, amido, guanidino, hydroxyl, thiol and carboxyl groups; and R D is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (C3-C6)cycloalkyl;

[0039] -Y is selected from CH, CH2, C(CH3)2 and CCH3;

[0040] - represents a single bond or a double bond along Y; and

[0041] - represents the α or β anomer, depending on the position of R1;

[0042] or its stereoisomers, salts, hydrates, solvates or crystals;

[0043] or

[0044] A compound having formula (II) or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof:

[0045] [Formula 2]

[0046]

[0047] in,

[0048] X'1 and X'2 are independently selected from: O, CH2, S, Se, CHF, CF2 and C=CH2;

[0049] R'1 and R' 13 Independently 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;

[0050] R'2, R'3, R'4, R'5, R'9, R' 10 , R' 11 , R' 12 are independently selected from: H, halogen, azido, cyano, hydroxyl, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Heteroalkyl, C1-C 12 Haloalkyl and OR; wherein R can be 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 )aryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 )alkylaryl or C(O)CHR AA NH2; R AA is a side chain selected from proteinogenic amino acids;

[0051] R'6 and R'8 are independently selected from: H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl;

[0052] R'7 and R' 14 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;

[0053] Y'1 and Y'2 are independently selected from: CH, CH2, C(CH3)2 or CCH3;

[0054] M' is selected from: H or a suitable counterion;

[0055] represents a single bond or a double bond, depending on Y'1 and Y'2; and

[0056] Denotes the α or β anomer, depending on the R'1 and R' 13 location;

[0057] and their combinations.

[0058] In a preferred first embodiment, the pharmaceutically acceptable derivative is a compound of formula (I).

[0059] In a variant of the first embodiment, X represents O.

[0060] In a variant of the first embodiment, R1 and R6 each independently represent H.

[0061] In a variant of the first embodiment, R2, R3, R4 and R5 each independently of one another represent H or OH.

[0062] In a variant of the first embodiment, Y represents CH.

[0063] In a variant of the first embodiment, Y represents CH2.

[0064] In a variant of the first embodiment, R7 represents H.

[0065] In a variant of the first embodiment, R7 represents P(O)(OH)2.

[0066] In a variation of the first embodiment,

[0067] X means O; and / or

[0068] R1 and R6 each independently represent H; and / or

[0069] R2, R3, R4 and R5 each independently represent H, or R2, R3, R4 and R5 each independently represent OH; and / or

[0070] Y represents CH or CH2; and / or

[0071] R7 represents P(O)R9R 10 , where R9 and R 10 Independently selected from: OH, OR 11 、NHR 13 NR 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 .

[0072] In a particularly preferred variant of the first embodiment, the compound of the invention is selected from compounds of the formulae IA to IH:

[0073] [Table 1]

[0074]

[0075] In a preferred second embodiment, the pharmaceutically acceptable derivative is a compound of formula (II).

[0076] In a variation of the second embodiment, X'1 and X'2 each independently represent O.

[0077] In a variation of the second embodiment, R'7 and R'14 each independently represent NH2.

[0078] In a variation of the second embodiment, R'1 and / or R'13 each independently represent H.

[0079] In a variation of the second embodiment, R'6 and / or R'8 each independently represent H.

[0080] In a 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 H.

[0081] In a variation of the second embodiment, R'2, R'3, R'4, R'5, R'9, R'10, R'11 each independently represent OH.

[0082] In a variation of the second embodiment, Y'1 and Y'2 each independently represent CH.

[0083] In a variation of the second embodiment, Y'1 and Y'2 each independently represent CH2.

[0084] In one variant of the second embodiment, the compound of the invention is selected from compounds having formulae II-A to II-F:

[0085] [Table 2]

[0086]

[0087] In one variation of the preferred first embodiment, the pharmaceutically acceptable derivative is α-NMN having the formula:

[0088] [Formula 3]

[0089]

[0090] In a preferred fourth embodiment, the pharmaceutically acceptable derivative is NMN-H:

[0091] [Formula 4]

[0092]

[0093] Advantageously, the pharmaceutically acceptable precursor is nicotinamide riboside (denoted NR):

[0094] [Formula 5]

[0095]

[0096] Or dihydronicotinamide riboside (denoted as -NR-H) having the formula:

[0097] [Formula 6]

[0098]

[0099] Advantageously, nicotinamide mononucleotide (NMN), a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof can be administered by a variety of routes: orally, ocularly, sublingually, parenterally, transdermally, vaginally, epidurally, intravesically, rectally, or by inhalation.

[0100] Preferably, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is administered orally or parenterally.

[0101] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used to treat and / or prevent pain in mammals, preferably humans.

[0102] In a preferred embodiment, the pain is nociceptive pain.

[0103] In a preferred embodiment, the pain is not neuropathic pain.

[0104] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used to reduce allodynia.

[0105] Advantageously, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof is used to reduce hyperalgesia.

[0106] Advantageously, the pain is visceral pain.

[0107] Advantageously, the pain is pain in the urinary system (or urogenital system).

[0108] Advantageously, the pain is pain caused by a urinary tract infection.

[0109] 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.

[0110] Advantageously, the at least one additional therapeutic agent is selected from the group consisting of antibiotics, antifungal agents, antiviral agents, and combinations thereof.

[0111] Advantageously, at least one therapeutic agent is an analgesic.

[0112] Advantageously, the analgesic is selected from the group consisting of paracetamol, aspirin, nonsteroidal anti-inflammatory drugs, cortisone derivatives and combinations thereof.

[0113] Advantageously, the nonsteroidal anti-inflammatory drug is selected from the group consisting of 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.

[0114] Advantageously, the cortisone derivative is selected from the group consisting of betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone and combinations thereof.

[0115] Advantageously, the analgesic is selected from the group consisting of codeine, dihydrocodeine, tramadol and combinations thereof.

[0116] Advantageously, the analgesic is selected from the group consisting of morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine, and combinations thereof.

[0117] The present invention also relates to a composition comprising the nicotinamide mononucleotide, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof as described above and at least one pharmaceutically acceptable excipient for preventing and / or treating pain.

[0118] Advantageously, the composition according to the invention is in the form of a tablet, capsule, sachet, granules, soft gelatin capsule, lozenge, lyophilisate, suspension, gel, syrup, solution, water / oil emulsion, oil / water emulsion, oil, cream, milk, spray, ointment, ampoule, suppository, eye drops, vaginal ovules, vaginal capsule, inhalation liquid, dry powder inhaler, pressurized metered dose inhaler.

[0119] Preferably, the composition according to the invention is in the form of a gastro-resistant capsule or a sublingual tablet.

[0120] Advantageously, the composition according to the invention is a pharmaceutical composition.

[0121] Advantageously, the composition according to the invention is a dietary supplement.

[0122] The present invention also relates to a composition comprising the nicotinamide mononucleotide as described above, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient and at least one other therapeutic agent, for preventing and / or treating pain.

[0123] definition

[0124] In the present invention, the following terms have the following meanings.

[0125] Unless otherwise indicated, nomenclature for substituents not explicitly defined herein is by naming the terminal portion of the functionality followed by the adjacent functionality proximal to the point of attachment.

[0126] "Alkyl" by itself or as part of another substituent refers to a hydrocarbon radical having the formula CnH2n+1, wherein n is a number greater than or equal to 1. Typically, the alkyl radicals of the present invention contain 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and even more preferably 1-2 carbon atoms. The alkyl radicals may be straight chain or branched and may be substituted as described herein. Alkyl radicals suitable for the purposes of the present invention may be selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; pentyl and its isomers, such as n-pentyl and isopentyl; hexyl and its isomers, such as n-hexyl and isohexyl; heptyl and its isomers (e.g., n-heptyl, isoheptyl); octyl and its isomers (e.g., n-octyl, isooctyl); nonyl and its isomers (e.g., n-nonyl, isononyl); decyl and its isomers (e.g., n-decyl, isodecyl); undecyl and its isomers; dodecyl and its isomers. Preferably, the alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched alkyl groups may be selected from the group consisting of, but 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. , 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl and 3,3-diethylhexyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Cx-Cy alkyl refers to an alkyl group containing x to y carbon atoms.

[0127] When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, it indicates that the alkyl group, as defined herein, has two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene and 1,2-dimethylethylene.

[0128] The term "alkenyl" as used herein refers to an unsaturated hydrocarbon group which may be linear or branched, containing one or more carbon-carbon double bonds. Suitable alkenyl groups contain 2-12 carbon atoms, preferably 2-8 carbon atoms, and even more preferably 2-6 carbon atoms. Examples of alkenyl groups are vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and other similar groups.

[0129] As used herein, the term "alkynyl" refers to a class of monovalent unsaturated hydrocarbon groups, wherein the unsaturation is caused by the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically and preferably have the same number of carbon atoms as alkenyl groups described above. Some examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and isomers thereof, 2-hexynyl and isomers thereof, and the like.

[0130] "Alkoxy" refers to an alkyl group as defined above, which is attached to another moiety via an oxygen atom. Examples of alkoxy groups include the following: methoxy, isopropoxy, ethoxy, tert-butoxy, etc. Alkoxy groups may be optionally substituted with one or more substituents. Alkoxy groups contained in the compounds of the present invention may optionally be substituted with solubilizing groups.

