WO2006079021A2 - Use of sirtuin-activating compounds for treating flushing and drug induced weight gain - Google Patents

Use of sirtuin-activating compounds for treating flushing and drug induced weight gain Download PDF

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Publication number
WO2006079021A2
WO2006079021A2 PCT/US2006/002267 US2006002267W WO2006079021A2 WO 2006079021 A2 WO2006079021 A2 WO 2006079021A2 US 2006002267 W US2006002267 W US 2006002267W WO 2006079021 A2 WO2006079021 A2 WO 2006079021A2
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compound
sirtuin
formula
further embodiment
attendant definitions
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French (fr)
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WO2006079021A3 (en
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David Sinclair
Michael Milburn
Robert S. Langer
Christoph H. Westphal
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Sirtris Pharmaceuticals Inc
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Sirtris Pharmaceuticals Inc
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Priority to CA002595486A priority Critical patent/CA2595486A1/en
Priority to EP06719216A priority patent/EP1841415A2/en
Priority to JP2007552335A priority patent/JP2008528510A/ja
Priority to AU2006206274A priority patent/AU2006206274A1/en
Publication of WO2006079021A2 publication Critical patent/WO2006079021A2/en
Publication of WO2006079021A3 publication Critical patent/WO2006079021A3/en
Anticipated expiration legal-status Critical
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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    • A61P15/18—Feminine contraceptives
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the drug that induces flushing is at least one of the following: nicotinic acid, raloxifene, an antidepressant, an anti-psychotic, a chemotherapeutic agent (e.g., cyclophosphamide or tamoxifen), a calcium channel blocker (e.g., amlodipine), or an antibiotic (e.g., levofloxacin).
  • nicotinic acid raloxifene
  • an antidepressant e.g., cyclophosphamide or tamoxifen
  • a calcium channel blocker e.g., amlodipine
  • an antibiotic e.g., levofloxacin
  • Figure 47 is a Western Blot showing the effects of resveratrol in the presence or absence of AMPK kinase, LKBl.
  • Mouse embryonic fibroblasts were incubated in the presence of AICAR, ethanol, 50, 100, 200 ⁇ M of resveratrol. Blots were stained for the presence of P-ACC, P-AMPK, AMPK, or tubulin as indicated on the left .
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed by Greene and Wuts in Protective Groups in Organic Synthesis (2 nd ed., Wiley: New York, 1991).
  • a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
  • An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 3 O for branched chain), and alternatively, about 20 or fewer.
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • a sirtuin-activating compound is a compound of formula 1 and the attendant definitions, wherein n is 1; A-B is ethenyl; M is O; R 3 , R 5 , R' 2 and R' 3 are OH; and Ri, R 2 , R 4 , R'i, R' 4 , and R' 5 are H (butein).
  • Ri, R 2 , R 3 , R 4 , R'i, R' 2 , R' 3 , R' 4 , R' 5 , and R"i represent 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;
  • L represents CR 2 , O, NR, or S
  • W represents CR or N
  • L represents CR 2 , O, NR, or S
  • a sirtuin-activating compound is a compound of formula 32 and the attendant definitions wherein R is H and Ri is 3-hydroxyphenyl.
  • Ri and R 2 are a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, lieterocyclylalkyl, heteroaryl, or heteroaralkyl; and L is O, S, or NR.
  • a sirtuin-activating compound is a compound of formula 33 and the attendant definitions wherein L is O.
  • a sirtuin-activating compound is a compound of formula 36 and the attendant definitions wherein R 4 is H.
  • Ri is H or a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl;
  • a sirtuin-activating compound is a compound of formula 37 and the attendant definitions wherein R 3 is 4-chlorophenyl.
  • a sirtuin-activating compound 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.
  • Li and L 2 are O, NR, or S; and n is an integer from 0 to 4 inclusive.
  • a sirtuin-activating compound is a compound of formula 40 and the attendant definitions wherein R 3 is H. In a further embodiment, a sirtuin-activating compound is a compound of formula
  • a sirtuin-activating compound is a compound of formula 41 and the attendant definitions wherein Li is S.
  • a sirtuin-activating compound is a compound of formula 41 and the attendant definitions wherein L 3 is O. In a further embodiment, a sirtuin-activating compound is a compound of formula 41 and the attendant definitions wherein n is 0 and Ri is cyano.
  • a sirtuin-activating compound is a compound of formula 49 and the attendant definitions wherein n is 1, R is methyl, Ri is C(O)OCH 3 , R 2 is C(O)OCH 3 , R 3 is methyl, R 4 is methyl, R 5 is CH 2 CH(CH 3 ) 2 , Li is S, and L 2 is S.
  • a sirtuin-activating compound is a compound of formula 55:
  • a sirtuin-activating compound is a compound of formula 55 and the attendant definitions wherein R is H, Ri is H, R 2 is OEt, R 3 is methyl, R 4 is H, and R 5 is H.
  • a sirtuin-activating compound is a compound of formula 55 and the attendant definitions wherein R is H, Ri is H, R 2 is OEt, R 3 is methyl, R 4 is H, R 5 is H, Li is S, L 2 is NH, L 3 is NH, and L 4 is S.
  • a sirtuin-activating compound is a compound of formula 56 and the attendant definitions wherein n is 0.
  • a sirtuin-activating compound is a compound of formula 57:
  • L 1 , L 2 , and L 3 are O, NR. 1 0, or S; and Rio is H or a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.
  • a sirtuin-activating compound is a compound of formula 58 and the attendant definitions wherein R 3 is methyl. In a further embodiment, a sirtuin-activating compound is a compound of formula
  • a sirtuin-activating compound is a compound of formula 58 and the attendant definitions wherein R is OH, Ri is CH 2 OH, R 2 is OH, and R 3 is methyl.
  • a sirtuin-activating compound is a compound of formula 58 and the attendant definitions wherein R is OH, Rj is CH 2 OH, R 2 is OH, R 3 is methyl, 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 Li is O.
  • R 3 is H or a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; n is an integer from 0 to 4 inclusive; and m is an integer from 1 to 5 inclusive.
  • a sirtuin-activating compound is a compound of formula
  • n 2, R is 3-hydroxy and 5-hydroxy, Ri is H, R 2 is H, and m is 1.
  • R 7 is H or a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl.
  • a sirtuin-activating compound is a compound of formula
  • a sirtuin-activating compound is a compound of formula 62 and the attendant definitions wherein R 2 is CH 2 OH.
  • a sirtuin-activating compound is a compound of formula 63 and the attendant definitions wherein R 2 is N-I -pyrrolidine.
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is Cl, Ri is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, and Li is CH 2 .
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is H, Ri is OH, and R 2 is N(Me) 2 .
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is H, Ri is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, and R 7 is OH.
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is H, Ri is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, and Li is CH 2 .
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is H, Ri is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7 is OH, and Li is CH 2 .
  • a sirtuin-activating compound is a compound of formula 64 and the attendant definitions wherein R is H, Ri is OH, R 2 is N(Me) 2 , R 3 is OH, R 4 is C(O)NH 2 , R 5 is OH, R 6 is OH, R 7
  • R is H or a substituted or unsubstituted alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
  • A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group.
  • the A moieties thus described optionally have leaving group characteristics.
  • A is further substituted with an electron contributing moiety.
  • Examples of A include i-xiv below:
  • A is a substituted nicotinamide group (i above, where Z is
  • A has two or more electron contributing moieties.

