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CN-121991146-A - Amino acid salts of nicotinic acid nucleosides as anti-aging agents

CN121991146ACN 121991146 ACN121991146 ACN 121991146ACN-121991146-A

Abstract

The present invention relates to amino acid salts of nicotinic acid nucleosides of formula I and compositions thereof, useful for treating conditions and diseases associated with nad+ deficiency, wherein M 1 、R 1 、R 2 and R 3 are as described herein. (I)

Inventors

  • S. M. MARCUCCIO
  • R. D. Joyce
  • M. Vatil
  • R. Dole
  • S. Tucker

Assignees

  • 江普斯塔特生育有限公司
  • 生命生物科学股份有限公司

Dates

Publication Date
20260508
Application Date
20190522
Priority Date
20180522

Claims (10)

  1. 1. A salt of formula (I): , Or an enantiomer, stereoisomer or tautomer thereof, Wherein the method comprises the steps of M 1 is a zwitterionic amino acid; R 1 、R 2 and R 3 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) R a 、-C(O)OR a 、-C(O)NR a R b or- [ CH 2 -CH 2 -O] k -R a , Or R 1 and R 2 or R 2 and R 3 together with the atoms to which they are attached form a 5-membered heterocycle 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 cycloalkyl, (C 0 –C 3 alkylene) heterocycloalkyl, (C 0 –C 3 alkylene) C 6 –C 14 aryl or (C 0 –C 3 alkylene) heteroaryl; R a and R b are independently at each occurrence H or C 1 –C 6 alkyl, wherein alkyl is optionally substituted with one or more substituents selected from (C 0 –C 3 alkylene) C 3 –C 8 cycloalkyl, (C 0 –C 3 alkylene) heterocycloalkyl, (C 0 –C 3 alkylene) C 6 –C 14 aryl or (C 0 –C 3 alkylene) heteroaryl, and K is an integer from 1 to 8.
  2. 2. The salt of claim 1, wherein R a is H.
  3. 3. The salt of claim 1, wherein R a is methyl.
  4. 4. A salt according to any one of claims 1 to 3, wherein M 1 is a zwitterionic amino acid of formula (II): (II), Wherein the method comprises the steps of R 4 and R 5 are independently at each occurrence H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 3 alkylene) C 3 -C 8 cycloalkyl, (C 0 -C 3 alkylene) heterocycloalkyl, (C 0 -C 3 alkylene) C 6 -C 14 aryl or (C 0 -C 3 alkylene) heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from cyano, halo, seH, (C 0 -C 3 alkylene) NR c R d 、(C 0 -C 3 alkylene) OR c 、(C 0 -C 3 alkylene) OC (O) R c 、(C 0 -C 3 alkylene) C (O) OR c 、(C 0 -C 3 alkylene) SR c 、(C 0 -C 3 alkylene) C (O) SR c 、(C 0 -C 3 alkylene) SC (O) R c 、(C 0 -C 3 alkylene) C (O) NR c R d 、(C 0 -C 3 alkylene) NC (O) NR c R d 、(C 0 -C 3 alkylene) C (NR c )NR c R d 、(C 0 -C 3 alkylene) NR c C(NR c )NR c R d 、(C 0 -C 3 alkylene) P (O) O n R c R d 、(C 0 -C 3 alkylene) S (O) m NR c R d 、(C 0 -C 3 alkylene) S (O) m OR c OR (C 0 -C 3 alkylene) BO p R c R d ; R 6 is H OR C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one OR more substituents selected from cyano, halo, (C 0 -C 3 alkylene) NR c R d OR (C 0 -C 3 alkylene) OR c , OR R 5 and R 6 together with the atoms to which they are attached form a 5-to 6-membered ring optionally substituted with one OR more substituents selected from cyano, halo, (C 0 -C 3 alkylene) NR c R d OR (C 0 -C 3 alkylene) OR c , and R c and R d 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 cycloalkyl, (C 0 -C 3 alkylene) heterocycloalkyl, (C 0 -C 3 alkylene) C 6 -C 14 aryl or (C 0 -C 3 alkylene) heteroaryl, and M, n and p are independently at each occurrence 0,1 or 2.
  5. 5. The salt of any one of claims 1 to 4, wherein R 4 is H.
  6. 6. The salt of any one of claims 1 to 5, wherein R 6 is H.
  7. 7. The salt of any one of claims 1 to 6, wherein R 5 is H.
  8. 8. The salt of any one of claims 1 to 6, wherein R 5 is C 1 -C 4 alkyl, (C 0 -C 3 alkylene) C 6 -C 14 aryl or (C 0 -C 3 alkylene) heteroaryl, or C 1 -C 4 alkyl substituted with one or more (C 0 -C 3 alkylene) SR c .
  9. 9. The salt of claim 8, wherein R 5 is C 1 -C 4 alkyl.
  10. 10. The salt of claim 1 or 9, wherein M 1 is 。

