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Title:
METHODS AND COMPOSITIONS OF IMPROVING FERTILITY
Document Type and Number:
WIPO Patent Application WO/2018/200357
Kind Code:
A1
Abstract:
Provided herein are methods and compositions related to treating and/or preventing infertility, improving fertility and/or increasing lactation in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising nicotinamide riboside and/or Pterostilbene.

Inventors:
MARCOTULLI ERIC (US)
ALMINANA DAN (US)
DELLINGER RYAN (US)
MORRIS MARK (US)
Application Number:
PCT/US2018/028809
Publication Date:
November 01, 2018
Filing Date:
April 23, 2018
Export Citation:
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Assignee:
ELYSIUM HEALTH INC (US)
International Classes:
C07H19/048; A61K38/45
Domestic Patent References:
WO2016049236A12016-03-31
WO2016149277A12016-09-22
WO2015186114A12015-12-10
WO2017062311A12017-04-13
Foreign References:
US20130059384A12013-03-07
Other References:
"Mitochondrial function and male fertility", CYTOPLAN, 9 November 2016 (2016-11-09), pages 1 - 5, XP055526721, Retrieved from the Internet [retrieved on 20180626]
Attorney, Agent or Firm:
JONES, Brendan T. et al. (US)
Download PDF:
Claims:
Claims:

1. A method of improving fertility in a subject comprising administering to the subject a composition comprising nicotinamide riboside.

2. The method of claim 1, wherein the composition further comprises pterostilbene.

3. The method of claims 1 or 2, wherein improving fertility comprises inducing ovulation in the subject.

4. The method of claims 1 or 2, wherein improving fertility comprises inducing oocyte and follicle maturation in the subject.

5. The method of claims 1 or 2, wherein improving fertility comprising increasing sperm count in the subject.

6. The method of claims 1 or 2, wherein improving fertility comprising increasing sperm motility.

7. A method of treating or preventing infertility in a subject comprising administering to the subject a composition comprising nicotinamide riboside.

8. The method of claim 7, wherein the composition further comprises pterostilbene.

9. The method of claims 7 or 8, wherein treating or preventing infertility comprises inducing ovulation in the subject.

10. The method of claims 7 or 8, wherein treating or preventing infertility comprises inducing oocyte and follicle maturation in the subject.

11. The method of claims 7 or 8, wherein treating or preventing infertility comprising increasing sperm count in the subject.

12. The method of claims 7 or 8, wherein treating or preventing infertility comprising increasing sperm motility.

13. A method of inducing ovulation in a subject comprising administering to the subject a composition comprising nicotinamide riboside.

14. The method of claim 13, wherein the composition further comprises pterostilbene.

15. A method of increasing sperm count in a subject comprising administering to the subject a composition comprising nicotinamide riboside.

16. The method of claim 15, wherein the composition further comprises pterostilbene.

17. A method of increasing lactation in a subject comprising administering to the subject a composition comprising nicotinamide riboside.

18. The method of claim 17, wherein the composition further comprises pterostilbene.

19. The method of any one of the preceding claims, wherein the subject is human.

20. A method of increasing the number of offspring in a litter in a non-human subject, comprising administering to the subject a composition comprising nicotinamide riboside.

21. The method of claim 13, wherein the composition further comprises pterostilbene.

22. The method of any one of claims 1 to 21, wherein the administration of the composition comprises administering one or more doses of the composition.

23. The method of claim 22, wherein each dose of the composition comprises at least 200 mg of nicotinamide riboside.

24. The method of claim 22, wherein each dose of the composition comprises at least 250 mg of nicotinamide riboside.

25. The method of claim 22, wherein each dose of the composition comprises at least 300 mg of nicotinamide riboside.

26. The method of claim 22, wherein each dose of the composition comprises at least 350 mg of nicotinamide riboside.

27. The method of claim 22, wherein each dose of the composition comprises at least 400 mg of nicotinamide riboside.

28. The method of claim 22, wherein each dose of the composition comprises at least 450 mg of nicotinamide riboside.

29. The method of claim 22, wherein each dose of the composition comprises at least 500 mg of nicotinamide riboside.

30. The method of claim 22, wherein each dose of the composition comprises at least 550 mg of nicotinamide riboside.

31. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 15 mg of pterostilbene.

32. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 25 mg of pterostilbene.

33. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 50 mg of pterostilbene.

34. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 75 mg of pterostilbene.

35. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 100 mg of pterostilbene.

36. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 125 mg of pterostilbene.

37. The method of any one of claims 22 to 30, wherein each dose of the composition comprises at least 150 mg of pterostilbene.

38. The method of any one of claims 22 to 37, wherein two or more doses of the composition are administered.

39. The method of any one of claims 22 to 38, wherein thirty or more doses of the composition are administered.

40. The method of any one of claims 22 to 39, wherein fifty or more doses of the composition are administered.

41. The method of any one of claims 22 to 40, wherein one hundred or more doses of the composition are administered.

42. The method of any one of claims 22 to 41, wherein the dose of the composition is administered at least once a week.

43. The method of any one of claims 22 to 41, wherein the dose is administered at least twice a week.

44. The method of any one of claims 22 to 41, wherein the dose is administered at least three times a week.

45. The method of any one of claims 22 to 41, wherein the dose is administered at least once a day.

46. The method of any one of claims 22 to 41, wherein the dose is administered at least twice a day.

47. The method of any one of claims 42 to 46, wherein the doses are administered for at least 7 days.

48. The method of any one of claims 42 to 46, wherein the doses are administered for at least 30 days.

49. The method of any one of claims 42 to 46, wherein the doses are administered for at least 60 days.

50. The method of any one of claims 42 to 46, wherein the doses are administered for at least 90 days.

51. The method of any one of claims 1 to 50, wherein the composition is formulated as a pill, a tablet, or a capsule.

52. The method of any one of claims 1 to 51, wherein the composition is administered orally.

53. The method of any one of claims 1 to 52, wherein the composition is self- administered.

Description:
METHODS AND COMPOSITIONS OF IMPROVING FERTIIITY

RELATED APPLICATION

This application claims the benefit of priority to U. S. Provisional Patent Application serial number 62/490384, filed April 26, 2017, hereby incorporated by reference in its entirety.

BACKGROUND

Infertility is a condition generally characterized by a couple not being able to become pregnant after a year of trying. Infertility is fairly common in the U. S. and affects thousands of Americans every year. After one year of having unprotected sex, an average of 15 percent of couples are unable to get pregnant. Infertility may have various causes, and the many treatments and intervention technologies are often costly, have adverse side effects, and varying success rates.

Accordingly, there is a great need for new compositions and methods for the treatment and prevention of infertility.

SUMMARY

Generally, the methods and compositions disclosed herein related to improving fertility, treating infertility, and/or preventing infertility in a subject (e.g., a male or female subject human or non-human animal) by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene). In some embodiments, improving fertility or treating and/or preventing infertility comprises inducing ovulation and/or oocyte and follicle maturation in a female subject. In some embodiments, improving fertility or treating and/or preventing infertility comprising increasing sperm count and/or sperm motility in a male subject.

In some aspects, provided herein are methods of increasing lactation in a subject (e.g., a lactating female subject) comprising administering to the subject a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal, such as a dairy animal (e.g., a cow, a buffalo, a goat, a sheep, a camel).

In certain embodiments of the compositions and methods provided herein, the composition comprises a compound of Formula I or Formula II (e.g., nicotinamide riboside) (e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside)). In some embodiments, the composition comprises a compound of Formula III (e.g., pterostilbene) (e.g., at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene)). In certain embodiments, the composition comprises both a compound of Formula I or

Formula II (e.g., nicotinamide riboside) (e.g., at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside)) and a compound of Formula III (e.g., pterostilbene) (e.g., at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene)).

In certain embodiments, the method comprises administering a plurality of doses of the composition. In some embodiments, at least 7 doses of the composition are

administered. In some embodiments, at least 30 doses of the composition are administered. In some embodiments, at least 60 or more doses of the composition are administered. In some embodiments, each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside). In some embodiments, each dose comprises at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene). In certain embodiments, each dose comprises at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg or at least 600 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside) at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 125 mg or at least 150 mg of a compound of Formula III (e.g., pterostilbene).

