Use of NMN for the prevention and/or treatment of joint pain induced by physical activity, and corresponding compositions
11730752 · 2023-08-22
Assignee
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61K31/706
HUMAN NECESSITIES
International classification
A61K31/706
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
Abstract
The invention relates to nicotinamide mononucleotide, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, for use in preventing and/or treating joint pain induced by physical activity, and compositions comprising same.
Claims
1. A method of treatment of joint pain induced by physical activity, comprising topically administrating nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein the pharmaceutically acceptable derivative of NMN is selected from dihydronicotinamide mononucleotide (NMN-H), alpha-NMN, a compound of formula (I): ##STR00079## or a stereoisomer, salt, hydrate, solvate, or pharmaceutically acceptable crystal thereof, wherein: X is selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R.sub.1 is selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR; wherein R is selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12)alkyl, C(O)NH(C.sub.1-C.sub.12)alkyl, C(O)O(C.sub.1-C.sub.12)alkyl, C(O)aryl, C(O)(C.sub.1-C.sub.12)aryl alkyl, C(O)NH(C.sub.1-C.sub.12)aryl alkyl, C(O)O(C.sub.1-C.sub.12)aryl alkyl, and C(O)CHR.sub.AANH.sub.2; wherein R.sub.AA is a side chain selected from a proteinogenic amino acid; R.sub.6 is selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R.sub.7 is selected from H, P(O)R.sub.9R.sub.10, and P(S)R.sub.9 R.sub.10, and ##STR00080## where n is an integer selected from 1, 2, or 3; wherein R.sub.9 and R.sub.10 are independently selected from OH, OR.sub.11, NHR.sub.13, NR.sub.13 R.sub.14, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.12, aryl (C.sub.1-C.sub.8)aryl alkyl, (C.sub.1-C.sub.8)aryl alkyl, (C.sub.1-C.sub.8) heteroalkyl, (C.sub.1-C.sub.8) heterocycloalkyl, heteroaryl, and NHCHR.sub.AR.sub.A′C(O)R.sub.12; wherein: R.sub.11 is selected from C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.10 alkyl aryl, C.sub.5-C.sub.12 substituted aryl, C.sub.1-C.sub.10 heteroalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.1-C.sub.10 haloalkyl, heteroaryl, —(CH.sub.2).sub.nC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)O(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nSC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15)alkyl, and —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15)alkyl aryl; wherein n is an integer selected from 1 to 8; P(O)(OH)OP(O)(OH).sub.2, halogen, nitro, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, —N(R.sub.11a).sub.2, C.sub.1-C.sub.6 acylamino, —COR.sub.11b, —O COR.sub.11b; NHSO.sub.2(C.sub.1-C.sub.6 alkyl), —SO.sub.2N(R.sub.11a).sub.2 SO.sub.2 wherein each R.sub.11a is independently selected from H and C.sub.1-C.sub.6 alkyl and R.sub.11b is independently selected from OH, C.sub.1-C.sub.6 alkoxy, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6 alkyl).sub.2; R.sub.12 is selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.4 alkyl aryl, and C.sub.5-C.sub.12 heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted with one or two groups selected from halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; and R.sub.A and R.sub.A′ are independently selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 thioalkyl, C.sub.1-C.sub.10 hydroxylalkyl, C.sub.1-C.sub.10 alkyl aryl, and C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.10 heterocycloalkyl, heteroaryl, —(CH.sub.2).sub.3NHC(═NH)NH.sub.2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, nitro, and cyano; or R.sub.9 and R.sub.10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R.sub.9-R.sub.10— represents CH.sub.2—CH.sub.2—CHR—; wherein