WO2010144959A1 - Analogues d'agents antifibrotiques - Google Patents

Analogues d'agents antifibrotiques Download PDF

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WO2010144959A1
WO2010144959A1 PCT/AU2010/000745 AU2010000745W WO2010144959A1 WO 2010144959 A1 WO2010144959 A1 WO 2010144959A1 AU 2010000745 W AU2010000745 W AU 2010000745W WO 2010144959 A1 WO2010144959 A1 WO 2010144959A1
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optionally substituted
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alkyl
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Spencer John Williams
Steven Zammit
Darren James Kelly
Ian William James
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Fibrotech Therapeutics Pty Ltd
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Publication of WO2010144959A1 publication Critical patent/WO2010144959A1/fr

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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to derivatives of the anti-fibrotic drug, Tranilast.
  • Fibrosis is a common response to a range of tissue insults that may lead to organ dysfunction.
  • Diseases that are characterised by such pathological fibrosis include hepatic cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and non-ischaemic), diabetic nephropathy, scleroderma, excessive scar tissue post surgery or device insertion, progressive kidney disease, glomerulonephritis, hypertension, heart failure due to ischaemic heart disease, valvular heart disease or hypertensive heart disease and hypertrophic scars.
  • the elaboration of pathological matrix also has a role in fibroproliferative tumor progression and metastasis. Studies conducted over more than a decade have consistently indicated a major role of TGF- ⁇ in organ fibrosis and dysfunction, such that blockade of its expression and action represent an important therapeutic target.
  • Existing agents for treating fibrosis may have any number of undesirable properties including toxicity, poor solubility or efficacy.
  • Tranilast n-[3,4-dimethoxycinnamoyl] anthranilic acid
  • Tranilast is used in Japan for the treatment of fibrotic skin disorders such as keloids and scleroderma.
  • Tranilast has also been shown to attenuate TGF- ⁇ -induced collagen synthesis in cardiac fibroblasts using an experimental model of diabetic cardiac disease.
  • Tranilast has also been shown to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, and to have antiproliferative activity.
  • the present invention provides a compound of Formula (I)
  • X ⁇ is NR 10 or (CH 2 ) P ;
  • T is a double bond, a triple bond or when T is a single bond, one pair of R 6 and R 7 are
  • A is selected from the group consisting of C 3 to C 12 cycloalkyl, C 3 to C 12 cycloalkenyl, C 1 to C 12 heterocycloalkyl, C 1 to C 12 heterocycloalkenyl, C 6 -C 18 aryl and C 6 to C 18 heteroaryl;
  • R 1 , R 4 ' and R 5 are each independently selected from the group consisting of: H, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 1 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 1 -C 12 heterocycloalkyloxy, optional
  • R 2 and R 3 are each independently selected from the group consisting of: H, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 1 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 1 -C 12 heterocycloalkyloxy, optionally substituted C 1
  • R 6 and R 7 are present when T is a double bond but R 6 and R 7 are not present when T is a triple bond, each R 6 and R 7 being independently selected from the group consisting of: H, NO 2 , CN, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 - C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C
  • R 8 is selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 - C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 1 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 1 -C 12 heterocycloalkyloxy, optionally substituted C 1 -C
  • R 9 is selected from the group consisting of OH, OR 13 , COOR 13 , CONR 13 R 14 , NR 13 R 14 , tetrazol-5-yl, SO 2 R 13 , SO 2 NR 13 R 14 and CONHOR 13 ;
  • R 10 is selected from the group consisting of H, a N-protecting group, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 - C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 - C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -C 12 heterocycloalkyl, optionally substituted C 1 -C 12 heterocycloalkenyl, optionally substituted C ⁇ -C 18 aryl, and optionally substituted CrC ⁇ heteroaryl;