In certain embodiments, a dose of the composition is administered at regular intervals over a period of time. In some embodiments, a dose of the composition is administered at least once a week. In some embodiments, a dose of the composition is administered at least twice a week. In certain embodiments, a dose of the composition is administered at least three times a week. In some embodiments, a dose of the composition is administered at least once a day. In some embodiments, a dose of the composition is administered at least twice a day. In some embodiments, doses of the composition are administered for at least 1 week, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks, for at least 1 month, for at least 2 months, for at least 3 months, for at least 4 months, for at least 5 months, for at least 6 months or for at least 1 year.

In certain embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is formulated as a pill, a tablet, or a capsule. In some embodiments, the composition is administered orally. In certain embodiments, the composition is self-administered.

DETAILED DESCRIPTION

General In certain aspects, the methods and compositions disclosed herein related to improving fertility, treating infertility, and/or preventing infertility in a subject by administering to the subject (e.g., orally administering to the subject) a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene). In some aspects, provide herein are methods of inducing ovulation and/or inducing oocyte and follicle maturation in a subject by administering to the subject a composition disclosed herein. In some embodiments, provided herein are methods of increasing sperm count and/or sperm motility in a subject by administering to the subject a composition disclosed herein. Also provide herein are methods of increasing lactation in a subject comprising administering to the subject a comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside), and/or a compound of Formula III (e.g., pterostilbene).

Definitions

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

As used herein, the term "administering" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. Administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material.

As used herein, the term "subject" means a human or non-human animal selected for treatment or therapy .

The phrases "therapeutically-effective amount" and "effective amount" as used herein means the amount of an agent which is effective for producing the desired therapeutic effect in at least a sub-population of cells in a subject at a reasonable benefit/risk ratio applicable to any medical treatment.

"Treating" a disease in a subject or "treating" a subject having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased or prevented from worsening.

As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, when administered to a statistical sample prior to the onset of the disorder or condition, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

Compositions

Provided herein are pharmaceutical compositions comprising a compound of

Formula I or Formula II {e.g., nicotinamide riboside) and/or a compound of Formula III {e.g., pterostilbene).

Nicotinamide riboside is a pyridine-nucleoside form of niacin {i.e., vitamin B 3 ) that serves as a precursor to nicotinamide adenine dinucleotide (NAD + ). As used herein, "nicotinamide riboside" also includes nicotinamide riboside salts, such as nicotinamide riboside chloride. The chemical structure of nicotinamide riboside is provided below:

In some embodiments, provided herein are pharmaceutical compositions comprising a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

Ri, R2, and R3 are selected from hydrogen, halogen, -CN, -NO2, -OR14, -N(Ri4)m, - Ri3, substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

Ri and R.5 are selected from hydrogen, halogen, -CN, -NO2, -OR14, -N(Ri4)m, substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

Re, Rs, R11, and R12 are selected from hydrogen, (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri4)m, -C(0)((Ci-C6)alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -OR14, and -N(Ri4) m ;

R7, R , and Rio are selected from -((Ci-C6)alkylene)N(Ri4)m, -OR14, and -N(R 14 ) m ;

Ri3 is selected from -ORi4, -N(Ri 4 )m, -C(0)(Ri 4 ), -C(0)(ORi 4 ), -C(0)N(Ri 4 )m, - S(0) 2 (ORM), -S(0)ORf 4, and - S(0) 2 N(Ri4)m;

Ri4 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; and

X is O, S, or N(R i4 );

m is 2 or 3;

provided that at least one of Ri, R 2 , and R3 is Rn. In some embodiments, Ri is R.o. In some embodiments, R2 is R13. In some embodiments, Rj is R 13 .

In some embodiments, R13 is selected from. -ORH, -N(R 14 )m, -C(0)(R 14 ), - C(0)(ORH), and -C(0)N(R 14 ) m . In some embodiments, R 13 is selected from -C(0)(R 14 ), - C(0)(ORi4), and -C(0)N(R i4 )m. In some embodiments, R13 is -C(0)N(Ri4)m.

In some embodiments, R7, R9, and Rio are each independently -ORH or -N(R 14 )m. In some embodiments, R7, R9, and Rso are -ORH.