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PCT/US2006/002267 2005-01-20 2006-01-20 Use of sirtuin-activating compounds for treating flushing and drug induced weight gain Ceased WO2006079021A2 (en)

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Application Number Priority Date Filing Date Title
CA002595486A CA2595486A1 (en) 2005-01-20 2006-01-20 Use of sirtuin-activating compounds for treating flushing and drug induced weight gain
EP06719216A EP1841415A2 (en) 2005-01-20 2006-01-20 Use of sirtuin-activating compounds for treating flushing and drug induced weight gain
JP2007552335A JP2008528510A (ja) 2005-01-20 2006-01-20 紅潮および／または薬物誘発性体重増加を処置するためのサーチュイン活性化化合物の使用
AU2006206274A AU2006206274A1 (en) 2005-01-20 2006-01-20 Use of sirtuin-activating compounds for treating flushing and drug induced weight gain

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US64591605P 2005-01-20 2005-01-20
US60/645,916 2005-01-20
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076681A3 (en) * 2005-01-13 2007-06-28 Sirtris Pharmaceuticals Inc Novel compositions for preventing and treating neurodegenerative and blood coagulation disorders
WO2008055445A1 (fr) * 2006-11-08 2008-05-15 Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences Méthode et composition pour accroître la sensibilité à l'insuline
EP2018861A1 (en) * 2007-07-26 2009-01-28 Laboratorios del Dr. Esteve S.A. 5HT6-Ligands such as sulfonamide derivatives in drug-induced weight-gain
WO2010011836A3 (en) * 2008-07-25 2010-05-06 Emory University Treating various disorders with 7,8-dihydroxyflavone and derivatives thereof
EP2801357A1 (en) 2013-05-10 2014-11-12 IMD Natural Solutions GmbH Carboxylated stilbenes for activating AMPK and sirtuins
US8912188B2 (en) 2011-03-02 2014-12-16 Bioenergenix, Llc Substituted quinoxaline carboxylic acids for the inhibition of PASK
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