JP2008542296A - Treatment of eye disorders with sirtuin activators - Google Patents

Abstract

Sirtuin modulators, particularly sirtuin activators, are useful for the treatment of visual impairment. In general, sirtuin modulators inhibit the progression of visual dysfunction caused by various eye disorders. The present invention also includes pharmaceutically acceptable formulations of sirtuin modulators, particularly ophthalmically acceptable formulations. The present invention discloses compositions and methods for treating eye disorders that result in visual impairment or blindness (blindness). Specifically, the present invention discloses a method for treating visual dysfunction due to retinal or optic nerve damage.

Description

(Background of the Invention)
According to research funded by the National Eye Institute, blindness is becoming a major public health problem with population aging. There, 3.3 million Americans over the age of 40 are reported to be blind or have low vision. In 2020, this number is expected to increase to 5.5 million.

  In this study, blindness and blindness were found to be strongly tied to age. People over the age of 80 represent more than 8% of the total US population, but represent 69% of the blind population. The most common eye diseases in Americans over 40 are age-related macular degeneration, glaucoma, cataracts and diabetic retinopathy. The causes of these diseases vary and include injury, exposure to toxins, underlying health conditions (eg, diabetes, arteriosclerosis), and genetic factors (eg, overproduction of aqueous humor). With the exception of cataracts where the lens can be removed and replaced, there is no cure for these diseases and blindness is generally permanent. The degree of permanent blindness is highly dependent on the degree of damage to one or both optic nerves and the retina.

  Accordingly, there is a need for protective compounds that inhibit, reduce, or otherwise treat visual dysfunction or progression. These protective compounds may affect or be toxic, including combating toxic side effects associated with certain chemotherapy regimens, or improving the quality of life of a population with progressive visual impairment. It may be useful in situations of injury caused by certain compounds.

(Summary of the Invention)
The present invention relates to the use of protective agents for treating (including inhibiting or reducing) visual dysfunction, particularly visual dysfunction caused by retinal or optic nerve damage. More particularly, the present invention relates to the use of sirtuin modulators (eg, direct or indirect sirtuin activators (STACs) or inhibitors) to treat visual dysfunction. The effectiveness of a sirtuin modulator disclosed herein may be due to its anti-apoptotic and anti-aging properties, but may also be due to another mechanism.

  Accordingly, one aspect of the present invention is to administer to a patient a therapeutic dose of a sirtuin modulator selected from a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. A method for treating visual impairment is described.

  In certain aspects of the invention, the visual dysfunction is caused by damage to the optic nerve or central nervous system. In certain embodiments, optic nerve damage is caused by high intraocular pressure, such as that caused by glaucoma. In other specific embodiments, optic nerve damage is often caused by nerve swelling associated with an infection or immune (eg, autoimmune) response, such as those that occur in optic neuritis or multiple sclerosis . In a further specific embodiment, the optic nerve damage is caused by ischemia, generally caused by a lack of blood supply, such as anterior ischemic optic neuropathy.

  In certain aspects of the invention, visual impairment is caused by retinal damage. In certain embodiments, retinal damage is caused by disruption of blood flow to the retina (eg, arteriosclerosis). In certain embodiments, retinal damage is caused by macular rupture (eg, exudative or non-exudative macular degeneration). Since retinal ganglion cell (RGC) axons include the optic nerve, damage to the retinal ganglion cell body can result in damage to the optic nerve.

  In certain aspects of the invention, sirtuin modulators can be used to inhibit (eg, preventative treatment) damage, disease or general aging of the eye that may ultimately result in visual dysfunction. Eye damage may be secondary to treatment with another disease or another pharmaceutical agent for the disease. Injuries can also be secondary to surgical procedures directly on the eye or elsewhere on the patient. Furthermore, as eye function declines, prevention of the effects of general aging and overuse of the eye may be beneficial to the patient.

  Furthermore, the improvement in the present invention relates to a method for enhancing treatment requiring administration of a chemotherapeutic agent having side effects that impair vision. This improvement includes administering a prophylactically or therapeutically effective amount of a sirtuin modulator to treat the side effects that impair the vision of the chemotherapeutic agent, preferably without compromising its effectiveness. Sirtuin modulators and chemotherapeutic agents may be provided in a variety of ways, including administering prior to, concurrently with, or subsequent to administering the chemotherapeutic agent. Also, sirtuin modulators and chemotherapeutic agents include, but are not limited to, a single drug preparation, eg, as a single dosage form, or each as a separate dose, with instructions for co-administering the two drugs It can be provided in various forms, including a kit with a letter.

  The invention also relates to a method of conducting a pharmaceutical business comprising manufacturing, testing, selling, distributing, and authorizing a sirtuin modulator and optionally a preparation or kit for administering an additional agent.

  Another aspect of the invention provides a composition comprising nanoparticles comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. Such particles typically have an average diameter of 50 nm to 500 nm, such as 100 nm to 200 nm.

  A further aspect of the invention provides a composition comprising a cyclodextrin and a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. Such compositions are preferably liquid or lyophilized powders (eg water-soluble powders).

  The present invention also provides a fast dissolving tablet comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. Such tablets typically have a mouth dissolution time of less than 1 minute, such as less than 30 seconds.

  Furthermore, the present invention provides an implantable device comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. In certain embodiments, the device is suitable for ocular implantation. These devices typically provide sustained release of the sirtuin modulator, eg, at least 1 month or at least 1 year (eg, 6 months to 2 years). These devices can be biodegradable or non-biodegradable (eg, interchangeable lenses).

  In another aspect of the invention, the invention provides a pharmaceutical composition comprising a micronized sirtuin modulator or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof, wherein said micronized sirtuin modulator Of the particles have an average diameter of less than about 30 microns.

  The invention further includes the use of the compositions disclosed herein in the manufacture of a medicament for treating visual dysfunction.

A. SUMMARY The present invention discloses compositions and methods for treating eye disorders that result in visual impairment or blindness (blindness). Specifically, the present invention discloses a method for treating visual dysfunction due to retinal or optic nerve damage.

B. Definitions The term “visual impairment” refers to diminished visual acuity, which is often only partially recoverable or non-recoverable by treatment (eg, surgery). Particularly severe visual impairment is referred to as “blindness” or “blindness”, which is a complete loss of visual acuity, visual acuity less than 20/200 that cannot be improved by corrective lenses, or 20 degrees in diameter (10 degrees radius) Less than field of view.

  As used herein, the term “inhibit” means reducing the risk of an abnormal biological or medical phenomenon such as blindness occurring in a cell, tissue, system, animal or human. .

  The term “treat” refers to the occurrence of a disease, disorder, or condition in a cell, tissue, system, animal, or human that may be suffering from a disease, disorder, and / or condition but has not yet been diagnosed. Stabilizing the disease, disorder or condition, ie, stopping its development; and alleviating one or more symptoms of the disease, disorder or condition, ie, the disease, disorder and / or condition It means to recover.

  As used herein, a therapeutic agent that “inhibits” a disorder or condition reduces the occurrence of the disorder or condition in a treated sample as compared to an untreated control sample in a statistical sample. Alternatively, a compound that delays or reduces the severity of one or more symptoms of a disorder or condition compared to an untreated control sample.

  With respect to the compounds disclosed herein, the term “as valency and stability permits” means that the in vitro or in vivo half-life at room temperature is at least 12 hours, or at least 24 hours, preferably It refers to a compound that can be stored at 0 ° C. for one week without decomposing over about 10%.

  The term “half-life” or “multiple half-lives” refers to the time required for half of a substance to be converted to another chemically different species in vitro or in vivo.

  The term “prodrug” refers to any compound that is converted to a more pharmacologically active compound under physiological conditions (ie, in vivo). A common method for making prodrugs is to select moieties that are hydrolyzed under physiological conditions to yield the desired bioactive drug.

  The term “metabolic derivative” refers to a compound obtained by enzymatic transformation of one or more of the parent compounds in vitro or in vivo.

  “Sirtuin modulator” refers to a compound that up-regulates (eg, activates or stimulates), down-regulates (eg, inhibits or suppresses) or otherwise alters a functional property or biological activity of a sirtuin protein. Say. Sirtuin modulators can act to directly or indirectly modulate sirtuin proteins. In certain embodiments, the sirtuin modulator may be a sirtuin activator or a sirtuin inhibitor.

  “Sirtuin” refers to a member of the sirtuin deacetylase protein family, or preferably the sir2 family, including yeast Sir2 (GenBank accession number P53685), nematode Sir-2.1 (GenBank accession number NP — 501912), As well as human SIRT1 (GenBank accession numbers NM_012238 and P_036370 (or AF0883106)) and SIRT2 (GenBank accession numbers NM_012237, NM_030593, NP_036369, NP_085096, and AF083107) proteins. Other family members include four additional yeast Sir2-like genes (homologous to Sir2) called “HST genes”, HST1, HST2, HST3 and HST4, and five other human homologs hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT7 are included (Brachmann et al., 1995, Genes Dev., 9: 2888 and Freye et al., 1999, BBRC, 260: 273). Preferred sirtuins share more similarity with SIRT1, i.e. hSIRT1, and / or Sir2, than with SIRT2, e.g. NRT that is present in SIRT1 but not in SIRT2, such as SIRT3 A member having at least part of the sequence.

  “SIRT1 protein” refers to a member of the sir2 family of sirtuin deacetylases. In one embodiment, the SIRT1 protein includes yeast Sir2 (GenBank accession number P53685), nematode Sir-2.1 (GenBank accession number NP — 501912), human SIRT1 (GenBank accession numbers NM — 012238 and NP — 036370 (or AF083106)), human SIRT2 (GenBank accession numbers NM — 012237, NM — 030593, NP — 036369, NP — 085096, and AF083107) proteins, and equivalents and fragments thereof are included. In another embodiment, the SIRT1 protein includes a polypeptide comprising a sequence consisting of, or consisting essentially of, the amino acid sequences set forth in GenBank accession numbers NP — 036370, NP — 501912, NP — 085096, NP — 036369, and P5385. The SIRT1 protein includes a polypeptide comprising all or part of the amino acid sequence set forth in GenBank accession numbers NP — 036370, NP — 501912, NP — 085096, NP — 036369, and P53685; 1 to about 2, 3, 5, 7, 10 Amino acid sequence described in GenBank accession numbers NP_036370, NP_501912, NP_085096, NP_036369, and P53685, with 1, 15, 20, 30, 50, 75 or more conservative amino acid substitutions; GenBank accession numbers NP_036370, NP_501919 , NP_085096, NP_036369, and P53685 at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99 Amino acid sequence identical, as well as functional fragments thereof. Polypeptides of the invention also include homologs (eg, homologous molecular species and paralogs), variants, or fragments of GenBank accession numbers NP — 036370, NP — 501912, NP — 085096, NP — 036369, and P53685.

  “Sirtuin activator” refers to a compound that increases the level of a sirtuin protein and / or increases at least one activity of a sirtuin protein. In exemplary embodiments, a sirtuin activator may increase at least one biological activity of a sirtuin protein by at least about 10%, 25%, 50%, 75%, 100%, or more. Exemplary biological activities of sirtuin proteins include deacetylation of histones, p53, etc .; extended lifespan; increased genomic stability; transcriptional silencing; and separation of oxidized proteins between mother and daughter cells Control.

  “Sirtuin inhibitor” refers to a compound that decreases the level of a sirtuin protein and / or decreases at least one activity of a sirtuin protein. In exemplary embodiments, a sirtuin inhibitor may reduce at least about 10%, 25%, 50%, 75%, 100%, or more of at least one biological activity of a sirtuin protein. Exemplary biological activities of sirtuin proteins include deacetylation of histones, p53, etc .; extended lifespan; increased genomic stability; transcriptional silencing; and separation of oxidized proteins between mother and daughter cells Control.

The term “ED ₅₀ ” means the dose of a drug that produces 50% of its maximum response or effect.

  For the purposes of the present invention, chemical elements were identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 67th edition, 1986-87, back cover.

C. Exemplary Embodiments A sirtuin modulator is a neurotoxic (eg, toxic to the optic nerve or area of the brain that processes visual input), including countering toxic side effects associated with certain chemotherapy regimens. Drug-induced injuries, vascular disorders (eg, angiogenesis such as those associated with arteriosclerosis, diabetes), increased intraocular pressure (eg, caused by certain drugs, surgery, glaucoma, inflammation), genetic predisposition, It is useful in improving the quality of life of the elderly in the context of infection and / or immune and autoimmune disorders or experiencing progressive visual impairment. The present invention contemplates the use of such sirtuin modulators in both blindness and visual impairment.

  Accordingly, in one embodiment, the present invention describes a method of treating visual dysfunction according to the conditions disclosed herein comprising administering a sirtuin modulator to a patient.

  In one embodiment, the sirtuin modulator is a sirtuin activator. Examples of sirtuin activators include resveratrol and analogs thereof and nicotinamide riboside and analogs thereof, particularly phosphorylated analogs thereof. Prodrugs of each of these activators are also suitable for use in the present invention.

  In another embodiment, the sirtuin modulator is a sirtuin inhibitor.

  In one embodiment, exemplary sirtuin activators are those described in Howitz et al., 2003, Nature, 425: 191, for example, resveratrol (3,5,4′-trihydroxy- trans-stilbene), butein (3,4,2 ′, 4′-tetrahydroxychalcone), picetanol (3,5,3 ′, 4′-tetrahydroxy-trans-stilbene), isoliquiritigenin (4,2) ', 4'-trihydroxychalcone), fisetin (3,7,3', 4'-tetrahydroxyflavone), quercetin (3,5,7,3 ', 4'-pentahydroxyflavone), deoxyrapaponin (3,5-dihydroxy-4′-methoxystilbene 3-O-β-D-glucoside); trans-stilbene; (3,3 ′, 5-trihydroxy-4′-methoxystilbene 3-O-β-D-glucoside); cis-stilbene; butein (3,4,2 ′, 4′-tetrahydroxychalcone); 4,2'4'6'-pentahydroxychalcone; chalcone; 7,8,3 ', 4'-tetrahydroxyflavone; 3,6,2', 3'-tetrahydroxyflavone; 4'-hydroxyflavone; , 4′-dihydroxyflavone; 5,7-dihydroxyflavone; morin (3,5,7,2 ′, 4′-pentahydroxyflavone); flavone; 5-hydroxyflavone; (−)-epicatechin (hydroxy site: 3,5,7,3 ', 4'); (-)-catechin (hydroxy site: 3,5,7,3 ', 4'); (-)-gallocatechin (hydroxy site: 3, 5, , 3 ′, 4 ′, 5 ′) (+)-catechin (hydroxy site: 3,5,7,3 ′, 4 ′); 5,7,3 ′, 4 ′, 5′-pentahydroxyflavone; luteolin (5,7,3 ′, 4′-tetrahydroxyflavone); 3,6,3 ′, 4′-tetrahydroxyflavone; 7,3 ′, 4 ′, 5′-tetrahydroxyflavone; kaempferol (3 5,7,4′-tetrahydroxyflavone); 6-hydroxyapigenin (5,6,7,4′-tetrahydroxyflavone); scutellarein; apigenin (5,7,4′-trihydroxyflavone); 6,2 ′, 4′-tetrahydroxyflavone; 7,4′-dihydroxyflavone; daidzein (7,4′-dihydroxyisoflavone); genistein (5,7,4′-trihydroxyflavano) Naringenin (5,7,4′-trihydroxyflavanone); 3,5,7,3 ′, 4′-pentahydroxyflavanone; flavanone; pelargonidin chloride (3,5,7,4′-tetrahydroxyflavin chloride) Hinokitiol (b-tujapricin; 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one); L-(+)-ergothioneine ((S) -a-carboxy-2, 3-dihydro-N, N, N-trimethyl-2-thioxo-1H-imidazole-4-ethanaminium inner salt); caffeic acid phenyl ester; MCI-186 (3-methyl-1-phenyl-2-pyrazoline-5- ON); HBED (N, N′-di- (2-hydroxybenzyl) ethylenediamine-N, N′-diacetic acid · H 2 O); Ambroxol (trans-4- (2-amino-3,5-dibromobenzylamino) cyclohexane-HCl; and U-83836E ((-)-2-((4- (2,6-di-1-pyrrolidinyl) -4-pyrimidinyl) -1-piperazinyl) methyl) -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol-2HCl). Their analogs and derivatives can also be used.

  Other sirtuin activators may have any of the following formulas 1-25, 30, 32-65, and 69-76, and pharmaceutically acceptable salts, prodrugs or metabolic derivatives thereof: Is included.

  In one embodiment, the sirtuin activator is a stilbene or chalcone compound of Formula 1:

［式中、出現するたびに、独立して、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ｍは、Ｏ、ＮＲ、またはＳを表し；
Ａ−Ｂは、二価アルキル、アルケニル、アルキニル、アミド、スルホンアミド、ジアゾ、エーテル、アルキルアミノ、アルキルスルフィド、ヒドロキシルアミン、またはヒドラジン基を表し；
ｎは、０または１である］。

[In the formula, each time it appears,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl Represents heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
M represents O, NR, or S;
AB represents a divalent alkyl, alkenyl, alkynyl, amide, sulfonamide, diazo, ether, alkylamino, alkylsulfide, hydroxylamine, or hydrazine group;
n is 0 or 1.]

In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions wherein n is 0. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions wherein n is 1. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein AB is ethenyl. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein AB is —CH ₂ CH (Me) CH (Me) CH ₂ —. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein M is O. In a further embodiment, the method comprises a compound of formula 1 and the attendant definitions, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₂ , R ₄ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₃ , R ₅ , R ′ ₂ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₁ , R ₃ , R ₅ , R ′ ₂ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₂ and R ′ ₂ are OH; R ₄ is O-β-D-glucoside; R ′ ₃ Is OCH ₃ . In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein R ₂ is OH; R ₄ is O-β-D-glucoside; R ′ ₃ is OCH ₃ is there.

In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is ethenyl; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H (trans stilbene). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions wherein n is 1; AB is ethenyl; M is O; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H (chalcone). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is ethenyl; R ₂ , R ₄ , and R ′ ₃ are OH Yes; R ₁ , R ₃ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H (resveratrol). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is ethenyl; R ₂ , R ₄ , R ′ _2, and R ′ ₃ Is OH; R ₁ , R ₃ , R ₅ , R ′ ₁ , R ′ ₄ and R ′ ₅ are H (picetanol). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions wherein n is 1; AB is ethenyl; M is O; R ₃ , R ₅ , R _'2 and R' ₃ is located in _{OH; R 1, R 2,} R 4, R '1, R' 4, and R _'5 is H (butein). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 1, AB is ethenyl; M is O; R ₁ , R ₃ , R ₅ , R ′ ₂ and R ′ ₃ are OH; R ₂ , R ₄ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H (3,4, 2 ′, 4 ′, 6′— Pentahydroxychalcone). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is ethenyl; R ₂ and R ′ ₂ are OH, and R ₄ Is O-β-D-glucoside and R ′ ₃ is OCH ₃ ; R ₁ , R ₃ , R ₅ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H (rapontin). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is ethenyl; R ₂ is OH, and R ₄ is O-β is -D- glucoside, R _'3 is located at _{OCH 3; R 1, R 3} , R 5, R' 1, R '2, R' 4, and R _'5 is H (deoxy La Pont Chin ). In a further embodiment, a sirtuin activator is a compound of formula 1 and the attendant definitions, wherein n is 0; AB is —CH ₂ CH (Me) CH (Me) CH ₂ —; R ₂ , R ₃ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₄ , R ₅ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H (NDGA).

  In another embodiment, the sirtuin activator is a flavanone compound of formula 2:

［式中、出現するたびに、独立して、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５、およびＲ”は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ｍは、Ｈ_２、Ｏ、ＮＲ、またはＳを表し；
Ｚは、ＣＲ、Ｏ、ＮＲ、またはＳを表し；
Ｘは、ＣＲまたはＮを表し；
Ｙは、ＣＲまたはＮを表す］。

[In the formula, each time it appears,
R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ , and R ″ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl Represents heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
M represents H ₂ , O, NR, or S;
Z represents CR, O, NR, or S;
X represents CR or N;
Y represents CR or N].

In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are both CH. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein M is O. In a further embodiment, a sirtuin activator is attendant definitions compound of Formula 2 and therewith, M is H _2. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein Z is O. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, and R ″ is H. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions. And R ″ is OH. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein R ″ is alkoxycarbonyl. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant. Definition, R ₁ is

である。さらなる実施形態では、サーチュイン活性化剤は、式２の化合物およびそれに付随する定義であり、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５およびＲ”がＨである。さらなる実施形態では、サーチュイン活性化剤は、式２の化合物およびそれに付随する定義であり、Ｒ_２、Ｒ_４、およびＲ’_３がＯＨである。さらなる実施形態では、サーチュイン活性化剤は、式２の化合物およびそれに付随する定義であり、Ｒ_４、Ｒ’_２、Ｒ’_３、およびＲ”がＯＨである。さらなる実施形態では、サーチュイン活性化剤は、式２の化合物およびそれに付随する定義であり、Ｒ_２、Ｒ_４、Ｒ’_２、Ｒ’_３、およびＲ”がＯＨである。さらなる実施形態では、サーチュイン活性化剤は、式２の化合物およびそれに付随する定義であり、Ｒ_２、Ｒ_４、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ”がＯＨである。

It is. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, and R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ″ are H. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein R ₂ , R ₄ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein R ₄ , R ′ ₂ , R ′ ₃ , and R ″ are OH. In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , and R ″ are OH. In a further embodiment, A sirtuin activator is a compound of formula 2 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ″ are OH.

In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is O; Z is O; R ″ is H; R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ″ are H (flavanone). In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is O; Z is O; R ″ is H; R ₂ , R ₄ , and R ′ ₃ are OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H (naringenin). A sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is O; Z is O; R ″ is OH; R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H ( ₃ , ₅ , 7, ₃ ′, 4′-penta Hydroxyflavanone). In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is H ₂ ; Z is O; R ″ is OH R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₄ and R ′ ₅ are H (epicatechin). A sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is H ₂ ; Z is O; R ″ is OH; R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH; R ₁ , R ₃ , R ′ ₁ , and R ′ ₅ are H (gallocatechin). In a further embodiment, a sirtuin activator is a compound of formula 2 and the attendant definitions, wherein X and Y are CH; M is H ₂ ; Z is O;

であり；Ｒ_２、Ｒ_４、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ”がＯＨであり；Ｒ_１、Ｒ_３、Ｒ’_１、およびＲ’_５がＨである（没食子酸エピガロカテキン）。

R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ″ are OH; R ₁ , R ₃ , R ′ ₁ , and R ′ ₅ are H (gallic acid Epigallocatechin).

  In another embodiment, the sirtuin activator is an isoflavanone compound of formula 3:

［式中、出現するたびに、独立して、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５、およびＲ”_１は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ｍは、Ｈ_２、Ｏ、ＮＲ、またはＳを表し；
Ｚは、Ｃ（Ｒ）_２、Ｏ、ＮＲ、またはＳを表し；
Ｘは、ＣＲまたはＮを表し；
Ｙは、ＣＲまたはＮを表す］。

[In the formula, each time it appears,
R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ , and R ″ ₁ are H, alkyl, aryl, heteroaryl, aralkyl, alkenyl Represents reel, heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
M represents H ₂ , O, NR, or S;
Z represents C (R) ₂ , O, NR, or S;
X represents CR or N;
Y represents CR or N].

  In another embodiment, the sirtuin activator is a flavone compound of formula 4:

［式中、出現するたびに、独立して、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ｍは、Ｈ_２、Ｏ、ＮＲ、またはＳを表し；
Ｚは、ＣＲ、Ｏ、ＮＲ、またはＳを表し；
Ｘは、ＣＲ”またはＮを表し、
Ｒ”は、Ｈ、アルキル、アリール、ヘテロアリール、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルである］。

[In the formula, each time it appears,
R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaralkyl represents _{halide, NO 2, SR, oR,} N (R) 2, or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
M represents H ₂ , O, NR, or S;
Z represents CR, O, NR, or S;
X represents CR ″ or N;
R ″ is H, alkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl].

In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is C. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CR. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein Z is O. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein M is O. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, and R ″ is H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions. And R ″ is OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, and R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , And R ′ ₅ is H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₃ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₃ , R ₄ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₃ , R ′ ₁ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₁ , R ₂ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₃ , R ′ ₁ , and R ′ ₂ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ′ ₃ is OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₄ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ and R ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₁ and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₄ is OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₂ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein R ₁ , R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH.

In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H (flavone). In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ′ ₂ , and R ' ₃ is OH; R ₁ , R ₃ , R ₄ , R' ₁ , R ' ₄ , and R' ₅ are H (fisetin). In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ , R ₄ , R ′ ₂ , R ′ ₃ and R ′ ₄ are OH; R ₁ , R ₃ , R ′ ₁ and R ′ ₅ are H (5,7,3 ′, 4 ′, 5′-pentahydroxyflavone) . In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ , R ₄ , R ′ ₂ And R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H (Luteolin). In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₃ , R ′ ₂ , and R _'3 be _{OH; R 1, R 2,} R 4, R' 1, R '4, and R' ₅ are H (3,6,3 ', 4'- tetrahydroxy-flavone). In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ₄ , R ′ ₂ And R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H (quercetin). In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ , R ′ ₂ , R ′ ₃ and R ′ ₄ are OH; R ₁ , R ₃ , R ₄ , R ′ ₁ and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ₄ , and R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ , R ₃ , R ₄ , And R ′ ₃ is OH; R ₁ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ , R ₄ , and R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₃ , R ′ ₁ , and R ' ₃ is OH; R ₁ , R ₂ , R ₄ , R' ₂ , R ' ₄ , and R' ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; and R ₂ and R ′ ₃ are OH R ₁ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H; In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₁ , R ₂ , R ′ ₂ , And R ′ ₃ are OH; R ₁ , R ₂ , R ₄ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₃ , R ′ ₁ , and R ' ₂ is OH; R ₁ , R ₂ , R ₄ , R' ₃ , R ' ₄ , and R' ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ′ ₃ is OH; ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₄ and R ′ ₃ are OH Yes; R ₁ , R ₂ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₂ and R ₄ are OH R ₁ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H; In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ₄ , R ′ ₁ And R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is CH; Z is O; M is O; R ₄ is OH; R ₁ , R ₂ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ₄ , R ′ ₂ , R ′ ₃ , and R ′ ₄ are OH; R ₁ , R ₃ , R ′ ₁ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₂ , R ′ ₂ , R ′ ₃ and R ′ ₄ are OH; R ₁ , R ₃ , R ₄ , R ′ ₁ and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 4 and the attendant definitions, wherein X is COH; Z is O; M is O; R ₁ , R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH; R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H.

  In another embodiment, the sirtuin activator is an isoflavone compound of formula 5:

［式中、出現するたびに、独立して、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ｍは、Ｈ_２、Ｏ、ＮＲ、またはＳを表し；
Ｚは、Ｃ（Ｒ）_２、Ｏ、ＮＲ、またはＳを表し；
Ｙは、ＣＲ”またはＮを表し、
Ｒ”は、Ｈ、アルキル、アリール、ヘテロアリール、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表す］。

[In the formula, each time it appears,
R ₁ , R ₂ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaralkyl represents _{halide, NO 2, SR, oR,} N (R) 2, or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
M represents H ₂ , O, NR, or S;
Z represents C (R) ₂ , O, NR, or S;
Y represents CR ″ or N;
R ″ represents H, alkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl].

In a further embodiment, a sirtuin activator is a compound of formula 5 and the attendant definitions, wherein Y is CR ″. In a further embodiment, a sirtuin activator is a compound of formula 5, and the attendant definitions. And Y is CH. In a further embodiment, a sirtuin activator is a compound of formula 5 and the attendant definitions, and Z is O. In a further embodiment, a sirtuin activator is of the formula The compound of 5 and the attendant definitions, wherein M is O. In a further embodiment, the sirtuin activator is the compound of formula 5 and the attendant definitions, wherein R ₂ and R ′ ₃ are OH . in a further embodiment, a sirtuin activator is attendant definitions compound of formula 5 and its, R _{2, R 4,} and R _'3 is in OH That.

In a further embodiment, a sirtuin activator is a compound of formula 5 and the attendant definitions, wherein Y is CH; Z is O; M is O; R ₂ and R ′ ₃ are OH Yes; R ₁ , R ₃ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound of formula 5 and the attendant definitions, wherein Y is CH; Z is O; M is O; R ₂ , R ₄ , and R ′ ₃ is OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H.

  In another embodiment, the sirtuin activator is an anthocyanidin compound of formula 6:

［式中、出現するたびに、独立して、
Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ’_２、Ｒ’_３、Ｒ’_４、Ｒ’_５、およびＲ’_６は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、またはアラルキルを表し；
Ａ⁻は、Ｃｌ⁻、Ｂｒ⁻、またはＩ⁻から選択される陰イオンを表す］。

[In the formula, each time it appears,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ , and R ′ ₆ are H, alkyl, aryl, heteroaryl, aralkyl , Alkaryl, heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R represents H, alkyl, aryl, heteroaryl, or aralkyl;
A ⁻ represents an anion selected from Cl ⁻ , Br ⁻ , and I ⁻ ].

In a further embodiment, a sirtuin activator is attendant definitions compound of Formula 6 and thereto, A ^- is Cl ^- is. In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein R ₃ , R ₅ , R ₇ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein R ₃ , R ₅ , R ₇ , R ′ ₃ , and R ′ ₄ are OH. In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein R ₃ , R ₅ , R ₇ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are OH.

In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein A ⁻ is Cl ⁻ ; R ₃ , R ₅ , R ₇ , and R ′ ₄ are OH; R ₄ , R ₆ , R ₈ , R ′ ₂ , R ′ ₃ , R ′ ₅ , and R ′ 6 are H. In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein A ⁻ is Cl ⁻ ; R ₃ , R ₅ , R ₇ , R ′ ₃ , and R ′ ₄ are OH R ₄ , R ₆ , R ₈ , R ′ ₂ , R ′ ₅ , and R ′ 6 are H. In a further embodiment, a sirtuin activator is a compound of formula 6 and the attendant definitions, wherein A ⁻ is Cl ⁻ ; R ₃ , R ₅ , R ₇ , R ′ ₃ , R ′ ₄ , and R ' ₅ is OH; R ₄ , R ₆ , R ₈ , R' ₂ , and R ' ₆ are H.

  In a further embodiment, the sirtuin activator is a stilbene, chalcone, or flavone compound represented by formula 7:

［式中、出現するたびに、独立して、
Ｍは、存在しないか、Ｏであり；
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒ_ａは、Ｈを表すか、２つのＲ_ａは単結合を形成し；
Ｒは、Ｈ、アルキル、アリール、ヘテロアリール、アラルキルを表し；
ｎは、０または１である］。

[In the formula, each time it appears,
M is absent or O;
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl Represents heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R _a represents H or two R _a form _a single bond;
R represents H, alkyl, aryl, heteroaryl, aralkyl;
n is 0 or 1.]

In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein n is 0. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein n is 1. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein M is absent. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein M is O. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R _a is H. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein M is O and two R _a form a single bond.

In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₅ is H. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₅ is OH. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₁ , R ₃ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₂ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein R ₂ and R ₄ are OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 0; M is absent; R _a is H; and R ₅ is H. Yes; R ₁ , R ₃ , and R ′ ₃ are OH; R ₂ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein n is 1; M is absent; R _a is H; and R ₅ is H; R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH;
R ₁ , R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is an activating compound represented by formula 7 and the attendant definitions, wherein n is 1; M is O; and two R _a form _a single bond. R ₅ is OH; R ₂ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₃ , R ₄ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H;

  Other sirtuin activators include compounds having a formula selected from the group consisting of formulas 8-25 and 30 described below.

Ｒ_１＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ_２＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ_３＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ_４＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ_５＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ’_１＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ’_２＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ’_３＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ’_４＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ’_５＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ｒ”_１＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ（Ｒ＝Ｈ、アルキル、アリール）、ＯＲ（Ｒ＝Ｈ、アルキル、アリール）、ＮＲＲ’（Ｒ、Ｒ’＝アルキル、アリール）、アルキル、アリール、カルボキシ
Ａ−Ｂ＝エテン、エチン、アミド、スルホンアミド、ジアゾ、アルキルエーテル、アルキルアミン、アルキルスルフィド、ヒドロキシアミン、ヒドラジン
Ｘ＝ＣＲ、Ｎ
Ｙ＝ＣＲ、Ｎ
Ｚ＝Ｏ、Ｓ、Ｃ（Ｒ）_２、ＮＲ
Ｒ＝Ｈ、アルキル、アリール、アラルキル

R ₁ = H, halogen, NO ₂ , SR (R = H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR ′ (R, R ′ = alkyl, aryl), alkyl, aryl, carboxy R ₂ = H, halogen, NO ₂ , SR (R = H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR ′ (R, R ′ = alkyl, aryl), alkyl, aryl, carboxy R ₃ = H, halogen, NO ₂ , SR (R = H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR ′ (R, R ′ = alkyl, aryl), alkyl, aryl, carboxy R ₄ = H, _{halogen, NO 2, SR (R =} H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR '(R, R ' = alkyl, aryl), alkyl Aryl, carboxy _R 5 = H, _{halogen, NO 2, SR (R =} H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR '(R, R ' = alkyl, aryl), alkyl, Aryl, carboxy R ′ ₁ ═H, halogen, NO ₂ , SR (R═H, alkyl, aryl), OR (R═H, alkyl, aryl), NRR ′ (R, R ′ = alkyl, aryl), alkyl , Aryl, carboxy R ′ ₂ ═H, halogen, NO ₂ , SR (R═H, alkyl, aryl), OR (R═H, alkyl, aryl), NRR ′ (R, R ′ = alkyl, aryl), alkyl, aryl, carboxy R _'3 = H, _{halogen, NO 2, SR (R =} H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR' (R, R '= alkyl , Aryl), alkyl, aryl, carboxy R _'4 = H, _{halogen, NO 2, SR (R =} H, alkyl, aryl), OR (R = H, alkyl, aryl), NRR' (R, R '= Alkyl, aryl), alkyl, aryl, carboxy R ′ ₅ ═H, halogen, NO ₂ , SR (R═H, alkyl, aryl), OR (R═H, alkyl, aryl), NRR ′ (R, R ′ = Alkyl, aryl), alkyl, aryl, carboxy R ″ ₁ ═H, halogen, NO ₂ , SR (R═H, alkyl, aryl), OR (R═H, alkyl, aryl), NRR ′ (R, R '= Alkyl, aryl), alkyl, aryl, carboxy A-B = ethene, ethyne, amide, sulfonamido, diazo, alkyl ether, alkylamine, alkylsulfur I de, hydroxylamine, hydrazine X = CR, N
Y = CR, N
Z = O, S, C (R) ₂ , NR
R = H, alkyl, aryl, aralkyl

［式中、出現するたびに、独立して、
Ｒ＝Ｈ、アルキル、アリール、ヘテロシクリル、ヘテロアリール、またはアラルキルであり；
Ｒ’＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、またはカルボキシである］。

[In the formula, each time it appears,
R = H, alkyl, aryl, heterocyclyl, heteroaryl, or aralkyl;
R ′ = H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, or carboxy].

