US2021230208A1PendingUtilityA1
Inorganic salts of nicotinamide mononucloetide as anti-aging agents
Est. expiryMay 15, 2038(~11.8 yrs left)· nominal 20-yr term from priority
C12N 5/0609A61K 31/706C12N 2500/40A61P 15/08C07H 1/00C07H 19/048C12N 5/0603C07F 9/65586C12N 2517/10C12N 2501/999C12N 2500/33C12N 2500/32
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Claims
Abstract
The present invention relates to inorganic salts of nicotinamide mononucleotides and compositions of Formula I, useful in the treatment of disorders and diseases associated with deficiencies in NAD + : wherein A, M, k, R 1 and R 2 are as described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A salt of Formula (I):
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8,
provided M 1 is not Na.
2 . The salt of claim 1 , wherein M 1 is a cation selected from the group consisting of Li + , K + , Rb + , Cs + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , Zn 2+ , and Ba 2+ .
3 . The salt of any one of claims 1 to 2 , wherein M 1 is K + .
4 . The salt of any one of claims 1 to 2 , wherein M 1 is Li + .
5 . The salt of any one of claims 1 to 2 , wherein M 1 is Rb + .
6 . The salt of any one of claims 1 to 5 , wherein R 1 is H.
7 . The salt of any one of claims 1 to 5 , wherein R 1 is C 1 -C 3 alkyl.
8 . The salt of any one of claims 1 to 5 , wherein R 2 is H.
9 . The salt of any one of claims 1 to 5 , wherein R 2 is C 1 -C 3 alkyl.
10 . The salt of claim 1 , selected from the group consisting of:
11 . A pharmaceutical composition comprising a salt of any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
12 . A method of treating or preventing an age-related infertility comprising administering to a subject in need thereof, an effective amount of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8.
13 . A method of treating or preventing infertility comprising administering to a subject in need thereof, an effective amount of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 3 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8.
14 . A method of improving oocyte or blastocyst quality and maturation comprising contacting the oocyte or blastocyst with an effective amount of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 1 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 1 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8
prior to implantation into a subject in need of treatment of age-related infertility.
15 . A method of improving oocyte or blastocyst quality and maturation comprising contacting
the oocyte or blastocyst with an effective amount of a salt of
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8
prior to implantation into a subject in need of treatment of age-related infertility.
16 . The method of claim 14 or 15 where the oocyte or blastocyst is cultured in an IVF media containing the salt.
17 . Use of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8
in the manufacture of a medicament for treating an age-related disorder.
18 . Use of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8
in the manufacture of a medicament for treating infertility.
19 . Use of a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8
in the manufacture of a medicament for treating age related infertility.
20 . A process for the preparation of a salt of Formula I:
comprising contacting the compound of Formula II
with a metal-alkali hydroxide under conditions effective to produce the product salt of Formula I.
21 . The process of claim 20 , wherein the metal-alkali hydroxide is added dropwise into a solution of the compound of Formula II.
22 . A cell culture medium for in vitro fertilization comprising:
a salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8; and
culturing agents.
23 . The cell culture medium of claim 22 , wherein the culturing agent is an inorganic salt, an energy substrate, an amino acid, a chelator, a pH indicator, an antibiotic, a serum, a vitamin, a growth factor, or any combination thereof.
24 . The cell culture medium of claim 23 , wherein the inorganic salt is calcium chloride, magnesium chloride, magnesium sulfate, potassium chloride, sodium bicarbonate, sodium chloride, monosodium phosphate, disodium phosphate, or any combination thereof.
25 . The cell culture medium of claim 23 , wherein the energy substrate is glucose, pyruvate, lactate, pyruvate, or any combination thereof.
26 . The cell culture medium of claim 23 , wherein the amino acid is an essential amino acid.
27 . The cell culture medium of claim 26 , wherein the essential amino acid is arginine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, or any combination thereof.
28 . The cell culture medium of claim 23 , wherein the amino acid is a non-essential amino acid.
29 . The cell culture medium of claim 28 , wherein the non-essential amino acid is alanine, asparagine, aspartate, glutamate, proline, serine, or any combination thereof.
30 . The cell culture medium of claim 23 , wherein the chelator is clathro chelate, acetyl acetone, amino polycarboxylic acid, ATMP, BAPTA, BDTH2, citric acid, cryptand, deferasirox, 2,3-dihydrobenzoic acid, 2,3-dimercapto-1-propane sulfonic acid, dimercapto succinic acid, DOTA, DTPMP, EDDHA, EDDS, EDTMP, etidronic acid, fura-2, gluconic acid, homocitric acid, imino diacetic acid, Indo-1, nitrile triacetic acid, pentetic acid (DTPA), phosphonate, phytochelati, poly aspartic acid, sodium poly aspartate, trisodium citrate, transferrin, EDTA, EGTA, or any combination thereof.
31 . The cell culture medium of claim 23 , wherein the pH indicator is phenol red, bromothymol blue, alizarin red, 9-aminoacridine, or any combination thereof.
32 . The cell culture medium of claim 23 , wherein the antibiotic is actinomycin D, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, penicillin, polymyxin B, streptomycin, or any combination thereof.
33 . The cell culture medium of claim 23 , wherein the serum is human serum albumin, bovine serum albumin, fetal bovine serum, synthetic serum, or any combination thereof.
34 . The cell culture medium of claim 23 , wherein the vitamin is ascorbic acid, biotin, menadione sodium bisulfite, mitomycin C, pyridoxamine dihydrochloride, retinyl acetate, (−)-riboflavin, (+)-sodium L-ascorbate, (+)-α-tocopherol, vitamin B 12 , thiamine hydrochloride, i-inositol, pyridoxal hydrochloride, nicotinamide, folic acid, D-calcium pantothenate, choline chloride, or any combination thereof.
35 . The cell culture medium of claim 23 , wherein the growth factor is adrenomedullin, angiopoietin, bone morphogenetic proteins, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), epidermal growth factor, ephrins, erythropoietin, fibroblast growth factor, growth differentiation factor-9, hepatocyte growth factor, insulin, insulin-like growth factors, interleukins, keratinocyte growth factor, migration-stimulating factor, macrophage-stimulating protein, myostatin, neurotrophins, t-cell growth factor, thrombopoietin, transforming growth factor, tumor necrosis factor-alpha, vascular endothelial growth factor, or any combination thereof.
36 . The cell culture medium of claim 22 , wherein the cell culture medium further comprises an oocyte, zygote, blastocyst, or any combination thereof.
37 . A salt of Formula I:
or enantiomer, stereoisomer, or tautomer thereof,
wherein
A is NR a R b ;
M 1 is an inorganic cation;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 0 -C 3 alkylene)C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , or —[CH 2 —CH 2 —O] n —R a ,
or R 1 and R 2 , together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
R a and R b are independently, at each occurrence, H, or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C 0 -C 3 alkylene)C 3 -C 8 cycloakyl, (C 0 -C 3 alkylene)heterocycloakyl, (C 0 -C 3 alkylene)C 6 -C 14 aryl, and (C 0 -C 3 alkylene)heteroaryl;
k is 1 or 2; and
n is an integer from 1 to 8.
made by the process of claim 20 .
38 . The salt of claim 37 , wherein the salt isCited by (0)
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