  • R 11 and R 12 are independently selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 1 -C 10 heteroalky
  • each R 13 , R 14 , R 15 are each independently selected from the group consisting of H, -OH, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 1 -C 12 heterocycloalkyl, optionally substituted C 1 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted d-C ⁇ heteroaryl;
  • n is an integer selected from the group consisting of O, 1 , 2, 3, and 4;
  • n is an integer selected from the group consisting of 1 , 2, 3, and 4;
  • n is an integer selected from the group consisting of 1 , 2, 3, 4, and 5;
  • p is an integer selected from the group consisting of O, 1 , 2, 3, 4, and 5;
  • R 2 and R 3 may also be independently selected from -X 3 -R 16 or -X 4 -R 17 ;
  • X 3 and X 4 may be the same or different and are selected from the group consisting of a bond C, O, N and S;
  • R 16 and R 17 may be the same or different and are selected from the group consisting of H, NHR 13 , NR 13 R 14 , OR 13 , halogen, C 1 to C 10 alkyl, C 3 to C 10 cyclokalkyl, C 3 to C 10 cycloalkylmethyl, C 3 to C 10 alkene, C 3 to C 10 alkyne, aryl, C 5 to C 20 alkaryl, fused C 5 to C 20 aryl or alkaryl and a hydrocarbon chain containing a heterocyclic or fused ring, any of which may be optionally substituted;
  • A has the general formula:
  • X 5 , X 6 , X 7 and X 8 may be independently C, S, O or N; R 18 is absent, H or COOR 13 and R 9 can be H when R 18 is COOR 13 , more preferably COOH; but A cannot be phenyl and R 1 to R 5 cannot be -CF 3 ;
  • X 5 , X 6 , X 7 and X 8 may be independently C, S, O or N and R 9 can be H when R 2 and R 3 are each independently a Ci-C 12 alkyloxy group containing at least one halogen atom, and more preferably when R 2 and R 3 are each -OCHF 2 .
  • At least one of R 1 , R 2 , R 3 , R 4 , and R 5 is selected from the group consisting of C 1 -C 12 alkyloxy containing at least one halogen atom, C 1 -C 12 alkenyloxy containing at least one halogen atom, and C 1 -C 12 alkynyloxy containing at least one halogen atom.
  • At least one of R 2 and R 3 is selected from the group consisting of a C 1 -C 12 alkyloxy group containing at least one halogen atom, a C 2 -C 12 alkenyloxy containing at least one halogen atom, a C 2 -C 12 alkynyloxy containing at least one halogen atom and a C 3 -C 12 cycloalkyloxy containing at least one halogen atom and the other R 2 or R 3 is selected from the group consisting of an optionally substituted C 1 -C 12 alkyloxy group, an optionally substituted C 2 -C 12 alkenyloxy, an optionally substituted C 2 - C 12 alkynyloxy and an optionally substituted C 3 -C 12 cycloalkyloxy.
  • the C 1 -C 12 alkyloxy group is of Formula (A):
  • R 24 , R 25 , and R 26 are each independently selected from the group consisting of: H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, and optionally substituted C 2 -C 12 alkenyl;
  • R 27 , R 28 , R 29 , and R 30 are each independently selected from the group consisting of: H, halogen, OH, NO 2 , CN 1 and NH 2 ; - at least one of R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , and R 30 is or contains a halogen atom;
  • - q is an integer selected from the group consisting of: O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • - r is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • q and r are 0, and at least two of R 24 , R 25 , and R 26 are a halogen.
  • the halogen may be selected from the group consisting of: fluorine, chlorine, bromine, and iodine.
  • the halogen is fluorine.
  • at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is selected from the group consisting Of-O-CHF 2, -OCF 3, -OCF 2 CHF 2 .
  • R 3 is the group -O-CHF 2 .
  • R 2 and R 3 are the group -Q-CHF 2 .
  • R 1 and R 5 are H and R 2 and R 3 are O- R 16 and O-R 17 , wherein R 16 and R 17 are independently and preferably selected from the group consisting of unsubstituted C 1 -C 6 alkyl, preferably methyl or ethyl; C 1 -C 6 fluoro substituted alkyl, preferably, F 3 CO, F 2 HCO, F 2 HCF 2 CO; or are fused to form a 5 or 6 membered ring, preferably R 2 and R 3 form a bridging difluoromethylenedioxy group or a bridging tetrafluoroethylenedioxy group.