［式中、出現するたびに、独立して、
Ｒ＝Ｈ、アルキル、アリール、ヘテロシクリル、ヘテロアリール、またはアラルキルである］。

[In the formula, each time it appears,
R = H, alkyl, aryl, heterocyclyl, heteroaryl, or aralkyl.

［式中、出現するたびに、独立して、
Ｒ’＝Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシであり；
Ｒ＝Ｈ、アルキル、アリール、ヘテロシクリル、ヘテロアリール、またはアラルキルである］。

[In the formula, each time it appears,
R ′ = H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy;
R = H, alkyl, aryl, heterocyclyl, heteroaryl, or aralkyl.

［式中、出現するたびに、独立して、
Ｌは、ＣＲ_２、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表す］。

[In the formula, each time it appears,
L represents CR ₂ , O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy].

［式中、出現するたびに、独立して、
Ｌは、ＣＲ_２、Ｏ、ＮＲ、またはＳを表し；
Ｗは、ＣＲまたはＮを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ａｒは、縮合アリールまたはヘテロアリール環を表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表す］。

[In the formula, each time it appears,
L represents CR ₂ , O, NR, or S;
W represents CR or N;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
Ar represents a fused aryl or heteroaryl ring;
R ′ represents H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy].

［式中、出現するたびに、独立して、
Ｌは、ＣＲ_２、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表す］。

[In the formula, each time it appears,
L represents CR ₂ , O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy].

［式中、出現するたびに、独立して、
Ｌは、ＣＲ_２、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表す］。

[In the formula, each time it appears,
L represents CR ₂ , O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy].

  In a further embodiment, the sirtuin activator is a stilbene, chalcone, or flavone compound represented by Formula 30:

［式中、出現するたびに、独立して、
Ｄは、フェニルまたはシクロヘキシル基であり；
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、
Ｈ、アルキル、アリール、ヘテロアリール、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、カルボキシル、アジド、エーテルを表すか；または任意の２つの隣接するＲもしくはＲ’基は、一緒になって縮合ベンゼンもしくはシクロヘキシル基を形成し；
Ｒは、Ｈ、アルキル、アリール、またはアラルキルを表し；
Ａ−Ｂは、エチレン、エテニレン、またはイミン基を表し；
ただし、Ａ−Ｂがエテニレンである場合は、Ｄはフェニルであり、Ｒ’_３はＨであり：Ｒ_１、Ｒ_２、Ｒ_４、およびＲ_５がＨである場合は、Ｒ_３はＯＨではなく；Ｒ_１、Ｒ_３、およびＲ_５がＨである場合は、Ｒ_２およびＲ_４はＯＭｅではなく；Ｒ_１、Ｒ_２、Ｒ_４、およびＲ_５がＨである場合は、Ｒ_３はＯＭｅではない］。

[In the formula, each time it appears,
D is a phenyl or cyclohexyl group;
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are
Represents H, alkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , carboxyl, azide, ether; or any two adjacent R or R 'Groups together form a condensed benzene or cyclohexyl group;
R represents H, alkyl, aryl, or aralkyl;
AB represents an ethylene, ethenylene, or imine group;
However, when AB is ethenylene, D is phenyl and R ′ ₃ is H: when R ₁ , R ₂ , R ₄ , and R ₅ are H, R ₃ is OH Not; when R ₁ , R ₃ , and R ₅ are H, R ₂ and R ₄ are not OMe; when R ₁ , R ₂ , R ₄ , and R ₅ are H, R ₃ is Not OMe].

  In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group.

  In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is an ethenylene or imine group.

  In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is an ethenylene group.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein R ₂ is OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein R ₂ and R ₄ are OH.

  In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group; AB is an ethenylene group.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein D is a phenyl group; AB is an ethenylene group; R ₂ and R ₄ are OH is there.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is Cl.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is H;

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is CH ₂ CH ₃ ;

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is F;

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is Me.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is an azide.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is SMe.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH ; R _'3 is NO _2.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is CH (CH ₃ ) ₂ ;

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is OMe.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₂ is OH; R ′ ₃ is OMe.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; R ₂ is OH; R ₄ Is carboxyl; R ′ ₃ is OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH ; R _'3 is a carboxyl.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ and R ′ ₄ together form a fused benzene ring.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OCH ₂ OCH. ₃ ; R ′ ₃ is SMe.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH ; R _'3 is a carboxyl.

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a cyclohexyl ring; and R ₂ and R ₄ are OH. .

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₃ and R ₄ are OMe. .

In a further embodiment, a sirtuin activator is a compound represented by formula 30 and the attendant definitions, wherein AB is ethenylene; D is a phenyl ring; and R ₂ and R ₄ are OH R ′ ₃ is OH.

  In another embodiment, the sirtuin activator is a compound of formula 32:

［式中、出現するたびに、独立して、
Ｒは、Ｈ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１およびＲ_２は、置換または非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヘテロアラルキルである］。

[In the formula, each time it appears,
R is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₁ and R ₂ are substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin activator is a compound of formula 32 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 32 and the attendant definitions, wherein R ₁ is 3-hydroxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 32 and the attendant definitions wherein R ₂ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 32 and the attendant definitions wherein R is H and R ₁ is 3-hydroxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 32 and the attendant definitions wherein R is H, R ₁ is 3-hydroxyphenyl and R ₂ is methyl.

  In another embodiment, the sirtuin activator is a compound of formula 33:

［式中、出現するたびに、独立して、
Ｒは、Ｈ、または置換もしくは非置換のアルキル、アルケニル、もしくはアルキニルであり；
Ｒ_１およびＲ_２は、置換または非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヘテロアラルキルであり；
Ｌは、Ｏ、Ｓ、またはＮＲである］。

[In the formula, each time it appears,
R is H, or substituted or unsubstituted alkyl, alkenyl, or alkynyl;
R ₁ and R ₂ are substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L is O, S, or NR].

  In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions, wherein R is alkynyl.

In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions wherein R ₁ is 2,6-dichlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions wherein R ₂ is methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions wherein L is O.

In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions, wherein R is alkynyl and R ₁ is 2,6-dichlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions wherein R is alkynyl, R ₁ is 2,6-dichlorophenyl and R ₂ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 33 and the attendant definitions, wherein R is alkynyl, R ₁ is 2,6-dichlorophenyl, R ₂ is methyl, and L is O It is.

  In another embodiment, the sirtuin activator is a compound of formula 34:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、およびＲ_２は、Ｈ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜５の整数である］。

[In the formula, each time it appears,
R, R ₁ , and R ₂ are H, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions, wherein R is 3,5-dichloro-2-hydroxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein R ₂ is H.

  In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl and R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl, R ₁ is H, R ₂ is H is there.

In a further embodiment, a sirtuin activator is a compound of formula 34 and the attendant definitions wherein R is 3,5-dichloro-2-hydroxyphenyl, R ₁ is H, R ₂ is H Yes, n is 1.

  In another embodiment, the sirtuin activator is a compound of formula 35:

［式中、出現するたびに、独立して、
Ｒは、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１は、置換または非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヘテロアラルキルであり；
Ｒ_２は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ、またはＳであり；
ｍは、０〜３の整数であり；
ｎは、０〜５の整数であり；
ｏは、０〜２の整数である］。

[In the formula, each time it appears,
R is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₁ is substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₂ is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl Is;
L is O, NR, or S;
m is an integer from 0 to 3;
n is an integer from 0 to 5;
o is an integer from 0 to 2].

  In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R ₁ is pyridine.

  In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein L is S.

  In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein m is 0.

  In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein o is 0.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl and R ₁ is pyridine.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl, R ₁ is pyridine and L is S.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl, R ₁ is pyridine, L is S, and m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl, R ₁ is pyridine, L is S, m is 0, and n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 35 and the attendant definitions wherein R is phenyl, R ₁ is pyridine, L is S, m is 0, and n is 1 and o is 0.

  In another embodiment, the sirtuin activator is a compound of formula 36:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_３、およびＲ_４は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｒ_１およびＲ_２は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｌ_１は、Ｏ、ＮＲ_１、Ｓ、Ｃ（Ｒ）_２、またはＳＯ_２であり；
Ｌ_２およびＬ_３は、Ｏ、ＮＲ_１、Ｓ、またはＣ（Ｒ）_２である］。

[In the formula, each time it appears,
R, R ₃ , and R ₄ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, heteroaralkyl;
R ₁ and R ₂ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;
L ₁ is O, NR ₁ , S, C (R) ₂ , or SO ₂ ;
L ₂ and L ₃ are O, NR ₁ , S, or C (R) ₂ ].

  In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R ₁ is 4-chlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R ₂ is 4-chlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein R ₃ is H.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein R ₄ is H.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein L ₁ is SO ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein L ₂ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein R is H and R ₁ is 4-chlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions wherein R is H, R ₁ is 4-chlorophenyl and R ₂ is 4-chlorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R is H, R ₁ is 4-chlorophenyl, R ₂ is 4-chlorophenyl, and R ₃ is H.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R is H, R ₁ is 4-chlorophenyl, R ₂ is 4-chlorophenyl, and R ₃ is H and R ₄ is H.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R is H, R ₁ is 4-chlorophenyl, R ₂ is 4-chlorophenyl, and R ₃ is H, R ₄ is H, and L ₁ is SO ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R is H, R ₁ is 4-chlorophenyl, R ₂ is 4-chlorophenyl, and R ₃ is H, R ₄ is H, L ₁ is SO ₂ , and L ₂ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 36 and the attendant definitions, wherein R is H, R ₁ is 4-chlorophenyl, R ₂ is 4-chlorophenyl, and R ₃ is H, R ₄ is H, L ₁ is SO ₂ , L ₂ is NH, and L ₃ is O.

  In another embodiment, the sirtuin activator is a compound of formula 37:

［式中、出現するたびに、独立して、
Ｒは、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｒ_１は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｒ_２およびＲ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ_１、またはＳであり；
ｎは、０〜４の整数である］。

[In the formula, each time it appears,
R is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl. Yes;
R ₁ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;
R ₂ and R ₃ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;
L is O, NR ₁ , or S;
n is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R is methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R ₁ is 3-fluorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R ₂ is H.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R ₃ is 4-chlorophenyl.

  In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein L is O.

  In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R is methyl and n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1 and R ₁ is 3-fluorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1, R ₁ is 3-fluorophenyl and R ₂ is H. is there.

In a further embodiment, a sirtuin activator is a compound of formula 37 and the attendant definitions wherein R is methyl, n is 1, R ₁ is 3-fluorophenyl and R ₂ is H. Yes, R ₃ is 4-chlorophenyl.

  In another embodiment, the sirtuin activator is a compound of formula 38:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ、またはＳである］。

[In the formula, each time it appears,
R and R ₁ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR, or S].

  In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions, wherein R is 3-methoxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions, wherein R ₁ is 4-t-butylphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions, wherein L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions, wherein R is 3-methoxyphenyl and R ₁ is 4-t-butylphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl, R ₁ is 4-t-butylphenyl and L ₁ is NH. .

In a further embodiment, a sirtuin activator is a compound of formula 38 and the attendant definitions wherein R is 3-methoxyphenyl, R ₁ is 4-t-butylphenyl and L ₁ is NH. , L ₂ is O.

  In another embodiment, the sirtuin activator is a compound of formula 39:

［式中、出現するたびに、独立して、
Ｒは、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１は、Ｈまたは置換もしくは非置換のアルキル、アリール、アルカリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキル；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ、またはＳであり；
ｎは、０〜４の整数である］。

[In the formula, each time it appears,
R is H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or Heteroaralkyl;
R ₁ is H or substituted or unsubstituted alkyl, aryl, alkaryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR, or S;
n is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R is methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R ₁ is 3,4,5-trimethoxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein L ₂ is NH.

  In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R is methyl and n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1 and R ₁ is 3,4,5-trimethoxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1, R ₁ is 3,4,5-trimethoxyphenyl, L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 39 and the attendant definitions wherein R is methyl, n is 1, R ₁ is 3,4,5-trimethoxyphenyl, L ₁ is S and L ₂ is NH.

  In another embodiment, the sirtuin activator is a compound of formula 40:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アルカリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_４は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ、またはＳであり；
ｎは、０〜３の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ is H or substituted or unsubstituted alkyl, aryl, alkaryl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₄ is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hetero Aralkyl;
L ₁ and L ₂ are O, NR, or S;
n is an integer from 0 to 3].

  In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions, wherein R ₁ is perfluorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R ₂ is H.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R ₃ is H.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein L ₂ is O.

  In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein n is 0.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions, wherein R is H and R ₁ is perfluorophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H, R ₁ is perfluorophenyl and R ₂ is H.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H, R ₁ is perfluorophenyl, R ₂ is H, and R ₃ is H. .

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H, R ₁ is perfluorophenyl, R ₂ is H, and R ₃ is H , L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H, R ₁ is perfluorophenyl, R ₂ is H, and R ₃ is H , L ₁ is O and L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 40 and the attendant definitions wherein R is H, R ₁ is perfluorophenyl, R ₂ is H, and R ₃ is H , L ₁ is O, L ₂ is O, and n is 0.

  In another embodiment, the sirtuin activator is a compound of formula 41:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、およびＲ_３は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ_２、またはＳであり；
ｍおよびｎは、０〜８の整数である］。

[In the formula, each time it appears,
R, R ₁ , and R ₃ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl , Heteroaryl, or heteroaralkyl;
R ₂ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR ₂ , or S;
m and n are integers from 0 to 8].

  In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein R ₁ is cyano.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein R ₂ is ethyl.

  In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0 and R ₁ is cyano.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0, R ₁ is cyano and R ₂ is ethyl.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0, R ₁ is cyano, R ₂ is ethyl, and m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0, R ₁ is cyano, R ₂ is ethyl, m is 0, L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0, R ₁ is cyano, R ₂ is ethyl, m is 0, L ₁ is S and L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 41 and the attendant definitions wherein n is 0, R ₁ is cyano, R ₂ is ethyl, m is 0, L ₁ is S, L ₂ is O, and L ₃ is O.

  In another embodiment, the sirtuin activator is a compound of formula 42:

［式中、出現するたびに、独立して、
ＲおよびＲ_２は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１およびＲ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、Ｌ_３、およびＬ_４は、Ｏ、ＮＲ_１、またはＳであり；
ｍは、０〜６の整数であり；
ｎは、０〜８の整数である］。

[In the formula, each time it appears,
R and R ₂ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hetero Aryl or heteroaralkyl;
R ₁ and R ₃ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , L ₃ , and L ₄ are O, NR ₁ , or S;
m is an integer from 0 to 6;
n is an integer from 0 to 8].

  In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein R ₁ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein R ₂ is CF ₃ and m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions, wherein R ₃ is 4-methylphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein L ₃ is NR ₁ .

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein L ₄ is NR ₁ .

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0 and R ₁ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1; R ₃ is 4-methylphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1; R ₃ is 4-methylphenyl; L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1; R ₃ is 4-methylphenyl; L ₁ is S and L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1; R ₃ is 4-methylphenyl; L ₁ is S, L ₂ is O; L ₃ is NR ₁ .

In a further embodiment, a sirtuin activator is a compound of formula 42 and the attendant definitions wherein n is 0, R ₁ is methyl, R ₂ is CF ₃ and m is 1; R ₃ is 4-methylphenyl; L ₁ is S, L ₂ is O; L ₃ is NR ₁ and L ₄ is NR ₁ .

  In another embodiment, the sirtuin activator is a compound of formula 43:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２およびＲ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ_２、またはＳである］。

[In the formula, each time it appears,
R and R ₁ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
R ₂ and R ₃ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR ₂ , or S].

  In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R ₁ is NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R ₂ is 4-bromophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R ₃ is 3-hydroxy-4-methoxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein L ₂ is NR ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano and R ₁ is NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano, R ₁ is NH ₂ and R ₂ is 4-bromophenyl.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano, R ₁ is NH ₂ , R ₂ is 4-bromophenyl, and R ₃ is 3-hydroxy-4-methoxyphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano, R ₁ is NH ₂ , R ₂ is 4-bromophenyl, and R ₃ is 3-hydroxy-4-methoxyphenyl and L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 43 and the attendant definitions wherein R is cyano, R ₁ is NH ₂ , R ₂ is 4-bromophenyl, and R ₃ is 3-hydroxy-4-methoxyphenyl, L ₁ is O, and L ₂ is NR ₂ .

  In another embodiment, the sirtuin activator is a compound of formula 44:

［式中、出現するたびに、独立して、
Ｒは、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ、またはＳであり；
ｎは、０〜５の整数である］。

[In the formula, each time it appears,
R is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₁ is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or hetero Aralkyl;
L ₁ , L ₂ , and L ₃ are O, NR, or S;
n is an integer from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein L ₁ is NR.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein L ₃ is NR.

  In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein n is 2.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl and R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R ₁ is C (O) OCH ₃ and L ₁ is NR It is.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R ₁ is C (O) OCH ₃ and L ₁ is NR And L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R ₁ is C (O) OCH ₃ and L ₁ is NR L ₂ is S and L ₃ is NR.

In a further embodiment, a sirtuin activator is a compound of formula 44 and the attendant definitions wherein R is 3-trifluoromethylphenyl, R ₁ is C (O) OCH ₃ and L ₁ is NR L ₂ is S, L ₃ is NR, and n is 2.

  In another embodiment, the sirtuin activator is a compound of formula 45:

［式中、出現するたびに、独立して、
Ｒは、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１およびＲ_２は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ_１、またはＳであり；
ｎは、０〜４の整数である］。

[In the formula, each time it appears,
R is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl Is;
R ₁ and R ₂ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR ₁ , or S;
n is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein n is 0.

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein R ₁ is 2-tetrahydrofuranylmethyl.

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions, wherein R ₂ is —CH ₂ CH ₂ C ₆ H ₄ SO ₂ NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein L ₂ is NR ₁ .

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein n is 0 and R ₁ is 2-tetrahydrofuranylmethyl.

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein n is 0, R ₁ is 2-tetrahydrofuranylmethyl and R ₂ is —CH ₂ CH ₂ C _6. H ₄ SO ₂ NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein n is 0, R ₁ is 2-tetrahydrofuranylmethyl and R ₂ is —CH ₂ CH ₂ C _6. H ₄ SO ₂ NH ₂ and L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 45 and the attendant definitions wherein n is 0, R ₁ is 2-tetrahydrofuranylmethyl and R ₂ is —CH ₂ CH ₂ C _6. H ₄ SO ₂ NH ₂ , L ₁ is S, and L ₂ is NR ₁ .

  In another embodiment, the sirtuin activator is a compound of formula 46:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、およびＲ_３は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ_４、またはＳであり；
Ｒ_４は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜４の整数であり；
ｍは、０〜３の整数であり；
ｏは、０〜４の整数であり；
ｐは、０〜５の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , and R ₃ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl , Heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR ₄ , or S;
R ₄ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 4;
m is an integer from 0 to 3;
o is an integer from 0 to 4;
p is an integer from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0.

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein R ₁ is Cl.

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein R ₂ is Cl.

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein p is 3.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein R ₃ is OH or I.

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0 and m is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0, m is 1 and o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1 and R ₁ is Cl.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1, R ₁ is Cl, and p is 3.

In a further embodiment, a sirtuin activator is a compound of formula 46 and the attendant definitions wherein n is 0, m is 1, o is 1, R ₁ is Cl, and p is 3 and R ₂ is OH or I.

  In another embodiment, the sirtuin activator is a compound of formula 47:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ_４、またはＳであり；
Ｒ_４は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｍおよびｎは、０〜４の整数である］。

[In the formula, each time it appears,
R and R ₁ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
L ₁ and L ₂ are O, NR ₄ , or S;
R ₄ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
m and n are integers from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2.

  In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein R is methyl or t-butyl.

  In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein m is 2.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein R ₁ is methyl or t-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein L ₂ is O.

  In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2 and R is methyl or t-butyl.

  In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl and m is 2.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, and R ₁ is methyl or t-Butyl.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, and R ₁ is methyl or t-butyl and L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 47 and the attendant definitions wherein n is 2, R is methyl or t-butyl, m is 2, and R ₁ is methyl or t-butyl, L ₁ is O, and L ₂ is O.

  In another embodiment, the sirtuin activator is a compound of formula 48:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、およびＲ_６は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_７は、Ｈまたは置換もしくは非置換のアルキル、アシル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ_７、またはＳであり、
ｎは、０〜４の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or non- Substituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₇ is H or substituted or unsubstituted alkyl, acyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR ₇ , or S;
n is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₂ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₃ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₄ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₅ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₆ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein R ₇ is C (O) CF ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein L ₃ is S.

  In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1 and R is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl and R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ and R ₃ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , and R ₄ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ and R ₅ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ , R ₅ is methyl, and R ₆ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ , R ₅ is methyl, R ₆ is methyl, and R ₇ is C (O) CF ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ , R ₅ is methyl, R ₆ is methyl, and R ₇ is C (O) CF ₃ and L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ , R ₅ is methyl, R ₆ is methyl, and R ₇ is C (O) CF ₃ , L ₁ is S, and L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 48 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is C (O) OCH ₃ , R ₄ is C (O) OCH ₃ , R ₅ is methyl, R ₆ is methyl, and R ₇ is C (O) CF ₃ , L ₁ is S, L ₂ is S, and L ₃ is S.

  In another embodiment, the sirtuin activator is a compound of formula 49:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、およびＲ_５は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ_６、またはＳであり；
Ｒ_６は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜４の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl , Aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR ₆ , or S;
R ₆ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R ₂ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R ₃ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R ₄ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein R ₅ is CH ₂ CH (CH ₃ ) ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein L ₃ is S.

  In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1 and R is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl and R ₁ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ and R ₃ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, and R ₄ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, and R ₅ is CH ₂ CH (CH ₃ ) ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, R ₅ is CH ₂ CH (CH ₃ ) ₂ , and L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, R ₅ is CH ₂ CH (CH ₃ ) ₂ , and L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, R ₅ is CH ₂ CH (CH ₃ ) ₂ , L ₁ is S, and L ₂ is S .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, R ₅ is CH ₂ CH (CH ₃ ) ₂ , L ₁ is S, and L ₂ is S .

In a further embodiment, a sirtuin activator is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, R ₁ is C (O) OCH ₃ and R ₂ is C (O) OCH ₃ , R ₃ is methyl, R ₄ is methyl, R ₅ is CH ₂ CH (CH ₃ ) ₂ , L ₁ is S, and L ₂ is S , L ₃ is S.

  In another embodiment, the sirtuin activator is a compound of formula 50:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ_３、またはＳであり；
Ｒ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜５の整数であり；
ｍは、０〜４の整数である］。

[In the formula, each time it appears,
R and R ₁ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
R ₂ is H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
L ₁ and L ₂ are O, NR ₃ , or S;
R ₃ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 5;
m is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein R is CO ₂ Et.

  In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein R ₂ is cyano.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1 and R is CO ₂ Et.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1, R is CO ₂ Et and m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1, R is CO ₂ Et, m is 0, and R ₂ is cyano.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1, R is CO ₂ Et, m is 0, R ₂ is cyano, L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 50 and the attendant definitions wherein n is 1, R is CO ₂ Et, m is 0, R ₂ is cyano, L ₁ is S and L ₂ is S.

  In another embodiment, the sirtuin activator is a compound of formula 51:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜４の整数であり；
ｍは、０〜２の整数である］。

[In the formula, each time it appears,
R and R ₁ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
n is an integer from 0 to 4;
m is an integer from 0 to 2].

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 2.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein R is Cl or trifluoromethyl.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein m is 2.

In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein R ₁ is phenyl.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 2 and R is Cl or trifluoromethyl.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 2, R is Cl or trifluoromethyl and m is 2.

In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 2, R is Cl or trifluoromethyl, m is 2, R ₁ is phenyl is there.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein R is F.

In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein R ₁ is 4-methylphenyl.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 1 and R is F.

  In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 1, R is F and m is 2.

In a further embodiment, a sirtuin activator is a compound of formula 51 and the attendant definitions wherein n is 1, R is F, m is 2 and R ₁ is 4-methylphenyl. .

  In another embodiment, the sirtuin activator is a compound of formula 52:

［式中、出現するたびに、独立して、
Ｒは、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１およびＲ_６は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２は、アルキレン、アルケニレン、またはアルキニレンであり；
Ｒ_３、Ｒ_４、およびＲ_５は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ、またはＳであり；
ｎおよびｐは、０〜３の整数であり；
ｍおよびｏは、０〜２の整数である］。

[In the formula, each time it appears,
R is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₁ and R ₆ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl Or heteroaralkyl;
R ₂ is alkylene, alkenylene, or alkynylene;
R ₃ , R ₄ , and R ₅ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl , Heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR, or S;
n and p are integers from 0 to 3;
m and o are integers from 0 to 2].

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH.

  In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R ₁ is I.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R ₂ is alkynylene.

  In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R ₄ is C (O) OEt.

  In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R ₅ is OH.

  In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein p is 0.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH and n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1 and R ₁ is I.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. It is.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. And m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1 and R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1, R ₃ is OH, and R ₄ is C (O) OEt.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. And m is 1, R ₃ is OH, R ₄ is C (O) OEt, and o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1, R ₃ is OH, R ₄ is C (O) OEt, o is 1, and R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. , M is 1, R ₃ is OH, R ₄ is C (O) OEt, o is 1, R ₅ is OH, and p is 0.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1, R ₃ is OH, R ₄ is C (O) OEt, o is 1, R ₅ is OH, p is 0, and L ₁ is NH It is.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1, R ₃ is OH, R ₄ is C (O) OEt, o is 1, R ₅ is OH, p is 0, and L ₁ is NH And L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 52 and the attendant definitions wherein R is CH ₂ CH ₂ OH, n is 1, R ₁ is I, and R ₂ is alkynylene. M is 1, R ₃ is OH, R ₄ is C (O) OEt, o is 1, R ₅ is OH, p is 0, and L ₁ is NH L ₂ is O and L ₃ is O.

  In another embodiment, the sirtuin activator is a compound of formula 53:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、およびＲ_５は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、Ｌ_３、およびＬ_４は、Ｏ、ＮＲ_６、またはＳであり；
Ｒ_６は、Ｈ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜５の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted An alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , L ₃ , and L ₄ are O, NR ₆ , or S;
R ₆ is H, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R ₁ is t-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R ₂ is Ot-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R ₃ is t-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R ₄ is C (O) OMe.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R ₅ is C (O) OMe.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein L ₄ is NH.

  In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl and R ₁ is t-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. It is.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. And R ₃ is t-butyl.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl and R ₄ is C (O) OMe.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, and R ₅ is C (O) OMe.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, R ₅ is C (O) OMe, and L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, R ₅ is C (O) OMe, L ₁ is NH, and L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, R ₅ is C (O) OMe, L ₁ is NH, L ₂ is O, L ₃ Is O.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, R ₅ is C (O) OMe, L ₁ is NH, L ₂ is O, L ₃ Is O and L ₄ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 53 and the attendant definitions wherein R is Ot-butyl, R ₁ is t-butyl and R ₂ is Ot-butyl. R ₃ is t-butyl, R ₄ is C (O) OMe, R ₅ is C (O) OMe, L ₁ is NH, L ₂ is O, L ₃ Is O, L ₄ is NH, and n is 1.

  In another embodiment, the sirtuin activator is a compound of formula 54:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２、Ｒ_４、およびＲ_５は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_３、Ｒ_６、およびＲ_７は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ、またはＳであり；
ｎおよびｏは、０〜４の整数であり；
ｍは、０〜３の整数である］。

[In the formula, each time it appears,
R and R ₁ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₂ , R ₄ , and R ₅ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl Alkyl, heteroaryl, or heteroaralkyl;
R ₃ , R ₆ , and R ₇ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl , Heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L is O, NR, or S;
n and o are integers from 0 to 4;
m is an integer from 0 to 3].

  In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R ₁ is ethyl.

  In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R ₃ is H.

  In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein o is 0.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R ₅ is Cl.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R ₆ is H.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R ₇ is methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein L is NH.

  In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl and R ₁ is ethyl.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl and m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, and R ₃ is H.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0 and R ₅ is Cl.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0, R ₅ is Cl, and R ₆ is H.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0, R ₅ is Cl, R ₆ is H, and R ₇ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0, R ₅ is Cl, R ₆ is H, R ₇ is methyl, and L is NH.

In a further embodiment, a sirtuin activator is a compound of formula 54 and the attendant definitions wherein R is ethyl, R ₁ is ethyl, m is 0, R ₃ is H, o Is 0, R ₅ is Cl, R ₆ is H, R ₇ is methyl, L is NH, and n is 1.

  In another embodiment, the sirtuin activator is a compound of formula 55:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_４、およびＲ_５は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_２およびＲ_３は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、Ｌ_３、およびＬ_４は、Ｏ、ＮＲ、またはＳである］。

[In the formula, each time it appears,
R, R ₁ , R ₄ , and R ₅ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₂ and R ₃ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl or heteroaralkyl;
L ₁ , L ₂ , L ₃ , and L ₄ are O, NR, or S].

  In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R ₂ is OEt.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R ₃ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R ₄ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R ₅ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein L ₂ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein L ₃ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein L ₄ is S.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H and R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H and R ₂ is OEt.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H and R ₅ is H.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H, R ₅ is H, and L ₁ is S.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H, R ₅ is H, L ₁ is S, and L ₂ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H, R ₅ is H, L ₁ is S, L ₂ is NH, and L ₃ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 55 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is OEt and R ₃ is methyl; R ₄ is H, R ₅ is H, L ₁ is S, L ₂ is NH, L ₃ is NH, and L ₄ is S.

  In another embodiment, the sirtuin activator is a compound of formula 56:

［式中、出現するたびに、独立して、
ＲおよびＲ_１は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ_２、またはＳであり；
Ｒ_２は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜４の整数であり；
ｍは、０〜５の整数である］。

[In the formula, each time it appears,
R and R ₁ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, Or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR ₂ , or S;
R ₂ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 4;
m is an integer from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein n is 0.

  In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein L ₃ is S.

  In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein m is 0 and n is 0.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein m is 0, n is 0 and L ₁ is NH.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions wherein m is 0, n is 0, L ₁ is NH, and L ₂ is S.

In a further embodiment, a sirtuin activator is a compound of formula 56 and the attendant definitions, wherein m is 0, n is 0, L ₁ is NH, L ₂ is S, L ₃ is S.

  In another embodiment, the sirtuin activator is a compound of formula 57:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、およびＲ_３は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ａは、アルキレン、アルケニレン、またはアルキニレンであり；
ｎは、０〜８の整数であり；
ｍは、０〜３の整数であり；
ｏは、０〜６の整数であり；
ｐは、０〜４の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , and R ₃ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl , Heterocyclylalkyl, heteroaryl, or heteroaralkyl;
A is alkylene, alkenylene, or alkynylene;
n is an integer from 0 to 8;
m is an integer from 0 to 3;
o is an integer from 0 to 6;
p is an integer from 0 to 4].

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein R is OH or methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein R ₁ is methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein R ₂ is C (O) CH ₃ .

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein p is 2.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein R ₃ is CO ₂ H.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein A is alkenylene.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2 and R is OH or methyl.

  In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl and m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1 and R ₁ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R ₁ is methyl, o is 1.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R ₁ is methyl, o is 1 and R ₂ is C (O) CH ₃ .

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R ₁ is methyl, o is 1, R ₂ is C (O) CH ₃ , and p is 2.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R ₁ is methyl, o is 1, R ₂ is C (O) CH ₃ , p is 2, and R ₃ is CO ₂ H.

In a further embodiment, a sirtuin activator is a compound of formula 57 and the attendant definitions wherein n is 2, R is OH or methyl, m is 1, R ₁ is methyl, o is 1, R ₂ is C (O) CH ₃ , p is 2, R ₃ is CO ₂ H, and A is alkenylene.

  In another embodiment, the sirtuin activator is a compound of formula 58:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、およびＲ_９は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、Ｏ、ＮＲ_１０、またはＳであり；
Ｒ_１０は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, A carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are O, NR ₁₀ , or S;
R ₁₀ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₁ is CH ₂ OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₂ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₃ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₆ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₇ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₈ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R ₉ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH and R ₁ is CH ₂ OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH and R ₂ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. is there.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH and R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, and R ₆ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, and R ₇ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, R ₇ is OH, and R ₈ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, R ₇ is OH, R ₈ is OH, and R ₉ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, R ₇ is OH, R ₈ is OH, R ₉ is methyl, and L ₁ is O .

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, R ₇ is OH, R ₈ is OH, R ₉ is methyl, and L ₁ is O , L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 58 and the attendant definitions wherein R is OH, R ₁ is CH ₂ OH, R ₂ is OH, and R ₃ is methyl. Yes, R ₄ is OH, R ₅ is OH, R ₆ is OH, R ₇ is OH, R ₈ is OH, R ₉ is methyl, and L ₁ is O , L ₂ is O and L ₃ is O.

  In another embodiment, the sirtuin activator is a compound of formula 59:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、およびＲ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ、Ｓ、またはＳｅであり；
ｎおよびｍは、０〜５の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , and R ₃ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L is O, NR, S, or Se;
n and m are integers from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R ₂ is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R ₃ is H.

  In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein L is Se.

  In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H and R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H, R ₁ is H and R ₂ is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is H, and R ₃ is H.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is H, R ₃ is H; L is Se.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is H, R ₃ is H; L is Se and n is 1.

In a further embodiment, a sirtuin activator is a compound of formula 59 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is H, R ₃ is H; L is Se, n is 1, and m is 1.

  In another embodiment, the sirtuin activator is a compound of formula 60:

［式中、出現するたびに、独立して、
Ｒは、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１およびＲ_２は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ_３、Ｓ、またはＳＯ_２であり；
Ｒ_３は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎは、０〜４の整数であり；
ｍは、１〜５の整数である］。

[In the formula, each time it appears,
R is hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl Is;
R ₁ and R ₂ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, Heteroaryl or heteroaralkyl;
L is O, NR ₃ , S, or SO ₂ ;
R ₃ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n is an integer from 0 to 4;
m is an integer from 1 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein R is Cl.