[0131] As used herein, "aryl" refers to a polyunsaturated aromatic hydrocarbon group having a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently bonded, which generally contains 5 to 18 atoms, preferably 5 to 12 atoms, more preferably 6 to 10 atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one or two other rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems listed herein. Examples of aryl include: phenyl, biphenyl, biphenylene, 5- or 6-tetralinyl; naphthalene-1-yl or naphthalene-2-yl; 4-indenyl, 5-indenyl, 6-indenyl, or 7-indenyl; 1-acenaphthyl, 2-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl, or 5-acenaphthyl; 3-acenaphthyl, 4- acenaphthenyl or 5-acenaphthenyl; 1-pentalenyl or 2-pentalenyl; 4-indanyl or 5-indanyl; 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl or 8-tetrahydronaphthyl; 1,2,3,4-tetrahydronaphthyl; 1,4-dihydronaphthyl; 1-pyrenyl, 2-pyrenyl, 3-pyrenyl, 4-pyrenyl or 5-pyrenyl.

[0132] 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.

[0133] "Alkylaryl" refers to an aryl group substituted with an alkyl group.

[0134] "Amino acid" refers to an alpha-amino carboxylic acid, that is, a molecule comprising a carboxylic acid functional group and an amino functional group located alpha to the carboxylic acid group, such as a proteinogenic amino acid or a non-proteinogenic amino acid.

[0135] "Proteinogenic amino acid" refers to an amino acid that is incorporated into proteins during the translation of messenger RNA in ribosomes in an organism, i.e., alanine (ALA), arginine (ARG), asparagine (ASN), aspartic acid (ASP), cysteine ​​(CYS), 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).

[0136] As used herein, "non-proteinogenic amino acids" refer to amino acids that are not naturally encoded or found in the genetic code of an organism. Without limitation, some examples of non-proteinogenic amino acids are: ornithine, citrulline, argininosuccinic acid, homoserine, homocysteine, cysteinesulfinic acid, 2-aminomucic acid, delta-aminolevulinic acid, beta-alanine, cystathionine, gamma-aminobutyric acid, dihydroxyphenylalanine (DOPA), 5-hydroxytryptophan, D-serine, ibotenic acid, alpha-aminobutyric acid, 2-aminoisobutyric acid, D-leucine, D-valine, D-alanine, and D-glutamic acid.

[0137] The term "cycloalkyl" used herein refers to a cycloalkyl group having 1 or 2 ring structures, i.e. a monovalent saturated or unsaturated hydrocarbon group. The term "cycloalkyl" includes monocyclic or bicyclic hydrocarbon groups. According to the present invention, the cycloalkyl group may contain 3 or more carbon atoms in the ring, and typically contains 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and particularly preferably cyclopropyl.

[0138] The term "pharmaceutically acceptable excipient" refers to an inert carrier or carrier material used as a solvent or diluent, in which the active ingredient is formulated and / or administered, and does not produce adverse, allergic or other reactions when it is administered to animals (preferably humans). It includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents and other similar ingredients. For human administration, the preparation must meet the specific standards of sterility, conventional safety and purity required by regulatory agencies 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 excipients" include all pharmaceutically acceptable excipients and all pharmaceutically acceptable carriers, diluents and / or adjuvants.

[0139] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine.

[0140] "Haloalkyl", alone or in combination, refers to an alkyl group having the meanings as defined above, wherein one or more hydrogen atoms are replaced by a halogen as defined above. As examples of such haloalkyl groups, the following groups may be mentioned: chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and similar radicals. 'Cx-Cy haloalkyl' and 'Cx-Cy alkyl' refer to an alkyl group containing from x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

[0141] "Heteroalkyl" refers to an alkyl group as described above in which one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen and sulfur atoms. In a heteroalkyl group, heteroatoms are bonded only to carbon atoms along the alkyl chain, that is, each heteroatom is separated from every other heteroatom by at least one carbon atom. However, the nitrogen heteroatom and the sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. A heteroalkyl group is bonded to another group or molecule only through a carbon atom, that is, the bonded atom is not selected from the heteroatoms contained in the heteroalkyl group.

[0142] The term "heteroaryl" as used herein, alone or as part of another group, refers to, but is not limited to, an aromatic ring of 5 to 12 carbon atoms or a ring system containing 1 or 2 rings fused or covalently bonded, which generally contain 5 or 6 atoms, at least one of which is aromatic; wherein one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. These rings may be fused to form aryl, cycloalkyl, heteroaryl or heterocyclyl rings. Without limitation, some examples of heteroaryl groups include furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3 ]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, 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-benzothiazolyl, thienylpyridinyl, purinyl, imidazo[l, 2-a] pyridyl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0143] 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."

[0144] The term "heterocyclic radical", "heterocycloalkyl" or "heterocycle" as used herein or as part of another group refers to a fully saturated or partially unsaturated non-aromatic ring group (e.g., 3 to 7-membered monocyclic ring, 7 to 11-membered bicyclic ring or containing a total of 3 to 10 ring atoms), which contains at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Any carbon atom of the heterocyclic radical may be substituted by an oxygenate (e.g., piperidone, pyrrolidone). The heterocyclic group may be connected to any heteroatom or carbon atom in the ring or in the ring system when valence permits. The rings of polycyclic heterocycles may be fused, bridged and / or connected by one or more spiro atoms. Exemplary heterocyclic groups include, but are not limited to, the following: 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-dioxoimidazolidinyl, 2-oxypiperidinyl, 2-oxypyrrolyl, indolyl, 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-pyrrolizinyl, tetrahydro-1,1-dioxythiophenyl, N-formylpiperazinyl and morpholin-4-yl.

[0145] The term "precursor" as used herein also refers to a pharmaceutically acceptable derivative of a compound of formula (I) or (II), such as an ester, whose in vivo biotransformation product is an active drug. The precursor is characterized by increased bioavailability and is easily metabolized into an active compound in vivo. Precursors suitable for the purposes of the present invention specifically include: carboxylic acid esters, especially alkyl esters, aryl esters, acyloxyalkyl esters and dioxole carboxylic acid esters; ascorbic acid esters.

[0146] "Pharmaceutically acceptable" refers to a state of being approved, or likely to be approved by a regulatory agency, or listed in a recognized pharmacopoeia for use in animals, more preferably in humans. It may be associated with a biologically or otherwise undesirable substance; that is, the substance can be administered to an individual without causing an adverse biological effect or a harmful / toxic interaction with one of the components of a composition containing it. Preferably, a "pharmaceutically acceptable" salt or excipient refers to any salt or excipient approved by the European Pharmacopoeia (known as the "European Pharmacopoeia") and the United States Pharmacopoeia (known in English as the "American Pharmacopoeia" (USP)).

[0147] The term "active ingredient" refers to a molecule or substance that, when administered to a subject, slows or stops the progression, aggravation, or worsening of one or more symptoms of a disease or condition; relieves the symptoms of a disease or condition; cures a disease or condition. According to one of these embodiments, the therapeutic ingredient is a natural or synthetic small molecule. According to another embodiment, the therapeutic ingredient is a biomolecule, such as an oligonucleotide, a small interfering RNA (siRNA), a micro RNA (miRNA), a DNA fragment, an aptamer, an antibody, and the like. "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 that may be cited include: acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, cyclamates, edisylate, ethanesulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, hyaluronates, hydrochlorides / chlorides, hydrobromides / bromides, hydroiodides / iodides, isethionates, lactates, malates, maleates, malonates, methanesulfonates, methylsulfates, naphthylates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogenphosphates / dihydrogenphosphates, pyroglutamates, sucrose, stearates, succinates, tannates, tartrates, toluenesulfonates, trifluoroacetates and salts of xinofoate. Suitable base addition salts are formed from bases that form non-toxic salts. For example, the following salts formed may be mentioned: aluminum, arginine, benzathine penicillin, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc. Hemi-salts of acids and bases may also be formed, such as hemisulphates and chemical calcium salts. Preferred pharmaceutically acceptable salts are hydrochlorides / chlorides, bromides / hydrobromides, bisulfates / sulfates, nitrates, citrates and acetates.

[0148] Pharmaceutically acceptable salts can be prepared by one or more of the following methods:

[0149] i. reacting the compound with the desired acid;

[0150] ii. reacting the compound with a desired base;

[0151] iii. removing an acid-labile or base-labile protecting group from a suitable precursor of the compound under basic or acidic conditions, or ring-opening a suitable cyclic precursor (eg, a lactone or lactam) using the desired acid; or

[0152] iv. Converting one salt of a compound to another by reacting the initial salt with an appropriate acid or passing it through an appropriate ion exchange column.

[0153] All of these reactions are usually carried out in solution. Salts may precipitate from solution and may be collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the salt may vary from completely ionized to nearly non-ionized.

[0154] "Solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, ethanol).

[0155] The term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced by any desired group which is substantially stable under the reaction conditions in an unprotected form or which is substantially stable when protected by a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chlorine, iodine, bromine or fluorine); alkyl; alkenyl; alkynyl as described above; hydroxyl; alkoxy; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be a condensed or non-condensed ring monocyclic or polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); or heterocycloalkyl, which may be a fused or non-fused ring monocyclic or polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); fused or non-fused monocyclic or polycyclic, aryl or heteroaryl (e.g., aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); substituted with a fused ring bridge or structure, for example -OCH2O-. These substituents may be optionally further substituted by substituents selected from these groups. In certain expressions, the term "substituent" or the adjective "substituted" refers to a substituent 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 , halogen, -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 11R 12 、-NR 13 C(O)OR 14 、-S(O)rR13、-NR 13 S(O)r 14 、-OS(O)rR 14 、S(O)rNR 11 R 12 , -O, -S, and -NR 13 , where r is 1 or 2; for each case, R 11 and R 12 R is 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 aralkyl, or optionally substituted heteroaralkyl; or R 11 and R 12 and the nitrogen to which it is attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and for each occurrence, R 13 and R 14 is 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 aralkyl, or optionally substituted heteroaralkyl. In some variations, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0156] The term "administering" or variations of that term (eg, "administering") means providing an active ingredient, either alone or as part of a pharmaceutically acceptable composition, to a patient who is to receive the active ingredient in the context of treating or preventing a condition, symptom or disease.