  • T is a double bond while in other embodiments T is a triple bond.
  • R 9 is selected from the group consisting of: COOR 11 and CONR 11 R 12 . In some embodiments R 9 is selected from the group consisting of: COOH, CONH 2 , and CONHCH 3 .
  • R 9 is NR 11 R 12 while in some embodiments R 9 is NH 2 .
  • n 1
  • R 8 is halogen
  • T is a single bond and one pair of R 6 and R 7 are fused to
  • R 2 and R 3 form a bridging difluoromethylenedioxy group or a bridging tetrafluoroethylenedioxy group.
  • R 6 is CH 3 .
  • R 7 is CH 3 or CN.
  • R 8 is H or Me.
  • m is 1 and R 9 is selected from COR 13 and CONR 13 R 14 .
  • R 9 is selected from the group consisting of COOH,
  • R 9 is the group tetrazol-5-yl. In some embodiments R 9 is selected from the group consisting of SO 2 R , SO 2 NR 1 R .
  • R 9 is selected from the group consisting of SO 2 Me, SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 .
  • R 9 is NR 13 R 14 and in more particular embodiments R 9 is NH 2 .
  • R 8 is a halogen.
  • X 2 is NH.
  • Preferred compounds of the invention have the formula (Ma)
  • a further aspect of the present invention is represented by a compound of the Formula (III)
  • A, T, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and X 2 are as defined above in relation to compounds of formula (I).
  • A, T, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and X 2 are as defined above in relation to compounds of formula (I).
  • a further aspect of the present invention may be represented by a compound of Formula (V)
  • Het represents a heterocyclic ring and T, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X 1 (YZ) and X 2 are as defined above in relation to compounds of formula (I).
  • R 6 and R 7 are H in the compounds of formulas (III), (IV), (V) and (Vl).
  • T is preferably a double bond in the compounds of formulas (III), (IV), (V) and (Vl).
  • X 2 is NH or NR 13 wherein R 13 is preferably C 1 to C 6 alkyl, most preferably a methyl group.
  • R 11 and R 12 are selected from the group consisting of H, CN or halogen.
  • R 11 and R 12 are H.
  • the halogen is preferably fluorine.
  • R 9 is preferably selected from the group consisting of CO 2 H, CO 2 R 13 , SO 2 R 13 , SO 2 NH 2 ,
  • R 13 is preferably C 1 to C 6 alkyl, most preferably a methyl group.
  • R 9 is selected from the group consisting Of CO 2 H, CO 2 R 13 , SO 2 R 13 , SO 2 NH 2 , SONHR 13 , SONR 13 2 and 5- tetrazolyl.
  • R 1 and R 5 are H and R 2 and R 3 are 0-R 16 and O-R 17 , wherein R 16 and R 17 are independently and preferably selected from the group consisting of unsubstituted C 1 -C 6 alkyl, preferably methyl or ethyl; C 1 -C 6 fluoro substituted alkyl, preferably, F 3 CO, F 2 HCO, F 2 HCF 2 CO; or are fused to form a 5 or 6 membered ring, preferably a fluoro substituted 1 ,4 dioxane or a fluoro substituted 1 ,3-dioxolane; or a C 1 to C 6 alkenyl, preferably -CH 2 CCH.
  • R 10 is H or a C 1 to C 6 alkyl, preferably, methyl.
  • A has the general formula selected from the group consisting of
  • X 5 , X 6 , X 7 and X 8 may be independently C, S, O or N.
  • A has the general formula
  • X 4 , X 5 , X 6 and X 7 may be C or N. More preferably, not more than two of X 4 , X 5 , X 6 and X 7 may be N.