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein R ₁ is NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein R ₂ is CO ₂ H.

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein L is SO ₂ .

  In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein m is 1.

  In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1 and R is Cl.

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl and R ₁ is NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R ₁ is NH ₂ and R ₂ is CO ₂ H is there.

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R ₁ is NH ₂ and R ₂ is CO ₂ H Yes, L is SO ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 60 and the attendant definitions wherein n is 1, R is Cl, R ₁ is NH ₂ and R ₂ is CO ₂ H Yes, L is SO ₂ and m is 1.

  In another embodiment, the sirtuin activator is a compound of formula 61:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、およびＲ_３は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
ｎおよびｍは、０〜５の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , and R ₃ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl , Heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
n and m are integers from 0 to 5].

  In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2.

  In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions, wherein R is 3-hydroxy and 5-hydroxy.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein R ₂ is H.

  In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein m is 0.

  In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions, wherein R ₃ is 4-hydroxy.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions, wherein R ₃ is 4-methoxy.

  In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2 and R is 3-hydroxy and 5-hydroxy.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy and R ₁ is H.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R ₁ is H, R ₂ Is H.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R ₁ is H, R ₂ Is H and m is 0.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R ₁ is H, R ₂ Is H and m is 1.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R ₁ is H, R ₂ Is H, m is 1 and R ₃ is 4-hydroxy.

In a further embodiment, a sirtuin activator is a compound of formula 61 and the attendant definitions wherein n is 2, R is 3-hydroxy and 5-hydroxy, R ₁ is H, R ₂ Is H, m is 1 and R ₃ is 4-methoxy.

  In another embodiment, the sirtuin activator is a compound of formula 62:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、およびＲ_６は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ_７、またはＳであり；
Ｒ_７は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted Or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L is O, NR ₇ , or S;
R ₇ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions wherein R ₁ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R ₂ is CH ₂ OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions wherein R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions wherein R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R ₆ is CH ₂ OH.

  In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions wherein L is O.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions wherein R is OH and R ₁ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, and R ₂ is CH ₂ OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is CH ₂ OH, and R ₃ is OH. is there.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is CH ₂ OH, and R ₃ is OH. Yes, R ₄ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is CH ₂ OH, and R ₃ is OH. Yes, R ₄ is OH and R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is CH ₂ OH, and R ₃ is OH. Yes, R ₄ is OH, R ₅ is OH, and R ₆ is CH ₂ OH.

In a further embodiment, a sirtuin activator is a compound of formula 62 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is CH ₂ OH, and R ₃ is OH. Yes, R ₄ is OH, R ₅ is OH, R ₆ is CH ₂ OH, and L is O.

  In another embodiment, the sirtuin activator is a compound of formula 63:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、およびＲ_２は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , and R ₂ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, Heterocyclylalkyl, heteroaryl, or heteroaralkyl.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R is CO ₂ H.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R ₁ is ethyl.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R ₂ is N-1-pyrrolidine.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R is CO ₂ H and R ₁ is ethyl.

In a further embodiment, a sirtuin activator is a compound and the attendant definitions to that of formula 63, R is CO 2 _H, R ₂ is N-1- pyrrolidine.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R ₁ is ethyl and R ₂ is N-1-pyrrolidine.

In a further embodiment, a sirtuin activator is a compound of formula 63 and the attendant definitions wherein R is CO ₂ H, R ₁ is ethyl and R ₂ is N-1-pyrrolidine.

  In another embodiment, the sirtuin activator is a compound of formula 64:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、およびＲ_７は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１、Ｌ_２、およびＬ_３は、ＣＨ_２、Ｏ、ＮＲ_８、またはＳであり；
Ｒ_８は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro Or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L ₁ , L ₂ , and L ₃ are CH ₂ , O, NR ₈ , or S;
R ₈ is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is Cl.

  In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₁ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₂ is N (Me) ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₄ is C (O) NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₆ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R ₇ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein L ₁ is CH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is Cl and R ₁ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is Cl, R ₁ is OH and R ₂ is N (Me) ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH and R ₄ is C (O) NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH, R ₄ is C (O) NH ₂ and R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, and R ₆ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, and R ₇ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, and L ₁ is CH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, L ₁ is CH ₂ , L ₂ is O is there.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions, wherein R is Cl, R ₁ is OH, R ₂ is N (Me) ₂ , and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, L ₁ is CH ₂ , L ₂ is O Yes, L ₃ is O.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H and R ₁ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH and R ₂ is N (Me) ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH and R ₄ is C (O) NH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ and R ₅ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, and R ₆ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, and R ₇ is OH.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, and L ₁ is CH ₂ .

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, L ₁ is CH ₂ , L ₂ is O is there.

In a further embodiment, a sirtuin activator is a compound of formula 64 and the attendant definitions wherein R is H, R ₁ is OH, R ₂ is N (Me) ₂ and R ₃ is OH, R ₄ is C (O) NH ₂ , R ₅ is OH, R ₆ is OH, R ₇ is OH, L ₁ is CH ₂ , L ₂ is O Yes, L ₃ is O.

  In another embodiment, the sirtuin activator is a compound of formula 65:

［式中、出現するたびに、独立して、
Ｒは、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_１、Ｒ_２、およびＲ_３は、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌ_１およびＬ_２は、Ｏ、ＮＲ、またはＳである］。

[In the formula, each time it appears,
R is H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₁ , R ₂ , and R ₃ are hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclyl Alkyl, heteroaryl, or heteroaralkyl;
L ₁ and L ₂ are O, NR, or S].

  In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R ₁ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R ₂ is CO ₂ H.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R ₃ is F.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein L ₂ is O.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl and R ₁ is methyl.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl, R ₁ is methyl and R ₂ is CO ₂ H.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl, R ₁ is methyl, R ₂ is CO ₂ H, R ₃ is F is there.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl, R ₁ is methyl, R ₂ is CO ₂ H, R ₃ is F Yes, L ₁ is O.

In a further embodiment, a sirtuin activator is a compound of formula 65 and the attendant definitions wherein R is methyl, R ₁ is methyl, R ₂ is CO ₂ H, R ₃ is F Yes, L ₁ is O and L ₂ is O.

  A preferred compound of formula 8 is dipyridamole; a preferred compound of formula 12 is hinokitiol; a preferred compound of formula 13 is L-(+)-ergothioneine; a preferred compound of formula 19 is caffeic acid phenol ester; The compound of formula 20 is MCI-186 and the preferred compound of formula 21 is HBED. The activating compound may be an oxidized form of the compounds of FIGS.

  Also included are pharmaceutically acceptable addition salts and complexes of compounds of Formulas 1-25, 30, 32-65, and 69-76. Where a compound may have one or more chiral centers, as specified, the compounds contemplated herein may be a single stereoisomer or a racemic mixture of stereoisomers.

  In one embodiment, the sirtuin activator is a stilbene, chalcone, or flavone compound represented by formula 7:

［式中、出現するたびに、独立して、
Ｍは、存在しないか、Ｏであり；
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ’_１、Ｒ’_２、Ｒ’_３、Ｒ’_４、およびＲ’_５は、Ｈ、アルキル、アリール、ヘテロアリール、アラルキル、アルカリール、ヘテロアラルキル、ハロゲン化物、ＮＯ_２、ＳＲ、ＯＲ、Ｎ（Ｒ）_２、またはカルボキシルを表し；
Ｒ_ａは、Ｈを表すか、２つのＲ_ａは単結合を形成し；
Ｒは、Ｈ、アルキル、またはアリールを表し；
ｎは、０または１である］。

[In the formula, each time it appears,
M is absent or O;
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ′ ₁ , R ′ ₂ , R ′ ₃ , R ′ ₄ , and R ′ ₅ are H, alkyl, aryl, heteroaryl, aralkyl, alkaryl Represents heteroaralkyl, halide, NO ₂ , SR, OR, N (R) ₂ , or carboxyl;
R _a represents H or two R _a form _a single bond;
R represents H, alkyl, or aryl;
n is 0 or 1.]

In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 0. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 1. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein M is absent. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein M is O. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R _a is H. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein M is O and two R _a form a single bond. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R ₅ is H. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R ₅ is OH. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R ₁ , R ₃ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein R ₂ , R ′ ₂ , and R ′ ₃ are OH.

In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 0; M is absent; R _a is H; and R ₅ is H. Yes; R ₁ , R ₃ , and R ′ ₃ are OH; R ₂ , R ₄ , R ′ ₁ , R ′ ₂ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 1, M is absent, R _a is H, and R ₅ is H. Yes; R ₂ , R ₄ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₃ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H. In a further embodiment, a sirtuin activator is a compound represented by formula 7 and the attendant definitions, wherein n is 1; M is O; two R _a form _a single bond; ₅ is OH; R ₂ , R ′ ₂ , and R ′ ₃ are OH; R ₁ , R ₃ , R ₄ , R ′ ₁ , R ′ ₄ , and R ′ ₅ are H.

  In another embodiment, exemplary sirtuin activators are isonicotinamide analogs, eg, US Pat. No. 5,985,848, the disclosure of which is incorporated herein by reference in its entirety. 6,066,722; 6,228,847; 6,492,347; 6,803,455; and US Patent Publication Nos. 2001/0019823; 2002/0061898; 2002 / 2003/0149261; 2003/0229033; 2003/0096830; 2004/0053944; 2004/0110772; 2004/0181063, and the like. In an exemplary embodiment, the sirtuin activator can be an isonicotinamide analog having any of the following formulas 69-72. In one embodiment, the sirtuin activator is an isonicotinamide analog of formula 69:

［式中、Ａは、窒素、酸素、または硫黄に結合したアリール、アルキル、環状、または複素環基である］。記載したＡ部分は、任意選択で脱離基の特徴を有する。本明細書中に包含される実施形態では、Ａは、電子供与部分でさらに置換されている。ＢおよびＣはどちらも水素であるか、またはＢもしくはＣの一方がハロゲン、アミノ、もしくはチオール基であり、ＢもしくはＣの他方が水素であり；Ｄは、第一級アルコール、水素、あるいはリン酸ジエステルまたは炭素、窒素、もしくは硫黄で置換されたリン酸ジエステル橋によってリン酸、ホスホリル基、ピロホスホリル基、またはアデノシン一リン酸に結合した酸素、窒素、炭素、または硫黄、あるいはリン酸ジエステルまたは炭素、窒素、もしくは硫黄で置換されたピロリン酸ジエステル橋によってアデノシン二リン酸に結合した酸素、窒素、炭素、または硫黄である。

[Wherein A is an aryl, alkyl, cyclic, or heterocyclic group bonded to nitrogen, oxygen, or sulfur]. The described A moiety optionally has the characteristics of a leaving group. In the embodiments encompassed herein, A is further substituted with an electron donating moiety. B and C are both hydrogen, or one of B or C is a halogen, amino, or thiol group and the other of B or C is hydrogen; D is a primary alcohol, hydrogen, or phosphorus Oxygen, nitrogen, carbon, or sulfur, or phosphodiester bound to phosphoric acid, phosphoryl, pyrophosphoryl, or adenosine monophosphate by an acid diester or phosphodiester bridge substituted with carbon, nitrogen, or sulfur Oxygen, nitrogen, carbon, or sulfur attached to adenosine diphosphate by a pyrophosphate diester bridge substituted with carbon, nitrogen, or sulfur.

  In one example, A is a substituted N-linked aryl or heterocyclic group, an O-linked aryl or heterocyclic group having the formula —O—Y, or an S-linked aryl or heterocyclic group having the formula —O—Y. B and C are both hydrogen, or one of B or C is a halogen, amino, or thiol group, the other of B and C is hydrogen; D is a primary alcohol or hydrogen It is. Non-limiting preferred examples of A are described below, wherein each R is H or an electron donating moiety, Z is alkyl, aryl, hydroxyl, OZ ′ (Z ′ is alkyl or aryl) , Amino, NHZ ′ (Z ′ is alkyl or aryl), or NHZ′Z ″ (Z ′ and Z ″ are independently alkyl or aryl).

  Examples of A include the following i to xiv:

［式中、Ｙは、脱離基の機能に矛盾しない基である］。

[Wherein Y is a group consistent with the function of the leaving group].

  Examples of Y include, but are not limited to, the following xv to xxvii:

［式中、ｉ〜ｘｘｖｉｉについて、Ｘは、ハロゲン、チオールもしくは置換チオール、アミノもしくは置換アミノ、酸素もしくは置換酸素、あるいはアリールまたはアルキル基もしくは複素環である］。

[Wherein for i to xxvii, X is a halogen, thiol or substituted thiol, amino or substituted amino, oxygen or substituted oxygen, or an aryl or alkyl group or heterocycle].

  In certain embodiments, A is a substituted nicotinamide group (where i, Z is H), a substituted pyrazolo group (above vii), or a substituted 3-carboxamidoimidazolo group (where x, Z are H). It is. Further, B and C are both hydrogen, or one of B or C may be a halogen, amino, or thiol group and the other of B and C may be hydrogen; D is a primary alcohol or hydrogen It is.

  In other embodiments, when one of B or C is hydrogen, the other of B or C may be a halogen, amino, or thiol group. In addition, D may be hydrogen, oxygen dioxygen, or oxygen, nitrogen, carbon bonded to phosphoric acid, phosphoryl, pyrophosphoryl, or adenosine monophosphate by a phosphodiester bridge substituted with carbon, nitrogen, or sulfur. Or sulfur, or phosphodiester or oxygen, nitrogen, carbon, or sulfur attached to adenosine diphosphate by a pyrophosphate diester bridge substituted with carbon, nitrogen, or sulfur. Alternatively, adenosine monophosphate or adenosine diphosphate analogs can be substituted for adenosine monophosphate or adenosine diphosphate groups.

  In some embodiments, A has more than one electron donating moiety.

  In other embodiments, the sirtuin activator is an isonicotinamide analog of formula 70, 71, or 72:

［式中、Ｚは、アルキル、アリール、ヒドロキシル、ＯＺ’（Ｚ’はアルキルもしくはアリールである）、アミノ、ＮＨＺ’（Ｚ’はアルキルもしくはアリールである）、またはＮＨＺ’Ｚ”（Ｚ’およびＺ”は独立してアルキルもしくはアリールである）であり；ＥおよびＦは、独立して、Ｈ、ＣＨ_３、ＯＣＨ_３、ＣＨ_２ＣＨ_３、ＮＨ_２、ＯＨ、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、Ｎ（ＣＨ_３）_２、Ｃ（ＣＨ_３）_２、アリールまたはＣ_３〜Ｃ_１０アルキルであり、ただし、好ましくは、ＥまたはＦの一方がＨである場合は、ＥまたはＦの他方はＨではない］；

Wherein Z is alkyl, aryl, hydroxyl, OZ ′ (Z ′ is alkyl or aryl), amino, NHZ ′ (Z ′ is alkyl or aryl), or NHZ′Z ″ (Z ′ and Z ″ is independently alkyl or aryl); E and F are independently H, CH ₃ , OCH ₃ , CH ₂ CH ₃ , NH ₂ , OH, NHCOH, NHCOCH ₃ , N (CH _{3) 2, C (CH 3} ) 2, aryl or _C 3 _{-C 10} alkyl, with the proviso that preferably, when one of E or F is H, the other of E or F is not H];

［式中、Ｇ、ＪまたはＫは、ＣＯＮＨＺであり、Ｚは、アルキル、アリール、ヒドロキシル、ＯＺ’（Ｚ’はアルキルもしくはアリールである）、アミノ、ＮＨＺ’（Ｚ’はアルキルもしくはアリールである）、またはＮＨＺ’Ｚ”（Ｚ’およびＺ”は独立してアルキルもしくはアリールである）であり、Ｇ、ＪおよびＫの残りの２つは、独立してＣＨ_３、ＯＣＨ_３、ＣＨ_２ＣＨ_３、ＮＨ_２、ＯＨ、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３である］；

[Wherein, G, J or K is CONHZ, Z is alkyl, aryl, hydroxyl, OZ ′ (Z ′ is alkyl or aryl), amino, NHZ ′ (Z ′ is alkyl or aryl] ), Or NHZ′Z ″ (Z ′ and Z ″ are independently alkyl or aryl), and the remaining two of G, J, and K are independently CH ₃ , OCH ₃ , CH ₂ CH _{3, NH 2, OH, NHCOH} , an NHCOCH _3];

［式中、Ｚは、アルキル、アリール、ヒドロキシル、ＯＺ’（Ｚ’はアルキルもしくはアリールである）、アミノ、ＮＨＺ’（Ｚ’はアルキルもしくはアリールである）、またはＮＨＺ’Ｚ”（Ｚ’およびＺ”は独立してアルキルもしくはアリールである）であり；Ｌは、ＣＨ_３、ＯＣＨ_３、ＣＨ_２ＣＨ_３、ＮＨ_２、ＯＨ、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３である］。

Wherein Z is alkyl, aryl, hydroxyl, OZ ′ (Z ′ is alkyl or aryl), amino, NHZ ′ (Z ′ is alkyl or aryl), or NHZ′Z ″ (Z ′ and Z ″ is independently alkyl or aryl); L is CH ₃ , OCH ₃ , CH ₂ CH ₃ , NH ₂ , OH, NHCOH, NHCOCH ₃ ].

In an exemplary embodiment, the compound is of formula 70 above where E and F are independently H, CH ₃ , OCH ₃ , or OH (provided that preferably one of E or F is H) Is the other of E or F is not H).

  In another exemplary embodiment, the compound is β-1′-5-methyl-nicotinamide-2′-deoxyribose, β-D-1′-5-methyl-nicotinamide-2′-deoxyribofuranoside. , Β-1′-4,5-dimethyl-nicotinamide-2′-deoxyribose or β-D-1′-4,5-dimethyl-nicotinamide-2′-deoxyribofuranoside.

  In yet another embodiment, the compound is β-1'-5-methyl-nicotinamide-2'-deoxyribose.

Without being bound by any particular mechanism, the electron donating moiety on A is believed to stabilize the compounds of the invention so that the compounds of the invention are less susceptible to hydrolysis from the remaining compounds. . This improved chemical stability increases the value of the compound because it can be used for longer periods of time in biological systems due to its resistance to hydrolyzability. One skilled in the art will be able to imagine a number of electron donating moieties that are expected to play a role in this stabilizing function. Non-limiting examples of suitable electron-donating moieties are methyl, ethyl, O- methyl, amino, NMe _2, hydroxyl, CMe _3, aryl and alkyl groups. Preferably, the electron donating moiety is a methyl, ethyl, O-methyl, amino group. In the most preferred embodiment, it is an electron donating moiety methyl group.

  Compounds of formula 69-72 are useful in both free and salt form. The term “pharmaceutically acceptable salt” is intended to apply to non-toxic salts derived from inorganic or organic acids, for example the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Salts derived from lactic acid, fumaric acid, succinic acid, tartaric acid, gluconic acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid are included. “Pharmaceutically acceptable salts” also include hydrates, solvates, co-crystals and polymorphs of sirtuin modulators.

  Also provided are compounds of formulas 69-72 which are tautomers, pharmaceutically acceptable salts, esters, and prodrugs of the inhibitor compounds disclosed herein.

  The bioavailability of compounds of formulas 69-72 can be enhanced by conversion to the prodrug form. Such prodrugs may have improved lipophilicity compared to unconverted compounds, and as a result, membrane permeability may be enhanced. One particularly useful form of prodrug is an ester derivative. Its utility depends on the action of one or more ubiquitous intracellular lipases that catalyze the hydrolysis of the ester group and release the active compound at or near its site of action. In one form of a prodrug, one or more hydroxy groups in the compound can be O-acylated to produce an acylated derivative.

  Prodrug forms of 5-phosphate ester derivatives of compounds of Formula 69-72 can also be made. These can be particularly useful because the anionic nature of 5-phosphate can limit its ability to cross cell membranes. Conveniently, such 5-phosphate derivatives can be converted to uncharged bis (acyloxymethyl) ester derivatives. The usefulness of such prodrugs is one or more ubiquitous intracellular catalysis that catalyzes the hydrolysis of the ester group and releases one molecule of formaldehyde and a compound of the invention at or near its site of action. Depends on lipase action. Specific examples of the utility of acyloxymethyl ester prodrug forms of such phosphorylated carbohydrate derivatives and general methods for making them have been described (Kang et al., 1998; Jiang et al., 1998). Li et al., 1997; Kruppa et al., 1997).

  In another embodiment, exemplary sirtuin activators are O-acetyl-ADP-, including 2'-O-acetyl-ADP-ribose and 3'-O-acetyl-ADP-ribose, and analogs thereof. Ribose analogue. Exemplary O-acetyl-ADP-ribose analogs include, for example, US Patent Publication Nos. 2004/0053944; 2002/0061898; and 2003, the disclosures of which are incorporated herein by reference in their entirety. No. 0149261. In an exemplary embodiment, the sirtuin activator can be an O-acetyl-ADP-ribose analog having any of the following formulas 73-76. In one embodiment, the sirtuin activator is an O-acetyl-ADP-ribose analog of formula 73:

［式中、
Ａは、Ｎ、ＣＨおよびＣＲから選択され、Ｒは、ハロゲン、任意選択で置換されたアルキル、アラルキルおよびアリール、ＯＨ、ＮＨ_２、ＮＨＲ^１、ＮＲ^１Ｒ^２ならびにＳＲ^３から選択され、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ任意選択で置換されたアルキル、アラルキルまたはアリール基であり；
Ｂは、ＯＨ、ＮＨ_２、ＮＨＲ^４、Ｈおよびハロゲンから選択され、Ｒ^４は、任意選択で置換されたアルキル、アラルキルまたはアリール基であり；
Ｄは、ＯＨ、ＮＨ_２、ＮＨＲ^５、Ｈ、ハロゲンおよびＳＣＨ_３から選択され、Ｒ^５は、任意選択で置換されたアルキル、アラルキルまたはアリール基であり；
ＸおよびＹは、Ｈ、ＯＨおよびハロゲンから独立して選択され（ただし、ＸおよびＹの一方がヒドロキシまたはハロゲンである場合は、他方は水素である）；
Ｚは、ＯＨであるか、またはＸがヒドロキシである場合は、Ｚは水素、ハロゲン、ヒドロキシ、ＳＱおよびＯＱから選択され、Ｑは、任意選択で置換されたアルキル、アラルキルまたはアリール基であり；
Ｗは、ＯＨまたはＨである（ただし、ＷがＯＨである場合は、ＡはＣＲであり、Ｒは上記定義のとおりである）］；
またはその互変異性体；または薬学的に許容されるその塩；もしくはそのエステル；もしくはそのプロドラッグである。

[Where:
A is selected from N, CH and CR, R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH ₂ , NHR ¹ , NR ¹ R ² and SR ³ , R ¹ , R ² and R ³ are each optionally substituted alkyl, aralkyl or aryl groups;
B is selected from OH, NH ₂ , NHR ⁴ , H and halogen, and R ⁴ is an optionally substituted alkyl, aralkyl or aryl group;
D is selected from OH, NH ₂ , NHR ⁵ , H, halogen and SCH ₃ , wherein R ⁵ is an optionally substituted alkyl, aralkyl or aryl group;
X and Y are independently selected from H, OH and halogen (provided that one of X and Y is hydroxy or halogen, the other is hydrogen);
Z is OH or when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ and OQ, Q is an optionally substituted alkyl, aralkyl or aryl group;
W is OH or H (provided that when W is OH, A is CR and R is as defined above)];
Or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof.

In certain embodiments, when B is NHR ⁴ and / or D is NHR ⁵ , R ⁴ and / or R ⁵ is C ₁ -C ₄ alkyl.

  In other embodiments, if one or more halogens are present, they are selected from chlorine and fluorine.

In another embodiment, when Z is SQ or OQ, Q is C ₁ -C ₅ alkyl or phenyl.

  In an exemplary embodiment, D is H, or when D is other than H, B is OH.

In another embodiment, B is OH, D is H, OH or NH _2, X is OH or H, Y is H, and most preferably, Z is OH, H or methylthio, Especially OH.

  In certain embodiments, W is OH, Y is H, X is OH, A is CR, and R is methyl or halogen, preferably fluorine.

  In other embodiments, W is H, Y is H, X is OH, and A is CH.

  In other embodiments, the sirtuin activator is an O-acetyl-ADP-ribose analog of formula 74:

［式中、Ａ、Ｘ、Ｙ、ＺおよびＲは、最初に上で示した式（７３）の化合物について定義されており；Ｅは、ＣＯ_２Ｈもしくは対応する塩形態、ＣＯ_２Ｒ、ＣＮ、ＣＯＮＨ_２、ＣＯＮＨＲまたはＣＯＮＲ_２から選択され；Ｇは、ＮＨ_２、ＮＨＣＯＲ、ＮＨＣＯＮＨＲまたはＮＨＣＳＮＨＲから選択される］またはその互変異性体、または薬学的に許容されるその塩、もしくはそのエステル、もしくはそのプロドラッグである。

[Wherein A, X, Y, Z and R are defined for the compound of formula (73) initially shown above; E is CO ₂ H or the corresponding salt form, CO ₂ R, CN , CONH ₂ , CONHR or CONR ₂ ; G is selected from NH ₂ , NHCOR, NHCONHR or NHCSNHR] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or It is a prodrug.

In certain embodiments, E is CONH ₂ and G is NH ₂ .

In other embodiments, E is CONH ₂ , G is NH ₂ , X is OH or H, most preferably Z is OH, H or methylthio, especially OH.

Exemplary sirtuin activators include the following:
(1S) -1,4-dideoxy-1-C- (4-hydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-D-ribitol (1S) -1-C- (2-Amino-4-hydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-dideoxy-1,4-imino-D-ribitol (1R) -1-C- (4-hydroxy Pyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-1,2,4-trideoxy-D-erythro-pentitol (1S) -1-C- (4-hydroxypyrrolo [3 , 2-d] pyrimidin-7-yl) -1,4-imino-1,4,5-trideoxy-D-ribitol (1S) -1,4-dideoxy-1-C- (4-hydroxypyrrolo [3 , 2-d] pyrimidin-7-yl) -1,4-imino-5 -Methylthio-D-ribitol (1S) -1,4-dideoxy-1-C- (2,4-dihydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-D-ribitol (1R) -1-C- (2,4-dihydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-1,2,4-trideoxy-D-ertro-pentitol ( 1S) -1-C- (2,4-dihydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-1,4,5-trideoxy-D-ribitol (1S) -1 , 4-dideoxy-1-C- (2,4-dihydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-5-ethylthio-D-ribitol (1R) -1-C -(2-amino-4-hydroxypyrrolo [ , 2-d] pyrimidin-7-yl} -1,4-imino-1,2,4-trideoxy-D-erythro-pentitol (1S) -1-C- (2-amino-4-hydroxypyrrolo [ 3,2-d] pyrimidin-7-yl) -1,4-imino-1,4,5-trideoxy-D-ribitol (1S) -1-C- (2-amino-4-hydroxypyrrolo [3 2-d] pyrimidin-7-yl) -1,4-dideoxy-1,4-imino-5-methylthio-D-ribitol (1S) -1,4-dideoxy-1-C- (7-hydroxypyrazolo) [4,3-d] pyrimidin-3-yl) -1,4-imino-D-ribitol (1R) -1-C- (7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-Imino-1,2,4-trideoxy-D-e Sulo-pentitol (1S) -1-C- (7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-imino-1,4,5-trideoxy-D-ribitol ( 1S) -1,4-dideoxy-1-C- (7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-imino-5-ethylthio-D-ribitol (1S)- 1,4-dideoxy-1-C- (5,7-dihydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-imino-D-ribitol (1R) -1-C- ( 5,7-Dihydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-imino-1,2,4-trideoxy-D-erythro-pentitol (1S) -1-C- ( 5,7-Dihydroxypyrazolo [4,3-d] pyrimidine 3-yl) -1,4-imino-1,4,5-trideoxy-D-ribitol (1S) -1,4-dideoxy-1-C- (5,7-dihydroxypyrazolo [4,3-d ] Pyrimidin-3-yl) -1,4-imino-5-methylthio-D-ribitol (1S) -1-C- (5-amino-7-hydroxypyrazolo [4,3-d] pyrimidine-3- Yl) -1,4-dideoxy-1,4-imino-D-ribitol (1R) -1-C- (S-amino-7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl)- 1,4-Imino-1,2,4-trideoxy-D-erythro-pentitol (1S) -1-C- (5-amino-7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl ) -1,4-Imino-1,4,5-trideoxy-D-li Thor (1S) -1-C- (5-amino-7-hydroxypyrazolo [4,3-d] pyrimidin-3-yl) -1,4-dideoxy-1,4-imino-5-methylthio-D -Ribitol (1S) -1-C- (3-amino-2-carboxamide-4-pyrrolyl) -1,4-dideoxy-1,4-imino-D-ribitol (1S) -1,4-dideoxy-1 -C- (4-hydroxypyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-D-ribitol 5-phosphate (1S) -1-C- (2-amino-4-hydroxy Pyrrolo [3,2-d] pyrimidin-7-yl) -1,4-imino-D-ribitol 5-phosphate (1S) -1-C- (3-amino-2-carboxamido-4-pyrrolyl) -1 , 4-dideoxy-1,4-i Roh -D- ribitol.
In yet other embodiments, the sirtuin activator is an O-acetyl-ADP-ribose analog of formula 75 and 76, their tautomers and pharmaceutically acceptable salts.

式（７３）または式（７４）の化合物の生体利用度は、プロドラッグ形態に変換することによって増強することができる。このようなプロドラッグは、式（７３）または式（７４）の化合物と比較して親油性が改善している可能性があり、その結果、膜透過性が増強される可能性がある。プロドラッグの特に有用な形態の１つは、エステル誘導体である。その有用性は、これらのエステル基（または複数のエステル）の加水分解を触媒して式（７３）および式（７４）の化合物をその作用部位でまたはその付近で放出させる、１つまたは複数の遍在性細胞内リパーゼの作用に依存する。

The bioavailability of the compound of formula (73) or formula (74) can be enhanced by conversion to the prodrug form. Such prodrugs may have improved lipophilicity compared to the compound of formula (73) or formula (74), and as a result, membrane permeability may be enhanced. One particularly useful form of prodrug is an ester derivative. Its utility is to catalyze the hydrolysis of these ester groups (or esters) to release compounds of formula (73) and formula (74) at or near their site of action. Depends on the action of ubiquitous intracellular lipase.

  In one form of the prodrug, one or more of the hydroxy groups in the compound of formula (73) or formula (74) are O-acylated to produce, for example, 5-O-butyric acid or 2,3-di-O— Butyric acid derivatives can be made.

  Prodrug forms of 5-phosphate ester derivatives of compounds of formula (73) or formula (74) can also be made, which are capable of crossing cell membranes due to the anionic nature of 5-phosphate. Can be limited, and can be particularly useful. Conveniently, such 5-phosphate derivatives can be converted to uncharged bis (acyloxymethyl) ester derivatives. The utility of such prodrugs is to catalyze the hydrolysis of these ester groups (or ester groups) to convert one molecule of formaldehyde and a compound of formula (73) or formula (74) at its site of action or Depends on the action of one or more ubiquitous intracellular lipases released in the vicinity.

In an exemplary embodiment, 2′-AADPR or 3′-designed to increase stability from esterase action by using well-known substitutions of the ester oxygen atom that are concomitant with esterase attack. Analog of AADPR. The esterase labile oxygen atoms in 2′-AADPR and 3′-AADPR are thought to be the ester oxygen linking the acetate group and ribose and the ester oxygen between the two phosphorus atoms. As known in the art, substitution of either or either of these ester oxygen atoms with CF ₂ , NH, or S increases the resistance to esterase action, resulting in a substantially more stable 2 It is expected to yield a '-AADPR or 3'-AADPR analog.

Accordingly, in some embodiments, the present invention is directed to analogs 2'-O-acetyl-ADP-ribose or 3'-O-acetyl-ADP-ribose that exhibit increased stability in cells. . Preferred analogs include CF ₂ , NH, or S instead of acetyl ester oxygen or oxygen between two phosphorus atoms. The most preferred substituents are CF _2. The substitution of acetyl ester oxygen is particularly preferred. In other preferred embodiments, the ester oxygen and the oxygen between the two phosphorus atoms are both independently substituted with CF ₂ , NH, or S.

  In another embodiment, the present invention relates to sirtuin-inhibiting compounds. Exemplary sirtuin-inhibiting compounds include compounds that inhibit the activity of class III histone deacetylases, such as nicotinamide (NAM), suranim; NF023 (G protein antagonist); NF279 (purinergic receptor antagonist) ); Trolox (6-hydroxy-2,5,7,8, tetramethylchroman-2-carboxylic acid); (−)-epigallocatechin (3,5,7,3 ′, 4 ′, 5 ′) (-)-(-)-Epigallocatechin gallate (hydroxy moieties 5, 7, 3 ′, 4 ′, 5 ′ and gallate esters at 3); cyanidin chloride (3, 5, 7, 3 ′, chloride) 4′-pentahydroxyflavylium); delphinidin chloride (3,5,7,3 ′, 4 ′, 5′-hexahydroxyflavybyl chloride) Myricetin (cannabiscetin; 3,5,7,3 ′, 4 ′, 5′-hexahydroxyflavone); 3,7,3 ′, 4 ′, 5′-pentahydroxyflavone; and gosipetin (3,3) 5,7,8,3 ′, 4′-hexahydroxyflavone), etc., all of which are further described in Howitz et al., 2003, Nature, 425: 191. Other inhibitors such as sirtinol and splitomicin are described in Grozinger et al., 2001, J. MoI. Biol. Chem. 276: 38837, Dedalov et al., 2001, PNAS, 98: 15113 and Hirao et al., 2003, J. MoI. Biol. Chem, 278: 52773. Analogs and derivatives of these compounds can also be used.