R is selected from H, (C.sub.5-C.sub.6) aryl, and (C.sub.5-C.sub.6) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; or R.sub.9 and R.sub.10 together with the phosphorus atoms to which they are attached form a 6-membered ring, wherein —R.sub.9-R.sub.10— represents-O—CH.sub.2—CH.sub.2—CHR—O—; wherein R is selected from H, (C.sub.5-C.sub.6) aryl, and (C.sub.5-C.sub.6) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy, and cyano; R.sub.8 is selected from H, OR, NHR.sub.13, NR.sub.13R.sub.14, NH—NHR.sub.13, SH, CN, N.sub.3, and halogen; wherein R.sub.13 and R.sub.14 are independently selected from H, (C.sub.1-C.sub.8) alkyl, and (C.sub.1-C.sub.8) alkyl aryl, and-CR.sub.B R.sub.C—C(O)—ORD, wherein R.sub.B and R.sub.C are independently hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy benzyl, indolyl, or imidazolyl, wherein the (C.sub.1-C.sub.6) alkyl and the (C.sub.1-C.sub.6) alkoxy can be optionally and independently of each other substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or R.sub.B and R.sub.C together with the carbon atom to which they are attached form a C.sub.3-C.sub.6 cycloalkyl group optionally substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl, and R.sub.D is hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.3-C.sub.6) cycloalkyl; Y is selected from CH, CH.sub.2, C(CH.sub.3).sub.2, and CCH.sub.3; represents a single or double bond depending on Y; and
represents the alpha or beta anomer depending on the position of R.sub.1 or a compound of formula (Ia): ##STR00081## or a stereoisomer, salt, hydrate, solvate, or crystal thereof, wherein X′.sub.1 and X′.sub.2 are independently selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R′.sub.1 and R′.sub.13 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR, wherein R is selected from H and C.sub.1-C.sub.8 alkyl, R′.sub.2, R′.sub.3, R′.sub.4, R′.sub.5, R′.sub.9, R′.sub.10, R′.sub.11, and R′.sub.12 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR, wherein R may be selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) aryl, C(O)NH(C.sub.1-C.sub.12) aryl alkyl, C(O)O(C.sub.1-C.sub.12) aryl alkyl, or a C(O)CHR.sub.AANH2 group, wherein R.sub.AA is a side chain selected from a proteogenic amino acid; R′.sub.6 and R′.sub.8 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, and OR, wherein R is selected from H, and C.sub.1-C.sub.8 alkyl; R′.sub.7 and R′.sub.14 are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N.sub.3, and halogen, wherein R and R′ are independently selected from H and (C.sub.1-C.sub.8) aryl alkyl; Y′.sub.1 and Y′.sub.2 are independently selected from CH, CH.sub.2, C(CH.sub.3).sub.2, or CCH.sub.3; M′ is selected from H or a suitable counterion;
represents a single or double bond depending on Y′.sub.1 and Y′.sub.2; and
represents an alpha or beta anomer depending on the position of R′.sub.1 and R′.sub.13; and combinations thereof.
3. The method according to claim 2, wherein the pharmaceutically acceptable derivative of NMN is selected from TABLE-US-00008 Compounds (anomers) Structure I-B (alpha)
4. The method according to claim 2, wherein the pharmaceutically acceptable derivative of NMN is selected from TABLE-US-00009 Compounds (anomers) Structure Ia-A (beta, beta)
5. The method according to claim 2, wherein the joint pain involves the neck, shoulder, scapula, elbow, wrist, hand joints, hip, sacroiliac joint, knee, ankle, foot joints, or combinations thereof, preferably the knee.
6. The method according to claim 2, wherein the physical activity is playing sports.
7. The method according to claim 2, wherein the nicotinamide mononucleotide (NMN), the pharmaceutically acceptable derivative thereof, or the pharmaceutically acceptable salt thereof can be used in combination with at least one other therapeutic agent.