In some embodiments, the compound of formula (I) is represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R2 and R3 are selected from hydrogen, halogen, -CN, -NO2, -ORH, -N(Ri 4 )m, -R13, substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R 4 and Rs are selected from hydrogen, halogen, -CN, -NO2, -ORH, -N(R. 14 )m, substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

Re, Rs, R11, and R12 are selected from hydrogen, -ORH, -N(R 14 )m, substituted or unsubstituted (Ci-C 6 )alkyl, -((Ci-C 6 )alkylene)N(Ri4)m, -C(0)((Ci-C 6 )alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

R13 is selected from -ORH, -N(Rn)m, -C(0)(Ri4), -C(0)(ORi4), -C(0)N(Ri 4 )m, - S(0) 2 (ORi4), -S(0)ORi4, and - S(0) 2 N(Ri4)m;

Ri4 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; and

m is 2 or 3.

In some embodiments of the compounds of formula (I) or (II), Ri, R2, and R3 are each independently, if present, selected from hydrogen, halogen, -CN, -NO2, -ORH, - N(Rn)m, -Ri3, and substituted or unsubstituted (Ci-Ce)alkyl. In some embodiments, Ri, R_, and R3 are each independently, if present, selected from hydrogen, -OR14, -N(R. 14 )m, and unsubstituted (Ci-C6)alkyl. In some embodiments, Ri, R2, and R 3 are each independently, if present, selected from substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl,

heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Ri, R2, and R3 are each independently, if present, hydrogen.

In some embodiments of the compounds of formula (I) or (II), Ri and Rs are each independently selected from hydrogen, halogen, -CN, -NO2, -ORi4, -N(Rj 4)m, and substituted or unsubstituted (Ci-Ce)alkyl. In some embodiments, R 4 and R? are each independently selected from hydrogen, -ORi 4 , -N(Ri 4 )m, and unsubstituted (Ci-Ce)alkyl. In some embodiments, R4 and R 5 are each independently selected from substituted or unsubstituted (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R 4 and R5 are each hydrogen.

In some embodiments of the compounds of formula (I) or (II), Re, Rs, Rn, and R12 are selected from hydrogen, -ORH, -N(Ri 4 )m, unsubstituted (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri 4 )m, -C(0)((Ci-C6)alkylene)N(Ri4)m, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Re, Rs, R11, and Ri?. are each independently selected from hydrogen, -ORM, -N(R 14 )m, unsubstituted (Ci-C 6 )alkyl, -((Ci- C6)alkylene)N(Ri 4 )m, and -C(0)((Ci-C6)alkylene)N(Ri4)m. In some embodiments, Re, Rs, R11, and R12 are each independently selected from hydrogen, -ORM, and -N(R. 14 ) m . In some embodiments, Re, Rs, Rii, and R12 are each independently selected from unsubstituted (Ci- C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, Re, Rs, Rii, and R12 are each hydrogen.

In some embodiments, R7, R9, and Rio are each independently -OR14 or -N(Rj4)m. In some embodiments, R7, Rs>, and Rio are each -ORH. In some embodiments, R7, Rs, and Rio are each -OH.

In some embodiments of the compounds of formula (I) or (II), RH is hydrogen or (Ci-Ce)alkyl.

In some embodiments of the compounds of formula (I) or (II), X is O or N(RM). In some embodiments, X is O.

In some embodiments of the compounds of formula (I) or (II), the compound is

Pterostilbene is a stilbenoid and an analog of polyphenol reservatrol that has better bioavailability due to the presence of two methoxy groups that allow it to have increased lipophilic and oral absorption as well as a longer half-life due to reduced oxidation. The chemical structure of pterostilbene is provided below:

In some embodiments, provided herein are pharmaceutical compositions comprising a compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R ! 5 is selected from halogen, -CN, -NO2, -ORie, -N(Rie) P , -S(0) 2 (ORi6), -S(0)ORi substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

Ri6 is selected from hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

n is an integer from 0 to 5; and

p is 2 or 3;

provided that at least one n is 1; and at least one Ris is -OR 16 ;

provided that the compound of formula (III) is not

In some embodiments of the compounds of formula (III), R15 is selected from, halogen, -CN, -NO2, -ORie, -N(Rj6) P , and substituted or unsubstituted (Ci-C6)alkyl. In some embodiments, R15 is selected from -OR16, -N(Ri6) P , and unsubstituted (Ci-C6)alkyl. In some embodiments, Rj .5 is selected from substituted or unsubstituted (Ci-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R15 is -ORie. In some embodiments, R15 is -ORie; and Rie is hydrogen or (Ci-Ce)alkyl. In some embodiments, Ris is -ORie; and Rie is (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In some embodiments, R15 is -ORie; and Rie is (Ci-Ce)alkyl. In some embodiments, R15 is -ORie: and Rie is (Ci-C 6 )alkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2.

