US 2017/0290850 A1 · NICOTINAMIDE MONONUCLEOTIDE DERIVATIVES AND THEIR USES

Abstract

The invention relates to compositions of nicotinamide mononucleotide derivatives and their methods of use. The invention also relates to methods of preparing nicotinamide mononucleotide derivatives. The invention relates to pharmaceutical compositions and nutritional supplements containing a nicotinamide mononucleotide derivative. The invention relates to methods of using nicotinamide mononucleotide derivatives that promote the increase of intracellular levels of nicotinamide adenine dinucleotide (NAD+) in cells and tissues for treating diseases and improving cell and tissue survival.

Claims25

Dependent claims

A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula I:

wherein V is selected from hydrogen, phenyl and monocyclic heteroaryl, wherein (i) each said monocyclic heteroaryl contains five or six ring atoms of which 1 or 2 ring atoms are heteroatoms selected from N, S, and O, and the remainder of the ring atoms are carbon, and (ii) each said phenyl or monocyclic heteroaryl is unsubstituted or is substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and cyano.

A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula II:

(a) R1 is hydrogen;
n-alkyl;
branched alkyl;
cycloalkyl;
or aryl, where aryl is optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl;
R1′ is independently hydrogen or alkyl selected from C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, and
R1″ is —OR′ or —N(R1′)2;
(b) R2 is hydrogen, C1-10 alkyl;
or C(O)CR3aR3bNHR1, where n is 2 to 4;
or
R3a or R3b and R2 together are (CH2)n forming a cyclic ring that includes the adjoining N and C atoms;
(c) R3a and R3b are
(i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups are optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano;
or
(ii) R3a and R3b both are C1-6 alkyl;
or
(iii) R3a and R3b together are (CH2)f so as to form a spiro ring;
or
(iv) R3a is hydrogen and R3b and R2 together are (CH2)n forming a ring that includes the adjoining N and C atoms;
or
(v) R3b is hydrogen and R3a and R2 together are (CH2)n forming a ring that includes the adjoining N and C atoms;
or
(vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
or
(vii) R3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
c is from 1 to 6,
d is from 0 to 2,
e is from 0 to 3,
f is from 2 to 5,
n is from 2 to 4, and
(d) R4 is hydrogen;
C1-10 alkyl optionally substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen;
C1-10 haloalkyl;
C3-10 cycloalkyl;
cycloalkyl alkyl;
cycloheteroalkyl;
aminoacyl;
aryl;
heteroaryl;
substituted aryl;
or substituted heteroaryl.

38 more elements

A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein each W1 and W2 is independently
(i) each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
or
(ii) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
or
(iii) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl wherein the chirality of the carbon to which said Rc and Rd is attached is S;
or
(iv) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C9)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl wherein the chirality of the carbon to which said Rc and Rd is attached is R;
or
(v) each R is H and each Rd is independently (C1-C8)alkyl;
or
(vi) each Rc is H and each Rd is independently (C1-C8)alkyl wherein the chirality of the carbon to which said Rc and Rd is attached is S;
or
(vii) each Rc is H and each Rd is independently (C1-C8)alkyl wherein the chirality of the carbon to which said Rc and Rd is attached is R;
and
each R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl or (C4-C8)carbocyclylalkyl.

13 more elements

A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein one of W1 or W2 is OR5
R5 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
and
the other of W1 or W2 is
(i) each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
or
(ii) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
or
(iii) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl wherein the chirality of the carbon to which said Rc and Rd is attached is S;
or
(iv) each Rc is H and each Rd is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl wherein the chirality of the carbon to which said Rc and Rd is attached is R;
or
(v) each Rc is H and each Rd is independently (C1-C8)alkyl;
or
(vi) each Rc is H and each Rd is independently (C1-C8)alkyl wherein the chirality of the carbon to which said Rc and Rd is attached is S;
or
(vii) each Rc is H and each Rd is independently (C1-C8)alkyl wherein the chirality of the carbon to which said Rc and Rd is attached is R;
and
each R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl or (C4-C8)carbocyclylalkyl.

16 more elements

A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein W1 and W2 are independently selected from the substituents in Table 1, and
each R21 is independently H or (C1-C8)alkyl;
each R22 is independently H, R21, R23 or R24, wherein each R24 is independently substituted with 0 to 3 R23;
each R23 is independently R23a, R23b, R23c or R23d, provided that when R23 is bound to a heteroatom, then R23 is R23c or R23d;
each R23a is independently F, Cl, Br, I, —CN, —N3 or —NO2;
each R23b is independently Y21;
each R23c is independently —R2x, —OR2x, —N(R2x)(R2x), —SR2x, —S(O)R2x;
—S(O)2R2x, —S(O)(OR2x), —S(O)2(OR2x), —OC(═Y21)R2x, —OC(═Y21)OR2x, —OC(═Y21)(N(R2x)(R2x));
—SC(═Y21)R2x;
—SC(═Y21)OR2x, —SC(═Y21)(N(R2x)(R2x)), —N(R2x)C(═Y21)R2x, —N(R2x)C(═Y21)OR2x, or —N(R2x)C(═Y21)(N(R2x)(R2x));
each R23d is independently —C(═Y21)R2x;
—C(═Y21)OR2x or —C(═Y21)(N(R2x)(R2x));
each R2x is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, heteroaryl;
or two R2x taken together with a nitrogen or oxygen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O, —S— or —NR21—;
and wherein one or more of the non-terminal carbon atoms of each said (C1-C8)alkyl may be optionally replaced with —O—, —S— or —NR21—;
each R24 is independently (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;
each R25 is independently R24, wherein each R24 is substituted with 0 to 3 R23 groups;
each R25a is independently (C1-C8)alkylene, (C2-C8)alkenylene, or (C2-C8)alkynylene, any one of which said (C1-C8)alkylene, (C2-C8)alkenylene, or (C2-C8)alkynylene is substituted with 0-3 R23 groups;
each W23 is independently W24 or W25;
each W24 is independently R25, —C(═Y21)R25, —C(═Y21)W25, —SO2R25, or —SO2W25;
each W25 is independently carbocycle or heterocycle wherein W25 is independently substituted with 0 to 3 R22 groups;
and
each Y21 is independently O or S.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/512,388Filed 5 Aug 2016

Priority

5 Aug 2015

Published

12 Oct 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

A61K 31/706
Having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides: containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/443
Containing further heterocyclic ring systems: containing a five-membered ring with oxygen as a ring hetero atom
A61K 31/661
Phosphorus compounds: phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
A61K 31/665
Phosphorus compounds: having oxygen as a ring hetero atom, e.g. fosfomycin

Nicotinamide mononucleotide derivatives and their uses

Life of this patent

Nicotinamide mononucleotide derivatives and their uses

Life of this patent

Abstract

Claims25