8. The method according to claim 2, wherein the joint pain is not due to any of the pathologies selected from a tumor, arthritis, gout, osteoarthritis, joint deformity, connective tissue disease, dorsopathy, neurodegenerative disease neuropathy, genetic disease, autoimmune disease, myopathy, osteopathy, osteoporosis, chondropathy, vasculopathy, viral infection, fungal infection, bacterial infection, parasite, side effect of a drug, surgical procedure, medical examination, calcification, trauma unless induced by physical activity, malformation, and combinations thereof.
9. A method of treatment of joint pain induced by physical activity, the method comprising the step of topically administering a composition comprising nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
10. The method according to claim 9, wherein the composition comprises nicotinamide mononucleotide (NMN), the pharmaceutically acceptable derivative thereof, or the pharmaceutically acceptable salt thereof, in an amount between 0.05% and 15% by weight.
11. The method according to claim 9, wherein the composition is in the form of a water-in-oil emulsion or an oil-in-water emulsion.
12. The method according to claim 9, wherein the composition further comprises at least one additional therapeutic agent.
13. The method according to claim 12, wherein the at least one additional therapeutic agent is selected from an analgesic, a non-steroidal anti-inflammatory, cortisone, a cortisone derivative, or combinations thereof.
14. The method according to claim 9, wherein the pharmaceutically acceptable derivative is selected from dihydronicotinamide mononucleotide (NMN-H), alpha-NMN, a compound of formula (I): ##STR00100## or a stereoisomer, salt, hydrate, solvate, or pharmaceutically acceptable crystal thereof, wherein: X is selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R.sub.1 is selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR; wherein R is selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12)alkyl, C(O)NH(C.sub.1-C.sub.12)alkyl, C(O)O(C.sub.1-C.sub.12)alkyl, C(O)aryl, C(O)(C.sub.1-C.sub.12)aryl alkyl, C(O)NH(C.sub.1-C.sub.12)aryl alkyl, C(O)O(C.sub.1-C.sub.12)aryl alkyl, and C(O)CHR.sub.AA NH.sub.2; wherein R.sub.AA is a side chain selected from a proteinogenic amino acid; R.sub.6 is selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R.sub.7 is selected from H, P(O)R.sub.9R.sub.10 and P(S)R.sub.9R.sub.10 and ##STR00101## where n is an integer selected from 1, 2, or 3; wherein R.sub.9 and R.sub.10 are independently selected from OH, OR.sub.11, NHR.sub.13, NR.sub.13 R.sub.14, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.12, aryl (C.sub.1-C.sub.8)aryl alkyl, (C.sub.1-C.sub.8)aryl alkyl, (C.sub.1-C.sub.8) heteroalkyl, (C.sub.1-C.sub.8) heterocycloalkyl, heteroaryl, and NHCHR.sub.AR.sub.A′C(O)R.sub.12; wherein R.sub.11 is selected from C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.10 alkyl aryl, C.sub.5-C.sub.12 substituted aryl, C.sub.1-C.sub.10 heteroalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.1-C.sub.10 haloalkyl, heteroaryl, —(CH.sub.2).sub.nC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nOC(O)O(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.nSC(O)(C.sub.1-C.sub.15)alkyl, —(CH.sub.2).sub.n C(O)O(C.sub.1-C.sub.15)alkyl, and —(CH.sub.2).sub.n C(O)O(.sub.1-C.sub.15)alkyl aryl; wherein n is an integer selected from 1 to 8; P(O)(OH)OP(O)(OH).sub.2, halogen, nitro, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, —N(R.sub.11a).sub.2, C.sub.1-C.sub.6 acylamino, —COR.sub.11b, —O COR.sub.11b; NHSO.sub.2 (C.sub.1-C.sub.6 alkyl), —SO.sub.2N(R.sub.11a).sub.2 SO.sub.2, wherein each R.sub.11a is independently selected from H and a C.sub.1-C.sub.6 alkyl, and R.sub.11b is independently selected from OH, C.sub.1-C.sub.6 alkoxy, NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl).sub.2; R.sub.12 is selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.4 alkyl aryl, and