  Sirtuin-inhibiting compounds may have a formula selected from the group of formulas 26-29, 31, and 66-68:

［式中、出現するたびに、独立して、
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ”は、アルキル、アルケニル、またはアルキニルを表す］；

[In the formula, each time it appears,
R ′ represents H, halogen, NO ₂ , SR, OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ″ represents alkyl, alkenyl, or alkynyl];

［式中、出現するたびに、独立して、
Ｌは、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＳＯ_３、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表し；
ａは、１〜７の整数を表し；
ｂは、１〜４の整数を表す］；

[In the formula, each time it appears,
L represents O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, SO ₃ , OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy;
a represents an integer of 1 to 7;
b represents an integer of 1 to 4];

［式中、出現するたびに、独立して、
Ｌは、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＳＯ_３、ＯＲ、ＮＲ_２、アルキル、アリール、またはカルボキシを表し；
ａは、１〜７の整数を表し；
ｂは、１〜４の整数を表す］；

[In the formula, each time it appears,
L represents O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, SO ₃ , OR, NR ₂ , alkyl, aryl, or carboxy;
a represents an integer of 1 to 7;
b represents an integer of 1 to 4];

［式中、出現するたびに、独立して、
Ｌは、Ｏ、ＮＲ、またはＳを表し；
Ｒは、Ｈ、アルキル、アリール、アラルキル、またはヘテロアラルキルを表し；
Ｒ’は、Ｈ、ハロゲン、ＮＯ_２、ＳＲ、ＳＯ_３、ＯＲ、ＮＲ_２、アルキル、アリール、アラルキル、またはカルボキシを表し；
ａは、１〜７の整数を表し；
ｂは、１〜４の整数を表す］；

[In the formula, each time it appears,
L represents O, NR, or S;
R represents H, alkyl, aryl, aralkyl, or heteroaralkyl;
R ′ represents H, halogen, NO ₂ , SR, SO ₃ , OR, NR ₂ , alkyl, aryl, aralkyl, or carboxy;
a represents an integer of 1 to 7;
b represents an integer of 1 to 4];

［式中、出現するたびに、独立して、
Ｒ_２、Ｒ_３、およびＲ_４は、Ｈ、ＯＨ、またはＯ−アルキルであり；
Ｒ’_３は、ＨまたはＮＯ_２であり；
Ａ−Ｂは、エテニレンまたはアミド基である］。

[In the formula, each time it appears,
R ₂ , R ₃ , and R ₄ are H, OH, or O-alkyl;
R ′ ₃ is H or NO ₂ ;
AB is an ethenylene or amide group].

In a further embodiment, an inhibitory compound is represented by formula 31 and the attendant definitions, wherein R ₃ is OH, AB is ethenylene, and R ′ ₃ is H.

In a further embodiment, an inhibitory compound is represented by formula 31 and the attendant definitions, wherein R ₂ and R ₄ are OH, AB is an amide group, and R ′ ₃ is H.

In a further embodiment, the inhibitory compound is represented by formula 31 and the attendant definitions, wherein R ₂ and R ₄ are OMe, AB is ethenylene, and R ′ ₃ is NO ₂ .

In a further embodiment, an inhibitory compound is represented by formula 31 and the attendant definitions, wherein R ₃ is OMe, AB is ethenylene, and R ′ ₃ is H.

  In another embodiment, the sirtuin inhibitor is a compound of formula 66:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、およびＲ_８は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carvone Acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions wherein R is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₁ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₂ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₃ is C (O) NH ₂ .

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₄ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions wherein R ₅ is NMe ₂ .

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₆ is methyl.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions wherein R ₇ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R ₈ is Cl.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions wherein R is OH and R ₁ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions wherein R is OH, R ₁ is OH and R ₂ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ .

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ and R ₄ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ , R ₄ is OH and R ₅ is NMe ₂ .

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ , R ₄ is OH, R ₅ is NMe ₂ and R ₆ is methyl.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ , R ₄ is OH, R ₅ is NMe ₂ , R ₆ is methyl, and R ₇ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 66 and the attendant definitions, wherein R is OH, R ₁ is OH, R ₂ is OH, and R ₃ is C (O) NH ₂ , R ₄ is OH, R ₅ is NMe ₂ , R ₆ is methyl, R ₇ is OH, and R ₈ is Cl.

  In another embodiment, the sirtuin inhibitor is a compound of formula 67:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、およびＲ_３は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルである］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , and R ₃ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl , Heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R is Cl.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R ₂ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R ₃ is Br.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R is Cl and R ₁ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R is Cl, R ₁ is H and R ₂ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 67 and the attendant definitions wherein R is Cl, R ₁ is H, R ₂ is H and R ₃ is Br.

  In another embodiment, the sirtuin inhibitor is a compound of formula 68:

［式中、出現するたびに、独立して、
Ｒ、Ｒ_１、Ｒ_２、Ｒ_６、およびＲ_７は、Ｈまたは置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｒ_３、Ｒ_４、およびＲ_５は、Ｈ、ヒドロキシ、アミノ、シアノ、ハロゲン化物、アルコキシ、エーテル、エステル、アミド、ケトン、カルボン酸、ニトロ、または置換もしくは非置換のアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、もしくはヘテロアラルキルであり；
Ｌは、Ｏ、ＮＲ、またはＳであり；
ｍは、０〜４の整数であり；
ｎおよびｏは、０〜６の整数である］。

[In the formula, each time it appears,
R, R ₁ , R ₂ , R ₆ , and R ₇ are H or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R ₃ , R ₄ , and R ₅ are H, hydroxy, amino, cyano, halide, alkoxy, ether, ester, amide, ketone, carboxylic acid, nitro, or substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl , Heterocyclylalkyl, heteroaryl, or heteroaralkyl;
L is O, NR, or S;
m is an integer from 0 to 4;
n and o are integers from 0 to 6].

  In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₁ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₂ is methyl.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein m is 0.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₄ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₅ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₆ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R ₇ is H.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein L is NH.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein n is 1.

  In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein o is 1.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H and R ₁ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H and R ₂ is methyl.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl and m is 0.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH and R ₅ is OH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH, R ₅ is OH and R ₆ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH, R ₅ is OH, R ₆ is H, and R ₇ is H.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH, R ₅ is OH, R ₆ is H, R ₇ is H, and L is NH.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH, R ₅ is OH, R ₆ is H, R ₇ is H, L is NH, and n is 1.

In a further embodiment, a sirtuin inhibitor is a compound of formula 68 and the attendant definitions wherein R is H, R ₁ is H, R ₂ is methyl, m is 0, and R ₄ Is OH, R ₅ is OH, R ₆ is H, R ₇ is H, L is NH, n is 1 and o is 1.

  The inhibitor compound may also be an oxidized form of the compound of FIG. The oxidized form of chlortetracycline can be an activator.

  In one embodiment, a sirtuin modulator for use in the present invention is represented by formula 77 or 78:

または薬学的に許容されるその塩である：
［式中、
Ｒ_３０１およびＲ_３０２は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアルケニル基、置換もしくは非置換のアルキニル基、置換もしくは非置換の非芳香族複素環基または置換もしくは非置換のアリール基であるか、あるいは、Ｒ_３０１およびＲ_３０２は、それらが結合している原子と一緒になって、置換もしくは非置換の非芳香族複素環基を形成し；
Ｒ_３０３、Ｒ_３０４、Ｒ_３０５およびＲ_３０６は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
Ｒ_３０７、Ｒ_３０８およびＲ_３１０は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から独立して選択され；
Ｒ_３０９は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_３１１、Ｒ_３１２、Ｒ_３１３およびＲ_３１４は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
ＲおよびＲ’は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基または置換もしくは非置換の非芳香族複素環基であり；
Ｘは、ＯまたはＳであり；
ｎは、１または２である］。

Or a pharmaceutically acceptable salt thereof:
[Where:
R ₃₀₁ and R ₃₀₂ independently represent —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aryl group, or R ₃₀₁ and R ₃₀₂ together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;
R ₃₀₃ , R ₃₀₄ , R ₃₀₅ and R ₃₀₆ represent -H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, -OR,- CN, —CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, — _{S (O) n R, -S} (O) n oR, -S (O) n NRR ', - NRR', - NRC (O) oR - a group consisting of ', NO ₂ and -NRC (O) R' Selected independently from;
R ₃₀₇ , R ₃₀₈ and R ₃₁₀ are —H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, Independently selected from the group consisting of -C (S) R, -C (S) OR and -C (O) SR;
R ₃₀₉ is -H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted non-aromatic heterocyclic group, halogen, -OR, -CN, -CO ₂ R, -OCOR , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S _{(O) n R, -S (} O) n NRR ', - NRR', - is selected from the group consisting of NRC (O) oR 'and -NRC (O) R';
R ₃₁₁ , R ₃₁₂ , R _313, and R ₃₁₄ are —H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —OSO ₃ H, —S (O) _n R , —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′, —NO ₂ and —NRC (O) R ′ ;
R and R ′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted non-aromatic heterocyclic group;
X is O or S;
n is 1 or 2.]

  A group of suitable compounds encompassed by Formulas 77 and 78 are those represented by Structural Formulas 79 and 80:

または薬学的に許容されるその塩である：
［式中、
Ｒ_２０１およびＲ_２０２は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアルケニル基、置換もしくは非置換のアルキニル基、置換もしくは非置換の非芳香族複素環基または置換もしくは非置換のアリール基であるか、あるいは、Ｒ_２０１およびＲ_２０２は、それらが結合している原子と一緒になって、置換もしくは非置換の非芳香族複素環基を形成し；
Ｒ_２０３、Ｒ_２０４、Ｒ_２０５およびＲ_２０６は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
Ｒ_２０７、Ｒ_２０８およびＲ_２１０は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から独立して選択され；
Ｒ_２０９は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_２１１、Ｒ_２１２、Ｒ_２１３およびＲ_２１４は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
ＲおよびＲ’は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基または置換もしくは非置換の非芳香族複素環基であり；
Ｘは、ＯまたはＳ、好ましくはＯであり；
ｎは、１または２である］。

Or a pharmaceutically acceptable salt thereof:
[Where:
R ₂₀₁ and R ₂₀₂ independently represent —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aryl group, or R ₂₀₁ and R ₂₀₂ together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;
R ₂₀₃ , R ₂₀₄ , R ₂₀₅ and R ₂₀₆ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, — CN, —CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, — _{S (O) n R, -S} (O) n oR, -S (O) n NRR ', - NRR', - NRC (O) oR - a group consisting of ', NO ₂ and -NRC (O) R' Selected independently from;
R ₂₀₇ , R ₂₀₈ and R ₂₁₀ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, Independently selected from the group consisting of -C (S) R, -C (S) OR and -C (O) SR;
R ₂₀₉ is, -H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, _{halogen, -OR, -CN, -CO 2 R} , -OCOR , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′ and —NRC (O) R ′ are selected;
R ₂₁₁ , R ₂₁₂ , R ₂₁₃ and R ₂₁₄ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —OSO ₃ H, —S (O) _n R , —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′, —NO ₂ and —NRC (O) R ′ ;
R and R ′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted non-aromatic heterocyclic group;
X is O or S, preferably O;
n is 1 or 2.]

In certain groups of compounds represented by formula 79 or 80, at least one of R ₂₀₇ , R ₂₀₈ and R ₂₁₀ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O ) R, -C (O) OR, -C (O) NHR, -C (S) R, -C (S) OR or -C (O) SR. Typically, at least one of R ₂₀₇ , R ₂₀₈ and R ₂₁₀ is —C (O) R or —C (O) OR. More typically, at least one of R ₂₀₇ , R ₂₀₈ and R ₂₁₀ is —C (O) R. In such compounds, R is preferably a substituted or unsubstituted alkyl, especially an unsubstituted alkyl group such as methyl or ethyl.

In another particular group of compounds represented by formula 79 or 80, R ₂₀₄ is halogen (eg, fluorine, bromine, chlorine) or hydrogen (including deuterium and / or tritium isotopes). Suitable compounds include those in which at least one of R ₂₀₇ , R ₂₀₈ and R ₂₁₀ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR. , -C (O) NHR, -C (S) R, -C (S) OR or -C (O) SR, wherein _R204 is halogen or hydrogen.

Typically, in the compounds represented by formulas 79 and 80, R _{203 to} R ₂₀₆ are —H. Further, R ₂₀₉ and R _{211 to} R ₂₁₄ are typically H. Specific compounds represented by formulas 79 and 80 are selected such that R _{203 to} R ₂₀₆ , R ₂₀₉ and R _{211 to} R ₂₁₄ are all —H. In these compounds, R ₂₀₄ , R ₂₀₇ , R ₂₀₈ and R ₂₁₀ have the values described above. In the exemplary embodiment, R _{201 to} R ₂₁₄ are each H.

R ₂₀₁ and R ₂₀₂ are typically —H or a substituted or unsubstituted alkyl group, more typically —H. Compounds having such values for R ₂₀₁ and R ₂₀₂ , R _{203 to} R ₂₀₆ , R ₂₀₉ and R _{211 to} R ₂₁₄ typically have the values described above.

In certain methods of the present invention, when X is _O, at least one of R 201 _{to R 214} is not -H.

In certain methods of the present _invention, when R 201 _{to R 205} and _R 207 _{to R 214} is -H _{each, R 206} is neither -NH ₂ Even -H.

  In one embodiment, the sirtuin modulator is represented by formula 81 or 82:

または薬学的に許容されるその塩である：
［式中、
Ｒ_１およびＲ_２は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアルケニル基、置換もしくは非置換のアルキニル基、置換もしくは非置換の非芳香族複素環基または置換もしくは非置換のアリール基であるか、あるいは、Ｒ_１およびＲ_２は、それらが結合している原子と一緒になって、置換もしくは非置換の非芳香族複素環基を形成し（ただし、Ｒ_１およびＲ_２の一方が−Ｈである場合は、他方は−Ｃ（Ｏ）ＯＣＨ_２ＣＨ_３で置換されたアルキル基ではない）；
Ｒ_３、Ｒ_４およびＲ_５は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
Ｒ_６は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_７、Ｒ_８およびＲ_１０は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から独立して選択され；
Ｒ_９は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_１１、Ｒ_１２、Ｒ_１３およびＲ_１４は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
ＲおよびＲ’は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基または置換もしくは非置換の非芳香族複素環基であり；
Ｘは、ＯまたはＳ、好ましくはＯであり；
ｎは、１または２であり、
ただし、Ｒ_１〜Ｒ_１４はそれぞれ−Ｈではなく、Ｒ_１０が−Ｃ（Ｏ）Ｃ_６Ｈ_５である場合は、Ｒ_１〜Ｒ_９およびＲ_１１〜Ｒ_１４はそれぞれ−Ｈではない。

Or a pharmaceutically acceptable salt thereof:
[Where:
R ₁ and R ₂ independently represent —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aryl group, or R ₁ and R ₂ together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group (provided that When _one of R ₁ and R ₂ is —H, the other is not an alkyl group substituted with —C (O) OCH ₂ CH ₃ );
R ₃ , R ₄ and R ₅ are —H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O _{) n R, -S (O)} n oR, -S (O) n NRR ', - NRR', - NRC (O) oR - independently from the group consisting of ', NO ₂ and -NRC (O) R'Selected;
R ₆ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO ₂ R, —OCOR. , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S _{(O) n oR, -S (} O) n NRR ', - NRC (O) oR', - NO 2 and -NRC (O) is selected from the group consisting of R ';
R ₇ , R ₈ and R ₁₀ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, Independently selected from the group consisting of -C (S) R, -C (S) OR and -C (O) SR;
R ₉ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO ₂ R, —OCOR. , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′ and —NRC (O) R ′ are selected;
R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —OSO ₃ H, —S (O) _n R , —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′, —NO ₂ and —NRC (O) R ′ ;
R and R ′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted non-aromatic heterocyclic group;
X is O or S, preferably O;
n is 1 or 2,
However, R _{1 to} R ₁₄ are not —H, and when R ₁₀ is —C (O) C ₆ H ₅ , R _{1 to} R ₉ and R _{11 to} R ₁₄ are not —H.

In certain embodiments, R ₁ is H.

In certain embodiments, R ₇ , R ₈ and R ₁₀ are independently —H, —C (O) R or —C (O) OR, typically —H or —C (O) R. , for example -H or -C (O) CH _3. In certain embodiments, R ₁ is —H and R ₇ , R _8, and R ₁₀ are independently —H, —C (O) R, or —C (O) OR.

In certain embodiments, R ₉ is H. In certain embodiments, when R ₁ is —H and / or R ₇ , R ₈ and R ₁₀ are independently —H, —C (O) R or —C (O) OR, R ₉ is —H.

In certain embodiments, R ₂ is H. In certain embodiments, R ₉ is —H, R ₁ is —H, and / or R ₇ , R _8, and R ₁₀ are independently —H, —C (O) R, or —C ( O) when it is OR, _{R 2} is -H. Typically, R ₉ is —H, R ₁ is —H, and R ₇ , R ₈ and R ₁₀ are independently —H, —C (O) R or —C (O) OR. In certain instances, R ₂ is —H.

In certain embodiments, R ₄ is —H or halogen, such as deuterium or fluorine.

  In one embodiment, the sirtuin modulator is represented by formula 83 or 84:

または薬学的に許容されるその塩である：
［式中、
Ｒ_１０１およびＲ_１０２は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアルケニル基、置換もしくは非置換のアルキニル基、置換もしくは非置換の非芳香族複素環基または置換もしくは非置換のアリール基であるか、あるいは、Ｒ_１０１およびＲ_１０２は、それらが結合している原子と一緒になって、置換もしくは非置換の非芳香族複素環基を形成し；
Ｒ_１０３、Ｒ_１０４、Ｒ_１０５およびＲ_１０６は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
Ｒ_１０７およびＲ_１０８は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から選択され、Ｒ_１０７およびＲ_１０８のうちの少なくとも１つが、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲまたは−Ｃ（Ｏ）ＳＲであり；
Ｒ_１０９は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_１１０は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から選択され（ただし、Ｒ_１１０は−Ｃ（Ｏ）Ｃ_６Ｈ_５ではない）；
Ｒ_１１１、Ｒ_１１２、Ｒ_１１３およびＲ_１１４は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
ＲおよびＲ’は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基または置換もしくは非置換の非芳香族複素環基であり；
Ｘは、ＯまたはＳであり；
ｎは、１または２である］。

Or a pharmaceutically acceptable salt thereof:
[Where:
R ₁₀₁ and R ₁₀₂ independently represent —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aryl group, or R ₁₀₁ and R ₁₀₂ together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;
R ₁₀₃ , R ₁₀₄ , R ₁₀₅ and R ₁₀₆ are —H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, — CN, —CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, — _{S (O) n R, -S} (O) n oR, -S (O) n NRR ', - NRR', - NRC (O) oR - a group consisting of ', NO ₂ and -NRC (O) R' Selected independently from;
R ₁₀₇ and R ₁₀₈ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, —C ( S) R, —C (S) OR and —C (O) SR, wherein at least one of R ₁₀₇ and R ₁₀₈ is a substituted or unsubstituted alkyl group, substituted or unsubstituted aryl A group, -C (O) R, -C (O) OR, -C (O) NHR, -C (S) R, -C (S) OR or -C (O) SR;
R ₁₀₉ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO ₂ R, —OCOR. , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′ and —NRC (O) R ′ are selected;
R ₁₁₀ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, —C (S) R. , -C (S) OR and -C (O) SR (wherein R ₁₁₀ is not -C (O) C ₆ H ₅ );
R ₁₁₁ , R ₁₁₂ , R ₁₁₃ and R ₁₁₄ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —OSO ₃ H, —S (O) _n R , —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′, —NO ₂ and —NRC (O) R ′ ;
R and R ′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted non-aromatic heterocyclic group;
X is O or S;
n is 1 or 2.]

  In another embodiment, the sirtuin modulator is represented by formula 85 or 86:

または薬学的に許容されるその塩である：
［式中、
Ｒ_１０１およびＲ_１０２は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアルケニル基、置換もしくは非置換のアルキニル基、置換もしくは非置換の非芳香族複素環基または置換もしくは非置換の置換アリール基であるか、あるいは、Ｒ_１０１およびＲ_１０２は、それらが結合している原子と一緒になって、置換もしくは非置換の非芳香族複素環基を形成し；
Ｒ_１０３、Ｒ_１０４、Ｒ_１０５およびＲ_１０６は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
Ｒ_１０７およびＲ_１０８は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から選択され、Ｒ_１０７およびＲ_１０８のうちの少なくとも１つが、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲまたは−Ｃ（Ｏ）ＳＲであり；
Ｒ_１０９は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＯＲ、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＳＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’および−ＮＲＣ（Ｏ）Ｒ’からなる群から選択され；
Ｒ_１１０は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）ＮＨＲ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲおよび−Ｃ（Ｏ）ＳＲからなる群から選択され（ただし、Ｒ_１１０は−Ｃ（Ｏ）Ｃ_６Ｈ_５ではない）；
Ｒ_１１１、Ｒ_１１２、Ｒ_１１３およびＲ_１１４は、−Ｈ、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換の非芳香族複素環基、ハロゲン、−ＣＮ、−ＣＯ_２Ｒ、−ＯＣＯＲ、−ＯＣＯ_２Ｒ、−Ｃ（Ｏ）ＮＲＲ’、−ＯＣ（Ｏ）ＮＲＲ’、−Ｃ（Ｏ）Ｒ、−ＣＯＲ、−ＯＳＯ_３Ｈ、−Ｓ（Ｏ）_ｎＲ、−Ｓ（Ｏ）_ｎＯＲ、−Ｓ（Ｏ）_ｎＮＲＲ’、−ＮＲＲ’、−ＮＲＣ（Ｏ）ＯＲ’、−ＮＯ_２および−ＮＲＣ（Ｏ）Ｒ’からなる群から独立して選択され；
ＲおよびＲ’は、独立して、−Ｈ、置換もしくは非置換のアルキル基、置換もしくは非置換のアリール基または置換もしくは非置換の非芳香族複素環基であり；
Ｘは、ＯまたはＳであり；
ｎは、１または２である］。

Or a pharmaceutically acceptable salt thereof:
[Where:
R ₁₀₁ and R ₁₀₂ independently represent —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted substituted aryl group, or R ₁₀₁ and R ₁₀₂ together with the atoms to which they are attached form a substituted or unsubstituted non-aromatic heterocyclic group;
R ₁₀₃ , R ₁₀₄ , R ₁₀₅ and R ₁₀₆ are —H, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, — CN, —CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, — _{S (O) n R, -S} (O) n oR, -S (O) n NRR ', - NRR', - NRC (O) oR - a group consisting of ', NO ₂ and -NRC (O) R' Selected independently from;
R ₁₀₇ and R ₁₀₈ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, —C ( S) R, —C (S) OR and —C (O) SR, wherein at least one of R ₁₀₇ and R ₁₀₈ is a substituted or unsubstituted alkyl group, substituted or unsubstituted aryl A group, -C (O) R, -C (O) OR, -C (O) NHR, -C (S) R, -C (S) OR or -C (O) SR;
R ₁₀₉ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —OR, —CN, —CO ₂ R, —OCOR. , —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —SR, —OSO ₃ H, —S (O) _n R, —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′ and —NRC (O) R ′ are selected;
R ₁₁₀ represents —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —C (O) R, —C (O) OR, —C (O) NHR, —C (S) R. , -C (S) OR and -C (O) SR (wherein R ₁₁₀ is not -C (O) C ₆ H ₅ );
R ₁₁₁ , R ₁₁₂ , R ₁₁₃ and R ₁₁₄ are —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted non-aromatic heterocyclic group, halogen, —CN, — CO ₂ R, —OCOR, —OCO ₂ R, —C (O) NRR ′, —OC (O) NRR ′, —C (O) R, —COR, —OSO ₃ H, —S (O) _n R , —S (O) _n OR, —S (O) _n NRR ′, —NRR ′, —NRC (O) OR ′, —NO ₂ and —NRC (O) R ′ ;
R and R ′ are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted non-aromatic heterocyclic group;
X is O or S;
n is 1 or 2.]

In compounds represented by Formulas 83-86, typically at least one of R ₁₀₇ and R ₁₀₈ is —C (O) R, such as —C (O) CH ₃ . In certain embodiments, R ₁₀₇ , R ₁₀₈ and R ₁₁₀ are independently —H or —C (O) R (eg, —C (O) CH ₃ ).

In certain embodiments, eg, R ₁₀₇ , R ₁₀₈ and R ₁₁₀ have the values described above, R ₁₀₁ and R ₁₀₂ are each H.

In certain embodiments, R ₁₀₉ is —H.

In certain embodiments, R _{103 to} R ₁₀₆ are each H.

In certain embodiments, R _{111 to} R ₁₁₄ are each H.

In certain _{embodiments, R 107,} R ₁₀₈ and _{R 110} have the above _{values, R 101} ~R _106, R ₁₀₉ and _R 111 _{to R 114} are each -H.

In certain embodiments, R ₁₀₄ is —H or halogen, typically deuterium or fluorine. The remaining values are as described above.

  For sirtuin modulators represented by Formula 87 or 88:

特定の実施形態におけるＲ_４は、−Ｈ（たとえば、重水素、トリチウム）またはハロゲン（たとえば、フッ素、臭素、塩素）である。

R ₄ in certain embodiments is —H (eg, deuterium, tritium) or halogen (eg, fluorine, bromine, chlorine).

In embodiments of the invention in which R _{1 to} R ₆ can each be —H, these are typically each —H. In embodiments of the invention in which one of R ₁ -R ₆ is not —H, typically the remaining values are each —H, and the non-H values are substituted or unsubstituted alkyl groups or halogens ( R ₁ and R ₂ are typically substituted or unsubstituted alkyl groups).

In certain embodiments, R _{11 to} R ₁₄ are each —H. When R _{11 to} R ₁₄ are each —H, R _{1 to} R ₆ typically have the values described above.

In certain embodiments, R ₉ is H. When R ₉ is —H, typically R _{11 to} R ₁₄ are each —H, and R _{1 to} R ₆ have the values described above.

  Specific examples of sirtuin modulators (eg, sirtuin activators and sirtuin inhibitors) are shown in FIGS.

  In certain embodiments, sirtuin modulators of the invention exclude compounds encompassed by Formulas 77-88.

  In certain embodiments, sirtuin modulators of the invention exclude one or more compounds disclosed in US Provisional Application No. 60 / 667,179, filed March 30, 2005.

  Also included are sirtuin modulator pharmaceutically acceptable addition salts and complexes as described herein. Where a compound may have one or more chiral centers, as specified, the compounds contemplated herein may be a single stereoisomer or a racemic mixture of stereoisomers.

  The compounds and salts thereof described herein include their corresponding hydrates (eg, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate) and Solvates are also included. Suitable solvents for preparing solvates and hydrates can generally be selected by those skilled in the art.

  The compounds and their salts can exist in amorphous or crystalline forms, including co-crystals and polymorphs.

Compounds that modulate sirtuins include derivatives of related secondary metabolites such as phosphate, sulfate, acyl (eg, acetyl, fatty acyl) and sugars (eg, glucuronate, glucose) (eg, hydroxyl groups) Derivatives), in particular sulfuric acid, acyl and sugar derivatives. In other words, the substituent —OH also includes —OSO ₃ ⁻ M ⁺ and —OPO ₄ ²⁻ M ²⁺ , where M ⁺ and M ²⁺ are suitable cation or cation pairs (preferably H ⁺ , NH ₄ ⁺ or alkali metal ions such as Na or K ⁺ ) and

などの糖である。これらの基は一般に、加水分解または代謝（たとえば酵素）切断によって−ＯＨへと切断可能である。

Such as sugar. These groups are generally cleavable to -OH by hydrolysis or metabolic (eg, enzymatic) cleavage.

  Where the sirtuin modulator has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are contemplated herein. Wherein the compound is a tautomer such as a keto-enol tautomer, for example

で存在し得る場合は、平衡状態として存在しているか、Ｒ’での適切な置換によって１つの型に固定されて存在しているかにかかわらず、それぞれの互変異性体が本明細書中で提供する方法に含まれることを企図する。ある任意の出現箇所における任意の置換基の意味は、他の任意の出現箇所におけるその意味、または任意の他の置換基の意味に依存しない。

Each tautomer is herein described regardless of whether it exists as an equilibrium or is fixed in one form by appropriate substitution at R ′. It is intended to be included in the provided method. The meaning of any substituent at any given occurrence does not depend on its meaning at any other occurrence, or the meaning of any other substituent.

  The methods provided herein also include prodrugs of the sirtuin modulators described herein. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug in vivo.

  In addition, analogs and derivatives of the sirtuin modulators described herein can also be used to activate members of the sirtuin protein family. For example, derivatives and analogs may make a compound more stable or improve its ability to traverse cell membranes or to undergo phagocytosis or phagocytosis. Exemplary derivatives include, for example, glycosylated derivatives described in US Pat. No. 6,361,815 for resveratrol. Other derivatives of resveratrol include cis- and trans-resveratrol and conjugates of them with sugars, such as to form glucosides (see, eg, US Pat. No. 6,414,037). . A glucoside polydatin called picaide or resveratrol 3-O-β-D-glucopyranoside can also be used. Sugars that the compounds can be conjugated include glucose, galactose, maltose, lactose and sucrose. Glycosylated stilbenes are described in Regev-Shoshini et al., Biochemical J. Biol. (Announced as BJ20033011 on April 16, 2003). Other derivatives of the compounds described herein are esters, amides and prodrugs. Resveratrol esters are described, for example, in US Pat. No. 6,572,882. Resveratrol and its derivatives are known in the art, for example, US Pat. Nos. 6,414,037; 6,361,815; 6,270,780; 6,572,882; and Brandolini et al. 2002, J. Am. Agric. Food. Chem. 50: 7407. Derivatives of hydroxyflavone are described, for example, in US Pat. No. 4,591,600. Resveratrol and other activating compounds can also be purchased from, for example, Sigma.

In certain embodiments, if a sirtuin modulator is naturally occurring, it may be at least partially isolated from its natural environment prior to use. For example, plant polyphenols can be isolated from plants and partially or significantly purified prior to use in the methods described herein. A modulator compound may be prepared synthetically, in which case it does not include other compounds with which it is naturally associated. In exemplary embodiments, the naturally-related compounds that the modulator composition comprises or is associated with are less than about 50%, 10%, 1%, 0.1%, 10 ⁻² %, or 10 ⁻³ %.

In certain embodiments, a sirtuin modulator of interest, such as a SIRT1 activator, has a substantial ability to inhibit PI3-kinase, inhibit aldolductase, and / or inhibit tyrosine protein kinase. For example, at concentrations effective to modulate the deacetylase activity of SIRT1 (eg, in vivo) and not at all. For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5-fold lower than the EC ₅₀ for inhibiting one or more of aldoreductase and / or tyrosine protein kinase. Even more preferably, it is selected to be at least 10 times, 100 times or even 1000 times lower. Assay methods for PI3-kinase activity, aldose reductase activity, and tyrosine kinase activity are well known in the art, and kits for performing such assays may be purchased. See, eg, US Patent Publication No. 2003/0158212 for the PI 3-kinase assay; US Patent Publication No. 2002/20143017 for the aldose reductase assay; tyrosine kinase assay kits are described in, for example, Promega (Madison, Wis .; World Wide Web Promega.com), Invitrogen (Carlsbad, Calif .; World Wide Web is invitrogen.com) or Molecular Devices (Sunnyvale, Calif .; World Wide Web is molecular devices.com).

In certain embodiments, a sirtuin modulator of interest has no substantial ability to transactivate EGFR tyrosine kinase activity, at a concentration effective to activate sirtuin deacetylase activity (eg, in vivo). No. For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5-fold lower, even more preferably at least 10 than the EC ₅₀ for transactivating EGFR tyrosine kinase activity. Select to be double, 100 times or even 1000 times lower. Assay methods for transactivation of EGFR tyrosine kinase activity are well known in the art, see, eg, Pai et al., Nat.
Med. 8: 289-93, 2002 and Vacca et al., Cancer Research, 60: 5310-5317, 2000.

In certain embodiments, the sirtuin modulator of interest has no substantial ability to cause coronary vasodilation, at a concentration effective to activate sirtuin deacetylase activity (eg, in vivo). For example, in a preferred embodiment, a sirtuin modulator can EC ₅₀ for for modulating the deacetylase activity of the sirtuin, at least 5 fold less than the EC ₅₀ for coronary vasodilation, even more preferably at least 10-fold, 100-fold or even Choose to be 1000 times lower. Vasodilation assay methods are well known in the art, see, eg, US Patent Publication No. 2004/0236153.

In certain embodiments, the sirtuin modulator of interest has no substantial antispasmodic activity at a concentration effective to modulate sirtuin deacetylase activity (eg, in vivo). For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5 times lower than the EC ₅₀ for antispasmodic activity (such as for gastrointestinal muscles), even more preferably Choose to be at least 10 times, 100 times, or even 1000 times lower. Methods for assaying antispasmodic activity are well known in the art, see, eg, US Patent Publication No. 2004/0248987.

In certain embodiments, the sirtuin modulator of interest has substantial ability to inhibit liver cytochrome P450 1B1 (CYP), at a concentration effective to modulate sirtuin deacetylase activity (eg, in vivo). No. For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5-fold lower, even more preferably at least 10-fold, 100-fold, than the EC ₅₀ for inhibiting P450 1B1. Alternatively, it is selected to be 1000 times lower. Assay methods for cytochrome P450 activity are well known in the art and kits for performing such assays may be purchased. See, for example, US Pat. Nos. 6,420,131 and 6,335,428 and Promega (Madison, Wis .; promega.com on the World Wide Web).

In certain embodiments, the sirtuin modulator of interest has a substantial ability to inhibit nuclear factor-κB (NF-κB) at a concentration effective to modulate sirtuin deacetylase activity (eg, in vivo). Not at all. For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5-fold lower, even more preferably at least 10-fold, EC ₅₀ for inhibiting NF-κB. Choose to be double or even 1000 times lower. Assay methods for NF-κB activity are well known in the art, and kits for performing such assays may be purchased (eg, Oxford Biomedical Research, from Ann Arbor, Mich.).

In certain embodiments, the sirtuin modulator of interest has an effective ability to inhibit histone deacetylase (HDAC) class I, HDAC class II, or HDACI and II to modulate sirtuin deacetylase activity. By concentration (eg in vivo), not at all. For example, in a preferred embodiment, the sirtuin modulator has an EC ₅₀ for modulating sirtuin deacetylase activity that is at least 5-fold lower, even more preferably at least 10-fold, than the EC ₅₀ for inhibiting HDACI and / or HDACII. , 100 times or even 1000 times lower. Methods for assaying HDACI and / or HDACII activity are well known in the art, and kits for performing such assays may be purchased. For example, BioVision, Inc. (Mountain View, California; biovision.com for the World Wide Web) and Thomas Scientific (Swedesboro, NJ; tomassci.com for the World Wide Web).