  • suitable compounds of formula (Ha) include
  • R 9 SO 2 Me, SO 2 NH 2 , 5-tetrazolyl
  • R 9 NH 2 , CONH 2 , CONHMe, CONHOH
  • Particular examples of compounds of formula (IV) are as follows
  • R 9 SO 2 Me, SO 2 NH 2 , 5-tetrazolyl
  • R 9 NH 2 , CONH 2 , CONHMe, CONHOH
  • R 9 SO 2 Me, SO 2 NH 2 , 5-tetrazolyl
  • R 9 NH 2 , CONH 2 , CONHMe, CONHOH
  • Specific compounds of formula (V) include
  • R 9 NH 2 , CONH 2 , CONHMe, CONHOH
  • R 9 SO 2 Me 1 SO 2 NH 2 , SONHMe, SONMe 2
  • R 9 SO 2 Me, SO 2 NH 2 , 5-tetrazolyl
  • R 9 NH 2 , CONH 2 , CONHMe, CONHOH wherein p is O or 1.
  • the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • the compounds of the present invention may have anti-fibrotic, anti-inflammatory, anti- proliferative or anti-neoplastic activity and may, therefore, find use as an alternative and/or adjunct to Tranilast.
  • the term "optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a polycyclic system), with one or more non-hydrogen substituent groups.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, such as a C 1 -C 14 alkyl, a C 1 -C 10 alkyl or a C 1 -C 6 unless otherwise noted.
  • suitable straight and branched C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • Mono- alkylamino means a -NH-Alkyl group, in which alkyl is as defined above.
  • Dialkylamino means a -N(alkyl) 2 group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group may be a C 1 -C 6 alkyl group.
  • the group may be a terminal group or a bridging group.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • Di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group.
  • acyl means an alkyl-CO- group in which the alkyl group is as described herein.
  • examples of acyl include acetyl and benzoyl.
  • the alkyl group may be a C 1 -C 6 alkyl group.
  • the group may be a terminal group or a bridging group.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched such as a group having 2-14 carbon atoms, 2-12 carbon atoms, or 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • Alkoxy refers to an -O-alkyl group in which alkyl is defined herein.
  • the alkoxy may be a C 1 -C 6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an -O- alkenyl group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C 2 -C 6 alkenyloxy groups. The group may be a terminal group or a bridging group.
  • Alkynyloxy refers to an -O-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 2 -C 6 alkynyloxy groups. The group may be a terminal group or a bridging group.
  • Alkoxycarbonyl refers to an -C(O)-O-alkyl group in which alkyl is as defined herein.
  • the alkyl group may be a C 1 -C 6 alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group.
  • Alkylsulfinyl means a -S(O)-alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group.
  • Alkylsulfonyl refers to a -S(O) 2 -alkyl group in which alkyl is as defined above.
  • the alkyl group may be a Ci-C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched and may have from 2-14 carbon atoms, 2-12 carbon atoms, or 2-6 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkylaminocarbonyl refers to an alkylamino-carbonyl group in which alkylamino is as defined above.
  • the group may be a terminal group or a bridging group.
  • Cycloaikyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle that may contain from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and may have from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • the group may be a terminal group or a bridging group.
  • alkyl and cycloaikyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloaikyl and alkyl moieties are as previously described.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group.
  • Halogen represents fluorine, chlorine, bromine or iodine.
  • Heterocycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen.
  • the heterocycloalkyl group may have from 1 to 3 heteroatoms in at least one ring. Each ring may be from 3 to 10 membered, such as 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4- oxazepane, and 1 ,4-oxathiapane.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkenyl refers to a heterocycloalkyl as described above but containing at least one double bond.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
  • the group may be a terminal group or a bridging group.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group that may have from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • the group may be a terminal group or a bridging group. As used herein reference to the normal chain when used in the context of a bridging group refers to the direct chain of atoms linking the two terminal positions of the bridging group.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) that may have from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl.
  • the group may be a terminal group or a bridging group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl. The group may be a terminal group or a bridging group.
  • Heteroaryl either alone or as part of a group refers to groups containing an aromatic ring (such as a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-,
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described.
  • the heteroarylalkyl groups may contain a lower alkyl moiety.
  • Exemplary heteroarylalkyl groups include pyridylmethyl.
  • the group may be a terminal group or a bridging group.
  • “Lower alkyl” as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, for example 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the group may be a terminal group or a bridging group.
  • the free amino group and/or the free carboxyl groups of the compounds of Formula (I) can be liberated either by deprotection of the amino group followed by deprotection of the acid moieties or vice versa.