C.sub.5-C.sub.12 heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted with one or two groups selected from halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; and R.sub.A and R.sub.A′ are independently selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 thioalkyl, C.sub.1-C.sub.10 hydroxylalkyl, C.sub.1-C.sub.10 alkyl aryl, and C.sub.5-C.sub.12 aryl, C.sub.3-C.sub.10 heterocycloalkyl heteroaryl, —(CH.sub.2).sub.3NHC(═NH)NH.sub.2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, nitro, and cyano; or R.sub.9 and R.sub.10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R.sub.9—R.sub.10— represents CH.sub.2—CH.sub.2—CHR—; wherein R is selected from H, (C.sub.5-C.sub.6) aryl and (C.sub.5-C.sub.6) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; or R.sub.9 and R.sub.10 together with the phosphorus atoms to which they are attached form a 6-membered ring, wherein —R.sub.9—R.sub.10— represents —O—CH.sub.2—CH.sub.2—CHR—O—; wherein R is selected from H, (C.sub.5-C.sub.6) aryl, and (C.sub.5-C.sub.6) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy, and cyano; R.sub.8 is selected from H, OR, NHR.sub.13, NR.sub.13 R.sub.14, NH—NHR.sub.13, SH, CN, N.sub.3, and halogen; wherein R.sub.13 and R.sub.14 are independently selected from H, (C.sub.1-C.sub.8) alkyl, and (C.sub.1-C.sub.8) alkyl aryl, and —CR.sub.B R.sub.C—C(O)—OR.sub.D, wherein R.sub.B and R.sub.C are independently hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy benzyl, indolyl, or imidazolyl, wherein the (C.sub.1-C.sub.6) alkyl and the (C.sub.1-C.sub.6) alkoxy can be optionally and independently of each other substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or R.sub.B and R.sub.C together with the carbon atom to which they are attached form a C.sub.3-C.sub.6 cycloalkyl group optionally substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl, and R.sub.D is hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.3-C.sub.6) cycloalkyl; Y is selected from CH, CH.sub.2, C(CH.sub.3).sub.2, and CCH.sub.3; represents a single or double bond depending on Y; and
represents the alpha or beta anomer depending on the position of R.sub.1 or a compound of formula (Ia): ##STR00102## or a stereoisomer, salt, hydrate, solvate, or crystal thereof, wherein X′.sub.1 and X′.sub.2 are independently selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R′.sub.1 and R′.sub.13 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkyl, C.sub.1-C.sub.8 heteroalkyl, and OR, wherein R is selected from H and C.sub.1-C.sub.8 alkyl, R′.sub.2, R′.sub.3, R′.sub.4, R′.sub.5, R′.sub.9, R′.sub.10, R′.sub.11, and R′.sub.12 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR, wherein R may be selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) aryl, C(O)NH(C.sub.1-C.sub.12) aryl alkyl, C(O)O(C.sub.1-C.sub.12) aryl alkyl, or a C(O)CHR.sub.AANH2 group, wherein R.sub.AA is a side chain selected from a proteogenic amino acid; R′.sub.6 and R′.sub.8 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, and OR, wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R′.sub.7 and R′.sub.14 are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N.sub.3, and halogen, wherein R and R′ are independently selected from H and (C.sub.1-C.sub.8) aryl alkyl; Y′.sub.1 and Y′.sub.2 are independently selected from CH, CH.sub.2, C(CH.sub.3).sub.2, or CCH.sub.3; M′ is selected from H or a suitable counterion;
represents a single or double bond depending on Y′.sub.1 and Y′.sub.2; and
represents an alpha or beta anomer depending on the position of R′.sub.1 and R′.sub.13; and combinations thereof.
15. The method of claim 14, wherein the pharmaceutically acceptable derivative of NMN is selected from TABLE-US-00010 Compounds (anomers) Structure I-B (alpha)
Description
FIGURES
(1)
EXAMPLE
(2) In the remainder of the present description, the examples are provided for illustrative purposes of the present invention and are in no way intended to limit the scope thereof.