In certain embodiments, the sirtuin modulator of interest has a substantial ability to activate SIRT1 homologous species in lower eukaryotes, particularly yeast or human pathogens, at a concentration effective to modulate the deacetylase activity of human SIRT1. (Eg in vivo) and not at all. For example, in a preferred embodiment, the SIRT1 modulator has an EC ₅₀ for modulating human SIRT1 deacetylase activity that is at least 5 times lower than an EC ₅₀ for activating yeast Sir2 (Candida, Budding yeast, etc.), even more Preferably, it is selected to be at least 10 times, 100 times or even 1000 times lower.

In certain embodiments, the SIRT1 modulator compound has the ability to modulate one or more sirtuin protein homologues, such as one or more of human SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7. Can do. In other embodiments, the SIRT1 modulator has a substantial ability to modulate other sirtuin protein homologs, such as one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, of human SIRT1. At concentrations effective to modulate deacetylase activity (eg in vivo), none at all. For example, a SIRT1 modulator has an EC ₅₀ for modulating human SIRT1 deacetylase activity at least 5 times lower than an EC ₅₀ for modulating one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7. Even more preferably, it may be chosen to be at least 10 times, 100 times or even 1000 times lower.

In other embodiments, the sirtuin modulator of interest inhibits a protein kinase; phosphorylates a mitogen activated protein (MAP) kinase; inhibits the catalytic or transcriptional activity of a cyclo-oxygenase such as COX-2; Inhibits nitric oxide synthase (iNOS); or has a substantial ability to inhibit platelet adhesion to type I collagen, at concentrations effective to activate sirtuin deacetylase activity (eg, in vivo) at all I don't have it. For example, in a preferred embodiment, a sirtuin modulator has an EC ₅₀ for modulating the deacetylase activity of a sirtuin at least 5 times lower, even more preferably at least 10 than the EC ₅₀ for performing any of these activities. Select to be double, 100 times or even 1000 times lower. Assay methods for protein kinase activity, cyclo-oxygenase activity, nitric oxide synthase activity, and platelet adhesion activity are well known in the art, and kits for performing such assays may be purchased. For example, protein kinase assay kits include Promega (Madison, Wis .; World Wide Web is promega.com), Invitrogen (Carlsbad, Calif .; World Wide Web is invitrogen.com); Molecular Devices (Sunnyvale, Calif .; World wide web is molecular; .Com) or Assay Designs (Ann Arbor, Michigan; World Wide Web is assaydesigns.com); Amersham Biosciences (Piscataway, NJ; World Wide Web is amershammb) com., Amersham Biosciences (Piscataway, NJ; World Wide Web is amershambiosciences.com) and R & D Systems (Minneapolis World, Minnesota). See US Pat. Nos. 5,321,010; 6,849,290; and 6,774,107.

  One aspect of the invention provides visual function by administering to a patient a therapeutic dose of a sirtuin modulator selected from a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. A method of inhibiting, alleviating or otherwise treating a disorder.

  In certain aspects of the invention, the visual dysfunction is caused by damage to the optic nerve or central nervous system. In certain embodiments, optic nerve damage is caused by high intraocular pressure, such as that caused by glaucoma. In other specific embodiments, optic nerve damage is often caused by nerve swelling associated with an infection or immune (eg, autoimmune) response, such as in optic neuritis.

  Glaucoma refers to a group of disorders associated with visual field defects, optic disc depression, and optic nerve damage. These are commonly referred to as glaucomatous optic neuropathy. Most glaucoma are usually but not always associated with increased intraocular pressure. Exemplary glaucoma forms include glaucoma and full-thickness corneal transplantation, acute closed angle, chronic closed angle, chronic open angle, angle retraction, aphasic and pseudophakic, drug-induced, anterior chamber bleeding, eye Internal tumor, juvenile, lens-particle, low tension, malignant, angiogenesis, lens melting, lens formation, pigmentation, plateau iris, primary congenital, primary release angle, pseudodesquamation Secondary congenital, suspected adult, unilateral, uveitis, ocular hypertension, ocular hypertension, Posner-Schlossmann syndrome and ocular hypertension and primary open-angle glaucoma Including scleral enlargement procedures.

  Intraocular pressure may also be increased by various surgical procedures such as phacoemulsification (ie, cataract surgery) and implantation of structures such as artificial lenses. In addition, any surgery, especially spinal cord injury, or prolonged prone, can lead to increased intraocular pressure.

  Optic neuritis (ON) is inflammation of the optic nerve and causes acute blindness. This is closely related to multiple sclerosis (MS) because ON is initially present in 15-25% of MS patients and 50-75% of ON patients are diagnosed with MS. It is. ON is also associated with infections (eg, viral infections, meningitis, syphilis), inflammation (eg, from vaccines), infiltration and ischemia.

  Another condition that results in optic nerve damage is anterior ischemic optic neuropathy (AION). There are two types of AION. Arteritic AION is due to giant cell arteritis (vasculitis) and results in acute blindness. Non-arteritic AION includes all ischemic optic neuropathies other than those due to giant cell arteritis. Although the pathophysiology of AION is unclear, it is thought that both inflammatory and ischemic mechanisms are incorporated.

  Other damage of the optic nerve is typically associated with demyelination, inflammation, ischemia, toxins, or optic nerve trauma. Exemplary conditions in which the optic nerve is damaged include demyelinating optic neuropathy (optic neuritis, retrobulbar optic neuritis), optic nerve meningioma, adult optic neuritis, pediatric optic neuritis, anterior ischemic optic neuropathy Posterior ischemic optic neuropathy, pressurized optic neuropathy, papillary edema, pseudopapillary edema and toxic / nutritive optic neuropathy.

  Other neurological conditions associated with blindness but not directly related to optic nerve damage include amblyopia, Bell's palsy, chronic progressive extraocular palsy, multiple sclerosis, pseudobrain tumor and trigeminal neuralgia. included.

  In certain aspects of the invention, visual impairment is caused by retinal damage. In certain embodiments, retinal damage is caused by disturbances in blood flow to the eye (eg, arteriosclerosis, vasculitis). In certain embodiments, retinal damage is caused by macular rupture (eg, exudative or non-exudative macular degeneration).

  Exemplary retinal diseases include exudative age-related macular degeneration, non-exudative age-related macular degeneration, retinal electrical prosthesis and RPE transplant age-related macular degeneration, acute multifocal plate pigment epithelium , Acute retinal necrosis, vest disease, branch retinal artery occlusion, branch retinal vein occlusion, cancer-related and related autoimmune retinopathy, central retinal artery occlusion, central retinal vein occlusion, central serous network Choroidopathy, Eales disease, macular membrane, lattice degeneration, giant aneurysm, diabetic macular edema, Irvine-gas macular edema, macular hole, subretinal neovascularization, diffuse unilateral subacute neuroretinitis, non-pseudo Lens encapsulated macular edema, putative ocular histoplasma syndrome, exudative retinal detachment, post-operative retinal detachment, proliferative retinal detachment, hiatogenic retinal detachment, traction retinal detachment, retinitis pigmentosa, CMV retinitis, retinoblast Tumor, retinopathy of prematurity, birdshot Includes retinopathy, background diabetic retinopathy, proliferative diabetic retinopathy, abnormal hemoglobin retinopathy, Purcell retinopathy, Valsalva retinopathy, juvenile retinal segregation, senile retinoschisis, Telson syndrome and white spot syndrome It is.

  Other exemplary diseases include ocular bacterial infections (eg, conjunctivitis, keratitis, tuberculosis, syphilis, gonorrhea), viral infections (eg, ocular herpes simplex virus, varicella-zoster virus, cytomegalovirus retinitis, human Immunodeficiency virus (HIV)), and HIV or other HIV-related and other immunodeficiency-related eye diseases include secondary progressive outer retinal necrosis. In addition, eye diseases include fungal infections (eg, Candida choroiditis, histoplasmosis), protozoal infections (eg, toxoplasmosis) and other diseases such as ocular toxocariasis and sarcoidosis.

  One aspect of the present invention relates to chemotherapeutic drugs (eg, neurotoxic drugs, intraocular pressures such as steroids) by administering a sirtuin modulator disclosed herein to a subject in need of such treatment at a therapeutic dose. Is a method of inhibiting, reducing or treating visual dysfunction in a subject who has been treated with a drug that increases

  Another aspect of the invention is performed in a prone position, such as eye surgery or spinal surgery, by administering to a subject in need of such treatment a therapeutic dose of a sirtuin modulator as disclosed herein. A method of inhibiting, reducing or treating visual dysfunction in a subject undergoing surgery, including Ocular surgery includes cataracts, iridotomy and lens replacement.

  Another aspect of the present invention relates to aging, including cataracts, dry eye, retinal damage, etc., by administering a therapeutic dose of a sirtuin modulator disclosed herein to a subject in need of such treatment. Treatment of eye diseases, including inhibition and prophylactic treatment.

  The formation of cataracts can occur in the eye lens, including decreased levels of the antioxidants ascorbic acid and glutathione, increased lipids, oxidized amino acids and proteins, increased sodium and calcium, loss of amino acids and decreased lens metabolism. Related to some biochemical changes. The lens lacking blood vessels is suspended in the extracellular fluid in the front of the eye. Nutrients such as ascorbic acid, glutathione, vitamin E, selenium, bioflavonoids and carotenoids are required to maintain the transparency of the lens. Low selenium results in a free radical-induced increase in hydrogen peroxide, which is neutralized by glutathione peroxidase, a selenium-dependent antioxidant enzyme. Lens protective glutathione peroxidase also depends on the amino acids methionine, cysteine, glycine and glutamic acid.

  Cataracts may also occur due to the inability to properly metabolize galactose found in dairy products containing lactose, a disaccharide composed of the monosaccharide galactose and glucose. Cataracts can be prevented, delayed, slowed down and even reversed if detected early and metabolically corrected.

  Retinal damage results from reactions initiated by free radicals in glaucoma, diabetic retinopathy and age-related macular degeneration (AMD), among others. The eye is part of the central nervous system and has limited regeneration ability. The retina consists of a large number of nerve cells, contains polyunsaturated fatty acids (PFA) at the highest concentration, and is easily oxidized. Free radicals are generated by the mitochondria in the rods and cones that generate the UV light that enters the eye and the energy necessary to convert the light into a visual action potential. Free radicals cause PFA peroxidation by hydroxyl or superoxide radicals, which in turn generate additional free radicals. Free radicals cause temporary or permanent damage to retinal tissue.

  Glaucoma is usually regarded as a disorder that causes an increase in intraocular pressure (IOP) that causes permanent damage to nerve fibers of the retina, but no increase in IOP occurs in 1/6 of all glaucoma cases. This disorder is now recognized as a disorder of reduced vascular perfusion and increased neurotoxic factors. Recent studies have associated elevated levels of glutamate, nitric oxide and peroxynitrate in the eye as the cause of retinal ganglion cell death. Neuroprotective agents may be a treatment for future glaucoma. For example, nitric oxide synthase inhibitors block the formation of peroxynitrite from nitric oxide and superoxide. In a recent study, retinal ganglion cell loss was reduced in animals treated with aminoguanidine, a nitric oxide synthase inhibitor. It was concluded that nitric oxide in the eye caused cytotoxicity in many tissues and neurotoxicity in the central nervous system.

  Diabetic retinopathy occurs when the underlying blood vessels develop microvascular abnormalities that mainly consist of microaneurysms and intraretinal hemorrhage. Oxidative metabolites are directly involved in the pathogenesis of diabetic retinopathy, and free radicals enhance the production of growth factors that result in increased proliferative activity. Nitric oxide produced by vascular endothelial cells can also cause relaxation of smooth muscle cells, resulting in vasodilation of vascular segments. Ischemia and retinal hypoxia occur after arterial basement membrane thickening, endothelial proliferation and pericyte loss. Insufficient oxygenation causes capillary occlusion or non-perfusion, arteriole-venule shunt, slow blood flow, and loss of RBC's ability to release oxygen. Lipid peroxidation of retinal tissue also occurs as a result of free radical damage.

  The macula is responsible for our sharp central vision and consists of photosensory cells (cones), while the underlying retinal pigment epithelium (RPE) and choroid nourish and assist in the removal of waste products. RPE gives the cone a vitamin A substrate for a light sensitive pigment and digests the outer tip that fell from the cone. RPE is exposed to high levels of UV radiation and secretes factors that inhibit angiogenesis. The choroid contains a dense vascular network that provides nutrients and removes waste products.

  In AMD, the tip of the fallen cone becomes indigestible by RPE, and the cells collect a large amount of undigested material, enlarge and die. A collection of undigested waste, called drusen, is formed under the RPE. Phototoxic damage also causes the accumulation of lipofuscin in RPE cells. Intracellular lipofuscin and drusen accumulation in Bruch's membrane interferes with oxygen and nutrient transport to retinal tissue, ultimately leading to RPE and photoreceptor dysfunction. In exudative AMD, blood vessels grow from the choriocapillaries via defects in the Bruch's membrane, grow under the RPE, and can exfoliate or bleed off the choroid.

  Macular pigments, one of the protective factors that prevent sunlight from damaging the retina, are carotenoids derived from nutrients such as lutein, fatty yellow pigments and zeaxanthin that serve as delivery vehicles for other important nutrients. Formed by accumulation. Vitamin C and E, β-carotene and lutein, and antioxidants such as zinc, selenium and copper are all found in healthy macula. In addition to providing nutrients, these antioxidants protect against free radical damage that initiates macular degeneration.

  Another aspect of the present invention is the prevention of eye damage caused by stress, chemical injury or radiation by administering a therapeutic dose of a sirtuin modulator disclosed herein to a subject in need of such treatment. Or treatment. Radiation or electromagnetic eye damage may include that caused by CRT, or exposure to sunlight or UV.

  In a particular aspect of the invention, the invention excludes one or more treatments of the following conditions: cataract, retinopathy, retinitis pigmentosa, ocular neuritis and ocular capillary bed vascular disease. The present invention contemplates excluding any one or more of the above conditions, including any combination thereof.

  In particular aspects of the invention, the invention provides the following conditions: insulin resistance, diabetes, obesity (including metabolic syndrome), cell death and / or dysfunction, aging, blood coagulation disorders, cardiovascular disease, Eliminate the treatment of vision conditions associated with one or more of stress, cancer, inflammation, neurodegeneration, viral diseases as well as fungal diseases. The present invention contemplates eliminating vision conditions associated with any one or more of the above conditions, including any combination thereof.

  In certain embodiments of the present invention, the present invention eliminates the treatment or prevention of one or more visual conditions disclosed in US Provisional Application No. 60 / 667,179, filed March 30, 2006. .

  Another aspect of the invention is a pharmaceutical dosage form comprising a therapeutically effective amount of a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. In one embodiment, the dosage form is a tablet, capsule or oral solution. In another embodiment, the dose may be adapted for intravenous infusion, parenteral delivery or oral delivery. Preferably, the dosage form is suitable for ophthalmic administration, such as a solution, gel or cream or an implantable device.

  In another embodiment, the therapeutically effective amount of a sirtuin modulator is about 0.1 mg to about 500 mg per kg body weight, about 1 mg to about 400 mg per kg body weight, about 10 mg to about 100 mg per kg body weight, or even 1 kg body weight. The range is from about 10 mg to about 75 mg per unit.

Another aspect of the present invention provides:
a. Producing a preparation of any of the sirtuin modulators disclosed herein; and b. A method of conducting a pharmaceutical business that involves marketing the benefits of using a preparation or kit in the treatment of visual impairment to health care providers.

In certain embodiments, the present invention provides
a. Providing a distribution network for selling said preparation; and b. Provided is a method of conducting a pharmaceutical business that includes providing instructions to a patient or physician for using a preparation or kit for treating visual impairment.

In certain embodiments, the present invention also provides
a. Determining the appropriate formulation and dosage of a sirtuin modulator for treating visual dysfunction;
b. Performing therapeutic profiling of the formulation identified in step (a) for efficacy and toxicity in animals; and c. A method of conducting a pharmaceutical business is provided that includes providing a distribution network for selling the preparation identified as having an acceptable therapeutic profile in step (b).

  In a further embodiment, the method includes the additional step of providing a sales department to sell the preparation to the health care provider.

In yet another embodiment, the present invention provides:
a. Determining the appropriate formulation and dose of sirtuin modulator to be administered in the treatment of visual impairment; and b. Provide a method for conducting a pharmaceutical business, including authorizing a third party to further develop and sell the formulation.

D. Exemplary Formulations In another aspect, the present invention provides a pharmaceutical composition. Compositions for use in the present methods are biological, such as water, buffered saline (eg, phosphate buffered saline), polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.) or suitable mixtures thereof. It can be conveniently formulated for administration with a pharmaceutically acceptable vehicle. The optimum concentration of active ingredient (s) in the selected medium can be determined empirically according to procedures well known to medicinal chemists. As used herein, “biologically acceptable medium” includes solvents, dispersion media, and the like that may be appropriate for the desired route of administration of the pharmaceutical preparation. Except where any conventional vehicle or drug is incompatible with the visual dysfunction being treated, its use in the pharmaceutical preparations of the present invention is contemplated. Suitable vehicles and their formulations, including other proteins, are described, for example, in the book “Remington's Pharmaceutical Sciences” (Remington's Pharmaceutical Sciences. Mack Publishing Company, USA, 1985, East, Pennsylvania, USA, 198). These vehicles include “deposit formulations” for injection.

  Exemplary formulations of the present invention include β-cyclodextrin (eg, 5-15% (about 10%) combined with nicotinamide riboside, resveratrol in phosphate buffered saline (PBS). 10-20 mM or 14-16 mM resveratrol in β-cyclodextrin), and cellulose derivatives combined with resveratrol nanoparticles (eg, hydroxypropylmethylcellulose (HPMC)) and dioctyl sodium sulfosuccinate (DOSS) ( For example, 15-25% resveratrol nanoparticles, 1-1.5% HPMC, 0.01-0.10% DOSS). Each of these blended grains can optionally include additional active agents, buffers (eg, PBS), preservatives, and the like. Preferably such a formulation is isotonic.

  The pharmaceutical formulations of the present invention can also include veterinary compositions, eg, sirtuin modulator pharmaceutical preparations suitable for veterinary use, eg, for treating pets such as domestic animals or dogs.

  The introduction method may be provided by a rechargeable or biodegradable device. In recent years, a variety of sustained release polymeric devices, including protein biopharmaceuticals, have been developed and tested in vivo for the controlled delivery of drugs. A variety of biocompatible polymers, including both biodegradable and non-degradable polymers (including hydrogels) can be used to form implant devices for sustained release of drugs at specific target sites.

  The introduction method may further be provided by a non-biodegradable device. Specifically, a sirtuin modulator can be administered through an implant-type lens. Sirtuin modulators can be coated onto the lens, dispersed throughout the lens, or both.

  The preparations of the invention may be given intraocularly (eg intravitreally), orally, parenterally, topically, or rectally. These are of course given in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules by injection, inhalation, eye wash, ointment, suppository, controlled release patch, etc .; administration by infusion or inhalation; topical administration by lotion or ointment; and rectal administration by suppository. Oral and topical administration is preferred.

  As used herein, the phrase “parenteral administration” or “parenteral administration” means modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, Intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, intrathecal, intraspinal and intrasternal injection And injection.

  As used herein, the terms “systemic administration”, “systemic administration”, “peripheral administration” and “peripheral administration” enter the patient's system and are therefore subject to metabolism and other similar processes. Thus, it means that a compound, drug or other substance is administered other than directly to the central nervous system, an example being subcutaneous administration.

  These compounds can be used in any suitable form including oral, nasal by spray, rectal, vaginal, parenteral, intracapsular and topical by powder, ointments or drops including ophthalmic, buccal and sublingual. Depending on the route of administration, it may be administered to humans and other animals for treatment.

  Sirtuin modulators can be administered topically to the eye or eyelid using, for example, drops, ointments, creams, gels, suspensions, and the like. The drug (or drugs) may be formulated with excipients such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidine, neutral poly (meth) acrylate esters, and other thickening agents. The drug (or drugs) can be injected into the eye, for example, injection under the conjunctiva or Tenon's capsule, intravitreal injection, or retrobulbar injection. The drug (or drugs) can be a polymer, matrix, microcapsule, or polyvinyl acetate polyanhydride, eg, glycolic acid, lactic acid, a combination of glycolic acid and lactic acid, liposomes, silicon, alone or in combination with polyethylene glycol Sustained release drug delivery systems, such as other delivery systems formulated from The delivery device can be implanted in the eye, eg, implanted under the conjunctiva, implanted in the eye wall, or sutured to the sclera for long term drug delivery.

  Ophthalmic compositions include conventional pharmaceutically acceptable excipients and additives known to those skilled in the art, such as those of the type described below, in particular carriers, stabilizers, solubilizers, etc. Tonicity enhancing agents, buffer substances, preservatives, thickeners, complexing agents and other excipients are used. Examples of such additives and excipients can be found in US Pat. Nos. 5,891,913, 5,134,124 and 4,906,613.

  In one embodiment, a formulation of the invention is prepared, for example, by mixing the active agent with corresponding excipients and / or additives to form a corresponding ophthalmic composition. The active agent is preferably administered in the form of eye drops and the active agent is dissolved in a conventional manner, for example in a carrier. The solution is adjusted and / or buffered to the desired pH, if appropriate, and a stabilizer, solubilizer or tonicity enhancing agent is added where appropriate. Where appropriate, preservatives and / or other excipients are added to the ophthalmic formulations of the present invention.

  Carriers used in accordance with one embodiment of the present invention are typically suitable for topical or conventional administration, eg, water, aqueous solutions such as phosphate buffered saline, water and water such as C1-C7-alkanols. Mixtures with miscible solvents, from about 0.5% to about 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, and, for example, methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methyl Vegetable or mineral oils, including other non-toxic ophthalmic water-soluble polymers such as hydroxypropylcellulose and cellulose derivatives such as hydroxypropylcellulose; salts of polyacrylic acid or acrylates such as ethyl acrylate or Methacrylates; polyacrylamides; natural products such as gelatin, alginate, pectin, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia; starch derivatives such as starch acetate and hydroxypropyl starch; and polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, Other composites such as polyethylene oxide, preferably cross-linked polyacrylic acid such as neutral carbopol, or mixtures of polymers thereof. Preferred carriers include, for example, water, methylcellulose, alkali metal salts of carboxymethylcellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral carbopol, or mixtures thereof. The concentration of the carrier is, for example, in the range of about 1 to about 100,000 times the concentration of the active ingredient.

  In one embodiment, solubilizers used in the ophthalmic composition of the present invention include, for example, tyloxapol, fatty acid glycerol poly lower alkylene glycol ester, fatty acid poly lower alkylene glycol ester, polyethylene glycol, glycerol ether, vitamin E and vitamin E tocopherol. Vitamin E derivatives such as polyethylene glycol 1000 succinate (TPGS) or mixtures of these compounds are included. A specific example of the solubilizer is a reaction product of castor oil and ethylene oxide. The reaction product of castor oil and ethylene oxide has proven to be a particularly good solubilizer that is tolerated very well in the eye. The concentration used depends in particular on the concentration of the active ingredient. The amount added is typically an amount sufficient to dissolve the active ingredient. For example, the concentration range of the solubilizer is from about 0.1 to about 5000 times the concentration of the active ingredient according to one embodiment of the invention.

  According to one embodiment of the present invention, lower alkylene means linear or branched alkylene having 7 or less carbon atoms. Examples are methylene, ethylene, 1,3-propylene, 1,2-propylene, 1,5-pentylene, 2,5 hexylene, 1,7-heptylene and the like. Lower alkylene is preferably linear or branched alkylene having 4 or less carbon atoms.

  Examples of the buffer substance include acetic acid, ascorbic acid, boric acid, hydrogen carbonate / carbonic acid, citric acid, gluconic acid, lactic acid, phosphoric acid, propionic acid, and tris (tromethamine) perborate buffer. Tromethamine and borate buffer are preferred buffers. The amount of buffer substance added is, for example, that required to ensure and maintain a physiologically acceptable pH. The pH range is typically in the range of about 5 to about 9, preferably about 6 to about 8.2, more preferably about 6.8 to about 8.1.

The isotonicity enhancer is, for example, an ionic compound such as an alkali metal or alkaline earth metal halide such as CaCl ₂ , KBr, KCi, LiCI, NaI, NaBr or NaCl, or boric acid. Nonionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, dextrose and the like. For example, an osmolarity of about 50 mOsmol to about 1000 mOsmol, preferably about 100 mOsmol to about 400 mOsmol, more preferably about 200 mOsmol to about 400 mOsmol, and even more preferably about 280 mOsmol to about 350 mOsmol in a ready-to-use ophthalmic composition. Sufficient isotonicity enhancer is added to give a concentration.

  Examples of preservatives are quaternary ammonium salts such as cetrimide, benzalkonium chloride or benzoxonium chloride, for example alkylmercury salts of thiosalicylic acid such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, such as Parabens such as methylparaben or propylparaben, alcohols such as chlorobutanol, benzyl alcohol or phenylethanol, guanidine derivatives such as chlorohexidine or polyhexamethylene biguanide, or sorbic acid. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection from secondary contamination caused by bacteria and fungi during use.

  Also included in the ophthalmic formulations of the present invention are, for example, emulsifiers, wetting agents, or polyethylene glycols such as, for example, 200, 300, 400 and 600, or 1000, 1500, 4000, 6000 and 10,000. Non-toxic excipients such as fillers such as Carbowax can be included. Other excipients that may be used if desired are listed below, but they are not intended to limit the range of possible excipients in any way. This includes complexing agents such as disodium EDTA or EDTA; antioxidants such as ascorbic acid, acetylcysteine, cysteine, sodium bisulfite, butyl-hydroxyanisole, butyl-hydroxytoluene or α-tocopherol acetate; cyclodextrin, Stabilizers such as thiourea, thiosorbitol, dioctyl sodium sulfosuccinate or monothioglycerol, vitamin E and vitamin E derivatives such as vitamin E tocopherol polyethylene glycol 1000 succinate (TPGS); or, for example, sorbitol laurate ester, triethanol oleate Other excipients such as amines or palmitates are included. Preferred excipients are complexing agents such as disodium EDTA and stabilizers such as cyclodextrin. Other preferred excipients also include penetration enhancers such as benzalkonium chloride, bridipolymers such as PEG lauryl ether, and dodecyl maltoside. The amount and type of excipient added depends on the specific requirements and generally ranges from about 0.0001% to about 90% by weight.

  As noted above, according to one embodiment, a simple formulation of the present invention includes an aqueous solvent that can be sterile water suitable for administration to the eye in which the active agent is dissolved, suspended or emulsified. . However, preferred formulations of the present invention include the active agent dissolved in formulations referred to in the art as artificial tear formulations. Such artificial tear formulations are all intended to be incorporated herein by reference, US Pat. Nos. 5,895,654; 5,627,611; and 5,591, No. 426, and the patents and publications cited and referenced in these patents.

In one embodiment, the artificial tear formulation of the present invention promotes good wettability and diffusion. In addition, the artificial tear formulation preferably has good retention and stability in the eye and does not cause significant discomfort to the user. Exemplary artificial tear compositions of the present invention include the following:
(1) polyvinylpyrrolidone, preferably in an amount of about 0.1 to 5% by weight of the solution;
(2) An amount of benzalkonium chloride, preferably about 0.01% to about 0.10% by weight;
(3) hydroxypropyl methylcellulose, preferably in an amount of about 0.2% to about 1.5% by weight of the solution;
(4) Glycerin, preferably in an amount of about 0.2% to about 1.0% by weight of the solution, and the composition is an aqueous solution having isotonic properties.

  Those skilled in the art will recognize a wide variety of formulations and artificial tear formulations that can be utilized in connection with the present invention.

  Additional ophthalmic formulations can be found in US Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697, and 2005/004074, the contents of which are incorporated herein by reference. No. 6,583,124. If desired, the liquid ophthalmic formulation may have properties similar to or compatible with tear fluid, aqueous humor or vitreous humor.

  The formulations of the present invention can be administered in a manner generally known to those skilled in the art. In one embodiment, the formulation is administered using eye drops. Eye drops can be configured in any suitable manner.

  It may be desirable to use a measured dose eye drop of the type described in US Pat. No. 5,514,118 or an illumination eye drop device of the type described in US Pat. No. 5,584,823. A range of various other eye drops of the type described in US Pat. Nos. 5,059,188; 4,834,727; 4,629,456; and 4,515,295 are also utilized. be able to. The patents cited herein that disclose eye drops are incorporated herein by reference, as are various patents and publications cited and described in these patents.

  A composition that can be used for injection into the vitreous comprises a physiologically tolerable carrier, together with the relevant agents described herein dissolved or dispersed as an active ingredient. The term “pharmaceutically acceptable” as used herein with respect to the vitreous refers to a composition, carrier that represents a substance that can be administered into the vitreous of a mammal without producing an undesirable physiological effect. Refers to diluents and reagents. Injectable pharmacological composition preparations typically contain the active ingredients dissolved or dispersed therein. The preparation can also be emulsified. The active ingredient can be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, sorbitol, glycerol and the like and combinations thereof. In addition, if desired, the composition can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient. The composition can also include a thickening agent such as hyaluronic acid. The therapeutic compositions of the present invention can include pharmaceutically acceptable salts of the components. Pharmaceutically acceptable salts include, for example, acid addition salts formed using inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, tartaric acid, and mandelic acid. Salts formed using free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium or ferric hydroxide, and organics such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine It can originate from a base or the like. The HCl salt is particularly preferred.

  Depending on the application form, the active compound is released in an immediate or sustained release manner. If it is desirable to reduce the frequency of injections, sustained release ophthalmic formulations are preferred.

One possibility to achieve sustained release kinetics is by micronizing the active compound. A finely divided liquid suspension, generally formed either by milling or precipitation, can be dried prior to formulating the composition into a solid dosage form for administration. Typically, the micronized active compound is formulated as a free-flowing liquid (eg, not a gel, pasta or gum) or as a solid dosage form (eg, a tablet or capsule). The Such formulations are preferably safe for internal use (eg, ingestion, injection).
A powder containing a micronized drug can be made by spray drying an aqueous dispersion of micronized drug to form a dry powder consisting of agglomerated drug molecules. Alternatively, the aqueous dispersion of drug can include a dissolved diluent (eg, lactose or mannitol) that forms diluent particles when spray dried, each of which contains at least one embedded drug particle. Including.
The micronized drug dispersion can also be lyophilized to obtain a powder suitable for formulation into a solid dosage form. Such powders contain agglomerated finely divided drug particles. A lyophilized powder can also be obtained by lyophilizing an aqueous dispersion of the drug, the aqueous dispersion further comprising a dissolved diluent (eg, lactose or mannitol). In these cases, the lyophilized powder consists of diluent particles, each of which contains at least one embedded drug particle.
Other known methods of processing liquid dispersions that can be used in the present invention include granulation (high shear granulation, fluid bed granulation, rotary granulation (roto granulation). granulation), and melt granulation (including but not limited to). Different methods, such as spray coating and extrusion spheronization, can also be used. Any other conventional method for drying or processing a liquid dispersion may also be used in the present invention.
The particles are preferably reduced in size at temperatures that do not significantly degrade the drug substance. A processing temperature of less than about 30 ° C. to less than about 40 ° C. is usually preferred. If desired, the processing equipment can be cooled using conventional cooling equipment if desired. This method is conveniently performed under conditions of working pressure that is safe and effective for the ambient temperature and milling process.
Typically, a micronized drug dispersion comprises different phases of a drug substance as described above having a surface modifier adsorbed on its surface. Useful surface modifiers are believed to include those that physically adsorb to the surface of the drug substance but do not chemically bond to the drug. Suitable surface modifiers can preferably be selected from known inorganic and organic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants (eg, nonionic and ionic surfactants). Representative examples of excipients include gelatin, casein, lecithin (phosphatide), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol Emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, for example, macrogol ether such as cetomacrogol 1000, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, for example, commercially available Tween (Tween 80), polyethylene glycol , Polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, calcium carboxymethylcellulose, carboxymethyl Examples include sodium tilcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium magnesium silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these excipients are described in Handbook of Pharmaceutical Exceeds, the book of which is published by the American Pharmaceutical Association and the book, which is co-published by the Pharmaceutical Pharmac, which is co-published by the American Pharmaceutical Association and The Pharmaceutical ) In detail. The surface modifiers are commercially available and / or can be prepared by techniques known in the art.
“Micronized” refers to reducing the diameter to particles having an average diameter of less than about 30 microns, preferably less than about 20 microns, more preferably less than about 10 microns, and even more preferably less than about 5 microns. means. The average diameter (eg, volume diameter) of the particles is typically at least about 400 nm, preferably at least about 500 nm, more preferably at least about 700 nm (eg, at least about 800 nm), or Even at least about 1000 nm. Exemplary preferred formulations of the present invention have an average diameter of about 0.8 (or 1.0) to about 5.0 microns (eg, about 0.8 (or 1.0) to about 2 microns). Having particles. Micronized drug forms promote better and more uniform absorption than forms with larger average sizes and wider distribution of particle sizes. In certain embodiments, a large percentage of the particles have a diameter within a defined range. For example, 80% of the particles (e.g., DV10-DV90) are about 0.1 microns to about 20 microns (e.g., about 0.2 microns to about 10 microns), especially about 0.2 microns to about 5 microns. Or even a diameter of about 0.2 microns to about 2 microns.
Although the drugs according to the present invention are sold in micronized form, conventional micronizers (eg Micronizer's Micron-Master line available from The Jet Pulverizer Company (Moorstown, NJ)) may be used. It may be micronized using, or may be processed by a third-party micronizer (e.g., Micron Technologies (Exton, Pa.)).
Many drug manufacturing machines, drug mills and drug micronizers grind materials into very fine particles, thus reducing bulk chemicals to the size required for pharmaceutical formulations. The particles can also be micronized by a chemically controlled process or a temperature controlled process. The main advantage of micronization is increased solubility / bioavailability due to increased surface area. These finished chemicals are combined and further processed in a mixer. The mixed ingredients may then be mechanically encapsulated, compressed into tablets, or made into solutions. As used herein, the term “micronized” can be considered to refer to a process that creates a uniform particle size of the drug, the desired size can be less than 10 microns, and The processing can be mechanically controlled, chemically controlled, temperature controlled, pH controlled, or any other commonly known method known to those skilled in the art. It can be processing.
Optimization and control of the micronization process (especially with respect to particle size) has become even more important in pharmaceutical development. Air jet micronization is a well-proven technique that consistently produces particles in the 1-30 micron range. Micron Technologies and Jet Pharma are contract micronizers. The main advantage of an air jet micronizer is that the shrinkage resulting from the contact between the metal and the product is limited, and the shrinkage of the particles occurs by collision between the particles without generating heat. Other advantages include the lack of moving parts and the ease of cleaning the surface.
The basic principle of a jet mill is simple. The powder particles are supplied tangentially to a flat cylindrical mill chamber by a venturi system by pressurized air or nitrogen. Accumulated in a helical motion inside the particle mill chamber by a number of nozzles located around the chamber. The micronization effect is caused by a collision between the incoming particles and the particles already accumulated in the spiral path. Centrifugal forces leave larger particles around the mill chamber, while smaller particles escape by exhaust from the center of the chamber. The particle size distribution is controlled by adjusting a number of parameters, two of which are pressure and feed rate.
In general, there are two types of air jet micronizers or tangential fluid energy mills (pancakes and loops). The main difference between the two is in the overall distribution. Loop mills are an excellent choice for removal of distribution tails. A further advantage is that both types of mills do not generate heat. These mills are available in many sizes ranging from 1 ″, 4 ″, 6 ″, 8 ″, 12 ″, and 15 ″ to 20 ″ and 1-30 Provides flexibility in designing the desired particle size in the micron range.
US Pat. Nos. 6,645,466, 6,623,760, 6,555,135 (incorporated by reference herein) describe other micronization procedures.
As used herein, the particle size of a micronized drug dispersion can be determined using conventional particle size measurement techniques well known in the art (eg, sedimentation field flow fractionation, Mean particle diameter as measured by photon correlation spectroscopy, disk centrifugation and dynamic and static light scattering (eg, laser diffraction such as Mie scattering).
Another possibility to achieve sustained release kinetics is to embed or encapsulate the active compound in nanoparticles. The nanoparticles can be administered as a powder, a powder mixture with excipients or a suspension. A colloidal suspension of nanoparticles is preferred because it can be easily administered through a small diameter cannula.