Description

Amino acid salts of nicotinic acid nucleosides as anti-aging agents The application is a divisional application of China patent application (application date: 2019, 5, 22 days, application name: amino acid salt of nicotinic acid nucleoside as an anti-aging agent) with application number 201980048688.1. RELATED APPLICATIONS The present application claims priority and benefit from U.S. provisional application No. 62/675,065 filed on 5/22 of 2018, the contents of which are incorporated herein by reference in their entirety. Technical Field The present invention relates to inorganic salts of ribonucleoside nicotinates and compositions thereof useful in the treatment of aging-related conditions and diseases. Background Aging is the result of complex interactions involving biological, physical and biochemical processes that lead to cellular and organ dysfunction, which manifests itself as a variety of diseases and other consequences. For example, female fertility is very sensitive to the effects of aging. For example, the american society for disease control reports that in women around the age of 35, the Assisted Reproductive Technology (ART) related pregnancy and labor percentage steadily decreases from about 25% of ART cycles, resulting in a decrease in live single birth to 14% at the age of 40 (center for disease control and prevention, american society for reproductive medicine, assisted reproductive technology society . 2011 Assisted Reproductive Technology National Summary Report. Atlanta (GA): US Dept of Health and Human Services; 2013)., which trend increases significantly at the age of greater than 40), and CDC reports that women over the age of 44 are very low in likelihood of success. It is understood that the deterioration of oocytes due to aging is a fundamental factor in the decrease of fertility. For example, oocytes are reported to be prone to chromosomal abnormalities in elderly women, exhibiting reduced mitochondrial quality, low ATP production, increased oxidative stress and reduced antioxidant levels (Nelson SM, Telfer EE, Anderson RA. The ageing ovary and uterus: new biological insights. Hum Reprod Update. 2013; 19:67-83.;Wilding M. Potential long-term risks associated with maternal aging (the role of the mitochondria). Fertil Steril. 2015; 103:1397-401;3. Meldrum DR, Casper RF, Diez-Juan A, Simon C, Domar AD, Frydman R. Aging and the environment affect gamete and embryo potential: can we intervene? Fertil Steril. 2016; 105:548-59). For all the foregoing reasons, oocytes represent excellent target tissues for assessing treatment modalities expected to have an impact on the aging process, and furthermore, offer the prospect of solving age-related infertility. One such possible therapeutic modality for treating aging includes agents that increase the therapeutic level of NAD +. NAD + is an important component of cellular processes necessary to support a variety of metabolic functions. The classical role of NAD + is a coenzyme that catalyzes the cellular redox reaction in many basic metabolic processes (such as glycolysis, fatty acid beta oxidation or tricarboxylic acid cycle) and is thus reduced to NADH. In addition to these functions, NAD + also plays a key role as a substrate for NAD + consuming enzymes such as poly ADP-ribose polymerase (PARP), sirtuin, and CD38/157 extracellular enzymes. These NAD + consuming enzymes are known to mediate many basic cellular processes. There are five major precursors and intermediates for the synthesis of NAD +, tryptophan, nicotinamide, nicotinic Acid (NA), nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN). NAD + can be synthesized de novo by a number of enzymatic steps to convert the amino acid tryptophan to nicotinic acid mononucleotide (NaMN). NaMN is converted to nicotinic acid dinucleotide (NaAD +) by NMN/NaMN adenosine transferase (NMNAT) and then amidized to NAD + by NAD + synthetase. In mammals, the primary pathway for NAD + biosynthesis is the salvage pathway for nicotinamide. Nicotinamide is converted to the key nad+ intermediate NMN by the rate limiting enzyme nicotinamide riboside transferase (NAMPT) in this pathway. The NMNAT then converts the NMN to NAD +. NAMPT plays a key role in regulating cellular nad+ levels. In another aspect, niacin is converted to NaMN by Niacin Phosphoribosyl Transferase (NPT). NR requires conversion to NMN by nicotinamide riboside kinases NMRK and NMRK2 (also known as NRK1 and NRK 2) that phosphorylate NR 16. Maintaining adequate NAD + biosynthesis is critical for cell survival and function. Deviations from normal NAD + homeostasis can affect not only the NAD +/NADH pool required for redox reactions, but also the activity of NAD + dependent enzymes that are critical to cell function. Now, it is common that NAD + levels at cellular, tissue/organ and organism levels decrease during aging. The activity of NAD + consuming enzymes is affected by this decline in NAD +, resulting in a variety of age-related