[0157] As used herein, the terms "treat," "cure," and "treatment" are meant to include alleviating, alleviating, or eliminating a condition, disease, or symptoms associated therewith.

[0158] As used herein, the terms "prevent," "suppress," and "prevent" refer to a method for delaying, arresting, or preventing the onset of a disorder, disease, or related symptoms; preventing a patient from contracting a disorder or disease; or reducing a patient's risk of contracting a particular disease or disorder.

[0159] In this article, the bonds of asymmetric carbons are represented by solid triangles. Point Triangle or zigzag line express. DETAILED DESCRIPTION OF THE INVENTION

[0161] The subject matter of the present invention relates to the use of nicotinamide mononucleotide (NMN), a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof for preventing and / or treating pain.

[0162] The subject matter of the present invention also relates to the use of 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 preventing and / or treating pain.

[0163] Nicotinamide adenine dinucleotide (NAD) is a coenzyme present in all living cells. NAD exists in cells in the oxidized form NAD+ or the reduced form NADH. The role of NAD is to participate in the redox reactions of metabolism as an electron carrier. In addition, NAD is also involved in many cellular processes, such as adenosine diphosphate (ADP) ribosylation, a post-translational modification of proteins.

[0164] NAD can be synthesized de novo by cells from amino acids such as tryptophan or aspartate. However, this synthesis is negligible because the major pathway for NAD synthesis is the salvage pathway, by which cells (primarily the nucleus) reuse compounds to re-form NAD from precursors. Precursors of NAD include nicotinic acid, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide.

[0165] NMN is one of the compounds capable of synthesizing NAD through the salvage pathway and has the following formula:

[0166] [Formula 7]

[0167]

[0168] The inventors have indeed 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 can achieve pain effects comparable to those of drugs commonly used to treat pain. More precisely, the use of NMN and the composition according to the present invention provides the ability to prevent pain because it provides a method for reducing the intensity of pain produced in response to painful stimuli. 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 for treating existing pain.

[0169] In addition, NMN is a molecule that naturally occurs in the human body, and the use of NMN has many advantages. In particular, patients have good tolerance to NMN and the composition according to the present invention. The use of NMN and the composition according to the present invention does not actually cause any allergies in patients. In addition, the use of NMN and the composition according to the present invention does not induce adverse side effects that are often encountered with conventional analgesics, such as ulcers, liver toxicity, blood thinning, drowsiness, nausea and vomiting.

[0170] In addition, unlike analgesics containing morphine or opium derivatives, NMN does not induce any physiological or psychological dependence. Therefore, the use of NMN and the composition according to the present invention for the prevention and / or treatment of pain is safe for patients.

[0171] Therefore, NMN and the composition according to the invention can be used in children and adults. NMN is indeed well tolerated by children. In the context of the present invention, when the patient is less than 16 years old, he is considered a child, and from 16 years old, he is considered an adult.

[0172] In a preferred embodiment, NMN is in the form of a zwitterion. The term "zwitterion" is understood to be a molecular chemical species having charges of opposite signs on non-adjacent atoms, usually located in the molecule.

[0173] Pharmaceutically acceptable excipients may be selected from fillers, lubricants, flavoring agents, colorants, emulsifiers, compression agents, diluents, preservatives, gelling agents, plasticizers, surfactants or combinations thereof. Those skilled in the art will know to determine the excipients to be selected based on the galenic dosage form to be selected.

[0174] In the context of the present invention, "excipient" refers to any substance other than NMN that is present in the composition and has no therapeutic effect. An excipient does not chemically react with NMN or any other additional therapeutic agent.

[0175] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt, and the combination of the present invention can be administered in a therapeutically effective amount. In the context of the present invention, a therapeutically effective amount means administering the composition to a patient in an appropriate amount sufficient to achieve the desired therapeutic effect, in this case, reducing pain perception.

[0176] In one embodiment, the amount of NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative, or its pharmaceutically acceptable salt used includes 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, more preferably 10 mg / kg / day to 20 mg / kg / day. Those skilled in the art can adjust the dose of NMN to be administered according to the age and weight of the patient and the intensity of the pain to be treated.

[0177] Suitable dosage levels can 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 dosage can be 0.05 to 0.5 mg / kg / day, 0.5 to 5 mg / kg / day, or 5 to 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, especially 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of active ingredient, for adjusting the dosage according to the symptoms of the patient to be treated. For example, the dosage may include 100 mg / day to 5000 mg / day, preferably 500 mg / day to 1000 mg / day. The compound may be administered according to a regimen of 1-4 times a day, preferably once, twice or three times a day, preferably three times a day. The duration of treatment depends on the doctor and is determined by the doctor. This may be one day to one year or even longer, preferably one week to three months, more preferably two weeks to six weeks. However, it is understood that specific dosage levels and frequency of administration and duration for a given patient may vary and will depend on a variety of factors, particularly the potency of the specific compound employed, the metabolic stability and duration of action of that compound, the subject's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination and subject being treated.

[0178] NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof can be administered at a daily dose of 10 mg / kg, with a minimum of 50 mg / kg and a maximum of 1000 mg / kg.

[0179] There are different pain scales to assess pain, depending on the patient's age and their cognitive status, and these scales are well known to those skilled in the art. There are scales for:

[0180] - Self-assessment (self-report) by a patient who is able to communicate the intensity or characteristics of pain, either an adult or a child 4-6 years (school age);

[0181] - Hetero-assessment, i.e. pain assessment by caregivers of adults who are unable to communicate (elderly, intensive care patients, people with multiple disabilities, etc.) or children under 4 years of age.

[0182] Specific scales for children to self-report pain include the vertical visual analog (VAS) scale, the number (NS) scale, the face pain scale, the poker chips scale, and a body scale in which children indicate the location of pain.

[0183] Heterotactic assessment scales for acute pain in children include the neonatal face coding system (NFCS), the neonatal pain scale (NIPS), a scale based on observations of facial expressions, leg and arm movements, crying, and consolability (i.e., “face, legs, activities, crying, consolability,” or FLACC), the comfort scale (or “comfort behaviors” scale), the Premature Infant Pain Profile (or PIPP), the Pediatric Outpatient Acute Pain Scale (or the Children’s Hospital of Eastern Ontario CHEOPS pain scale), and the French pediatric pain scale ENVENDOL (children’s evaluation of pain). Heterotactic assessment scales for chronic pain in children include: the French Neonatal Pain and Discomfort Scale EDIN (Evaluation de Douleur et d'Inconfort du Nouveau-né), objective pain scales, the Amiel-Tison system and reverse scoring, the Gustave-Roussy Children's Pain Rating Scale (Douleur Enfant Gustave-Roussy-DEGR), the French Children's Pain Heterotactic Assessment Scale HEDEN (Hétéro Evaluation de la Douleurde l'Enfant), and the Saint-Antoine Pain Questionnaire (Questionnaire de la Douleur de Saint-Antoine-QDSA).

[0184] Self-assessment (self-report) scales for adults include the vertical visual analog scale, the numeric rating scale (NRS), and the simple verbal rating scale (VRS). Heterotonic assessment scales for adults include: the Algoplus test, the Doloplus test, and the Elderly Behavioral Pain Assessment Scale (ECPA). Finally, there is a specific test for assessing neuropathic pain: the DN4 test (Douleur Neuropathique 4 Questions).

[0185] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt and the composition of the present invention can be administered once a day or multiple times a day. Specifically, NMN and the composition of 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.

[0186] The dose given and how often it is given depends on the intensity of the pain the patient is experiencing.

[0187] application

[0188] According to the present invention, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt and the composition of the present invention are used to prevent and / or treat pain. In one embodiment, the pain is not neuropathic pain. Preferably, the pain is nociceptive pain.

[0189] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt and the composition of the present invention can be used in particular to reduce sensitivity to pain. In one embodiment, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt and the composition comprising it according to the present invention are used to reduce touch pain. In the context of the present invention, touch pain is a painful sensation produced in response to a stimulus that does not normally cause pain. In other words, in the case of touch pain, 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 the composition comprising it according to the present invention can restore the patient's normal pain tolerance threshold, eliminate or at least reduce the touch pain phenomenon. Various different techniques well known to those skilled in the art are used to evaluate human touch pain. For example, human touch pain can be measured by stimulating with different filaments after a wound (postoperative surface), intradermal injection of capsaicin or heating of the skin (von Frey test principle). Allodynia can also be measured by questionnaires in which patients indicate their pain score after, for example, immersing their hand in ice, or heating an area at a given temperature for a given period of time, or applying a defined pressure to different sites (arm, knee, perineum, anus, etc.). Another possible assessment method is to stimulate an area with a known non-pain-inducing stimulus and assess the pain felt by the patient by questionnaire.