  Nanoparticles are particles having a diameter from about 5 nm to about 1000 nm. As used hereinafter, the term “nanoparticle” refers to a particle formed by a polymer matrix in which an active compound is dispersed, also known as “nanosphere”, and surrounded by a polymer membrane. Also referred to as nanoparticles composed of a core containing active compounds, also known as “nanocapsules”. For administration into the vitreous of the eye, the nanoparticles preferably have a diameter of about 50 nm to about 500 nm, especially about 100 nm to about 200 nm.

  Nanoparticles can be prepared by in situ polymerization of dispersed monomers or by using preformed polymers. Since polymers prepared in situ often contain non-biodegradable and / or toxicologically serious byproducts, nanoparticles from preformed polymers are preferred. Nanoparticles from preformed polymers can be prepared by various techniques such as emulsion evaporation, solvent displacement, salting out and emulsion diffusion.

  Emulsion evaporation is a standard technique for preparing nanoparticles from preformed polymers. According to this technique, the polymer and active compound are dissolved in a water-immiscible organic solvent, which is emulsified in an aqueous solution. The coarse emulsion is then exposed to a high energy source such as an ultrasonic device, or the particle size is reduced through a high pressure homogenizer or microfluidizer. The organic solvent is then removed by heat and / or vacuum, resulting in the formation of nanoparticles having a diameter of about 100 nm to about 300 nm. Since methylene chloride and chloroform are insoluble in water, have good solubilizing properties, easily emulsify and are highly volatile, they are usually used as organic solvents. However, these solvents are criticized from the viewpoint of their physiological tolerance. Furthermore, the high shear forces required for particle size reduction can lead to polymer and / or active compound damage.

  The solvent replacement method is described in European Patent EP 0274961A1. In this method, the active compound and polymer are dissolved in an organic solvent that is miscible with water in all proportions. As a result of introducing this solution into an aqueous solution containing a stabilizer under gentle agitation, nanoparticles are spontaneously generated. Examples of suitable organic solvents and stabilizers are acetone or ethanol. Advantageously, chlorinated solvents and shear stress can be avoided. The mechanism of nanoparticle formation is explained by the interfacial turbulence that occurs during solvent displacement (Fessi et al., Int. J. Pharm., 55: R1-R1, 1989). Recently, a solvent replacement technique has been disclosed in International Publication No. WO 97 / 03657A1, where an organic solvent and a polymer containing an active compound are introduced into an aqueous solution without stirring.

  The salting-out technique is firstly International Publication No. WO88 / 08011A1. In this technique, a solution of a water-insoluble polymer and active compound in a water-miscible organic solvent such as acetone is mixed with a concentrated aqueous viscous solution or gel containing a colloidal stabilizer and a salting-out agent. A sufficient amount of water is added to the resulting oil-in-water emulsion to introduce diffusion into the aqueous phase and rapid diffusion of the organic solvent into the aqueous phase, resulting in interfacial turbulence and nanoparticle formation. The organic solvent and salting-out agent remaining in the nanoparticle suspension is then eliminated by repeated washing with water. Alternatively, the solvent and salting out agent can be eliminated by crossflow filtration.

  In the emulsifying diffusion method, the polymer is dissolved in a water-saturated partially water-soluble organic solvent. When this solution is mixed with an aqueous solution containing a stabilizer, an oil-in-water emulsion is formed. Addition of water to the emulsion causes the solvent to diffuse into the aqueous external phase and at the same time nanoparticle formation occurs. During grain formation, each emulsion droplet results in several nanoparticles. Since this phenomenon cannot be fully explained by the convective effect caused by interfacial turbulence, diffusion of organic solvent from the droplets of the coarse emulsion brings the active compound's molecular and polymer phases into the aqueous phase, and as a result It has been proposed that supersaturated local regions arise, from which the polymer agglomerates in the form of nanoparticles (Quintanar-Guerrero et al., Colloid. Polym. Sci., 275: 640-647, 1997). Advantageously, a pharmaceutically acceptable solvent such as propylene carbonate or ethyl acetate is used as the organic solvent.

  In the method described above, nanoparticles can be formed using various types of polymers. Nanoparticles made from biocompatible polymers are preferred for use in the methods of the present invention. The term “biocompatible” refers to a substance that, after being introduced into a biological environment, does not have a serious impact on the biological environment. From biocompatible polymers, polymers that are also biodegradable are particularly preferred. The term “biodegradable” refers to a substance that can be broken down enzymatically or chemically into smaller molecules and subsequently eliminated after introduction into a biological environment. Examples are poly (lactic acid) (PLA), poly (glycolic acid) (PGA), polycaprolactone (PCL), copolymer of lactic acid and glycolic acid (PLGA), copolymer of lactic acid and caprolactone, polyεcaprolactone, polyhydroxybutyric acid and Natural polymers such as polyesters from hydroxycarboxylic acids, such as poly (ortho) esters, polyurethanes, polyanhydrides, polyacetals, polydihydropyrans, polycyanoacrylates, alginates and other polysaccharides including dextran and cellulose, collagen As well as albumin.

  Further methods of preparing nanoparticles include dispersing a therapeutic or diagnostic agent in a liquid dispersion medium and reducing the particle size of the therapeutic or diagnostic agent to an effective average particle size of less than about 400 nm. Applying mechanical means in the presence of. The particle size can be reduced in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition.

  It is preferred, but not essential, that the particle size of the selected sirtuin modulator, as determined by sieving analysis, be less than about 10 mm. If the coarse particle size exceeds about 100 mm, it is preferable to reduce the particle size to less than 100 mm using a conventional milling method such as air jet or fragmentation mill.

  The sirtuin modulator can then be added to the liquid medium in which it is essentially insoluble to form a premix. The concentration of the therapeutic or diagnostic agent in the liquid medium can vary from about 0.1 to 60%, preferably 5 to 30% (w / w). It is preferred, but not essential, that the surface modifier is present in the premix. The concentration of the surface modifier can vary from about 0.1 to about 90 wt%, preferably 1 to 75 wt%, more preferably based on the combined total weight of the sirtuin modulator and the surface modifier. 20 to 60% by weight. The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.

  The premix can be used directly by subjecting it to mechanical means to reduce the average particle size in the dispersion to below 1000 nm. When using a ball mill for the attrition, it is preferable to use the premix directly. Alternatively, the therapeutic or diagnostic agent and, optionally, the surface modifier, using a suitable stirrer, such as a roller mill or a Cowles type mixer, a uniform dispersion is observed in which no large agglomerates are visible to the naked eye. Can be dispersed in a liquid medium. If a recirculating media mill is used for the attrition, it is preferred that the premix be subjected to such a pre-mill dispersion step. Alternatively, the therapeutic or diagnostic agent and, optionally, the surface modifier, using a suitable stirrer, such as a roller mill or Coles-type mixer, in a liquid medium until a uniform dispersion is observed where no large agglomerates are visible to the naked eye Can be dispersed. If a recirculating media mill is used for the attrition, it is preferred that the premix be subjected to such a pre-mill dispersion step.

  The mechanical means applied to reduce the particle size of the sirtuin modulator can conveniently take the form of a dispersion mill. Suitable dispersion mills include ball mills, attritor mills, vibration mills, and media mills such as sand mills and bead mills. The intended result is that a media mill is preferred due to the relatively short mill time required to produce the desired reduction in particle size. For media mills, the apparent viscosity of the premix is preferably from about 100 to about 1000 centipoise. For ball mills, the apparent viscosity of the premix is preferably from about 1 to about 100 centipoise. Such a range tends to provide an optimal balance between efficient particle fragmentation and media erosion.

  Attrition times can vary widely and depend primarily on the specific mechanical means and processing conditions selected. A ball mill may require a processing time of 5 days or more. Meanwhile, using a high shear media mill. The desired results were obtained with a processing time of less than 1 day (1 minute to several hours of residence time).

The particles must be reduced in size at temperatures where the sirtuin modulator is not significantly degraded. Usually, processing temperatures of about 30-40 ° C. are preferred. If desired, the processing equipment can be cooled using conventional cooling equipment. This method is conveniently performed under conditions of ambient pressure and processing pressures that are safe and effective for the mill process. For example, in ball mills, attritor mills and vibratory mills, ambient working pressures are typical. Temperature control is also contemplated, for example by covering the mill chamber with ice water or immersing it in ice water. Processing pressures from about 1 psi (0.07 kg / cm ² ) to about 50 psi (3.5 kg / cm ² ) are contemplated. About 10psi (0.7kg / ^cm 2) ~ about 20psi1.4kg / cm ²⁾ of processing pressure.

  If the surface modifier is not present in the premix, the amount described in the premix must be added to the dispersion after attrition. The dispersion can then be mixed, for example by shaking vigorously. Optionally, the dispersion can be subjected to an sonication step using, for example, an ultrasonic feeder. For example, the dispersion can be subjected to ultrasonic energy having a frequency of 20-80 kHz for about 1-120 seconds.

  After completion of the attrition, the grinding media is separated from the milled particulate product (dried or liquid dispersion) using conventional separation techniques such as by filtration, sieving through a mesh screen, and the like.

  In a particular method, a sirtuin modulator is prepared in the form of submicron particles by grinding the drug in the presence of a grinding media having an average particle size of less than about 75 microns.

Another method of forming nanoparticle dispersion is by microprecipitation. This is because a stable dispersion of a sirtuin modulator, in the presence of a surfactant that does not contain any toxic solvents or dissolved heavy metal impurities, modifies the surface, and enhances the stability of the colloids: A method of preparation by procedural steps:
1. Dissolving the therapeutic or diagnostic agent in a basic aqueous solution while stirring;
2. Adding the formulation # 1 to the surfactant (or surface modifier) solution with stirring to form a clear solution;
3. Neutralize Formulation # 2 above with a suitable acid solution while stirring.

This procedure can be followed by the following steps:
4). 4. removing salts formed by dialysis or diafiltration; Concentrating the dispersion by conventional means.

  By this microprecipitation process, a dispersion of a sirtuin activator having a Z-average particle diameter of less than 400 nm (measured by photon correlation spectroscopy) is stable when maintained at room temperature or refrigerated conditions. Arise. Such dispersions also demonstrate the limitation of particle size increase under autoclave decontamination conditions used in standard blood pool pharmaceuticals.

  In one embodiment, the above procedure is followed by step 4 comprising removing the formed salt by diafiltration or dialysis. This is done by standard dialysis equipment in the case of dialysis and by diafiltration using standard diafiltration equipment known in the art. Preferably, the final step is a step of concentrating to the desired concentration of the drug dispersion. This is done either by diafiltration or evaporation using standard equipment known in the art.

  In another embodiment of the microprecipitation process, a crystal growth regulator is used. Crystal growth regulators are defined as compounds that are incorporated into the crystal structure of a pharmaceutical microprecipitated crystal in a coprecipitation process, thereby preventing the growth or expansion of the microcrystal precipitate by a so-called Ostwald ripening process. Crystal growth regulators (or CGM) are chemicals that are at least 75% identical in chemical structure to pharmaceuticals. “Identical” means that the structures are identical with respect to the respective atoms and their linkages. Structural identity is characterized as 75% of the chemical structure based on molecular weight is identical to a therapeutic or diagnostic agent. The remaining 25% of the structure may be absent or replaced by another chemical structure in the CGM. The crystal growth regulator is dissolved together with the therapeutic agent or diagnostic agent in Step # 1 above.

  Suitable surface modifiers can preferably be selected from known organic and inorganic drug excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and ionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin (phosphatide), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacro Galle emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, for example, macrogol ether such as cetomacrogol 1000, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, for example, commercially available Tween (trademark), polyethylene glycol , Polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethyl Sodium cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceuticals, published in detail in The American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, published in 1988 by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. ing.

Specific surface modifiers include polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronic ™ F68 and F108 which are block copolymers of ethylene oxide and propylene oxide, propylene oxide and ethylene oxide to ethylenediamine available from BASF. Polyxamines such as Tetronic (TM) 908 (also known as Poloxamine (TM) 908), a tetrafunctional block copolymer derived by sequential addition, of dextran, lecithin, sodium sulfosuccinic acid available from American Cyanimid Aerosol, a dioctyl ester
Dialkyl esters of sodium sulfosuccinic acid, such as OT ™, Duponol ™ P, sodium lauryl sulfate available from DuPont, Triton ™ X-200, alkylaryl polyether sulfonate available from Rohn and Haas Tween ™ 20 and Tween ™ 80, polyoxyethylene sorbitan fatty acid esters available from ICI Specialty Chemicals; Carbowax ™ 3550 and 934, polyethylene glycols available from Union Carbide; Croda Inc. Crodesta ™ F-110, a mixture of sucrose stearic acid and sucrose distearic acid available from Croda, Inc. Includes available Crodesta (TM) SL-40, as well as _{C 18 H 37 CH 2 (CON} (CH 3) CH 2 (CHOH) 4 (CH 2 OH) 2 SA9OHCO from. Proven particularly useful Surface modifiers that may be used include Tetronic ™ 908, Tween ™, Pluronic ™ F-68, and polyvinylpyrrolidone Other useful surface modifiers include decanoyl-N— N-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside; heptanoyl-N-methylgluca N-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hex Non-yl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thio Glucopyranoside; and the like.

  Another useful surface modifier is tyloxapol (a nonionic liquid polymer of the alkylaryl polyether alcohol type; also known as superone or triton). Another surface modifier is surfactant 10- commercially available as p-isononylphenoxypoly (glycidol) or lOG ™, also known as Olin-1OG ™, from Olin Chemicals, Tamford, Conn. G.

  Two or more surface modifiers can be used in combination.

  Auxiliary surface modifiers can be used to confer resistance to particle aggregation during sterilization, including dioctyl sulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl trimethyl ammonium bromide and dimyristoyl phosphatidyl glycerol And charged phospholipids. Two or more auxiliary surface modifiers can be used in combination.

  A further description of nanoparticle preparation can be found, for example, in US Pat. No. 6,264,922, the contents of which are incorporated herein by reference.

  Liposomes are an additional drug delivery system that can be easily injected. Thus, in the inventive method, the active compound can also be administered into the vitreous of the eye in the form of a liposome delivery system. Liposomes are well known to those skilled in the art. Liposomes can be formed from a variety of phospholipids, such as cholesterol, phosphatidylcholine stearylamine, and the like. Liposomes that can be used in the methods of the invention include, but are not limited to, all types of liposomes including small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.

  Liposomes are used for various therapeutic purposes, specifically to deliver therapeutic agents to target cells. Advantageously, liposome-drug formulations offer the potential for improved drug delivery properties including, for example, controlled drug release. In order for liposomes to reach a target region, cell or site, it is often necessary to extend circulation time. This is particularly necessary when the target area, cell or site is not located near the site of administration. For example, when liposomes are administered systemically, it is desirable to coat the liposomes with a coating of a hydrophilic polymer chain, such as a hydrophilic drug, such as polyethylene glycol (PEG), in order to extend the blood circulation life of the liposome. Such surface-modified liposomes are commonly referred to as “long-term circulating” or “sterically stabilized” liposomes.

  One surface modification of liposomes is the attachment of PEG chains, typically having a molecular weight of about 1000 Daltons (Da) to about 5000 Da and up to about 5 mole percent (%) of the lipids that make up the liposomes ( For example, “See Stealth Liposomes, CRC Press, Classic, D. and Martin, F. Ed., Boca Raton, Florida, 1995 and references cited therein.” The pharmacokinetics of such liposomes are: Dose-dependent reduction of liposome uptake by the liver and spleen via the mononuclear phagocyte system (MPS) and modification of the surface that tends to be rapidly removed from the blood and accumulated in the liver and spleen Characterized by significant prolongation of blood circulation time compared to no liposomes .

The molecular weight of the PEG moiety can be, for example, 750-20,000 daltons, such as 1000-10,000 daltons, specifically 2000-5000 daltons. In one embodiment, the conjugate may comprise multiple types of PEG moieties (eg, PEG molecular weight 5K and PEG molecular weight 2K). The PEG moiety may further comprise a suitable functional group such as, for example, methoxy, N-hydroxyl succinimide (NHS), carbodiimide, to facilitate conjugation of PEG with lipids or targeting agents. Table 2 of Harasym et al., Advanced Drug Delivery Reviews, 32: 99-118, 1998 provides examples of suitable functional groups. Functionalized PEG moieties are described in, for example, Shearwater Polymer Inc. (Huntsville, Alab.) And Avanti Polar Lipid Inc. (Alabama, Alabama). In an exemplary embodiment, the PEG moiety is N- [methoxy (polyethylene glycol) -5K] (PEG _5K ). Feldman et al., 1997, Gene Therapy, 4 (3): 189-198; Lemieux et al., 2000, Gene Therapy, 7 (11): 986-91; Mogimi et al., 2000, Trends In Biotechnology, 18: 412-420; Torchilin, 1998, Journal of Microencapsulation, 15 (1): 1-19; and Claesson et al., 1996, Colloids & Surfaces A-Physical & Engineering-3, 112 (2). Place PEG moieties in other types of hydrophilic polymers, including, for example, poloxamers and poloxamines as described on pages 139 It may be e.

The PEG moiety can be conjugated with a suitable lipid to form a “pegylated lipid”. Preferably, the PEG moiety is covalently attached to the lipid. Suitable lipids include dioleoylphosphatidyl-ethanolamine (DOPE), cholesterol, and ceramide. Lipids containing polar ends that can be utilized for conjugation with PEG (eg, phosphatidylethanolamine including DOPE, DPPE and DSPE) are preferred to facilitate the synthesis of PEGylated lipids. For non-limiting examples of suitable functionalized lipids, see Harasym et al., Advanced Drug Delivery Reviews, 32: 99-118, 1998. In certain embodiments, the lipid is 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) or dimyristoyl phosphatidylethanolamine (DMPE). In certain embodiments, the PEGylated lipid is 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N- [methoxy (polyethylene glycol) -5K] (DSPE-PEG _5K ) or dimyristoyl phosphatidylethanolamine. -N- containing [methoxy (polyethylene _{glycol) -5K] (DSPE-PEG 5K} ).

The PEG moiety can be conjugated to the lipid by methods known in the art. For example, Woodle, 1998, Adv. Drug Delivery
Reviews, 32: 139-152 and references cited therein; Haselgruber et al., 1995, Bioconjug Chem, 6: 242-248; Shahinian et al., 1995, Biochim Biophys Acta, 1239: 157-167. Zalipsky et al., 1994, FEBS Lett. 353: 71-74; Zalipsky et al., 1997, Bioconjug Chem. 8 (2): 111-118; Zalipsky et al., 1995, Bioconjug Chem. 6: 705-708; Hansen et al., 1995, Biochim Biophys Acta. 1239 (2): 133-44; Allen et al., 1995, Biochim Biophys Acta, 1237 (2): 99-108; Zalipsky, 1995, Bioconjug Chem, 6 (2): 150-65; Zalipsky 1993, Bioconjug Chem, 4 (4): 296-9; and Zalipsky, 1995, “Stealth Liposomes.” (Edited by Lasic, D. et al.) CRC Press, Boca Raton, FL, pages 93-102. I want to be. Pegylated lipids are also available from Shearwater Polymer Inc., for example. (Huntsville, Alabama).

  For example, compounds other than lipids, such as peptides, hydrophobic anchors or polymers, carbohydrates, metals or other ions, allow compounds to be immobilized on the lipid complex and presented on the surface of the lipid complex As long as it is understood, it can be used for conjugation with PEG.

  While not wishing to be bound by theory, the charge shielding effect provided by PEG can enhance the circulating half-life of the conjugate. In addition, shielding may increase, for example, the resistance to degradation of nucleic acids by nucleases or other species (eg hyaluronic acid, poly (Asp)) present in vitro or in vivo (decrease sensitivity) and / or complex Interactions between individual composite particles or interactions with other species present in vitro or in vivo that can result in an increase in particle size or aggregation of the composite particles can be reduced or prevented. Thus, in a preferred embodiment, the complex includes a neutral surface. In another preferred embodiment, the complex is charge shielded.

  In certain embodiments, the complex is masked to increase the circulating half-life of the complex, or is masked to increase resistance to nucleic acid degradation, eg, degradation by nucleases.

  As used herein, the terms “shielded” and its synonymous terms, such as “shielded”, refer to the term “shielded moiety” where the complex and serum complement or in vitro or The ability to reduce non-specific interactions with other species present in serum in vivo. The shielding moiety may reduce the interaction or binding between the complex and these species by one or more mechanisms including, for example, non-specific steric or non-specific electronic interactions. . Examples of such interactions include non-specific electrostatic interactions, charge interactions, van der Waals interactions, steric hindrances and the like. In order for a moiety to act as a shielding moiety, it is not necessary to identify a mechanism or mechanisms that may reduce interaction, association, or binding with serum complement or other species. Whether a moiety can act as a shielding moiety can be determined by determining whether or to what extent the complex binds to a serum species.

  Other moieties that act as shielding moieties can be identified by their ability to block serum complement binding or the serum complement pathway, such as the C3A or C5 protein of the complement pathway. If a part is not recognized (eg, does not bind) by at least one of serum complement or a component of the serum complement pathway, that part is likely to act as a shielding part. In certain instances, if a moiety does not bind or interact with at least one of the C3A or C5 proteins, it is likely that the moiety is not bound by or does not interact with serum complement.

  Incorporating moieties that do not bind, associate or interact with serum complement or other serum species on the surface of the complexes described herein results in shielding of the complex. In other words, complex components (eg, lipids) that are recognized or interacted with by serum components are instead serum components (eg, serum proteins such as albumin, serum complement, hormones, vitamins, Such as cofactors), and thus cannot access serum components, and thereby does not bind, associate, or interact with these components, including serum complement. Thus, the complex can be described as “shielded”. A portion that can provide shielding can be referred to as a “shielding portion”.

  The shielding described above can also be measured by the level of complement opsonization as described herein. In certain embodiments, the shielding moiety reduces complement opsonization by about 30%, about 40%, about 50%, about 60%, about 65%, about 70%, about 75%, or about 80%. In other embodiments, the shielding moiety reduces complement opsonization by at least 40%, at least 50%, at least 55%, or at least 60%.

  Note that the “shielding portion” can be multifunctional. For example, the shielding portion may also function as a target factor, for example. A shielding portion may also be referred to as multifunctional with respect to the mechanism (or mechanisms) by which it shields the composite. Without wishing to be limited to the proposed mechanism or theory, examples of such multifunctional shielding moieties are pH sensitive endosomal membrane disruptive synthetic polymers, such as PPAA or PEAA. Certain poly (alkylacrylic acids) disrupt the endosomal membrane while leaving the outer cell surface membrane intact (Stayton et al., 2000, J. Control. Release, 65: 203-220; Murthy et al., 1999). J. Control. Release, 61: 137-143; International Publication No. WO99 / 34831), thus increasing the bioavailability of cells and their function as target factors. However, PPAA reduces the binding between serum complement and the complex in which it is taken up, thus functioning as a shielding moiety.

As will be appreciated by those skilled in the art, it is important that incorporating the shielding moiety does not exclude the ability of the complex to be delivered to the cell. Thus, in some embodiments, the complex incorporating the shielding moiety further comprises a target agent. For example, the complex can include a cell surface receptor ligand (eg, folic acid, RGD peptide, LHRH peptide, etc.) that can be conjugated to, for example, lipids or PEGylated lipids, and optionally can also incorporate PPAA. In certain embodiments, the lipid-target agent conjugate is DSPE-PEG _5K -RGD or DSPE-PEG _5K -folic acid.

  The amount or ratio of shielding moiety incorporated into the complex formulation can be limited so that delivery of the complex to the cell is not excluded. Thus, in certain examples, the composite is less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 7%, less than about 5%, less than about 4%, less than about 3% Or contain less than about 2% shielding. In certain embodiments, the amount of shielding portion is about 10%, about 8%, about 5% or about 2%. The composite may also include a plurality of shielding portions. In certain embodiments, the amount of shielding portion is at least 2%, at least 5% or at least 8% or at least 10%.

  In certain embodiments, the shielding moiety may be conjugated with another component of the complex, such as a lipid or PEGylated lipid. In certain instances, the shielding moiety can be conjugated with a colipid or PEGylated colipid. In other embodiments, the shielding moiety is not conjugated to any other component of the complex.

  In certain embodiments, the conjugate is shielded by incorporating a compound that includes a polyethylene glycol moiety (PEG) or by incorporating a synthetic polymer. In particular examples of the conjugates described herein, the shielded conjugate is, for example, a membrane disruptive synthetic polymer, a pH sensitive membrane disruptive synthetic polymer, a pH sensitive endosomal membrane disruptive synthetic polymer, or poly (alkylacrylic acid) One or more synthetic polymers may be included, including polymers. Specific examples of film disrupting polymers include poly (alkylacrylic acid) polymers such as poly (ethylacrylic acid) (PEAA) and poly (propylacrylic acid) (PPAA).

  It is also possible that the complex toxicity may be reduced by shielding the complex.

  The pegylated lipid and / or the target factor-pegylated lipid conjugate and / or the target factor-lipid conjugate are, for example, from about 0.01 to about 30 mol% of total lipid, more preferably from about 1 to about 30 mol of total lipid. % May be included. The pegylated lipid and / or the target factor-pegylated lipid conjugate and / or the target factor-lipid conjugate may be, for example, about 1 to about 20 mol%, about 1 to about 10 mol% of total lipid, about 2 to about 2 of total lipid. It may comprise about 5 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 10 mol%, about 15 mol% or about 20 mol%. The complex can comprise a conjugated target agent and a PEGylated lipid without a target agent-pegylated lipid conjugate. The complex can also include a target factor-pegylated lipid conjugate and a target factor-lipid conjugate. The complex may comprise multiple target factor-pegylated lipid conjugates or target factor-lipid conjugates. When multiple PEGylated lipids are present in the complex, the PEG moieties may be the same or different. In one non-limiting example, the target factor-pegylated lipid conjugate may include PEG with a molecular weight of 5 KDa, and the conjugated PEGylated lipid without target factor may include PEG with a molecular weight of 750 Da to 2 KDa. . The complex can also include a PEGylated lipid conjugated to a lipid and a target agent. In one embodiment, the complex comprises a target factor-pegylated lipid conjugate and a target factor-lipid conjugate. Alternatively, in other embodiments, the complex comprises a targeting agent that is not conjugated to a lipid or PEGylated lipid and comprises a PEGylated lipid.

  Another method of producing sirtuin modulator formulations, particularly solutions, such as resveratrol or its derivatives is by using cyclodextrins. Cyclodextrin means α-, β-, or γ-cyclodextrin. Cyclodextrins are described in detail in Pitha et al., US Pat. No. 4,727,064, which is incorporated herein by reference. Cyclodextrins are cyclic oligomers of glucose, and these compounds form inclusion complexes with any drug of the molecule that can fit into the cavity seeking the lipophilicity of the cyclodextrin molecule.

  By amorphous cyclodextrin is meant an amorphous mixture of cyclodextrins and the mixture is prepared from α-, β-, or γ-cyclodextrin. In general, amorphous cyclodextrins are prepared by non-selective addition, particularly alkylation of the desired cyclodextrin. The reaction is carried out so as to obtain a mixture comprising a plurality of components and thus preventing the crystallization of cyclodextrin. Various alkylated and hydroxyalkyl-cyclodextrins can be made, of course, depending on the starting cyclodextrin species and the additive used. Amorphous cyclodextris suitable for the composition according to the invention include, among others, hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin, carboxyamidomethyl-β-cyclodextrin, carboxymethyl -Β-cyclodextrin, hydroxypropyl-β-cyclodextrin as well as diethylamino-β-cyclodextrin. Substituted γ-cyclodextrins may also be suitable, including hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of γ-cyclodextrin.

  The cyclodextrin of the composition according to the invention can be α-, β-, or γ-cyclodextrin. α-cyclodextrin contains 6 glucopyranose units, β-cyclodextrin contains 7 glucopyranose units, and γ-cyclodextrin contains 8 glucopyranose units. The molecules are cleaved with a core opening of 4.7-5.3 angstroms, 6.0-6.5 angstroms, and 7.5-8.3 angstroms in alpha-, beta-, or gamma-cyclodextrin, respectively. It is thought to form a shaped cone. The composition according to the invention may comprise a mixture of two or more of α-, β-, or γ-cyclodextrin. Typically, however, the composition according to the invention comprises only one of α-, β-, or γ-cyclodextrin.

  Unmodified α-, β-, or γ-cyclodextrin is less preferred in the composition according to the invention because the unmodified form tends to crystallize and is relatively insoluble in aqueous solutions. Preferred by the composition according to the invention are chemically modified or substituted α-, β-, and γ-cyclodextrins. Chemical substitution of the glucopyranose unit of the cyclodextrin ring with 2, 3, and 6 hydroxyl groups results in an increase in the solubility of the cyclodextrin compound.

  The most preferred cyclodextrin in the composition according to the invention is an amorphous cyclodextrin compound. By amorphous cyclodextrin is meant an amorphous mixture of cyclodextrins and the mixture is prepared from α-, β-, or γ-cyclodextrin. In general, amorphous cyclodextrins are prepared by non-selective alkylation of the desired cyclodextrin species. Suitable alkylating agents for this purpose include, but are not limited to, propylene oxide, glycidol, iodoacetamide, chloroacetic acid, and 2-diethylaminoethyl chloride. The reaction is carried out so as to obtain a mixture comprising a plurality of components and thus preventing the crystallization of cyclodextrin. A variety of alkylated cyclodextrins can be made, of course, depending on the starting cyclodextrin species and the alkylating agent used. Amorphous cyclodextrins suitable for the composition according to the invention include inter alia hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β-cyclodextrin, carboxyamidomethyl-β-cyclodextrin, carboxymethyl- There are β-cyclodextrin, hydroxypropyl-β-cyclodextrin as well as diethylamino-β-cyclodextrin.

  An example of resveratrol dissolved in the presence of cyclodextrin is described by Marier et al., J. Mol. Pharmacol. Exp. Therap. 302: 369-373, 2002, where a 6 mg / mL solution of resveratrol was prepared using 0.9% saline containing 20% hydroxylpropyl-β-cyclodextrin did.

  As noted above, certain compositions for purposes of the present invention preferably comprise an aqueous preparation of a substituted amorphous cyclodextrin and one or more sirtuin modulators. The relative amounts of sirtuin modulator and cyclodextrin vary depending on the relative amounts of the respective sirtuin modulator and the effect of cyclodextrin on the compound. In general, the ratio of the weight of the sirtuin modulator compound to the weight of the cyclodextrin compound ranges from 1: 1 to 1: 100. It is possible for the sirtuin modulator to be recycled that the weight to weight ratio of the compound selected from the sirtuin modulator to the cyclodextrin is in the range of 1: 5 to 1:50, more preferably in the range of 1:10 to 1:20. It is believed to be most effective in increasing sex.

  Preferably, a cyclodextrin formulation of a sirtuin modulator (eg, resveratrol) has a sirtuin modulator at a concentration of at least 30 mM (more preferably at least 50 mM). Certain cyclodextrin formulations of the present invention comprise a sirtuin modulator of at least 100 mM (eg, at least 125 mM, 150 mM or even 200 mM).

  Importantly, when an aqueous solution containing a sirtuin modulator and a cyclodextrin is administered parenterally, particularly by the intravenous route, the cyclodextrin is substantially free of pyrogenic contaminants. Various forms of cyclodextrin, such as amorphous cyclodextrin, are available from Sigma-Aldrich, Inc. May be purchased from several vendors including (St. Louis, Montana, USA). A method for the production of hydroxypropyl-β-cyclodextrin is disclosed in Pitha et al., US Pat. No. 4,727,064, incorporated herein by reference.

  In order to produce a formulation according to the invention, a pre-weighed amount of cyclodextrin compound substantially free of pyrogens is placed in a suitable sterile container free of pyrogens. Methods for removing pyrogens from containers and closure components are well known to those skilled in the art and are fully described in the United States Pharmacopoeia 23 (United States Pharmacopial Convention, Rockville, MD, USA). In general, pyrogen removal is achieved by exposing the pyrogen-removing object to a temperature in excess of 400 ° C. for a time sufficient to completely incinerate all organic material. U. S. P. As measured in bacterial endotoxin units, the formulation does not contain more than 10 bacterial endotoxin units per gram of amorphous cyclodextrin. It is said that cyclodextrin is substantially free of pyrogens. S. P. 10 U. per gram using the method. S. P. Means containing less than bacterial endotoxin units. Preferably, the cyclodextrin is 0.1 to 5 U./mg under the conditions specified in US Pharmacopoeia 23. S. P. Contains bacterial endotoxin units.