In some embodiments, p is 2. In some embodiments, p is 3.

In one aspect, the provided herein are pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described herein (e.g., nicotinamide riboside and/or pterostilbene), formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. In another aspect, the agents described herein can be administered as such, or administered in mixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with other agents. Conjunctive therapy thus includes sequential, simultaneous and separate, or co-administration of one or more compounds of the invention, wherein the therapeutic effects of the first administered has not entirely disappeared when the subsequent compound is administered.

As described in detail below, the pharmaceutical compositions described herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; or (3) sublingually.

In some embodiments, the composition comprises additional agents. For example, the composition may comprise a nutritional agent, such as an antioxidant. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The formulations of the compounds described herein may be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the agent which produces a therapeutic effect.

In certain embodiments, a formulation described herein comprises an excipient, including, but not limited to, cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an agent of the invention. In some embodiments, an aforementioned formulation renders orally

bioavailable an agent of the invention. Methods of preparing these formulations or compositions may include the step of bringing into association a compound of the invention with the carrier and, optionally, one or more accessory ingredients.

Liquid dosage forms for oral administration of the formulations provided herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations provided herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. A compound of the invention may also be administered as a bolus, electuary, or paste.

In solid dosage forms of the invention for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,

carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,

disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. Compositions described herein may also be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

Pharmaceutical compositions provided herein suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Therapeutic Methods

Provided herein are methods of preventing and/or treating infertility in a subject by administering to the subject (e.g., a subject in need thereof) a composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)). Provided herein are methods of improving fertility in a subject by administering to the subject (e.g., a subject in need thereof) a composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)). In some embodiments, the subject is a mammal (e.g., a human, a non- human mammal). The subject may be male or female. In some embodiments, the subject has impaired fertility (e.g., reduced sperm count, reduced sperm motility, reduced ovulation, reduced follicle and/or oocyte maturation). In some embodiments, the subject is infertile or sterile.

In some embodiments, provided herein are methods of increasing overall sperm health and/or sperm count in a subject by administering to the subject (e.g., a subject in need thereof) a composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)). Increasing sperm count may be achieved by increasing the

concentration of spermatozoa in seminal fluid, increasing the absolute number of spermatozoa in semen and/or increasing the volume of semen per ejaculate. The methods and compositions disclosed herein may increase overall sperm count by increasing or inducing spermatogenesis. In some embodiments, administering the compositions disclosed herein increase or improve sperm motility (e.g., increasing the percentage of spermatozoa moving in semen or increasing the amount of time spermatozoa are moving) in a subject. In some embodiments, administering the compositions disclosed herein maintains or improves overall sperm health, sperm count, and/or sperm motility in the testes and/or epididymis post spermatogenesis. In some embodiments, provided herein are methods of inducing and/or increasing the likelihood of ovulation in a subject by administering to the subject (e.g., a subject in need thereof) a composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e-g, pterostilbene)). In some embodiments, provided herein are methods of inducing follicle and oocyte maturation (e.g., folliculogenesis) in a subject by administering to the subject (e.g., a subject in need thereof) a composition disclosed herein (i.e., a composition comprising a compound of Formula I or Formula II (e.g., nicotinamide riboside) and/or a compound of Formula III (e.g., pterostilbene)).

Disclosed herein are compositions and methods to aid in in vitro fertilization procedures and practices. In some aspects, provide herein are methods of treating, preserving, or improving gamete (i.e., sperm and/or oocyte) likelihood of fertilization in an in vitro procedure. In some embodiments, compositions disclosed herein are added to semen (e.g., semen obtained from a donor subject) in preparation of for artificial insemination or intrauterine insemination (IUI). In some embodiments, compositions disclosed herein are added to semen in preparation intracytoplasic sperm injection into an oocyte.