  • suitable amino protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl ( 1 CBz 1 ), 4-phenylbenzyloxycarbonyl, 2- methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4- chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4- dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4cyanobenzyloxycarbonyl, t-butoxycarbonyl ('tBoc'), 2-(4-xenyl)
  • amino protecting group employed is not critical so long as the dehvatised amino group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other amino protecting group(s).
  • Preferred amino-protecting groups are t-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.
  • carboxyl protecting groups examples include methyl, ethyl, n-propyl, i-propyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4- dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4- methylenedioxybenzyl, benzhydryl, 4,4'-dinnethoxybenzhyclryl, 2,2'4,4'- tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4 I 4'-dimethoxytrityl, 4,4,'4"- trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl
  • Preferred carboxyl protecting groups are methyl and t-butyl. Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-lnterscience: 1991 ; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Theime Medical Pub., 2000.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • formulae (I), (II), (Ma), (III), (IV), (V) and (Vl) are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • the compounds of the various embodiments include pharmaceutically acceptable salts, prodrugs, N-oxides and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I).
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987.
  • pharmaceutically acceptable refers generally to a substance or composition that is compatible chemically and/or toxicologically with the other ingredients including a formulation, and/or the subject being treated.
  • compounds of the present invention refers generally to compounds, prodrugs thereof, pharmaceutically acceptable salts of the compounds and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labelled compounds.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • derivative thereof when used in reference to compounds of the present invention refers generally to prodrugs, pharmaceutically acceptable salts of the compounds and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs.
  • the compounds of the present invention may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are commercially available or can be synthesised using known procedures or adaptations thereof. Whilst the preparation of particular compounds is outlined below, the skilled person will also recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T. W. Greene's Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
  • the cinnamoyl benzamide (1) can be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon, RhCI(PPh 3 ) 3 , or by any other methods known in the art (see J. March, Advanced Organic Chemistry, John Wiley & Sons, New York 1985, pp. 694).
  • the compounds of the invention and intermediates in their synthesis can be isolated from a reaction mixture using standard work-up and purification procedures. Suitable procedures include solvent extraction, chromatography (thin or thick layer chromatography, HPLC, flash chromatography, MPLC 1 etc.), recrystallisation etc.
  • the present invention includes salts of the compounds of Formula (I).
  • the salts may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or they may be useful for identification, characterisation or purification.
  • the salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts.
  • acid addition salts are prepared by the reaction of an acid with a compound of Formula (I).
  • the alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of Formula (I).
  • Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.
  • suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids
  • organic acids such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or
  • the present invention also includes esters of the compounds of Formula (I), such esters being for example aliphatic esters such as alkyl esters.
  • the esters of the compounds of Formula (I) may be pharmaceutically acceptable metabolically labile esters. These are ester derivatives of compounds of Formula (I) that are hydrolysed in vivo to afford the compound of Formula (I) and a pharmaceutically acceptable alcohol.
  • metabolically labile esters include esters formed with alkanols in which the alkanol moiety may be optionally substituted by an alkoxy group, for example methanol, ethanol, propanol and methoxyethanol.
  • the compounds of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
  • the person skilled in the art will recognise that the chemical reactions described may be readily adapted to prepare a number of other compounds.
  • the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • a list of suitable protecting groups in organic synthesis can be found in T. W. Greene's Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1991.
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
  • Matrix synthesis may be stimulated by platelet derived growth factor (PDGF). Accordingly, mesangial cells incubated with PDGF can be used to demonstrate proline incorporation, which is an indicator of matrix synthesis and thereby a model for fibrosis; or
  • Matrix synthesis may be stimulated by both angiotensin Il or transforming growth factor beta (TGF- ⁇ ). Accordingly, neonatal cardiac fibroblasts incubated with angiotensin Il or TGF- ⁇ can be used to demonstrate proline incorporation, which is an indicator of matrix synthesis and thereby a model for fibrosis.