  Sufficient sterile water for injection is added to the amorphous cyclodextrin substantially free of pyrogens until the desired concentration of cyclodextrin is in solution. To this solution, a pre-weighed amount of a compound selected from sirtuin modulators such as resveratrol is added with stirring and, if necessary, left still until dissolved.

  The solution is then filtered through a sterile 0.22 micron filter into a sterile holding container and then filled into a pyrogen-free sterile vial and the cap closed. For products stored for extended periods of time, sirtuin modulators and cyclodextrin solutions may be added pharmaceutically acceptable preservatives prior to filtration, filling and capping, or aseptically added after filtration.

  As mentioned above, the present invention provides improved water soluble formulations of sirtuin modulators and methods of preparing and using such formulations. The advantage of these water-soluble formulations is that the drug is entrapped within the cyclodextrin in dissolved form. It has been observed that these compositions provide very low toxicity forms of pharmacologically active agents that can be delivered by slow infusion or bolus injection forms or other parenteral or oral delivery routes. Has been.

  A further description of cyclodextrins for dissolving compounds can be found in US 2005/0026849, the contents of which are incorporated herein by reference.

  Regardless of the route of administration chosen, the compounds of the present invention, and / or the pharmaceutical compositions of the present invention, which can be used in an appropriate hydrated form, are described below or other forms known to those skilled in the art. It is blended into a pharmaceutically acceptable dosage form by a conventional method.

  The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is such that the amount of activity effective to produce the desired therapeutic response for a particular patient, composition, and route of administration without being toxic to the patient. It can be varied to obtain the ingredients.

  The dose level selected will depend on the activity of the particular compound of the invention used, the route of administration, the time of administration, the excretion rate of the particular compound used, the duration of the treatment, the other drugs used in combination with the particular composition used And / or depends on a variety of factors, including the substance, the age, sex, weight, condition, overall health and previous medical history of the patient being treated, and similar factors well known in the medical field.

  A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a dose of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and dose until the desired effect is achieved. Can be gradually increased.

  In general, a suitable daily dose of a compound of the invention is the lowest dose of the compound that is effective to produce a therapeutic effect. Such effective dose generally depends on the factors discussed above. Generally, the dose (eg, intravenous, subcutaneous, oral, intraocular) of a compound of the present invention in a patient will range from about 0.0001 to about 100 mg per kilogram body weight per day. In certain embodiments, the dose of the compound is greater than 100 mg per kilogram body weight per day. The dose may also be a specific dose (e.g. 18 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 75 mg / kg, 100 mg / kg, 150 mg / kg or more) can be selected to have a biological effect of resveratrol.

  If desired, an effective daily dose of the active compound may optionally be administered in sub-doses 2, 3, 4, 5, 6 or more administered separately at appropriate intervals throughout the day. Can be administered in unit dosage form. In certain embodiments, it is preferred that the sirtuin modulator is delivered in a single daily dose.

  The term “treatment” is intended to encompass prophylaxis, therapy and cure. Patients receiving this treatment are primates, especially humans, and other mammals such as horses, cows, pigs, sheep; and any animal in need thereof, including poultry and common pets.

  The compounds of the invention (ie sirtuin modulators) can be administered as such or mixed with a pharmaceutically acceptable and / or sterilized carrier and administered in conjunction with other therapeutic agents. You can also. Co-treatment includes the administration of the active compounds sequentially, simultaneously and separately so that the therapeutic effect of the first dose is not completely resolved during subsequent doses.

  Sirtuin modulators can be administered in conjunction with treatments to reduce intraocular pressure. The first treatment group includes blocking the production of the aqueous component. For example, topical β-adrenergic antagonists (timolol and betaxolol) reduce the production of aqueous humor. Topical timolol causes a decrease in IOP at 30 minutes with a peak effect of 1-2 hours. A reasonable regimen is 2 doses of 1 drop of Tioptic 0.5% every 30 minutes. Acetazolamide, a carbonic anhydrase inhibitor, also reduces production of aqueous humor and should be given in conjunction with topical β-antagonists. An initial dose of 500 mg is administered, followed by 250 mg every 6 hours. The medicament may be given orally, intramuscularly or intravenously. In addition, α2-agonists (eg, apraclonidine) act by reducing the production of aqueous humor. These effects are additive to locally administered beta blockers. They are approved for use to regulate pressure spikes after anterior chamber laser treatment, but have been reported to be effective in the treatment of acute angle-closure glaucoma. A reasonable regimen is 1 drop, 2 doses every 30 minutes.

  The second treatment group for reducing intraocular pressure includes a reduction in vitreous volume. Hyperosmotic agents can be used to treat acute attacks. These drugs draw water from the eyeball by making the blood osmotic. In many cases, a dose of 1 mL / kg oral glycerol is used in a cold 50% solution (mixed with lemon juice for better taste). Glycerol is converted to glucose in the liver. People with diabetes may need additional insulin if they become hyperglycemic after receiving glycerol. Oral isosorbide is a metabolically inactive alcohol that can also be used as an osmotic agent in patients with acute angle-closure glaucoma. The usual dose is p. o. At 100 g (220 cc of 45% solution). This inert alcohol should not be confused with isosorbide dinitrate, a nitrate-based heart disease drug used for angina and congestive heart failure. Intravenous mannitol at doses of 1.0-1.5 mg / kg is also effective and is well used by patients with nausea and vomiting. These hyperosmotic agents should be used with caution in all patients with a history of congestive heart failure.

  The third treatment group includes promoting aqueous component efflux from the eye. Miotic agents can extract the iris from the iris cornea angle and help relieve trabecular meshwork blockage by the peripheral iris. Pilocarpine 2% (blue eyes) to 4% (brown eyes) can be administered every 15 minutes for the first 1-2 hours. More frequent administration or higher doses can induce systemic cholinergic crisis. NSAIDs are sometimes used to reduce inflammation.

  Exemplary therapeutic agents for reducing intraocular pressure include ALPHAGAN® P (Allergan) (brimonidine tartrate ophthalmic solution), AZOPT® (Alcon) (brinzolamide ophthalmic suspension), BETAGAN (Allergan) (levobunolol hydrochloride ophthalmic solution, USP), BETIMOL (registered trademark) (Vistakon) (Timolol ophthalmic solution), BETOPTIC S (registered trademark) (Alcon) (betaxolol HCl), brimonidine tartrate (Bausch & Lomb) ), Carteolol hydrochloride (Bausch & Lomb), COSOPT (registered trademark) (Merck) (dorzolamide hydrochloride-timolol maleate ophthalmic solution), LUMIGAN (registered trademark) (Allergan) (bimatoprost eye) Solution), OPTIPRANOLOL (registered trademark) (Bausch & Lomb) (metipranolol ophthalmic solution), timolol GFS (Falcon) (timolol maleate gel forming solution), TIMOPTIC (registered trademark) (Merck) (for timolol maleate) Solution), TRAVATAN® (Alcon) (travoprost ophthalmic solution), TRUSOPT® (Merck) (dorzolamide hydrochloride ophthalmic solution) and XALATA® (Pharmacia & Upjohn) (latanoprost ophthalmic solution) included.

  Drugs currently marketed for glaucoma can be used in combination with sirtuin modulators. An example of a glaucoma drug is DARANIDE® tablets (Merck) (dichlorophenamide).

  Drugs currently marketed for optic neuritis can be used in combination with a sirtuin modulator. Examples of drugs for optic neuritis include DECADDRON® phosphate injection (Merck) (dexamethasone sodium phosphate), DEPO-MEDROL® (Pharmacia & Upjohn) (methylprednisolone acetate), HYDROCORTONE® tablets (Merck) (hydrocortisone), ORAPRED® (Biomarin) (sodium prednisolone phosphate sodium oral solution) and PEDIAPRED® (Celltech) (sodium prednisolone phosphate, USP).

  Drugs currently marketed for CMV retinopathy can be used in combination with a sirtuin modulator. Treatment of CMV retinopathy includes CYTOVENE® (ganciclovir capsule) VALCYTE® (Roche Laboratories) (Valganciclovir hydrochloride tablets).

  Drugs currently marketed for multiple sclerosis can be used in combination with sirtuin modulators. Examples of such drugs include DANTRIUM® (Procter & Gamble Pharmaceuticals) (dantrolene sodium), NOVANTRON® (Serono) (mitoxantrone), AVONEX® (Biogen Idec) (interferon β- 1a), BETASERON® (Berlex) (interferon β-1b), COPAXONE® (Teva Neuroscience) (galatiramel acetate injection) and REBIF® (Pfizer) (interferon β-1a) It is.

  In addition, macrolides and / or mycophenolic acids having multiple activities can be co-administered with a sirtuin modulator. Macrolide antibiotics include tacrolimus, cyclosporine, sirolimus, everolimus, ascomycin, erythromycin, azithromycin, clarithromycin, clindamycin, lincomycin, dirithromycin, josamycin, spiramycin, diacetyl-midecamycin, tylosin, roxithroth Includes mycin, ABT-773, tethromycin, leucomycin, and lincosamide.

  As used herein, the phrase “therapeutically effective amount” includes a compound of the invention that is effective in producing some degree of ear protection at a reasonable benefit / risk ratio applicable to any medical treatment. The amount of a compound, substance, or composition is meant.

  The phrase “pharmaceutically acceptable” is used herein within the scope of sound medical judgment and without excessive toxicity, irritation, allergic response, or other problems or complications. Used to refer to compounds, substances, compositions, and / or dosage forms corresponding to reasonable benefit / risk ratios suitable for use in contact with animal tissue.

  As used herein, the phrase “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, such as a liquid or solid filler, diluent, excipient, solvent or encapsulant, By composition or vehicle is meant. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) carboxy Cellulose and its analogs such as sodium methylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; )oleic Esters such as ethyl and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible materials used in drug formulations. In certain embodiments, the pharmaceutical preparation is non-pyrogenic, ie does not substantially increase the patient's body temperature.

  As noted above, certain embodiments of the composition may include a basic functional group such as amino or alkylamino, thus forming a pharmaceutically acceptable salt with a pharmaceutically acceptable acid. Have the ability. The term “pharmaceutically acceptable salts” in this regard refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or the purified compounds of the invention in free base form can be reacted separately with a suitable organic or inorganic acid, It can be prepared by isolating the salt formed thereby. Typical salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid Salt, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionic acid Salts, and lauryl sulfonates (see, for example, Berge et al., 1977, “Pharmaceutical Salts”, J Pharm. Sci., 66: 1-19).

  Pharmaceutically acceptable salts of the title compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, eg, derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and acetic acid, propionic acid, succinic acid, glycolic acid, Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfone Included are salts prepared from acids, organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isothionic acid.

  In other examples, the compounds of the present invention may contain one or more acidic functional groups and thus have the ability to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these cases refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. These salts are similarly prepared in situ during the final isolation and purification of the compound, or the purified compound in free acid form is converted to a pharmaceutically acceptable metal cation hydroxide, It can be prepared by reacting separately with a suitable base, such as a carbonate or bicarbonate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., Supra).

  Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, seasonings, flavorings, preservatives and antioxidants are also present in the composition. be able to.

  Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium metabisulfite, sodium sulfite; (2) ascorbyl palmitate, butyl Oil-soluble antioxidants such as hydroxylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol; and (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, Metal chelating agents such as phosphoric acid are included.

  Pharmacological doses or formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The dose may conveniently be present in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100%, this amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

  The methods of preparing these formulations or compositions include the step of bringing into association the compound of the present invention with a carrier and optionally one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

  Formulations of the present invention suitable for oral administration include capsules, cachets, pills, tablets, lozenges (with seasonings, usually sucrose and acacia or tragacanth), powders, granular forms, or aqueous or non-aqueous As a solution or suspension in liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastel tablet (using gelatin and glycerin, or an inert base such as sucrose and acacia) And / or may be present as a mouthwash, each containing a pre-determined amount of a compound of the invention as an active ingredient. The compounds of the present invention may also be administered as boluses, abrasives or pastes.

  For solid dosage forms of the invention (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the active ingredient may be one or more pharmaceutically acceptable carriers, such as sodium citrate or phosphorus. Mixed with dicalcium acid and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; Binding agents such as methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) wetting agents such as glycerol; (4) agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate Disintegrants such as: (5) Paraffin (6) Absorption enhancers such as quaternary ammonium compounds; (7) Wetting agents such as cetyl alcohol and glycerol monostearate; (8) Absorbents such as kaolin and bentonite clay; ) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersions. It can be prepared using an agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent.

Other solid dosage forms of the pharmaceutical composition of the present invention, such as tablets and dragees, capsules, pills and granules, optionally, can be scored or enteric coatings and other coatings well known in the pharmaceutical formulation arts, etc. , Coatings and shells. They also provide, for example, sustained or controlled release of the active ingredient therein using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres that provide the desired release profile. You may mix | blend as follows. These can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. . These compositions may also optionally include opacifiers, in an active delayed manner, in which only the active ingredient (or active ingredients), or preferentially, in certain parts of the gastrointestinal tract The composition may be released at the same time. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
A powder containing a micronized drug can be made by spray drying an aqueous dispersion of micronized drug to form a dry powder consisting of agglomerated drug molecules. Alternatively, the aqueous dispersion of drug can include a dissolved diluent (eg, lactose or mannitol) that forms diluent particles when spray dried, each of which contains at least one embedded drug particle. Including.
The micronized drug dispersion can also be lyophilized to obtain a powder suitable for formulation into a solid dosage form. Such powders contain agglomerated and micronized drug particles. A lyophilized powder can also be obtained by lyophilizing an aqueous dispersion of the drug, the aqueous dispersion further comprising a dissolved diluent (eg, lactose or mannitol). In these cases, the lyophilized powder consists of diluent particles, each of which includes at least one embedded drug particle.
Other known methods of processing liquid dispersions that can be used in the present invention include granulation (high shear granulation, fluidized bed granulation, rotary granulation, and melt granulation, including Including, but not limited to). Different methods, such as spray coating and extrusion spheronization, can also be used. Any other conventional method for drying or processing a liquid dispersion may also be used in the present invention.

  A rapidly disintegrating or dissolving dosage form is useful for rapid absorption of pharmaceutically active agents, particularly buccal and sublingual absorption. The immediate solvent form is beneficial for patients such as elderly and pediatric patients who have difficulty swallowing typical solid dosage forms such as caplets and tablets. In addition, the immediate solvent form, for example, a chewable dosage form in which the length of time that the active agent remains in the patient's mouth plays an important role in determining the amount of taste masking and the extent to which the patient dislikes the rough throat feeling of the active agent. The disadvantages associated with are avoided.

  To overcome such problems, manufacturers have developed several rapidly dissolving solid dose oral formulations. These can be found in Cima Labs, Fuiz Technologies Ltd. , Prophragm, R .; P. Scherer, Yamanouchi-Shackle, and McNeil-PPC, Inc. Available from manufacturers. These manufacturers all sell different types of fast dissolving solid oral dosage forms.

Cima Labs is OraSolv ™, an effervescent direct compression tablet with a mouth dissolution time of 5-30 seconds, and DuraSolv, a direct compression tablet with a taste-masked active agent and a mouth dissolution time of 15-45 seconds ( Trademark). Cima's US Pat. No. 5,607,697, “Test Making Microparticles for Oral Dosage,” the contents of which are incorporated herein by reference.
"Forms" describes a solid dosage form consisting of coated microparticles that disintegrate in the mouth. The particulate core of the oral dosage form of the Cima patent has a pharmaceutical and one or more sweetening compounds with a negative heat of solution, the sweetening compounds being a mixture of mannitol, sorbitol, artificial sweeteners and menthol, sugar and menthol It can be a mixture, or methyl salicylate. The particulate core is at least partially coated with a substance that delays dissolution in the mouth and masks the taste of the pharmaceutical. Thereafter, the microparticles are compressed to form a tablet. The Cima patent discloses that other excipients can also be added to the tablet formulation.

  International Publication No. WO 98/46215, “Rapidly Dissolving Robust Dosage Form”, the contents of which are incorporated herein by reference, is a hard material having an active ingredient and at least a matrix of non-direct compression fillers and lubricants. It is directed to compressed immediate-melt formulations. Non-direct compression fillers, as opposed to direct compression (DC grade) fillers, are typically not free-flowing and usually require further processing to form free-flowing granules.

  Cima also describes foaming dosage forms (US Pat. Nos. 5,503,846, 5,223,264, and 5,178,878, the contents of each of which are incorporated herein by reference. ) And fast dissolving dosage form tableting aids (US Pat. Nos. 5,401,513 and 5,219,574, both of which are incorporated herein by reference), and water soluble drugs US patents and international patents directed to a rapidly dissolving dosage form of WO 98/14179, "Taste-Masked Microcapsule Composition and Methods of Manufacturing", the contents of which are incorporated herein by reference I also have an application.

Fuiz Technologies, now part of BioVail, is a direct compression tablet containing a processed excipient called Shearform ™, Flash
Dose (trademark) is sold. Shearform ™ is a mixed candy cotton candy-like substance that has been converted to amorphous fibers. U.S. Patents describing this technology include U.S. Pat. No. 5,871,781, "Apprata for Making Rapid Dissolving," each of which is incorporated herein by reference.
"Dosage Units"; U.S. Patent No. 5,869,098; "Fast-Dissolving Combinable Units Under High-Speed / High-Pressure Conditions"; U.S. Patent No. 5,866,163, 5,851; And 5,622,719, all “Process and Apparatus for Making Rapid Dissolving Dosage Units and Product Thereform”; US Pat. No. 5,567,439, “Delivery of Control”; No. 587,172, “Process for Forming Qu It includes ckly Dispersing Comestible Unit and Product Therefrom ".

  Programm sells Flashtab ™, a fast dissolving tablet with a disintegrant such as carboxymethylcellulose, a swelling agent such as modified starch, and a taste masked active agent. The tablet disintegration time is less than 1 minute (US Pat. No. 5,464,632, the contents of which are incorporated herein by reference).

  R. P. Scherer sells Zydis ™, a lyophilized tablet with a mouth dissolution time of 2-5 seconds. Lyophilized tablets are expensive to manufacture and difficult to package because the tablets are sensitive to moisture and temperature. US Pat. No. 4,642,903 (RP Scherer Corp.), the contents of which are incorporated herein by reference, describes the process of dispersing gas throughout a lyophilized solution or suspension. Reference is made to the ready-mix formulation to be prepared. US Pat. No. 5,188,825 (RP Scherer Corp.), the contents of which are incorporated herein by reference, binds or conjugates a water soluble active agent to or together with an ion exchange resin. Refers to a lyophilized dosage form prepared by forming a substantially water-insoluble complex, which is then mixed with a suitable carrier and lyophilized. US Pat. No. 5,631,023 (RP Scherer Corp.), the contents of which are incorporated herein by reference, is made by adding xanthan gum to a suspension of gelatin and active agent. Refers to lyophilized drug dosage forms. Finally, US Pat. No. 5,827,541 (RP Scherer Corp.), the contents of which are incorporated herein by reference, describes a method for preparing solid drug dosage forms of hydrophobic materials. Disclosure. The method includes lyophilizing a dispersion comprising a hydrophobic active ingredient and a surfactant in a non-aqueous phase; and a carrier material in the aqueous phase.

  Yamanouchi-Shaklee sells Wowtab ™, a tablet with a combination of a low moldability sugar and a high mold sugar. US patents that address this technology include US Pat. No. 5,576,014, “Intrabuccally Dissolved Compressed Molding and Production Process Theof,” both of which are incorporated herein by reference, and US Pat. No. 5,446,464, “Intravenously Disintegrating Preparation and Production Thereof”.

  Other companies that possess rapid dissolution technology include Janssen Pharmaceuticals. The United States patent assigned to Janssen describes a fast dissolving tablet with two polypeptide (or gelatin) components and one filler, the two components having the same symbolic net charge, One component is more soluble in aqueous solution than the second component. US Pat. No. 5,807,576, “Rapidly Dissolving Table”; US Pat. No. 5,635,210, “Method of Making a Rapid Dissolving Table”, each of which is incorporated herein by reference. U.S. Pat. No. 5,595,761, “Particulate Support Matrix for Making a Rapid Dissolving Table”; U.S. Pat. No. 5,587,180, “Process for Mapping a Participate Supra U.S. Pat.No. 5,776,491, See Rapidly Dissolving Dosage Form. "

  Europe America, Inc. Holds a U.S. patent directed to a fast dissolving foam composition having a mixture of sodium bicarbonate, citric acid, and ethyl cellulose, U.S. Pat. No. 5, the contents of which are hereby incorporated by reference. , 639,475 and 5,709,886).

  L. A. B. Pharmaceutical Research holds U.S. patents directed to effervescent fast-dissolving formulations with pharmaceutically active ingredients and effervescent couples that include effervescent acids and effervescent bases, each of which is a US Pat. Nos. 5,807,578 and 5,807,577, which are incorporated herein by reference).

  Schering Corporation relates to buccal tablets having an active agent, excipient (which can be a surfactant) or at least one of sucrose, lactose or sorbitol and either magnesium stearate or sodium dodecyl sulfate Possessing technology (US Pat. Nos. 5,112,616 and 5,073,374, each of which is incorporated herein by reference).

  Laboratoire L. LaFon possesses technology directed to a conventional dosage form made by lyophilization of an oil-in-water emulsion, and at least one of the two phases contains a surfactant (the contents of which are described herein). U.S. Pat. No. 4,616,047, incorporated by reference). In this type of formulation, the active ingredient is maintained in a frozen suspension and is tableted without steps such as micronization or compression that can damage the active agent.

  Takeda Chemicals Inc. , Ltd., Ltd. Possesses technology directed to a method for making fast-dissolving tablets, in which the active agent and moistened soluble carbohydrates are compressed into tablets and then dried (incorporated herein by reference). US Pat. No. 5,501,861).

  Finally, Elan, US Pat. No. 6,316,029, “Rapidly Disintegrating Oral Dosage Form”, the contents of which are incorporated by reference, discloses an immediate solvent form containing a nanoparticulate active agent.

  In one example of the preparation of an instant dissolving tablet, granules for an instant dissolving tablet made by either spray drying or a pre-compression process are mixed with excipients and compressed into tablets using a conventional tablet making mechanism. Granules can be combined with various carriers, including combinations of low density, high moldability sugars, low moldability sugars, polyols, and then compressed directly into tablets that exhibit improved dissolution and disintegration profiles. .

  Tablets according to the present invention typically have a firmness of about 2 to about 6 strong-cobb units (scu). Tablets within this firmness range rapidly disintegrate or dissolve when chewed. In addition, tablets disintegrate rapidly in water. On average, a typical 1.1-1.5 gram tablet disintegrates in 1-3 minutes without stirring. This rapid disintegration facilitates active substance delivery.

  The granules used to make the tablet can be, for example, a low density alkaline earth metal salt or a mixture of carbohydrates. For example, a mixture of alkaline earth metal salts includes a combination of calcium carbonate and magnesium hydroxide. Similarly, according to the method of the present invention incorporating the use of a combination of A) spray dried ultralight calcium carbonate / maltodextrin, B) magnesium hydroxide and C) Sorbitol Instant, xylitol and mannitol, Soluble tablets can be prepared. These materials combine to produce a low density tablet that dissolves very easily and promotes rapid disintegration of the active ingredient. In addition, pre-compressed granules and spray-dried granules can be combined in the same tablet.

  For the preparation of fast dissolving tablets, sirtuin modulators useful in the present invention can be in the form of solids, particles, granules, crystals, oils or solutions and the like. Sirtuin modulators for use in the present invention can be spray-dried products or adsorbates pre-compressed to a harder granular form that reduces the taste of the drug. The pharmaceutically active ingredient for use in the present invention can be spray dried with a carrier that prevents the active ingredient from being easily extracted from the tablet when chewed.

  In addition to being added directly to the tablets of the present invention, the drug itself can be processed by a pre-compression process to increase the density before being incorporated into the formulation.

  The pre-compression process used in the present invention can be used to deliver such drug substances so that the release of poorly soluble drug substances is improved over conventional dosage forms. This allows lower dose levels to be used to deliver equivalent bioavailable levels of the drug, thus allowing the toxicity levels of both currently marketed drugs and new chemicals to be reduced. there is a possibility. A poorly soluble drug substance can be used in the form of nanoparticles, which are nanometer-sized particles.

  In addition to granules prepared from the active ingredient and low density alkaline earth metal salts and / or water soluble carbohydrates, fast dissolving tablets should be formulated using conventional carriers or excipients and well-established pharmaceutical techniques. Can do. Conventional carriers or excipients include, but are not limited to, diluents, binders, adhesives (ie, cellulose and acrylic derivatives), lubricants (ie, magnesium or calcium stearate, vegetable oil, polyethylene glycol, Various substances such as talc, sodium lauryl sulfate, polyoxyethylene monostearate), disintegrants, colorants, seasonings, preservatives, sweeteners and buffers and adsorbents are included.

  A further description of the preparation of rapidly dissolving tablets can be found, for example, in US Pat. No. 5,939,091, the contents of which are incorporated herein by reference.

  Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms can contain, for example, water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, Such as 3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, malt oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. It may contain inert diluents commonly used in the field.

  In addition to inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring, and preservatives.

  Suspensions, in addition to the active compound, for example suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, crystalline cellulose, aluminum meta-hydroxide, bentonite, agar, tragacanth, and mixtures thereof Can be included.

  Formulations of the pharmaceutical composition of the invention for rectal or vaginal administration may be provided as suppositories, which contain one or more compounds of the invention, eg cocoa butter, polyethylene glycol, suppositories May be prepared by mixing with one or more suitable non-irritating excipients or carriers comprising an agent wax or salicylate, and is solid at room temperature but liquid at body temperature, and therefore Dissolves in the rectal or vaginal body cavity to release the active ingredient.

  Formulations of the present invention suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing carriers known to be suitable in the art.

  Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

  Ointments, pastes, creams and gels are used in addition to the active compounds according to the invention for animal and vegetable oils, oils, waxes, paraffins, starches, tragacanth, cellulose analogues, polyethylene glycols, silicon, bentonite, silicic acid, talc and Excipients such as zinc oxide, or mixtures thereof may be included.

  Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The spray can further comprise conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches have the added advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms can be made by dissolving or dispersing the composition in the proper medium. Absorption enhancers can also be used to increase the flux of the composition across the skin. Such flow rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  Ophthalmic formulations, ophthalmic ointments, powders, solutions, drops and the like are also contemplated as being within the scope of the present invention. Examples of ophthalmic formulations are as described above.

  A pharmaceutical composition of the present invention suitable for parenteral administration is one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or for sterile injection just before use. May contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the intended recipient's blood, or suspensions or thickeners Contains one or more compounds of the invention in combination with a sterile powder.

  Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical composition of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, As well as injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Inhibition of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

  In some instances, it may be desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to sustain the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. In that case, the absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystal morphology. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

  Injectable depot forms are made by forming microencapsule matrices of the target compound in biodegradable polymers such as polylactic acid-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

  Implanted devices that include a sirtuin modulator are also included in the present invention. In one example, the device is a biodegradable implant device for treating an ophthalmic condition comprising an active agent dispersed within a biodegradable polymer matrix and having a diameter of at least about 75% of the active agent particles. Is less than about 10 μm. The biodegradable implant device is sized for implantation in the eyeball region. The eyeball area consists of anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, conjunctiva, subendothelial space, episcleral space, corneal space, supracorneal space, sclera, flat part, surgically induced avascular It can be any one or more of the region, the macula, and the retina. The biodegradable polymer can be, for example, a poly (lactic acid-co-glycolic acid) (PLGA) copolymer. The ratio of lactic acid monomer to glycolic acid monomer in the polymer can be about 50/50% by weight. Further, the PLGA copolymer can be about 20 to about 90% by weight of the biodegradable implant device. Alternatively, the PLGA copolymer can be about 40% by weight of the biodegradable implant device.

  In another example, the drug delivery device is formed, in whole or in part, by extruding the drug core and outer tube simultaneously. The outer tube can be permeable, semi-permeable, or impermeable to the drug. The drug core may include a polymer matrix that does not significantly affect the drug release rate. The outer tube, the polymer matrix of the drug core, or both can be biodegradable. The simultaneously extruded product can be divided into drug delivery devices. The device may be left uncoated so that its respective ends are open, or the device is coated, for example, with a layer that is permeable to drugs, semi-permeable to drugs, or biodegradable. obtain.

  In a further example, a surgically implanted intraocular device has a reservoir container having a diffusible polyvinyl alcohol or polyvinyl acetate wall and containing a sirtuin modulator in milligram quantities. As another example, milligram quantities of drug (or drugs) having dimensions of about 2 mm x 4 mm, such as polycaprolactone, poly (glycol) acid, poly (lactic acid), or polyanhydride Or a polymer matrix composed of lipids such as sebacic acid. Typically, such devices are implanted on the sclera or in the eye. This is usually done by giving the patient either a surface or local anesthetic and making a small (3-4 mm incision) behind the cornea. Thereafter, a matrix containing the drug (or drugs) is inserted through the incision and sutured to the sclera using 9-0 nylon.

  Additional descriptions of implantable devices are incorporated herein by reference, eg, US Publication Nos. 2004/0009222, 2004/0180075, 2005/0048099, 2005/0064010. And in 2005/0025810.

  When the compounds of the invention are administered as pharmaceuticals to humans and animals, they are pharmaceutically acceptable on their own or, for example, 0.1-99.5% (more preferably 0.5-90%) of the active ingredient. The pharmaceutical composition can be provided in combination with a carrier.

  The addition of the active compounds of the invention to the animal feed is preferably done by preparing a suitable feed premix containing an effective amount of the active compound and incorporating the premix into the complete feed.

  Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be mixed into the feed. Methods by which such feed premixes and complete feeds can be prepared and administered are described in reference books ("Applied Animal Nutrition", WH Freeman and CO., San Francisco, USA, 1969). Or “Livestock Feeds and Feeding”, O and B books, Corvallis, Oregon, USA, 1977, etc.).

  The use of the composition of the present invention is not limited to the treatment of visual impairment. The compositions of the present invention may be used, for example, for aging or stress related diseases or disorders, diabetes, obesity, neurodegenerative diseases and disorders, cardiovascular diseases, blood clot (blood coagulation) disorders, inflammation, cancer, and / or It can also be used to treat and / or inhibit various diseases and disorders, including flushing. Further exemplary uses of the compositions of the present invention are disclosed in US Publication No. 2005/0096256.

Example 1
Preparation of resveratrol-cyclodextrin formulation 100 milligrams of resveratrol was weighed into a 5 mL scintillation tube. 1.5 mL of absolute ethanol was added to the tube and shaken until resveratrol was completely dissolved. Five grams of pyrogen-free hydroxypropyl-β-cyclodextrin (Sigma-Aldrich, Inc., sold by St. Louis, Montana, USA) was weighed on an analytical balance and placed in a graduated cylinder. Water was added with shaking until the volume was 90 ml. The above ethanol solution of resveratrol was added to an aqueous solution containing hydroxypropyl-β-cyclodextrin while stirring. Water was added to the clear solution to make a total volume of 100 mL. The solution was sterile filtered through a 0.22 micron filter. The suspension was frozen below −40 ° C. and lyophilized. Prior to further use, the lyophilized cake was reconstituted with sterile water for injection.

(Example 2)
Resveratrol-cyclodextrin complex oral and suppository formulation 100 mg of resveratrol was weighed and placed in a sterile test tube. Resveratrol was added to 2-3 mL of purified absolute ethanol. 50 ml of a 9.8% solution of hydroxypropyl-β-cyclodextrin was prepared in a 150 mL sterile beaker and the solution was heated to 70-80 ° C. with stirring on a hot plate. Resveratrol in ethanol was slowly added to the beaker with stirring. The solution was sterile filtered through a 0.22 μm filter. The solution was frozen below −40 ° C. and lyophilized. The lyophilized cake is used as a powder in tablets, capsules and coated pill formulations, where the lyophilized powder is referred to as resveratrol-cyclodextrin complex.

(Example 3)
Tablet Preparation The tablet composition was combined from the following components: 6.25 parts resveratrol-cyclodextrin complex; 79.75 parts lactose; 30.00 parts potato starch; 3.00 parts gelatin; magnesium stearate 1 .00 parts; total 120.0 parts. Strongly milled resveratrol-cyclodextrin complex and 10 times its weight of lactose and mixed the milled mixture with the remaining amount of lactose and potato starch. . The resulting mixture was moistened with a 10% aqueous solution of gelatin to form a wet mass through a 1.5 mm mesh screen and the resulting granules were dried at 40 ° C. The dry granules were again passed through a 1 mm mesh screen, mixed with magnesium stearate and the composition was compressed into 120 mg tablets on a conventional tablet machine. Each tablet contains 0.125 mg resveratrol and is an oral unit dose composition with an effective therapeutic effect.

Example 4
Preparation of Coated Pills The pill core composition was combined from the following ingredients: 6.25 parts resveratrol-cyclodextrin complex; 26.25 parts lactose; 15.00 parts corn starch; 2.00 parts polyvinylpyrrolidone; stearin 0.50 parts of magnesium acid; total 50.0 parts Milling resveratrol-cyclodextrin complex and lactose strongly, mixing the milled mixture with corn starch and mixing the mixture with 15% aqueous solution of polyvinylpyrrolidone Moistened and forced through a 1 mm mesh screen to form a wet mass, and the resulting granules were dried at 40 ° C. and passed through the screen again. The dry granules are mixed with magnesium stearte and the resulting composition is compressed into a 50 mg pill core, which is then coated in a conventional manner with a thin shell consisting essentially of a mixture of sugar and talcum. And finally polished with beeswax. Each coated pill is an oral unit dose composition containing 0.125 mg resveratrol complexed with hydroxypropyl-cyclodextrin and having an effective therapeutic effect.

(Example 5)
Preparation of the Drop Solution The solution was combined from the following ingredients: 0.625 parts resveratrol-cyclodextrin complex; 0.3 parts sodium saccharin; 0.1 parts sorbic acid; 30.0 parts ethanol; 0 parts; distilled water q. s. ad 100.0 parts Resveratrol-cyclodextrin complex and seasoning were dissolved in ethanol, and sorbic acid and saccharin sodium were dissolved in distilled water. The two solutions were mixed uniformly with each other and the mixed solution was filtered until there was no suspension. 1 ml of filtrate contains 0.125 mg resveratrol and is an oral unit dose composition with effective therapeutic effect.