(3) A satisfaction study was conducted in a group of 12 volunteers, aged 37±9 years, composed of eight men and four women. The main objective of this study was to evaluate the satisfaction of the persons with regard to the progression of their acute knee pain during the morning and/or evening application of a gel containing 5% by weight of NMN.
(4) The average BMI of the participants was 26.0±3.9. More precisely, six participants were of normal weight, four participants were overweight, and two participants were obese. None of these patients had chronic pathology such as osteoarthritis, inflammatory pathology altering their cartilage, muscles, tendons, ligaments, or bones, or requiring surgery.
(5) The average length of time during which knee pain had existed at the time of the study was 6.3±1.9 days, with a median of 7 days, whereas the subjects' current pain dated back to 6±2 days before inclusion. Most of the pain occurred after physical activity (91.7%). One person had spontaneous pain. The 11 other volunteers had pain after playing sports or physical activity.
(6) A composition in the form of an oil-in-water emulsion comprising 5% NMN was formulated as follows, the ingredients being designated by their INCI names: aqua, paraffinum liquidum, cetyl alcohol, glyceryl stearate, benzyl PCA, ceteareth-20, ceteareth-12, cetyl palmitate, cocoglycerides, cetearyl alcohol, sodium hydroxide, NMN.
(7) The mass percentages are calculated by taking the mass of the ingredient in relation to the total mass of the composition and multiplying by 100.
(8) The study was conducted over 10 days. At inclusion (DO), the selected subjects provided their demographic characteristics (age, weight, height), indicated the duration and intensity of pain on a visual analog scale, and completed the WOMAC and Lequesne questionnaires. Although none of the patients had osteoarthritis or arthritis, the Lequesne and WOMAC questionnaires were used to assess the effect of NMN on knee joint pain in different ways.
(9) The WOMAC score is a validated scale for evaluating gonalgia and is recognized by the Haute Autorité de Santé and the Société Française de Rhumatologie. The WOMAC score is composed of 24 questions, the answers to which are visual analog scales ranging from 0 (minimum) to 100 (maximum), in 3 evaluation areas: pain with 5 questions, stiffness with 2 questions and daily function with 17 questions. The total score is calculated by averaging the 24 responses and is evaluated from 0 (no impact) to 100 (maximum impact). The higher the WOMAC score, the greater the functional impact.
(10) The WOMAC “pain” dimension was the most significant at inclusion and amounted to 57.1±7.4, the “stiffness” dimension to 54.3±19.1, and the “function” dimension to 41.5±17.9. The total WOMAC score was 45.8±14.3 at inclusion.
(11) The Lequesne algofunctional index is used for the clinical follow-up of gonalgia and as an evaluation tool for the indication of a prosthesis. The Lequesne score varies from 0 to 22, the higher the score, the more extreme or even unbearable the handicap. From 8 to 10, the handicap is qualified as significant and for an index greater than or equal to 10, a prosthesis can be indicated.
(12) The Lequesne score at inclusion was 8.0±2.4, and 2 of the subjects had a score greater than or equal to 10 (16.7%).
(13) During the following 9 days, the persons fill in the visual analog scale of pain every evening and note the occurrence of any discomfort or the use of painkillers.
(14) On the 10th day, the volunteers fill out the WOMAC questionnaire, the Lequesne questionnaire, the visual analog scale (VAS) of pain, the perceived improvement of the pain measured by the PGI-I (Patient Global Improvement Impression) index, satisfaction with the progression of the gonalgia on a Lickert scale, as well as the ease of application and penetration of the gel, appreciation of the texture and smell of the gel, repeated use thereof if the same pain reappeared, and recommendation to others who would have the same type of pain. The PGI-I is an index to assess the response to treatment. The Likert scale is a psychometric tool for measuring attitudes in individuals, consisting of one or more statements for which the respondent expresses agreement or disagreement.