  • TGF- ⁇ transforming growth factor beta
  • the cyclopropanation step is performed with with excess CH 2 N 2 and a catalytic quantity of Pd(OAc) 2 in a 1 :1 mixture of CH 2 CI 2 and diethyl ether. It is also preferred that an esterification step in which the cinnamic acid derivative is reacted with sulphuric acid in methanol to provide the corresponding methyl ester precedes the cyclopropanation step.
  • a hydrolysis step in which the cyclopropanated derivative is hydroiysed with aqueous NaOH/MeOH to provide the cyclopropanated carboxylic acid derivative follows the cyclopropanation step.
  • step (b) condensing the compound obtained in step (a) with a compound of formula
  • a method of preparing a compound of Formula Ma including the steps of: (a) reacting a compound of the formula
  • step (b) condensing the acid chloride prepared in step (a) with a compound of the formula
  • a method for preparing a compound of formula III including the steps of; (a) reacting a terminal alkene of the formula
  • step (b) condensing the sulfonyl chloride prepared in step (a) with a compound of formula
  • a method of preparing a compound of Formula III including the steps of: (a) reacting a sulfonate compound of the formula
  • step (b) condensing the sulfonyl chloride compound prepared in step (a) with a compound of the formula
  • the method of preparing the compound of Formula III as described immediately above may also include an initial step of reacting an aldehyde compound of the formula ⁇ to provide the sulfonate compound of the formula
  • a method for preparing a compound of formula IV in which X 2 is NH that includes the steps of; (a) reacting a terminal alkene of the formula
  • step (b) condensing the compound prepared in step (a) with a compound of the formula
  • step (b) converting the ketone prepared in step (a) to a compound of the formula
  • Compounds of formula V may also be prepared by Knoevenagel condensation of a suitable aldehyde with malonic acid then coupling of the cinnamic acid with an aryl amine according to scheme 9 below.
  • a further form of the invention provides a method of preparing a compound of formula
  • Electrospray ionization (ESI) high resolution mass spectra (HRMS) were obtained on a Finnigan hybrid LTQ-FT mass spectrometer (Thermo Electron Corp.).
  • Proton nuclear magnetic resonance ( 1 H NMR) and proton decoupled carbon nuclear magnetic resonance ( 13 C NMR) spectra were obtained on Unity 400, Innova 400 or Innova 500 instruments (Melbourne, Australia) operating at 400 or 500 MHz for 1 H and at 100 or 125 MHz for 13 C. All signals were referenced to solvent peaks (CDCI 3 : 7.26 ppm for 1 H and 77.0 ppm for 13 C; DMSO-cfe: 2.49 ppm for 1 H and 39.5 ppm for 13 C).
  • Infrared (IR) spectra were obtained using a PerkinElmer Spectrum One FT-IR spectrometer with zinc selenide/diamond Universal ATR Sampling Accessory. Melting points were obtained using a Reichert-Jung hot stage apparatus and are corrected.
  • Analytical thin layer chromatography (TLC) was conducted on 2 mm thick silica gel GF 254 . Compounds were visualised with solutions of 20% w/w phosphomolybdic acid in ethanol, 20% w/w potassium permanganate in water or under UV (365 nm). Flash chromatography was performed with Merck Silica Gel 60. Petrol refers to the fraction boiling at 40-60 0 C. All other reagents were used as received.
  • the reaction was stirred at -78 0 C for 1 h, warmed to 0 0 C and stirred for 16 h.
  • the reaction was quenched with water and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated.
  • the aqueous phase was ashed with 50% EtOAc/petrol and the organic phase was discarded.
  • the aqueous phase was acidified with 1 M HCI and extracted with CH 2 CI 2 .
  • the combined organic fractions were washed with water, brine, dried and concentrated.
  • a well-characterized cloned rat mesangial cell line [30] (gift of D Nikolic-Patterson) is cultured in DMEM with FBS, 100U/ml_ penicillin, and 100ug/mL streptomycin in a humidified 5% CO 2 atmosphere at 37°C. Cells are plated into 24-well culture dishes in DMEM/10%FBS at low density and allowed to adhere overnight. Cells are used between passages 20 and 40.