[0190] In one embodiment, NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, and a composition of the present invention are used to reduce hyperalgesia. In the context of the present invention, hyperalgesia is defined as increased pain in response to a painful stimulus.

[0191] In one embodiment, pain is visceral pain. In the context of the present invention, visceral pain is caused by activation of nociceptors in the chest, abdomen and pelvic organs. The pain may particularly include a sense of distension, a sense of cutting, a burning sensation and a combination thereof. "Distension" refers to any symptom, such as stretching, cramping, pulling, compression or squeezing, and twisting. Visceral pain may particularly be caused by sudden traction of the mesentery, stretching of the serosal membrane, secondary expansion caused by compression of the viscera, and expansion of hollow organs such as the stomach or intestines. From a clinical point of view, visceral pain may be caused by inflammation, infection, disruption of normal mechanical processes (such as gastrointestinal dysmotility, tumors and ischemia).

[0192] In one embodiment, visceral pain is pain felt in the female or male urogenital tract. The urinary system (or urogenital system) includes the kidneys, ureters, bladder, urethra, female reproductive system, male reproductive system, ovaries, and testicles.

[0193] The pain may be indicative of interstitial cystitis in particular. Interstitial cystitis or painful bladder syndrome is an inflammatory disease of the bladder characterized by abnormal urination (urgency and / or frequency) and significant pain in the lower abdomen and bladder, and in women, the urethra (the tube that carries urine from the bladder to the outside of the body) or vagina, sometimes accompanied by dysuria. The severity of symptoms varies from person to person. The pain may also be attributed to inflammation of the urogenital tract that is not caused by bacteria, fungi, or viruses. For example, pain can be caused by non-microbial cystitis.

[0194] In one embodiment, visceral pain is pain caused by a urinary tract infection. Urinary tract infections can be caused by bacterial, fungal or viral infections or a combination thereof. Urinary tract infections may affect multiple organs of the urogenital system, such as the kidneys, ureters, bladder, urethra and prostate. It is usually manifested as pain during urination, with or without a burning sensation. Urinary tract infections can be cystitis, urethritis, pyelonephritis, prostatitis or a combination thereof.

[0195] Cystitis is the most common urinary tract infection. This is an inflammation of the bladder. Cystitis may be caused by the proliferation of intestinal bacteria (e.g., Escherichia coli) that are present in large numbers around the anus. In women, the bacteria enter the bladder from the anal area through the urethra, causing local inflammation. In men, cystitis is usually caused by bacterial infections such as chlamydia or gonococcal infections. Cystitis may sometimes be caused by fungal infections such as Candida albicans.

[0196] Urethritis refers to inflammation of the urethra (that is, the tube that connects the bladder to the urethra). Since the prostate gland in men is located near the urethra, inflammation may also affect the prostate gland, in which case the condition is equivalent to prostatitis.

[0197] Pyelonephritis is inflammation of the renal pelvis (that is, the cavity in the kidney that collects urine). It is usually caused by a bacterial infection, especially untreated cystitis. In this case, the bacteria travel up the ureter and infect the kidney.

[0198] In a preferred embodiment, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt, and the composition of the present invention are used to treat or prevent pain caused by cystitis. Therefore, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt, and the composition of the present invention provide a method for treating pain caused by urinary tract infection.

[0199] Methods of administration and dosage forms

[0200] NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt, and the composition of the present invention are administered by various routes: oral, ocular, inhalation, sublingual, intravenous, intraarterial, intramuscular, subcutaneous, transdermal, vaginal, epidural, topical, intravesical, or rectal. Preferably, NMN and the composition according to the present invention are administered by oral route.

[0201] The composition according to the present invention can be in the form of tablets, capsules, sachets, granules, soft capsules, lyophilized agents, lozenges, suspensions, gels, syrups, solutions, water / oil emulsions, oil / water emulsions, oils, creams, milks, sprays, ointments, ampoules, suppositories, eye drops, vaginal ovules, vaginal capsules, inhaled liquids, dry powder inhalers, pressurized metered dose inhalers. Preferably, the composition according to the present invention is in the form of enteric-coated capsules or sublingual tablets.

[0202] The term "enteric" (gastro-resistant) is understood to mean a pharmaceutical dosage form that is insoluble in the stomach. This pharmaceutical dosage form is designed to be delayed release, that is, it has a coating or coating composition that can resist the acidic pH of the stomach (pH<2) and can dissolve in the intestine. Enteric solubility is determined according to the test established by the European Pharmacopoeia. In short, the enteric solubility of the capsule is measured in 0.1M hydrochloric acid at 37°C as a disintegration medium in a disintegration device. The medium simulates the physicochemical conditions of the stomach. The capsules are incubated in the medium for 1 hour. The capsules should not show signs of disintegration or cracking that may cause the contents of the capsule to be lost. The capsules are then incubated for 1 hour in a phosphate buffer solution with a pH of 6.8 and a temperature of 37°C, which simulates the intestinal environmental conditions according to the recommendations of the European Pharmacopoeia. The capsules should completely disintegrate in less than one hour.

[0203] The term "sublingual tablet" is to be understood as a pharmaceutical dosage form which is placed under the tongue so that the active ingredient is absorbed by the sublingual mucosa, in particular by the sublingual veins and arteries.

[0204] The composition of the present invention can also be a pharmaceutical dosage form designed for immediate release: the pharmaceutical dosage form facilitates the rapid absorption of nicotinamide adenine dinucleotide (NAD) precursors, thereby shortening the onset of action. The immediate release pharmaceutical dosage form specifically includes dispersible tablets, oral dispersible tablets, effervescent tablets and oral lyophilized tablets.

[0205] The composition of the invention may also be a pharmaceutical dosage form designed for sustained release (delayed release). The dissolution and absorption of the NAD precursor occurs in the intestine, thereby limiting gastric irritation or degradation of the active ingredient that is vulnerable at acidic pH. These are mainly enteric forms, that is, tablets or granules are coated with a polymer film that is insoluble in acidic media but is permeable to water in alkaline media or lipid media degraded by intestinal lipases.

[0206] The composition of the present invention can also be a pharmaceutical dosage form designed for sequential sustained release. Pharmaceutical dosage forms with sequential release (release at precise time intervals) and sustained release (active ingredient is continuously released until depleted) promote the diffusion release of active ingredients over time to ensure that effective plasma concentrations are maintained in the patient's body for a longer period of time. The pharmaceutical dosage form provides a method for patients to relieve pain over a longer period of time and use drug doses at intervals.

[0207] The skilled artisan will determine the appropriate mode of administration and dosage form of the drug based on the anatomical location of the pain to be treated and the patient's relevant information. In this regard, reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0208] The compositions of the present invention can be formulated with carrier materials or carriers, excipients and diluents suitable for these preparations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gum tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, polyethylene glycol, cellulose, water (sterile), methylcellulose, methyl and propyl hydroxybenzoate, talc, magnesium stearate, edible oils, vegetable oils and mineral oils, or suitable mixtures thereof. The preparations may optionally contain other substances commonly used in pharmaceutical preparations, such as lubricants, wetting agents, emulsifiers and suspending agents, dispersants, disintegrants, fillers, fillers, preservatives, sweeteners, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated in a manner that allows rapid, continuous or slow (delayed) release of the active compound contained therein.

[0209] The compositions of the present invention are preferably in unit dosage form and may be packaged in an appropriate manner, such as boxes, blister packs, vials, bottles, sachets, ampoules, or in any other suitable carrier or container suitable for single or multiple dose packaging (which may be appropriately labeled); optionally with one or more package inserts containing product-related information and / or instructions for use.

[0210] Treatment Combinations

[0211] Advantageously, NMN, its pharmaceutically acceptable precursor, its pharmaceutically acceptable derivative or its pharmaceutically acceptable salt, and the composition of the present invention are used in combination with at least one other therapeutic agent. In one embodiment, the composition of 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 other therapeutic agent.

[0212] Advantageously, at least one therapeutic agent is selected from the group consisting of: antibiotics, antifungals, antivirals, and combinations thereof. Thus, the use of NMN, its pharmaceutically acceptable precursors, its pharmaceutically acceptable derivatives, or its pharmaceutically acceptable salts, and the compositions of the present invention can reduce nociceptive pain associated with bacterial, fungal, or viral infections, or combinations thereof. For example, NMN, its pharmaceutically acceptable precursors, its pharmaceutically acceptable derivatives, or its pharmaceutically acceptable salts, or the compositions of the present invention can be used in combination with antibiotics. The combination may prove useful for topical application, for example, a lozenge for the throat, which, on the one hand, can reduce the microbial load in cases of bacterial angina and relieve pain associated with local inflammation. NMN, its pharmaceutically acceptable precursors, its pharmaceutically acceptable derivatives, or its pharmaceutically acceptable salts, or the compositions of the present invention may also be used in combination with antifungals. For example, the combination may prove useful for the treatment or prevention of urinary tract, vaginal, skin fungal diseases, and the like.

[0213] In one embodiment, the antibiotic may be selected from the group consisting of: beta-lactams, cyclins, macrolides, related macrolides, quinolones, fluoroquinolones, quinolines, aminoglycosides, fusidic acid, lincosamides, choleretics, polymyxins, sulfonamides, whether or not associated with trimethoprim, antileper, fosfomycin, mupirocin, nitrofurantoin, nitrofurans, nitroimidazoles, oxazolidinones, glycopeptides, lipopeptides, polymyxins, and anti-tuberculosis drugs.