(15) Compliance with treatment was 95.8±8.2% on average during the study.
(16) Pain, as measured by the VAS scale, decreased steadily over the 10 days of application of the product, from 66.8±5.0 at inclusion to 18.9±18.8, i.e., a significant reduction of 47.9±20.1 points (p<0.0001). The mean time to achieve a 50% reduction in pain compared to inclusion was 5±2 days. The results expressed as mean and standard deviation, day by day and for all volunteers, are summarized in Table 3 below:
(17) TABLE-US-00007 TABLE 3 Standard Medi- Mini- Maxi- Pain N Average deviation an mum mum Inclusion D 0 12 66.8 5.0 65.5 61.0 80.0 D 1 12 53.8 12.8 57.5 22.0 64.0 D 2 12 52.5 12.0 50.0 25.0 71.0 D 3 12 43.8 9.8 43.5 29.0 60.0 D 4 12 40.1 14.1 39.0 11.0 61.0 D 5 12 35.6 13.3 36.5 9.0 60.0 D 6 12 36.0 15.7 34.5 12.0 72.0 D 7 12 29.8 15.7 24.5 14.0 69.0 D 8 12 23.5 14.5 19.0 0.0 55.0 D 9 12 22.2 17.7 19.5 0.0 51.0 End of study D 10 12 18.9 18.8 18.0 0.0 56.0
(18) These results are further represented by the graph in
(19) At the end of 10 days of applying the composition according to the invention, the “pain” dimension of the WOMAC went from 57.1±7.4 at inclusion to 14.3±13.8 at the end of the study, i.e., a significant reduction of 42.7±17.1 points (p<0.0001). The reductions for the other dimensions were also significant, from 54.3±19.1 to 20.8±21.8 for the WOMAC “stiffness” dimension (difference of 33.5±27.8, p<0.01) and from 41.5±17.9 to 11.0±15.9 for the WOMAC “function” dimension (difference of 30.4±21.7, p<0.001). The total WOMAC score also decreased significantly from 45.8±14.3 to 12.5±15.0, i.e., a decrease of 33.2±20.2 points (p<0.001) and a reduction of 72.7% of the score.
(20) The Lequesne algofunctional score decreased significantly between inclusion and the end of the study, from 8.0±2.4 to 3.8±2.9 (p<0.001), i.e., a 52.5% reduction in the score. At the end of the study, two thirds of the patients (66.7%) had no handicap or only a slight handicap.
(21) At the end of the study, 91.7% of the volunteers felt an improvement in their pain, including 2 considerably (16.7%), 8 very much (66.7%) and 1 slightly (8.3%). 91.7% of the volunteers were satisfied with the progression of their gonalgia, including 41.7% very satisfied.
(22) Organoleptically, all patients found the gel easy to apply (83.3% very easy), easily penetrated the skin (75% very easy), had a pleasant texture (50% very pleasant) and a pleasant smell (66.7% pleasant and 33.3% quite pleasant).
(23) All patients would be inclined to use the gel again if they had the same joint pain (41.7% of them very likely) and to recommend it to a relative who had the same knee pain (41.7% of them very likely).
(24) No volunteers experienced any side effects following the use of the composition according to the invention, nor did they develop any allergies.
(25) NMN, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, as well as compositions comprising same, are therefore effective in reducing joint pain induced by physical activity or sports.
(26) Indeed, regardless of the pain measurement scale used, a significant reduction in pain induced by physical activity was measured in the study participants.
(27) Although these results were obtained by measuring joint pain in the knee, NMN, a pharmaceutically acceptable derivative thereof, or a pharmaceutically acceptable salt thereof, as well as compositions comprising same, can be used to treat or prevent other types of joint pain such as, for example, shoulder, elbow, ankle, neck, or other joint pain.