Inorganic salts of nicotinamide mononucloetide as anti-aging agents

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 NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• k is 1 or 2;
• and
• n is an integer from 1 to 8.

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 NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C3cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• k is 1 or 2;
• and
• n is an integer from 1 to 8.

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 NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C1-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C1-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)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.

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 NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)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.

Use of a salt of Formula I:

• or enantiomer, stereoisomer, or tautomer thereof,
• wherein
• A is NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)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.

Use of a salt of Formula I:

• or enantiomer, stereoisomer, or tautomer thereof,
• wherein
• A is NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• k is 1 or 2;
• and
• n is an integer from 1 to 8
• in the manufacture of a medicament for treating infertility.

Use of a salt of Formula I:

• or enantiomer, stereoisomer, or tautomer thereof,
• wherein
• A is NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)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.

A cell culture medium for in vitro fertilization comprising:

• a salt of Formula I:
• or enantiomer, stereoisomer, or tautomer thereof,
• wherein
• A is NRaRb;
• M1 is an inorganic cation;
• R1 and R2 are independently H, C1-C6alkyl, C1-C6haloalkyl, (C0-C3alkylene)C(O)C1-C6alkyl, —C(O)ORa, —C(O)NRaRb, or —[CH2—CH2—O]n—Ra,
• or R1 and R2, together with the atom to which they are attached, form a 5-membered heterocyclic ring optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• Ra and Rb are independently, at each occurrence, H, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from (C0-C3alkylene)C3-C8cycloakyl, (C0-C3alkylene)heterocycloakyl, (C0-C3alkylene)C6-C14aryl, and (C0-C3alkylene)heteroaryl;
• k is 1 or 2;
• and
• n is an integer from 1 to 8;
• and
• culturing agents.