[0214] In one embodiment, the antifungal agent can be selected from the group consisting of amphotericin B, flucytosine, azole derivatives, terbinafine, selenium sulfide, trichlocarban, nystatin, griseofulvin, amorolfine, salicylic acid, ciclopiroxolamine, amorolfine, tolfanate, and combinations thereof.

[0215] The antifungal azole derivative may be particularly selected from the group consisting of bifonazole, clotrimazole, econazole, fenticonazole, fluconazole, isoconazole, itraconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, voriconazole and combinations thereof.

[0216] Antiviral drugs can be selected from CCR5 receptor (CC chemokine receptor type 5) antagonists, systemic antiviral drugs, 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.

[0217] In one embodiment, the composition of the present invention comprises at least one analgesic. The analgesic substance may belong to the World Health Organization's classification of Class I, Class II, Class III analgesics, or a combination thereof.

[0218] In one embodiment, the Class I analgesic is selected from the group consisting of paracetamol, aspirin, nonsteroidal anti-inflammatory drugs, cortisone derivatives, and combinations thereof.

[0219] The nonsteroidal anti-inflammatory drug can be selected from the group consisting of 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.

[0220] The cortisone derivative may be selected from the group consisting of betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone.

[0221] Class II analgesics may be selected from the group consisting of codeine, dihydrocodeine, tramadol, and combinations thereof.

[0222] Class III analgesics may be selected from the group consisting of morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine, and combinations thereof.

[0223] In the context of the present invention, "excipient" refers to any substance other than NMN that is present in the composition and has no therapeutic effect. An excipient does not chemically react with NMN or any other additional therapeutic agent.

[0224] Excipients may be selected from fillers, lubricants, flavoring agents, colorants, emulsifiers, compression agents, diluents, preservatives, gelling agents, plasticizers, surfactants or combinations thereof. Those skilled in the art will know to determine the excipients to be selected based on the pharmaceutical dosage form to be selected.

[0225] The composition according to the invention may be a pharmaceutical composition. In this case, the excipient is a pharmaceutically acceptable excipient as described above.

[0226] The composition according to the invention may be a dietary supplement.

[0227] NMN derivatives and precursors

[0228] According to the present invention, the NMN derivative can be selected from: α-nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (expressed as NMN-H), a compound having formula (I) or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable crystal thereof:

[0229] [Formula 1]

[0230]

[0231] in:

[0232] -X is selected from: O, CH2, S, Se, CHF, CF2 and C=CH2;

[0233] -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;

[0234] - R2, R3, R4 and R5 are independently selected from the group consisting of: H, halogen, azido, 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; R AA is a side chain selected from proteinogenic amino acids;

[0235] -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;

[0236] -R7 is selected from H, P(O)R9R 10 and P(S)R9R 10 ;in,

[0237] -R9 and R 10 Independently selected from: OH, OR 11 、NHR 13 NR 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 ;in:

[0238] -R 11 Selected from the following group: (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)2; halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R 11a )2, C1-C6 acylamino, -COR 11b 、-O COR 11b ; NHSO2(C1-C6 alkyl), -SO2N(R 11a )2SO2; wherein each R 11a are independently selected from: H and (C1-C6) alkyl, and R 11b Independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2;

[0239] -R 12 Selected from H, C1-C 10 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 Haloalkyl, C3- C 10 Cycloalkyl, C 3- C 10 Heterocycloalkyl, C5-C 18 Aryl, C1-C4 alkylaryl and C5-C 12 Heteroaryl; wherein the aryl or heteroaryl is optionally substituted by one or two groups selected from the group consisting of halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; and

[0240] -R A and R A' Independently selected from: H, (C 1- C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) alkynyl, (C 3- C 10 )cycloalkyl, (C1-C 10 ) thioalkyl, (C 1- C 10 ) hydroxyalkyl, (C1-C 10 ) alkylaryl and (C5-C 12 ) aryl, (C 3- C 10 )heterocycloalkyl, heteroaryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from proteinogenic amino acids or non-proteinogenic amino acids; wherein the aryl group is optionally substituted with a group selected from the group consisting of hydroxyl, (C1-C 10 )alkyl, (C6-C1)alkoxy, halogen, nitro and cyano; or

[0241] -R9 and R 10 Together with the phosphorus atom to which it is attached, it forms a 6-membered ring, wherein –R9-R 10 - represents -CH2-CH2-CHR-; wherein R is selected from: H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano; or

[0242] R9 and R 10 Together with the phosphorus atom to which it is attached, it forms a 6-membered ring, wherein –R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from: H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0243] -R8 is selected from H, OR, NHR 13 NR 13 R 14 NH-NHR 13 , SH, CN, N3 and halogen; among which R 13 and R 14 are independently selected from: H, (C1-C8)alkyl, (C1-C8)alkylaryl, and -CR B R C -C(O)-OR D , where R B and R C R is independently a hydrogen atom, a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a benzyl group, an indolyl group, or an imidazolyl group; wherein the (C1-C6) alkyl group and the (C1-C6) alkoxy group may be optionally and independently substituted with one or more of the following: halogen, amino, amido, guanidino, hydroxyl, thiol or carboxyl, and the benzyl group is optionally substituted with one or more halogen or hydroxyl groups; or R B and R C Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group optionally substituted with one or more halogen, amino, amido, guanidino, hydroxyl, thiol and carboxyl groups; and R D is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (C3-C6)cycloalkyl;

[0244] -Y is selected from CH, CH2, C(CH3)2 and CCH3;

[0245] - represents a single bond or a double bond along Y; and

[0246] - represents the α or β anomer, depending on the R1 position;

[0247] or its stereoisomers, salts, hydrates, solvates or crystals;

[0248] or

[0249] A compound having formula (II) or a stereoisomer thereof, a salt thereof, a hydrate thereof, a solvate thereof or a crystal thereof:

[0250] [Formula 2]

[0251]

[0252] in,

[0253] X'1 and X'2 are independently selected from: O, CH2, S, Se, CHF, CF2 and C=CH2;

[0254] R'1 and R' 13 Independently 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;

[0255] R'2, R'3, R'4, R'5, R'9, R' 10 , R' 11 , R' 12 are independently selected from: H, halogen, azido, cyano, hydroxyl, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Heteroalkyl, C1-C 12 Haloalkyl and OR; wherein R can be 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 )aryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 )alkylaryl or C(O)CHR AA NH2; R AA is a side chain selected from proteinogenic amino acids;

[0256] R'6 and R'8 are independently selected from: H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl;

[0257] R'7 and R' 14 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;

[0258] Y'1 and Y'2 are independently selected from: CH, CH2, C(CH3)2 or CCH3;

[0259] M' is selected from: H or a suitable counterion;

[0260] represents a single bond or a double bond, depending on Y'1 and Y'2; and

[0261] Denotes the α or β anomer, depending on the R'1 and R' 13 location;

[0262] and their combinations.

[0263] In a preferred first embodiment, the pharmaceutically acceptable derivative is a compound of formula (I).

[0264] In a variant of the first embodiment, X represents O.

[0265] In a variant of the first embodiment, R1 and R6 each independently represent H.

[0266] In a variant of the first embodiment, R2, R3, R4 and R5 each independently of one another represent H or OH.

[0267] In a variant of the first embodiment, Y represents CH.

[0268] In a variant of the first embodiment, Y represents CH2.

[0269] In a variant of the first embodiment, R7 represents H.

[0270] In a variant of the first embodiment, R7 represents P(O)(OH)2.

[0271] In one variant of the first embodiment, the compound of the invention is selected from compounds having formulae IA to IH:

[0272] [Table 1]

[0273]

[0274] In a preferred variant of the preferred first embodiment, the pharmaceutically acceptable derivative is α-NMN having the following formula:

[0275] [Formula 3]

[0276]

[0277] In a preferred second embodiment, the pharmaceutically acceptable derivative is a compound of formula (II).

[0278] In a variation of the second embodiment, X'1 and X'2 each independently represent O.

[0279] In a variation of the second embodiment, R'7 and R'14 each independently represent NH2.

[0280] In a variation of the second embodiment, R'1 and / or R'13 each independently represent H.

[0281] In a variation of the second embodiment, R'6 and / or R'8 each independently represent H.

[0282] In a 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 H.

[0283] In a 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.

[0284] In a variation of the second embodiment, Y'1 and Y'2 each independently represent CH.

[0285] In a variation of the second embodiment, Y'1 and Y'2 each independently represent CH2.

[0286] In one variant of the second embodiment, the compound of the invention is selected from compounds having formulae II-A to II-F:

[0287] [Table 2]

[0288]

[0289] In a preferred fourth embodiment, the pharmaceutically acceptable derivative is NMN-H:

[0290] [Formula 4]

[0291]

[0292] Advantageously, the pharmaceutically acceptable precursor is nicotinamide riboside (denoted NR):

[0293] [Formula 5]

[0294]

[0295] Or dihydronicotinamide riboside (denoted as -NR-H) having the formula:

[0296] [Formula 6]

[0297]

[0298] Or a combination thereof. Preferably, the precursor is nicotinamide riboside (NR).

[0299] Preferably, the NMN derivative is dihydronicotinamide mononucleotide (NMN-H) and / or α-NMN.

[0300] Compound preparation method for preparing compounds having formula (I) and (II)

[0301] The derivatives of formula (I) or formula (II) can be prepared according to any method known to those skilled in the art.