(Example 6)
Suppository Preparation The suppository composition was combined from the following ingredients: 6.25 parts resveratrol-cyclodextrin complex; 4.75 parts lactose; 1689.0 parts suppository base (eg cocoa butter); total 1700. 0 parts Resveratrol-cyclodextrin complex and lactose were mixed and the mixture was milled. Using an immersion homogenizer, the milled mixture was stirred uniformly into a suppository base that had been previously melted and cooled to 40 ° C. The resulting composition was cooled at 37 ° C. and 1700 mg of it was poured into a cooled suppository mold where it was allowed to cure. Each suppository contains 0.125 mg resveratrol and is a rectal unit dose composition with an effective therapeutic effect.

(Example 7)
Capsule Preparation The capsule composition was combined from the following ingredients: 6.25 parts resveratrol-cyclodextrin complex; 94.75 parts lactose, 200.00 parts microparticulate β- (1,3 / 16) glucan; Baker's yeast) R-α lipoic acid 100.00 parts; total 400.0 parts Resveratrol-cyclodextrin complex and 10 times its weight of lactose were strongly milled, and the milled mixture was used as the rest Mixed with an amount of lactose, particulate β-glucan and R-α lipoic acid. The mixed powder was milled again and the composition was filled into 400 mg capsules using a conventional capsule making machine. Each capsule contains 0.125 mg resveratrol and is an oral unit dose composition with an effective therapeutic effect.

(Example 8)
(Preparation of micronized drug and drug suspension)
16 grams of micronized resveratrol was produced by Micron Technologies (Exton, PA). The mill equipment used was a Fluid Energy Jet Mill (Subclass: Tentative Jet) with a 4 inch mill size and compressed nitrogen gas / compressed air (dew point> 40 ° C.) as the milling gas. The material was manually fed into the hopper and placed on the feed tray. The material was drawn into a circular chamber sealed with pressurized milling gas. The powder becomes suspended in the high velocity fluid stream in the mill chamber. The mill operates on the principle of impact and attrition due to high velocity collisions between particles suspended in a fluid stream that breaks the powder into smaller particles. Centrifugal force separates larger and heavier particles from smaller and lighter particles. Small particles are drawn by letting the fluid flow escape to the center of the mill, where they are ejected into the filter bag and then the material is collected in the drum. Large particles are thrown outwards, and they recirculate and re-impact, causing destruction of those particles.
Samples during processing are removed during the micronization process and analyzed to ensure that the micronization parameters are adequate to achieve the intended degree of particle size reduction. The particle size distribution is measured in a Malvern Mastersizer particle size analyzer. The mill conditions are then adjusted to give a material with an acceptable micron size. Final particle size relative to initial particle size of unprocessed starting material 13.72 microns (DV50) (having a range of 1.92 microns (DV10) to 39.01 microns (DV90)) 1.12 microns (DV50) (having a range of 0.31 microns (DV10) to 4.64 microns (DV90)).
Suspensions of either micronized resveratrol or unprocessed resveratrol were prepared for use in animal studies. Specifically, a 20% w / v solution of 2% HPMC (3 cpi) /0.2% DOSS; 0.5% HPMC (4000 cpi); 20% Tween 80; or 0.5% methylcellulose (15 cpi) Prepared with either.
Example 9
Preparation of resveratrol cyclodextran solution and lyophilized powder Two resveratrol formulations (resveratrol solution in either 40% Captisol or 10% captisol) for evaluation as prototype drug products Selected. Specifically, a low concentration resveratrol solution (20 mM or 4.57 mg / mL) in 10% captisol (w / v) was produced on a 20 mL scale and lyophilized vials were produced (1 mL per vial) . Lyophilized vials containing 10% captisol control day vehicle were also produced. A highly concentrated resveratrol solution (150 mM) in 40% captisol (w / v) was produced on a 500 mL scale and served as a lyophilized product (5 mL per vial). A lyophilized vehicle containing 40% Captisol control vehicle was also produced.
The low concentration resveratrol solution was prepared by adding 136.99 mg resveratrol to 30 mL 10% captisol (CyDex, Lot # CY-04A-05006) and mixed for 1 hour at ambient temperature. The initial solution had a pH of 5.02 and a concentration of 15.4 mM in resveratrol. This solution was filtered through a 0.20 μm nylon syringe filter (Fisher # 09-719C) to give a solution of 14.9 mM, pH 4.83 in resveratrol. The 10% captisol control vehicle solution had a pH of 4.78 before filtration and a pH of 4.76 after filtration. The filtered solution was dispensed into vials (1.0 mL solution in 3 mL vial (Wheaton # 223684)) and lyophilized. At the end of the lyophilization cycle, the vial was sealed under vacuum and crimped over the septum with a cap.
The lyophilized resveratrol product was an off-white cake. This material was reconstituted for approximately 20 seconds after the addition of 1.0 mL of water. This reconstituted resveratrol solution was clear with no visible particles, had a pH of 5.91, and the measured concentration was 14.4 mM resveratrol. The lyophilized control vehicle product was a white cake. This material was reconstituted for approximately 20 seconds after the addition of 1.0 mL of water. The reconstituted control vehicle was clear with no visible particles and had a pH of 5.82.
A high concentration resveratrol formulation (150 mM SRT501 in 40% captisol on a 500 mL scale) was prepared as follows. 40% Captisol (w / v) was prepared by placing 500 g Captisol (CyDex, Lot # CY-04A-05006) in a 4 L beaker. A large stir bar was placed in the beaker and then it was placed on a large stir plate. Room Milli-Q water was added to bring the volume in the beaker to approximately 1.3 mL. The solution was mixed vigorously for 1 hour until clear. Several times, the stir bar was removed using a spatula to remove undissolved material from the container slide. This solution was transferred to a 2 L graduated cylinder. Approximately 100 mL of water was used to rinse the beaker and added to the graduated cylinder to a final volume of 1.4 L. This solution was mixed thoroughly until clear.
The high-concentration resveratrol solution is mixed with 600 mL of 40% captisol and 24.0 g resveratrol in a 1 L beaker and stirred vigorously (if all substances are dissolved, the target concentration is 40% captisol (w / V) in 175 mM resveratrol). The solution was stirred for 35 minutes and then sonicated for an additional hour. The solution was stirred for an additional 50 minutes and then sonicated for an additional hour. At this point, solid material was still present in the sample. An aliquot was removed for analysis. The pH was measured to be 4.76 and the concentration was determined to be 55 mM resveratrol by HPLC. Since the solution appeared cloudy at this point, the three parts were separated to try an alternative mixing method. About 200 mL was transferred to a 500 mL volumetric flask and sonicated for 45 minutes, about 300 mL was vigorously stirred with an overhead mixer for 90 minutes, and about 100 mL was homogenized for 25 minutes. None of the three parts looked transparent. A sample of the homogenized solution was removed for concentration analysis and had a concentration of 74 mM resveratrol. These parts were combined and stirred at ambient temperature overnight protected from light. The next morning, the solution was sterile filtered through a Nalgene 90 mm filter unit (Cat # 167-0020; 0.02 PES membrane) using aseptic technique in a laminar flow hood. The concentration was measured again and determined to be 168 mM resveratrol in 40% captisol.
A control vehicle (40% captisol (w / v)) was also prepared as follows. 700 mL of 40% captisol was transferred to a 1 L beaker. The solution was sonicated for a total of 2 hours. The solution was then stored overnight at ambient temperature. The solution was sterile filtered through a Nalgene 90 mm filter unit (Cat # 167-0020; 0.02 PES membrane) using aseptic technique in a laminar flow hood. In a laminar flow hood, 5 mL of control vehicle or resveratrol solution was placed in a 30 mL glass vial that had been sterilized by autoclaving. The vial was lyophilized in 3 batches according to a previously developed lyophilization cycle. The vial was stoppered, sealed and labeled under vacuum. The resveratrol / captisol vial contained an off-white appearance cake. This sample was quickly reconstituted into a slightly yellow clear medical solution by the addition of water. To obtain the original concentration of 40% captisol, 3.7 mL of water must be added to the vial.
(Example 10)
Nicotinamide riboside neuroprotects retinal ganglion cells during acute optic neuritis Background Optic neuritis is common in multiple sclerosis (MS), a demyelinating disease mediated by autoimmunity of the central nervous system Is an inflammatory disorder of the optic nerve that is associated with Patients suffering from optic neuritis typically suffer from progressive visual loss over 1-2 weeks and then recover most or all of visual acuity over several weeks. More than 40% of patients have some persistent vision change (sensitivity, color vision, contrast sensitivity or visual field loss), and patients with repeated episodes of optic neuritis are likely to have permanent vision loss. Recent studies suggest that nerve damage in MS and optic neuritis lesions is responsible for permanent dysfunction.

  Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS induced by immunization with proteolipid protein (PLP). Animals, like MS patients, have an immune response that results in inflammation, demyelination, and nerve damage in the brain, spinal cord, and optic nerve. Optic neuritis induced in EAE mice results in the loss of retinal ganglion cells (RGC), the neurons whose axons form the optic nerve.

Preliminary studies The techniques for labeling RGCs and performing histological determination of optic neuritis have been refined for use in SJL / J mice suffering from EAE induced by proteolipid protein peptides (PLP). A detailed evaluation of the time course of RGC loss in optic neuritis has been performed and is described below.

  PLP induces the relapse / remission process of EAE in SJL / J mice: SJL / J mice were immunized with PLP by subcutaneous injection and observed daily for clinical signs of EAE. The results demonstrated that mice developed clinical symptoms of EAE as early as 9 days after immunization, with clinical symptoms peaking on days 14-15 (FIG. 17A). Clinical assessment is on a scale of 0-5 ("5" is moribund, "4" is limb paralysis and "0" is clearly healthy animal). Thereafter, the clinical EAE score decreases until day 25 when the second recurrence of symptoms begins. Mice are considered to have relapsed when the clinical scale has increased by 1 for 2 days or more after appearance has stabilized or improved for a period of 5 days or longer.

  A high incidence of optic neuritis is detected in EAE mice: SJL / J mice immunized with PLP were sacrificed at various time points. The optic nerve was isolated, fixed, embedded in paraffin, cut and stained with hematoxylin and eosin (H & E). Optic neuritis (presence of infiltration of inflammatory cells) is detected on day 9 after immunization, with the incidence peaking in more than 70% of the optic nerve on day 11 (FIG. 17B).

  Inflammation precedes RGC loss in eyes with optic neuritis: RGCs were retrogradely labeled with Fluorgold (FG) by stereotactic injection into the upper hill before induction of EAE. Mice were sacrificed at various time points and the retina and optic nerve were isolated. The entire retina was placed on a slide glass, and the number of RGCs was counted by observation with a fluorescence microscope. In eyes with optic neuritis, no loss of RGC was detected 9 or 11 days after immunization compared to control eyes or eyes of EAE mice that did not develop optic neuritis (FIG. 18). Significant loss of RGC was detected on day 14 (43% reduction over control) and progressed to day 18 (52% reduction over control).

  Study Summary: The neuroprotective effect of nicotinamide riboside was examined in EAE mice suffering from optic neuritis. 6-8 week old SJL / J mice were labeled with 2.5 μl of 1.25% FG solution injected into the upper hill. To induce EAE, mice were immunized with 300 μg PLP emulsified in complete Freund's adjuvant (CFA) a few days later, and control mice (no EAE) were treated with phosphate buffered saline (PBS) in CFA. Sham immunized. All mice received 200 ng intraperitoneal pertussis toxin (PT) on the day of immunization (day 0) and again on day 2.

  The eye was treated with nicotine by intravitreal injection (ivt) of a stock solution of either 0.1 M or 0.4 M nicotinamide riboside (Group 2, 4 and 5) in PBS at a volume of 0.8 μl / injection. Treated with amide riboside. As a result, the estimated final eyeball concentration of nicotinamide riboside is 19 mM or 76 mM. Control mice without drug treatment received either no ivt injection (Group 1) or a sham injection of PBS (Group 3). Treatment with nicotinamide riboside and PBS control injections was given ivt on days 0, 4, 7 and 11. Mice were scored daily for clinical EAE and sacrificed on day 14 by ketamine and xylazine overdose.

  The retina was dissected and placed entirely for fluorescence microscopy. RGC numbers were quantified by counting FG-labeled cells in 12 standard fields for each retina. The optic nerve was dissected and processed for histology. To determine acute optic neuritis, cut sections stained with H & E were evaluated for the presence of inflammatory cells. To determine whether nicotinamide riboside prevented neuronal loss, RGCs were compared between PBS treated with optic neuritis and nicotinamide riboside treated eyes.

  Results: As shown in FIG. 19, there was no difference in RGC numbers between control and non-EAE eyes treated with nicotinamide riboside (Groups 1 and 2). PBS treated EAE eyes with optic neuritis (268 ± 59 RGCs; group 3) experienced significant RGC loss relative to controls (691 ± 81; group 1), p <0.01. RGC loss was reduced by 100 mM nicotinamide riboside treatment (505 ± 36; group 4) and completely blocked by 400 mM nicotinamide riboside treatment (710 ± 67; group 5), p <0. 01. The incidence of optic neuritis and clinical EAE did not differ between nicotinamide riboside treated mice and controls. FIG. 20 is fluorgold-labeled of (A) optic neuritis eyes treated with placebo (PBS) (representing group 3) and (B) optic neuritis eyes treated with nicotinamide riboside (representing group 5). RGC is shown.

  Conclusion: Nicotinamide riboside provides RGC neuroprotection in a dose-dependent manner during acute optic neuritis in EAE. Nicotinamide riboside is not toxic to RGC and does not prevent infiltration of inflammatory cells. Sirtuin activation plays a potential therapeutic role in the prevention of neurodegeneration in optic neuritis and MS and may be useful in conjunction with anti-inflammatory therapy.

(Example 11)
Resveratrol provides neuroprotection of retinal ganglion cells (RGC) during acute optic neuritis. Resveratrol, a second sirtuin activator, is the same experimental autoimmune encephalomyelitis (EAE) as in the previous example. ) Tested in an optic neuritis model. A diagram of the experimental design is shown in FIG. 6-8 week old SJL / J mice were labeled with 2.5 μl of 1.25% fluorgold (FG) solution injected into the upper hill. To induce EAE, mice were immunized 7 days later with 300 μg proteolipid protein (PLP) emulsified in complete Freund's adjuvant (CFA) and control mice (no EAE) were phosphate buffered saline in CFA. Mock immunization with water (PBS). All mice received 200 ng of intraperitoneal pertussis toxin (PT) on the day of immunization (day 0) and again on day 3.

Test Material Preparation 5 μl of 770 nM resveratrol formulation was dissolved in 495 μl vehicle to give a final concentration of 7.7 mM resveratrol (stock solution). Three test doses were diluted:
1) 600 μM resveratrol = 10 μl stock solution + 118 μl vehicle; 2) 77 μM resveratrol = 10 μl stock solution + 990 μl vehicle;
3) 38 μM resveratrol = 200 μl 77 μM resveratrol + 200 μl vehicle.

Test Compound Administration Eyes were treated by intravitreal injection (iv) of resveratrol or PBS control at a volume of 0.8 μl / injection. Treatment with 38 μM, 77 μM or 600 μM resveratrol and PBS was given on days 0, 3, 7, and 11.

Evaluation Criteria Mice were scored daily on a 5-point scale for clinical EAE: no disease = 0; partial tail paralysis = 0.5; tail paralysis or swaying gait = 1.0; partial Tail paralysis and swaying gait = 1.5; Tail paralysis and swaying gait = 2.0; Partial limb paralysis = 2.5; Single limb paralysis = 3.0; Limb partial paralysis = 3.5; bilimb paralysis = 4.0; moribund state = 4.5; death = 5.0. The clinical EAE scores for individual mice are shown in Table I.

さらなる結果を図２２に示す。

Further results are shown in FIG.

  Mice were sacrificed by ketamine and xylazine overdose. The retina was dissected and placed entirely for fluorescence microscopy. RGCs were quantified by counting FG-labeled cells in 12 standard fields for each retina. The optic nerve was dissected and processed for histology. Cut sections stained by H & E were scored for the presence of inflammatory cells to determine acute optic neuritis as follows: non-inflamed eyes (ie no optic neuritis) = 0; mild inflammation = 1; moderate inflammation = 2; severe inflammation = 3. To determine whether resveratrol prevented neuronal loss, RGCs were compared between PBS treated with optic neuritis and resveratrol treated eyes.

Results The neuroprotective effect of resveratrol was examined during optic neuritis in EAE, an animal model of MS. RGCs were retrogradely labeled with FG by injection into the upper hill. EAE was induced by immunizing SJL / J mice with PLP. The eyes were treated by intravitreal injection of PBS, 38 μM, 77 μM or 600 μM resveratrol on days 0 (day of immunization), 3, 7 and 11. Mice were sacrificed on day 14. Optic neuritis was detected by infiltration of optic nerve inflammatory cells, and fluorescently labeled RGCs were counted. There was no difference in RGC numbers between control eyes treated with resveratrol and non-EAE eyes. PBS treated EAE eyes with optic neuritis (385 ± 117 RGCs) experienced significant RGC loss relative to controls (686 ± 113; p <0.01). RGC loss was not significantly prevented by 38 μM resveratrol treatment (452 ± 136; p = 0.2098). RGC loss was significantly reduced by 77 μM resveratrol treatment (585 ± 198; p = 0.0028) and completely blocked by 600 μM resveratrol treatment (644 ± 148; p = 0.0001) ). The incidence of optic neuritis and clinical EAE did not differ between resveratrol treated mice and controls. Statistical analysis was performed using ANOVA. The results demonstrate that resveratrol provides RGC neuroprotection in a dose-dependent manner during acute optic neuritis in EAE. Resveratrol is not toxic to RGC and does not prevent infiltration of inflammatory cells.

(Example 12)
Testing the neuroprotective effects of nicotinamide riboside and nicotinamide mononucleotide in a retinal ganglion cell injury model Summary:
The following examples demonstrate resveratrol, NMN and nicotinamide riboside sclerosis on ganglion cell survival in the retina of Swiss white mice after intravitreal NMDA injection.

Test compound administration:
Stock solutions for administration are nicotinamide riboside (125 mM in water) and NMN (125 mM in water).
Endpoint RGC density was determined by immunohistochemistry using brn-3 labeled retinal ganglion cells (RGC). RGCs were counted at 12 standard retinal positions per flat slide.

Methods Administration of test substance On days 0, 2 and 4, 2 μl of test substance or vehicle (2% HPMC, 0.2% DOSS) were administered to all 3-month-old adult Swiss white mice (1 treatment). Injected into the vitreous cavity of an anesthetized animal (intraperitoneal ketamine, xylazine) of 25-30 g per n, n = 12) using a microsyringe driver attached to a micropipette.

Sham injection:
Vehicle (2 μl, n = 12) was injected into the right eye of all mice on days 0, 2, and 4 using a microsyringe driver attached to a micropipette. To serve as a control for nicotinamide riboside and NMN, water (n = 4) was applied to the right eye of all mice on days 0, 2 and 4 using a microsyringe driver attached to a micropipette. Injected.

RGC injury model Intravitreal NMDA injection (100 nM in 2 μl) was administered to the right eye of all mice (animals receiving test substance or sham injection) using a microsyringe driver attached to a micropipette. This injection induces reproducible RGC apoptosis, and this peak is 12-24 hours after injection.

RGC density:
This was quantified from retinal flat slides made 6 days after NMDA injection. RGCs were identified by anti-brn-3 staining ³ . RGC density was determined for 12 retinal positions per flat slide (3 per quadrant set at a fixed distance from the optic disc). To make flat slides, mice were perfusion fixed with 4% paraformaldehyde, eyes were removed and fixed overnight with 4% paraformaldehyde. The retina was then harvested and placed on a gelatin-primed slide, labeled and counted.

表ＩＩＩ． ラットにおける、種々のレスベラトロール配合物の、経口投薬についての薬物動態学パラメーターの比較

理解され得るように、種々の投薬経路および／または配合物が、異なるＰＫパラメーターを生じさせるために使用され得る。例えば、ＩＰ投薬では、カプティソール配合されたレスベラトロール溶液は、未処理のレスベラトロール懸濁物よりも大きなＣｍａｘおよびＡＵCを達成する。ＤＭＳＯレスベラトロール溶液は、中間のＣｍａｘおよびＡＵＣを与える。しかしながら、このレスベラトロール懸濁物は、Ｔ_１／２によって測定した場合に、血漿において検出可能薬物の最長期間を示した。経口投薬では、カプティソール溶液が再度、未処理レスベラトロール懸濁物の経口投薬と比較して、より高いＣｍａｘを与える。しかしながら、このレスベラトロール懸濁物は、より高い全体のＡＵＣおよび血漿中の検出可能薬物の期間を与える。これらの結果に基づくと、レスベラトロールは、異なる様式で配合され得るか、または異なる経路によって送達され得、絶対血漿レベル（ａｂｓｏｌｕｔｅ ｐｌａｓｍａ ｌｅｖｅｌ）（Ｃｍａｘ）または曝露期間（ＡＵＣまたはＴ_１／２）のいずれかを最大にし得る。
参照による援用
以下に記載のものを含めた本明細書中で言及するすべての出版物および特許は、それぞれの個別の出版物または特許を参考として組み込むと具体的かつ個別に指定した場合と同様に、その全体が本明細書中に参考として援用される。矛盾する場合は、本明細書中の任意の定義を含めた本出願が支配する。
以下もまた、参考として援用される：ＰＣＴ公報ＷＯ ２００５／００２６７２；２００５／００２５５５；および２００４／０１６７２６、ならびに米国特許出願公開２００５／００９６２５６号。 Summary of mice for each test substance:
Injection was only in the right eye (according to the ARVO statement of animal use in eye and vision studies).
(Example 13)
Treatment of mice and rats with micronized resveratrol particle formulation Mice dosing Generally, the indicated dosing was administered to 3 mice per group and blood was collected at the indicated time points. 18-22 grams of male C57BL / 6 mice (Charles River Labs, Willington, Mass.) Were used for all mouse studies. Samples were sent to Charles River Labs (CRL) for analysis.
Specifically, mice were dosed (once every 2 minutes) by either intraperitoneal administration (IP), subcutaneous injection (SQ), or oral gavage (PO). Use CO2 overdose, mice were sacrificed at the appropriate time (before 40 seconds from the time, mice were placed in a CO ₂ chamber). Approximately 0.5 ml of blood was quickly collected with a heart stick using a 25G 1 ml syringe. The needle was removed and the sample was added to a microtainer blood tube (Becton Dickinson catalog number BD365965) equipped with lithium heparin and a plasma separator. Samples were placed on ice until centrifuged. Plasma was transferred to a snap tube and frozen on dry ice.
Drug stocks used include the following:
Resveratrol micronized particle suspension (20% w / v; average particle size 1.12 microns, Dv50) in 2% HPMC (3 cpi) + 0.2% DOSS;
Resveratrol micronized particle suspension (20% w / v; average particle size 1.12 microns, Dv50) in 0.5% HPMC (4000 cpi);
Resveratrol micronized particle suspension (20% w / v; average particle size 1.12 microns, Dv50) in 20% Tween 80; and resveratrol untreated particle suspension (20% w / v; average) Particle size 13.72 microns, Dv50) in 0.5% methylcellulose (15 cpi).
Stocks were diluted in an appropriate vehicle to allow dosing (by injection or oral gavage) of 0.2 ml of the formulation at the indicated dose. For example, for a 500 mg / kg dose, a 0.2 ml injection of a 50 mg / ml suspension was used. Three mice per group were sacrificed at the following time points: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 360 minutes and 720 minutes. Serum values were determined and plotted for all time points where drug could be detected.
A comparison of different resveratrol formulations administered by gavage is shown in FIGS. Specifically, micronized resveratrol (average particle size of about 1.0 μm) in either HPMC alone or HPMC / DOSS dosed by oral gavage at the indicated dose in mice. A comparison of untreated resveratrol in methylcellulose (average particle size of about 13 μm) is shown in FIG. Comparison of micronized resveratrol (Micro; average particle size approximately 1.0 μm) in either Tween 80 or HPMC / DOSS dosed by gavage at the indicated dose in mice. It shows in FIG.
A comparison of micronized resveratrol in HPMC / DOSS (average particle size of about 1.0 μm) dosed by gavage or IP injection at the indicated doses in mice is shown in FIG.
Rat Dosing In general, the indicated doses were administered to 3 or 4 rats per group and blood was collected at the indicated time points. Male, approximately 300 grams Sprague Dawley rats (Charles River Labs, Wilmington, Mass.) Were used for all rat studies. Dosing, sample collection and analysis were performed at Charles River Labs.
Specifically, rats were dosed by either intraperitoneal injection (IP) or oral gavage (PO). Approximately 300-500 μl of blood was collected at the indicated time points. Samples were placed on ice until centrifugation. Plasma was transferred to a snap tube and frozen on dry ice.
Drug stocks used include the following:
Resveratrol untreated particle suspension (20% w / v; average particle size 13.72 microns, Dv50) in 0.5% methylcellulose (15 cpi)
Resveratrol cyclodextran solution (175 mM resveratrol in 40% captisol, pH about 6.0)
Resveratrol dissolved in DMSO (100 mM resveratrol).
Stocks were diluted in the appropriate vehicle to allow dosing at the indicated doses. Samples are collected at 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes, 720 minutes and 1440 minutes for IP dosing and 15 for PO dosing Collected at minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and 720 minutes. Serum values were determined and plotted for all time points where drug could be detected.
A comparison of various formulations of resveratrol in rats after IP or PO dosing at the indicated doses is shown in FIGS. 26 and 27 and Tables II and III, respectively.
Table II. Comparison of pharmacokinetic parameters for IP dosing of various resveratrol formulations in rats

Table III. Comparison of pharmacokinetic parameters for oral dosing of various resveratrol formulations in rats

As can be appreciated, various dosing routes and / or formulations can be used to generate different PK parameters. For example, for IP dosing, captivol formulated resveratrol solution achieves greater Cmax and AUC than untreated resveratrol suspension. DMSO resveratrol solution gives intermediate Cmax and AUC. However, this resveratrol suspension showed the longest period of detectable drug in plasma as measured by T _1/2 . For oral dosing, the captisol solution again gives a higher Cmax compared to the oral dosing of the untreated resveratrol suspension. However, this resveratrol suspension gives a higher overall AUC and a period of detectable drug in plasma. Based on these results, resveratrol can be formulated in different ways, or delivered by different routes, with absolute plasma level (Cmax) or duration of exposure (AUC or T _1/2 ) Either of them can be maximized.
INCORPORATION BY REFERENCE All publications and patents mentioned in this specification, including those listed below, are intended to be as if they were specifically and individually specified to incorporate each individual publication or patent by reference. The entirety of which is incorporated herein by reference. In case of conflict, the present application, including any definitions herein, will control.
The following are also incorporated by reference: PCT publications WO 2005/002672; 2005/002555; and 2004/016726, and US Patent Application Publication No. 2005/0096256.

FIG. 1 is a diagram showing a plant polyphenol sirtuin 1 (SIRT1) activator. FIG. 2 shows stilbene and chalcone SIRT1 activators. FIG. 3 is a diagram showing a flavone SIRT1 activator. FIG. 4 is a diagram showing a flavone SIRT1 modulator. FIG. 5 shows isoflavones, flavanones and anthocyanidin SIRT1 modulators. FIG. 6 is a diagram showing a catechin (flavan-3-ol) SIRT1 modulator. FIG. 7 shows a free radical protection SIRT1 modulator. FIG. 8 is a diagram showing a SIRT1 modulator. FIG. 9 is a diagram showing a SIRT1 modulator. FIG. 10 is a diagram showing a resveratrol analog SIRT1 activator. FIG. 11 is a diagram showing a resveratrol analog SIRT1 activator. FIG. 12 is a diagram showing a resveratrol analog SIRT1 activator. FIG. 13 is a diagram showing a resveratrol analog SIRT1 modulator. FIG. 14 is a diagram showing a resveratrol analog SIRT1 modulator. FIG. 15A is a diagram showing a sirtuin activator. FIG. 15B is a diagram showing a sirtuin activator. FIG. 15C is a diagram showing a sirtuin activator. FIG. 15D shows a sirtuin activator. FIG. 15E shows a sirtuin activator. FIG. 15F is a diagram showing a sirtuin activator. FIG. 15G is a diagram showing a sirtuin activator. FIG. 16 is a diagram showing sirtuin inhibitors. FIG. 17A shows the change over time in the mean score of clinical experimental autoimmune encephalomyelitis (EAE) after immunization with proteolipid protein (PLP), and FIG. 17B developed optic neuritis It is a figure which shows the ratio of the eye of an EAE mouse | mouth. FIG. 18 shows a significant decrease in retinal ganglion cells (RGC) over time in optic neuritis eyes compared to control eyes and EAE eyes that did not develop optic neuritis. FIG. 19 shows that nicotinamide riboside is effective for preservation of RCG in an acute optic neuritis model. FIG. 20 shows (A) an optic neuritis eye treated with placebo (PBS) (representing group 3 of Example 8) and (B) an optic neuritis eye treated with nicotinamide riboside (Example 8, group 5). FIG. 2 is a diagram showing RGC labeled with fluorgold. FIG. 21 is a schematic diagram of an experiment described in Example 9. FIG. 22 is a diagram showing the number of RGCs in the eyes of all treatment groups of Example 9. FIG. 23 shows the raw resveratrol (Res; average particle diameter about 13 um) in methylcellulose (MC) and either methylcellulose (MC) or HPMC / DOSS after gavage in mice at the indicated doses. FIG. 3 shows a comparison of plasma profile with micronized resveratrol (Micro; average particle diameter of about 1.0 um) in FIG. FIG. 24 shows the plasma profile of micronized resveratrol (Micro; mean particle diameter approximately 1.0 um) in either Tween 80 or HPMC / DOSS after gavage in mice at the indicated doses. It is a figure which shows a comparison. FIG. 25 shows a comparison of the micronized resveratrol plasma profile in HPMC / DOSS after either gavage or intraperitoneal injection in mice at the indicated doses. FIG. 26 shows a comparison of various formulations of resveratrol in rats after intraperitoneal administration of the indicated doses. FIG. 27 shows a comparison of various formulations of resveratrol in rats after oral administration of the indicated doses.

Claims (39)

A composition comprising a cyclodextrin and a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof, wherein the composition is a liquid and the sirtuin modulator is resveratrol; The composition comprises at least 30 mM sirtuin modulator. The composition of claim 1, wherein the cyclodextrin is a substituted cyclodextrin. The composition of claim 2, wherein the cyclodextrin is substituted at the 2-hydroxyl group, 3-hydroxyl group or 6-hydroxyl group of the glycopyranose moiety. The composition of claim 2, wherein the cyclodextrin is amorphous. The composition of claim 2, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. The composition of claim 1, wherein the sirtuin modulator is a sirtuin activator. 7. The composition of claim 6, wherein the sirtuin activator is resveratrol, an analog thereof, or a prodrug of resveratrol or an analog thereof. 7. The composition of claim 6, wherein the sirtuin activator is nicotinamide riboside, an analog thereof, or a prodrug of nicotinamide riboside or an analog thereof. The composition of claim 1, wherein the composition is a liquid. The composition of claim 9, wherein the liquid comprises at least 30 mM of the sirtuin modulator. 11. The composition of claim 10, wherein the liquid comprises at least 100 mM of the sirtuin modulator. The composition of claim 1, wherein the composition is a lyophilized powder. A method for treating visual dysfunction by administering to a patient a therapeutic dose of a composition comprising a cyclodextrin and a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. A fast dissolving tablet comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. 15. The fast dissolving tablet of claim 14, wherein the tablet has an oral dissolution rate of less than 1 minute. 16. A fast dissolving tablet according to claim 15, wherein the tablet has an oral dissolution rate of less than 30 seconds. 15. The fast dissolving tablet according to claim 14, wherein the tablet has a hardness of 2 Strong-Cobb units to 6 Strong-Cobb units. The fast-dissolving tablet according to claim 14, wherein the sirtuin modulator is a sirtuin activator. 19. The fast dissolving tablet according to claim 18, wherein the sirtuin activator is resveratrol, an analog thereof, or a prodrug of resveratrol or an analog thereof. The fast dissolving tablet according to claim 18, wherein the sirtuin activator is nicotinamide riboside, an analog thereof, or a prodrug of nicotinamide riboside or an analog thereof. A method for treating visual impairment by administering to a patient a therapeutic dose of a fast dissolving tablet comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. An implantable device comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. The device of claim 22, wherein the device is suitable for implantation into the eye. 24. The device of claim 22, wherein the device is biodegradable. 23. The device of claim 22, wherein the device releases the sirtuin modulator for at least a month. 26. The device of claim 25, wherein the device releases the sirtuin modulator for at least one year. 26. The device of claim 25, wherein the device releases the sirtuin modulator over a period of 6 months to 2 years. 23. The device of claim 22, wherein the sirtuin modulator is a sirtuin activator. 29. The device of claim 28, wherein the sirtuin activator is resveratrol, an analog thereof, or a prodrug of resveratrol or an analog thereof. 29. The device of claim 28, wherein the sirtuin activator is nicotinamide riboside, an analog thereof, or a prodrug of nicotinamide riboside or an analog thereof. A method for treating visual dysfunction by implanting a patient with an implantable device comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. A pharmaceutical composition comprising a micronized sirtuin modulator or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof, wherein the particles of the micronized sirtuin modulator have an average diameter of less than about 30 microns , Pharmaceutical composition. 34. The pharmaceutical composition of claim 32, wherein the micronized sirtuin modulator particles have an average diameter of less than about 10 microns. 34. The pharmaceutical composition of claim 33, wherein the micronized sirtuin modulator particles have an average diameter of about 1 micron to about 5 microns. 35. The pharmaceutical composition of claim 34, wherein the micronized sirtuin modulator particles have an average diameter of about 1 micron to about 2 microns. 33. The pharmaceutical composition of claim 32, wherein the composition is a free flowing liquid. 35. The pharmaceutical composition of claim 32, wherein the composition is a solid dosage form. 34. The pharmaceutical composition of claim 32, wherein the particles are formed by air jet micronization. A method for treating visual impairment by administering to a patient a therapeutic dose of a pharmaceutical composition comprising a micronized sirtuin modulator or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. Wherein the micronized sirtuin modulator particles have an average diameter of less than about 30 microns.

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