In some embodiments, the compositions disclosed herein may be used to enhance mitochondrial numbers, mitochondrial activity, cellular energy levels or cellular energy- producing potential in oocytes, postnatal female germline stem cells (also referred to herein as OSCs) and/or preimplantation embryos prior to conducting and/or following methods of in vitro fertilization. It has been recently discovered that adult female mammals retain rare germline or oogonial stem cells (OSCs) that routinely produce new oocytes in a manner analogous to germline stem cell support of sperm production in the adult testis, and these OSCs may be new targets for in vitro fertilization therapies (Spradling, Nature 2004

428: 133-134). In some embodiments, provided herein are methods of increasing the overall viability of an oocyte removed from a subject (e.g., an oocyte removed in preparation for in vitro fertilization). In some embodiments, an oocyte is treated or stored with a composition disclosed herein prior to in vitro fertilization. In one example, provided herein are methods of in vitro fertilization, the method involving the steps of: incubating an oocyte from a subject with a composition disclosed herein; and fertilizing the oocyte in vitro to form a zygote. In another example, the methods provided herein include a method of in vitro fertilization, the method involving the steps of (a) incubating an OSC from a subject with composition disclosed herein; (b) obtaining a composition containing OSC mitochondria from the OSC; (c) transferring the composition into an isolated oocyte (e.g., an oocyte extracted from a subject); and (d) fertilizing the oocyte in vitro to form a zygote.

In some embodiments, the composition disclosed herein may be added to a solution used for in vitro fertilization procedures for oocyte preparation and/or storage, such as cell culture medium, oocyte retrieval solution, oocyte washing solution, oocyte in vitro maturation medium, ovarian follicle in vitro maturation medium, oocyte in vitro fertilization medium, embryo culture medium, cleavage medium, vitrification solution, cryopreservation solution and/or embryo thawing medium.

Gametes may be stored for any period of time with the compositions disclosed herein before in vitro fertilization is performed.

In some aspects, provided herein are methods of increasing lactation in a subject by administering to the subject {e.g., a subject in need thereof) a composition disclosed herein {i.e., a composition comprising a compound of Formula I or Formula II {e.g., nicotinamide riboside) and/or a compound of Formula III {e.g., pterostilbene)). In some embodiments, increasing lactation comprising increasing the rate at which milk is secreted and/or produced from the mammary glands of a subject. In some embodiments, increasing lactation comprises increasing the volume of secreted milk in the subject. In some embodiments, the subject is a human. In some embodiments the subject is a non-human animal, such as a dairy animal {e.g., a cow, a buffalo, a goat, a sheep, a camel).

In some aspects, provided herein are methods of improving animal fecundity and/or breeding outcomes in animal husbandry by administering the compositions disclosed herein to a subject(s) {e.g., a non-human subject). In some embodiments, increasing litter size in a subject {e.g., a non-human subject, such as a domesticated animal). In some embodiments, the subject is a mammal. The subject may be a rodent, lagomorph, feline, canine, porcine, ovine, bovine, equine, or primate. For example, a composition disclosed herein may be administered to a female subject to increase number of offspring per litter or reproductive cycle. Alternately, the compositions disclosed herein may be administered to male subjects to increase spermatozoa production to obtain semen samples with increased virility for use in artificial insemination.

Actual dosage levels and administration regimen of the compositions disclosed herein may be varied so as to obtain an amount of a compound of Formula I or Formula II {e.g., nicotinamide riboside) and/or a compound of Formula III {e.g., pterostilbene) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In some embodiments, administration of the composition comprises administration of the composition in one or more dose(s). In some embodiments, administration of the composition comprises administration of the composition in one or more, five or more, ten or more, twenty or more, thirty or more, forty or more, fifty or more, one hundred or more, or one thousand or more dose(s). In some embodiments, the dose comprises at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, or at least 850 mg of a compound of Formula I or Formula II (e.g., nicotinamide riboside). In some embodiments, the dose comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 1 10 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, or at least 250 mg of a compound of Formula III (e.g., pterostilbene) .

The compositions disclosed herein may be administered over any period of time effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The period of time may be at least 1 day, at least 10 days, at least 20 days, at least 30, days, at least 60 days, at least three months, at least six months, at least a year, at least three years, at least five years, or at least ten years. The dose may be administered when needed, sporadically, or at regular intervals. For example, the dose may be administered monthly, weekly, biweekly, triweekly, once a day, or twice a day.

Incorporation by Reference

All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.