[0302] Compound preparation method for preparing a compound having formula (I)

[0303] The derivatives of formula (I) can be prepared according to the method described in international patent application WO 2017 / 024255A1.

[0304] Specifically, the derivatives having formula (I) and α-NMN can be prepared according to the method described below.

[0305] Specifically, compounds of formula (I) described herein can be prepared from substrates AE as described below. Those skilled in the art will appreciate that these reaction schemes are not intended to be limiting and may be varied without departing from the spirit and scope of the present invention.

[0306] According to one embodiment, the present invention relates to a process for preparing a compound having formula (I) as described above.

[0307] The process involves, in a first step, monophosphorylating a compound of formula (a) in the presence of phosphorus oxychloride and a trialkyl phosphate to produce a phosphorus oxychloride of formula (B),

[0308] [Formula 8]

[0309]

[0310] Among them, X, R1, R2, R3, R4, R5, R6, R8, Y, and As defined above in the compound of formula (I).

[0311] In the second step, the phosphoryl dichloride of formula (B) is hydrolyzed to produce the phosphate of formula (C),

[0312] [Formula 9]

[0313]

[0314] Among them, X, R1, R2, R3, R4, R5, R6, R8, Y, and As defined above in the compound of formula (I).

[0315] According to one embodiment, the compound having formula (A) is synthesized by various methods known to those skilled in the art.

[0316] According to one embodiment, the compound of formula (A) is synthesized by reacting a pentose of formula (D) with a nitrogen-containing derivative of formula (E), wherein R, R2, R3, R4, R5, R6, R7, Y are as defined above in the compound of formula (I), thereby obtaining a compound of formula (A-1), which is selectively deprotected to obtain a compound of formula (A),

[0317] [Formula 10]

[0318]

[0319] Among them, X, R1, R2, R3, R4, R5, R6, R8, Y, and As defined above in the compound of formula (I).

[0320] 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. Without limitation, triarylmethyl includes: trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4',4"-trimethoxytrityl. Without limitation, some examples of silyl include: trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

[0321] According to one embodiment, any hydroxyl group attached to the pentose is protected by a suitable protecting group known to those skilled in the art.

[0322] The selection and exchange of protecting groups are well within the knowledge and expertise of those skilled in the art. Protecting groups can also be removed by methods well known to those skilled in the art, for example, using an acid (e.g., an inorganic or organic acid), a base or a fluoride source.

[0323] In a preferred embodiment, the nitrogen-containing derivative of formula (E) is coupled with a pentose of formula (D) by reaction in the presence of a Lewis acid to generate a compound of formula (A-1). Non-limitingly, some examples of Lewis acids include trimethylsilyl trifluoromethanesulfonate (TMSOTf), BF3.OEt2, TiCl4 and FeCl3.

[0324] In one embodiment, the method of the present invention further comprises a reduction step, wherein the compound of formula (A) is reduced by various methods well known to those skilled in the art to obtain a compound of formula (A') wherein CH2 is CH2, and R1, R2, R3, R4, R5, R6, R8, Y, and is as defined above in the compound of formula (I).

[0325] According to one embodiment, the present invention relates to a process for preparing compounds having formula IA, IC, IE, IG.

[0326] In the first step, nicotinamide having formula E is coupled with ribose tetraacetate having formula D by a coupling reaction in the presence of a Lewis acid to generate a compound having formula A-1:

[0327] [Formula 11]

[0328]

[0329] In the second step, the compound of formula A-1 is subjected to ammoniacal treatment, thereby producing a compound of formula IA:

[0330] [Formula 12]

[0331]

[0332] In the third step, the compound of formula IA is monophosphorylated in the presence of phosphorus oxychloride and a trialkyl phosphate to produce the phosphorus oxychloride of formula IA':

[0333] [Formula 13]

[0334]

[0335] In the fourth step, the phosphorus oxychloride of formula B is hydrolyzed to produce a compound of formula IC:

[0336] [Formula 14]

[0337]

[0338] In one embodiment, a reduction step is performed to reduce the compound having formula IA, thereby producing a compound having formula IE.

[0339] The compound of formula IE is then monophosphorylated and hydrolyzed as described in the fourth step to provide the compound of formula IG.

[0340] According to one embodiment, the compound of formula (I) is selected from compounds IA to IH in the following table:

[0341] [Table 1]

[0342]

[0343] In a preferred embodiment, the compound of the present invention is a compound having formula IA, IC, IE and IG in the above table, or a pharmaceutically acceptable salt and / or solvate thereof. In a more preferred embodiment, the compound is a compound having formula IC, or ID, or a pharmaceutically acceptable salt and / or solvate thereof.

[0344] Derivative preparation method for preparing derivatives having formula (II)

[0345] Specifically, compounds of Formula II described herein can be prepared from substrates X-XIII as described below. Those skilled in the art will appreciate that these illustrations are not intended to be limiting and that changes may be made in detail without departing from the spirit and scope of the invention.

[0346] According to one embodiment, the present invention relates to a process for preparing a compound having formula I as described above.

[0347] The method comprises: first, monophosphorylating a compound having the formula X in the presence of phosphorus oxychloride in a trialkyl phosphate to produce a compound phosphorus oxychloride XI,

[0348] [Formula 15]

[0349]

[0350] Among them, X'1, R'1, R'2, R'3, R'4, R'5, R'6, R'7, Y'1, and As described above.

[0351] In the second step, hydrolysis of the phosphoryl dichloride XI obtained in the first step provides a phosphate compound having the formula XII,

[0352] [Formula 16]

[0353]

[0354] Among them, X'1, R'1, R'2, R'3, R'4, R'5, R'6, R'7, Y'1, M', and As described above.

[0355] The phosphate compound of formula XII obtained in the second step is then reacted with the above-mentioned phosphorus oxychloride compound of formula XIII obtained in the first step,

[0356] [Formula 17]

[0357]

[0358] Among them, X'2, R'8, R'9, R' 10 , R' 11 , R' 12 , R' 13 , R' 14 、Y'2、 and as described above in Formula II, to provide a compound having Formula II as above.

[0359] According to one embodiment, the method further comprises a reduction step of reducing the compound of formula II using various methods known to experts to obtain a compound of formula II, wherein Y'1 and Y'2 are identical and each represents CH2, wherein 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 As described herein in Formula II.

[0360] In 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. Without limitation, some examples of triarylmethyl groups include: trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4"-trimethoxytrityl. Without limitation, some examples of silyl groups include: trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0361] According to one representative approach, any hydroxyl groups attached to the pentose ring are protected by suitable protecting groups known to those skilled in the art.

[0362] The selection and exchange of protecting groups is well within the knowledge and expertise of those skilled in the art. Any protecting group may also be removed by methods well known in the art, for example, using an acid (eg, an inorganic or organic acid), a base or a fluoride source.

[0363] According to a preferred embodiment, the nitrogen compound of formula XV is added to pentose XIV by a coupling reaction in the presence of a Lewis acid to provide a compound of formula X-1. Non-limitingly, some examples of suitable Lewis acids include trimethylsilyl trifluoromethanesulfonate (TMSOTf), BF3.OEt2, TiCl4 and FeCl3.

[0364] According to one embodiment, the present invention relates to a method for preparing a compound having formula VIII or a pharmaceutically acceptable salt and / or solvate thereof,

[0365] [Formula 18]

[0366]

[0367] In the first step, nicotinamide of formula XV is added to ribose tetraacetate XIV in the presence of a Lewis acid via a coupling reaction to provide a compound of formula X-1:

[0368] [Formula 19]

[0369]

[0370] In the second step, the compound of formula X-1 is treated with ammonia to provide a compound of formula X:

[0371] [Formula 20]

[0372]

[0373] In the third step, the compound of formula X is monophosphorylated in the presence of phosphorus oxychloride in a trialkyl phosphate to provide compound phosphoryl dichloride XI:

[0374] [Formula 21]

[0375]

[0376] In the fourth step, the phosphorus oxychloride compound XI obtained in the third step is partially hydrolyzed to provide a phosphate compound having the formula XII:

[0377] [Formula 22]

[0378]

[0379] In the fifth step, the phosphate compound having the formula XII obtained in the fourth step is reacted with the phosphorus oxychloride compound having the formula XI obtained in the third step to obtain the compound having the formula VIII.

[0380] According to another specific embodiment, the present invention relates to a process for preparing a compound having formula IX or a pharmaceutically acceptable salt and / or solvate thereof,

[0381] [Formula 23]

[0382]

[0383] According to one variant, the compound of formula IX is obtained from a compound of formula VIII previously synthesized as described above.

[0384] In this embodiment, to provide a compound of formula IX, the compound of formula VIII is reduced using a suitable reducing agent known to those skilled in the art to give a compound of formula IX.

[0385] According to one embodiment, the preferred compounds of the present invention are compounds II-A to II-F listed in Table 2 below:

[0386] [Table 2]

[0387]

[0388] Attached photos

[0389] [ Fig. 1 ] is a graph showing the nociception scores and nociception thresholds of rats induced by cyclophosphamide administration and animals treated with a vehicle.

[0390] [ Fig. 2 ] is a graph showing the evolution of nociception score and nociception threshold in rats 2 hours and 4 hours after administration of cyclophosphamide compared with a vehicle.

[0391] [ Fig. 3 ] shows the nociceptive thresholds of animals treated with cyclophosphamide when vehicle, NMN or ibuprofen were administered at T0, T=2 hours or T=4 hours after cyclophosphamide administration.

[0392] [ Fig. 4 ] shows the nociception scores of animals treated with cyclophosphamide when vehicle, NMN or ibuprofen were administered at T0, T=2 hours or T=4 hours after cyclophosphamide administration.

[0393] [ Figure 5A ] is a graph showing the baseline nociceptive threshold of each experimental group.

[0394] [ Figure 5B ] is a graph showing the baseline nociception scores of all experimental groups.

[0395] [ Fig. 6A ] is a graph showing the nociceptive threshold of the effects of NMN, compound A, and compound B on CYP-induced touch pain at 2 hours.

[0396] [ Figure 6B ] is a graph showing the nociceptive threshold of the effects of NMN, compound A, and compound B on CYP-induced touch pain at 4 hours.

[0397] [ Fig. 7A] is a graph showing the effect of NMN on CYP-induced visceral pain at 2 hours (nociception score).

[0398] [ Figure 7B ] is a graph showing the effect of NMN on CYP-induced visceral pain at 4 hours (nociception score).

[0399] [ Fig. 8A ] is a graph showing the effect of Compound A on CYP-induced visceral pain at 2 hours (nociception score).

[0400] [ Figure 8B ] is a graph showing the effect of Compound A on CYP-induced visceral pain at 4 hours (nociception score).

[0401] [ Fig. 9A ] is a graph showing the effect of Compound B on CYP-induced visceral pain at 2 hours (nociception score).

[0402] [ Fig. 9B ] is a graph showing the effect of Compound B on CYP-induced visceral pain at 2 hours (nociception score). Example

[0403] In the rest of this specification, the examples provided are intended to illustrate the present invention rather than to limit the scope of the present invention.

[0404] Example 1

[0405] The effectiveness of using NMN according to the invention was evaluated in a rat nociceptive pain model. More precisely, the model used was a visceral pain model. The administration of cyclophosphamide (CYP) was used as a method to simulate cystitis in rats.

[0406] The positive control was ibuprofen, a nonsteroidal anti-inflammatory drug commonly used to relieve nociceptive pain. The negative control was the vehicle for NMN and ibuprofen, i.e., distilled water.

[0407] In this study, 7-week-old female Sprague-Dawley rats were divided into three groups, each including 6 rats:

[0408] - A control group received 5 ml of distilled water (vehicle);

[0409] - A group treated with 500 mg / kg NMN; and

[0410] - Group treated with 300 mg / kg of ibuprofen.

[0411] NMN is in the form of a zwitterion.

[0412] After 24 hours of acclimatization, the pain tolerance threshold of each animal was measured using von Frey filaments before the start of the study. Measurements before any exposure to painful stimuli can obtain the animal's baseline pain tolerance threshold level and serve as a negative control.

[0413] Von Frey filaments are used as a device for measuring the sensitivity of the skin to touch. Using Von Frey filaments, touch pain and hyperalgesia in rodents can be detected. In short, each filament corresponds to a given force. These filaments are applied to the skin of the animal in an increasing order of force. In fact, rodents have a reflex of withdrawal when unexpected contact occurs. The withdrawal in response to the force applied by the rodent indicates the animal's tolerance threshold for pain. The use of Von Frey filaments is commonly used to measure pain in rodents (Deuis JR, Dvorakova LS, and Vetter I, (2017) Methods Used to Evaluate Pain Behaviors in Rodents, Front. Mol. Neurosci. 10: 284)).

[0414] In this study, eight fibers were used in ascending order of increasing force, namely 1 g, 2 g, 4 g, 6 g, 8 g, 10 g, 15 g and 26 g, and each was applied three times to the animal's abdomen near the bladder. The animal's response was evaluated as follows:

[0415] Score 0: No response

[0416] Score 1: Abdominal contraction

[0417] Score 2: Trampling or animal position change

[0418] Score 3: Abdomen twitches, flexes or rounds, or licks the area stimulated by the von Frey filaments.

[0419] For each rat, the results are expressed as follows:

[0420] Nociceptive threshold: The first force level at which an animal's response is observed (response score greater than or equal to 1). This indicates the lowest pain tolerance threshold for measuring touch pain;

[0421] Nociception score: Percentage of the maximum response for each filament. This represents the overall pain response.

[0422] Each group of animals received vehicle or 500 mg / kg of NMN or 300 mg / kg of ibuprofen by oral route. After administration of the test compound (vehicle, NMN or ibuprofen), each rat was injected with cyclophosphamide by intraperitoneal route. Cyclophosphamide causes strong inflammation in the bladder and simulates the pain caused by urinary tract infection (e.g., cystitis).

[0423] The von Frey filament test was repeated 2 hours and then 4 hours after the injection of cyclophosphamide to measure the pain response of the animals.

[0424] The results were analyzed by one-way analysis of variance (i.e., one-way ANOVA) supplemented with Dunnett's test, or two-way ANOVA. For statistical significance, * indicates p<0.05, ** indicates p<0.01, and *** indicates p<0.001 compared with the vehicle-treated group.

[0425] like Figure 1A As shown in Figure 2, administration of cyclophosphamide induced an immediate response in the rats after the first filament of 1 g force was applied, whereas the responses of the animals before exposure showed that the animals did not respond to pain until 10 g was applied before cyclophosphamide administration: thus, the injection of cyclophosphamide reduced the threshold for pain to touch. This result is indicated by Figure 1B Confirmed, Figure 1B It was shown that the administration of cyclophosphamide lowered the pain tolerance threshold from 10 g to 3 g. In other words, the injection of cyclophosphamide significantly lowered the touch pain threshold of rats. Therefore, animals treated with cyclophosphamide were more sensitive to pain.

[0426] Figure 2A and 2B The results showed that the threshold of pain continued to decrease, and 4 hours after the injection of cyclophosphamide, the animals' tolerance to pain was even lower than 2 hours after the injection.

[0427] Figure 1A It was also shown that at the same force, the animals felt greater pain: therefore, the injection of cyclophosphamide triggered hyperalgesia. Figure 2B The effect was shown to persist over time, with pain scores in treated rats four hours later being higher than those two hours after injection.

[0428] Thus, the injection of cyclophosphamide leads on the one hand to a decrease in allodynia and an increase in hyperalgesia in the treated animals, and this effect worsens over time.

[0429] Figures 3 and 4 show the effects of NMN and ibuprofen administration on pain thresholds and scores in rats treated with cyclophosphamide.

[0430] like Figure 3A , 3BAs shown in Figures 3 and 3C, the administration of NMN was able to significantly increase the response threshold to nociceptive pain at T0, T = 2 hours after injection, and T = 4 hours after injection. In an expected manner, ibuprofen was also able to significantly increase the pain tolerance threshold of rats treated with cyclophosphamide at T0, T = 2 hours after injection, and T = 4 hours after injection. These results indicate that the administration of NMN provides the ability to reduce touch pain.

[0431] like Figure 4A As shown, NMN, ibuprofen and vehicle showed similar nociceptive score curves at T0 (the moment of cyclophosphamide injection). This indicates that animals do not experience pain in response to the administration of NMN or ibuprofen. On the other hand, Figure 4B and 4C It was shown that administration of NMN acts in the same manner as ibuprofen to reduce nociception scores 2 and 4 hours after administration of cyclophosphamide.

[0432] Thus, administration of NMN and compositions comprising NMN enables to reduce allodynia and hyperalgesia to a large extent in a similar manner as ibuprofen.

[0433] Example 2

[0434] Synthesis of the compounds of the present invention

[0435] Materials and methods

[0436] All reagents were obtained from commercial suppliers and used without further purification. Thin layer chromatography was performed on TLC silica gel 60 F254 plastic plates (0.2 mm layer thickness) from Merck. Column chromatography purification was performed on silica gel 60 (70-230 mesh ASTM, Merck). Melting points were determined on a digital device (Electrothermal IA 8103) and were uncorrected, or on a WME-type Kofler heating stage (Wagner & Munz). 1 H. 19 F and 13 C nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy confirmed the structures of all compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer; and NMR spectra were recorded on a BRUKER AC 300 or 400 spectrometer at 300 or 400 MHz using CDCl3, CD3CN, D2O or DMSO-d6 as solvents. 1 H spectrum, recorded at 75 or 100 MHz 13 C spectrum, recorded at 282 or 377 MHz 19 F spectrum. Chemical shifts (δ) are expressed in parts per million relative to the signal, (i) for1 H, indirectly with CHCl3 (δ7.27); (ii) for 13 C, indirectly using CDCl3 (δ77.2); (iii) for 19 F, CFCl3 (internal standard) was used directly (δ0). Chemical shifts are expressed 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 by the "Service central d'Analysis de Solaize", CNRS, France, and recorded on a Waters spectrometer using an electrospray ionization time-of-flight (ESI-TOF) mass spectrometer.

[0437] plan

[0438] Step 1: Synthesis of the compound having formula X-1

[0439] The compound of formula XIV (1.0 equiv) is dissolved in dichloromethane. Nicotinamide of formula XV (1.50 equiv) and TMSOTf (1.55 equiv) 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 provide crude nicotinamide ribose tetraacetate of formula X-1.

[0440] Step 2: Synthesis of compounds having formula X

[0441] The crude NR tetraacetate having the formula X-1 was dissolved in methanol and cooled to -10°C. Then 4.6 M ammonia in methanol (3.0 eq.) was added at -10°C and the mixture was stirred at this temperature until the reaction was complete. Dowex HCR (H + ) until the pH reaches 6-7. 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 until it is dry. The residue is dissolved in acetonitrile and concentrated to dryness of the solid content. The residue is dissolved in acetonitrile to provide a crude nicotinamide ribose triflate having formula X.

[0442] Step 3: Synthesis of compounds having formula XI

[0443] A solution of crude nicotinamide ribose triflate in acetonitrile was diluted with trimethyl phosphate (10.0 eq.). Acetonitrile was distilled under vacuum, and the mixture was cooled to -10°C. Phosphorus oxychloride (4.0 eq.) was added at -10°C, and the mixture was stirred at -10°C until the reaction was complete.

[0444] Step 4 and Step 5: Synthesis of compounds having Formula IA

[0445] The mixture is hydrolyzed by adding a 50 / 50 mixture of acetonitrile and water followed by 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 provide a crude mixture of NMN and di-NMN having formula IA.

[0446] Isolation of di-NMN having Formula IA

[0447] NMN and di-NMN of formula IA were separated by purification by elution with water on Dowex 50wx8. The fractions containing di-NMN were concentrated to dryness of solid contents. The residue was purified by column chromatography on silica gel (isopropanol / water gradient). The pure fractions were combined and concentrated. The residue was lyophilized to obtain di-NMN in the form of a beige solid.

[0448] Biological data

[0449] The aim of this study was to evaluate the effects of oral administration of nicotinamide mononucleotide (NMN), α-NMN (Compound A), and Compound IA (Compound B) at a dose of 500 mg / kg on visceral pain responses in a cyclophosphamide (CYP)-induced acute cystitis model in female Sprague-Dawley rats.

[0450] Materials and methods

[0451] Animals: Female Sprague-Dawley rats, 7 weeks old

[0452] Pharmacological treatment:

[0453] NMN: 500 mg / kg

[0454] α-NMN: 500 mg / kg

[0455] Compound IA: 500 mg / kg

[0456] Carrier: distilled water

[0457] Administration: Orally [po] (administered by mouth), 5 ml / kg

[0458] Dosing frequency: once on D0, 15 minutes before intraperitoneal injection (ip) of CYP.

[0459] CYP-induced acute cystitis: CYP was injected intraperitoneally at 150 mg / kg in a final volume of 5 ml / kg saline solution.

[0460] Mechanical stimulation using von Frey filaments

[0461] Rats were placed in individual Plexiglas boxes with wire mesh floors and allowed to acclimate to the chamber for at least 30 minutes before any testing began. Eight von Frey filaments with increasing force levels were used, namely 1, 2, 4, 6, 8, 10, 15, and 26 grams. Each calibrated filament was applied three times to the lower abdominal area near the bladder.

[0462] Assessment of each nociceptive behavior

[0463] - Rating 0 = No response

[0464] - Score 1 = Abdominal contraction

[0465] - Score 2 = Trampling or animal relocation

[0466] - Rating 3 = Gasping or screaming or flexing of abdomen, or licking of area stimulated by von Frey filaments

[0467] For each rat, the results are expressed as follows:

[0468] - Nociceptive threshold: First von Frey force level, stimulus is perceived as painful (obtains a score of ≥ 1) => reduced threshold = pain to touch

[0469] - Nociception score: % of maximum response of each filament (for 3 combined applications, total = 9) => overall response to pain

[0470] Experimental groups (6 rats per group):

[0471] Group 1: Vehicle (5 ml / kg) + CYP

[0472] Group 2: NMN (500 mg / kg) + CYP

[0473] Group 3: Compound A (500 mg / kg) + CYP

[0474] Group 4: Compound B (500 mg / kg) + CYP

[0475] result

[0476] Baseline nociceptive parameters of all experimental groups (before CYP injection): Results showed ( Figure 5Aand 5B ), the baseline nociceptive responses were similar in all experimental groups (before CYP injection).

[0477] CYP-induced visceral pain at 2 and 4 hours after injection (compared to baseline values ​​in vehicle-treated group): The results showed that CYP (150 mg / kg, ip) caused a significant decrease in the nociceptive threshold compared to the baseline response at both time points ( Figure 2A ) and nociceptive scores increased significantly ( Figure 2B ).

[0478] Effects of NMN, Compound A and Compound B on CYP-induced touch pain (nociceptive threshold): The results showed that compared with the vehicle:

[0479] NMN (500 mg / kg, po) resulted in Fig. 6A ) and +4 hours ( Figure 6B ) showed a slight increase in the nociceptive threshold, and the effect at +4 hours was slightly above statistical significance (p = 0.063);

[0480] Compound A (500 mg / kg, po) resulted in +2 hours ( Fig. 6A ) and +4 hours ( Figure 6B )’s nociceptive threshold is increased;

[0481] Compound B (500 mg / kg, po) resulted in only +4 hours ( Figure 6B ) showed a significant increase in the nociceptive threshold, with no effect at +2 hours ( Fig. 6A ).

[0482] Effects of NMN, Compound A and Compound B on CYP-induced visceral pain (nociception score): The results showed (Figures 7, 8 and 9) that, compared with the vehicle:

[0483] NMN (500 mg / kg, po) resulted in +2 hours ( Fig. 7A ) and +4 hours ( Figure 7B ) had a significant decrease in nociception scores;

[0484] Compound A (500 mg / kg, po) resulted in +2 hours ( Fig. 8A ) and +4 hours ( Figure 8B ) showed a decrease in nociception scores, reaching statistical significance only at +4 hours;

[0485] Compound B (500 mg / kg, po) resulted in +4 hours ( Fig. 9B ) significantly decreased nociception scores (no effect was induced at +2 hours ( Fig. 9A )).

[0486] Summary of results

[0487] Baseline nociceptive responses were similar in all experimental groups (before CYP injection).

[0488] The effects of CYP (150 mg / kg, ip) at 2 and 4 hours were characterized by:

[0489] - At +2 and +4 hours, the nociceptive threshold was significantly reduced;

[0490] - Nociception scores increased significantly at +2 and +4 hours;

[0491] Compared to vehicle, the effects of NMN (500 mg / kg, po) in CYP-injected rats resulted in:

[0492] - There was a slight increase in nociceptive thresholds at +2 and +4 hours, with the effect at +4 hours slightly above statistical significance (p=0.063);

[0493] - Nociception scores at +2 and +4 hours were significantly reduced.

[0494] The effects of Compound A (500 mg / kg, po) compared to vehicle in rats receiving CYP injections were characterized by:

[0495] - Increased nociceptive thresholds at +2 and +4 hours, with only the effect at +4 hours reaching significance levels;

[0496] -Nociception scores were reduced at +2 and +4 hours, reaching statistical significance only at +4 hours.

[0497] In CYP-injected rats, the effects of Compound B (500 mg / kg, po) resulted in:

[0498] - Significant decrease in nociceptive threshold at +4 hours (no effect observed at +2 hours);

[0499] -Nociception scores were significantly reduced at +4 hours (no effect was observed at +2 hours).

[0500] in conclusion

[0501] A single intraperitoneal injection of CYP (150 mg / kg) resulted in visceral pain at 2 and 4 h after injection, with the effect being more pronounced at +4 h.

[0502] A single oral administration of NMN (500 mg / kg) alleviated CYP-induced visceral pain at both time points, achieving a higher significance level at +4 h.

[0503] Administration of α-NMN (Compound A) reduced CYP-induced visceral pain at both +2 and +4 hours, but only reached a significant level at +4 hours.

[0504] In CYP-injected rats, oral treatment with Compound IA (Compound B) had no beneficial effect at +2 hours, but showed significant antinociceptive activity at a later time point (ie, +4 hours).

[0505] Thus, the inventors have demonstrated that the use of NMN and pharmaceutically acceptable derivatives thereof (eg, α-NMN and Compound IA) and compositions of the present invention comprising the same provide the ability to reduce nociceptive pain, particularly to reduce visceral pain caused by cystitis.

[0506] Therefore, the use of NMN and its pharmaceutically acceptable derivatives (such as α-NMN and compound IA) and the compositions of the present invention comprising the same can treat and prevent pain, especially nociceptive pain.

Claims

1. Use of nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating pain, wherein the pain is nociceptive pain, wherein the pharmaceutically acceptable derivative is selected from dihydronicotinamide mononucleotide A compound of formula (I) or formula (II), and combinations thereof, wherein the compound of formula (I) is selected from: The compound of formula (II) is selected from:

2. The use according to claim 1, for reducing pain to touch.

3. The use according to claim 1 or 2, for reducing hyperalgesia.

4. The use according to claim 1 or 2, wherein The pain is visceral pain.

5. The use according to claim 4, wherein The pain is pain caused by a urinary tract infection.

6. The use according to claim 1 or 2, in combination with at least one other therapeutic agent.

7. The use according to claim 6, wherein The at least one additional therapeutic agent is selected from the group consisting of antibiotics, antifungal agents, antiviral agents, and combinations thereof.

8. The use according to claim 6, wherein At least one therapeutic agent is an analgesic.

9. Use of a composition for the manufacture of a medicament for preventing and / or treating pain, wherein the pain is nociceptive pain, the composition comprising nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable derivative is selected from dihydronicotinamide mononucleotide A compound of formula (I) or formula (II), and combinations thereof, wherein the compound of formula (I) is selected from: The compound of formula (II) is selected from:

10. The use according to claim 9, wherein The composition also comprises at least one additional therapeutic agent.

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