  • the subconfluent cells are starved overnight in DMEM/0.1%FBS containing 15OuM L-ascorbic acid, prior to 4 hours of pre-treatment with or without tranilast or the FT compounds, followed by the addition of 5ng/mL ThTGF-P 1 I (R&D Systems) and 1uCi/mL of L-(2,3,4,5- 3 H)-proline. Control wells have the compounds but no TGF-P 1 added. Cells are incubated for a further 44 hours during which time their appearance is visually monitored.
  • the cells are then washed three times in ice-cold PBS, twice in ice cold 10% TCA and solubilized in 75OuL 1M NaOH for 45 minutes at 37 0 C or overnight at 4 0 C. A 50OuL aliquot is neutralized with 50OuL 1M HCI and 1OmL scintillation fluid (Instagel Plus - Perkin-Elmer) added. Counts are performed on a beta counter.
  • a BioRad protein assay is performed on a 100-15OuL aliquot of the remaining solubilized cells. The sample is neutralized with an equal amount of 1 M HCI prior to the assay.
  • the BSA standards used to construct the standard curve have the same amount of 1 M NaOH and 1 M HCI added as is present in the samples for assay.
  • Proline incorporation is expressed as cpm/ug protein. In order to compare inter-assay results, the incorporation is expressed as percentage reduction of TGF stimulated proline incorporation, where TGF alone gives 0% reduction and the zero control gives 100% reduction.

Abstract

La présente invention porte sur des analogues d'agents antifibrotiques ayant la formule (I) avec les substituants tels que décrits dans la description. La présente invention porte également sur des procédés pour leur préparation.
PCT/AU2010/000745 2009-06-18 2010-06-16 Analogues d'agents antifibrotiques WO2010144959A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012103583A1 (fr) * 2011-02-02 2012-08-09 Bionomics Limited Modulateurs allostériques positifs du récepteur nicotinique à l'acétylcholine α-7 et leurs utilisations
US8299112B2 (en) 2010-09-16 2012-10-30 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
WO2013112959A1 (fr) * 2012-01-26 2013-08-01 Angion Biomedica Corp. Composés antifibrotiques et leurs utilisations
US9499538B2 (en) 2012-03-20 2016-11-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9840481B2 (en) 2016-03-22 2017-12-12 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
JP2018516241A (ja) * 2015-04-17 2018-06-21 ダウ アグロサイエンシィズ エルエルシー 農薬の効用を有する分子ならびに関連する中間体、組成物及びプロセス
WO2018144620A1 (fr) * 2017-02-03 2018-08-09 Shire Human Genetic Therapies, Inc. Composés anti-fibrotiques
EP3485883A1 (fr) 2010-11-24 2019-05-22 OccuRx Pty Ltd Procédés de traitement de maladies oculaires associées à l'inflammation et à la prolifération vasculaire
KR102657257B1 (ko) 2015-04-17 2024-04-16 코르테바 애그리사이언스 엘엘씨 살충 유용성을 갖는 분자, 및 그와 관련된 중간체, 조성물 및 방법

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5248825A (en) * 1990-09-20 1993-09-28 Merrell Dow Pharmaceuticals Inc. Calcium uptake inhibitors
US5663414A (en) * 1990-02-08 1997-09-02 Eisai Co., Ltd. Benzenesulfonamide derivatives
EP0816329A1 (fr) * 1996-06-18 1998-01-07 Hoechst Aktiengesellschaft Dérivés de l'acide benzoique, procédé de leur préparation et leur usage pour le traitement de maladies
US6127392A (en) * 1997-08-05 2000-10-03 American Home Products Corporation Anthranilic acid analogs
US6326510B1 (en) * 1997-02-10 2001-12-04 Centre International De Recherches Dermatologiques Bi-aromatic compounds, compositions containing them and uses
US20020099089A1 (en) * 1999-07-27 2002-07-25 Norbert Hauel Carboxylic acid amides, pharmaceutical compositions containing these compounds, their use and preparation
US6646009B2 (en) * 2001-02-28 2003-11-11 Temple University — Of Commonwealth System of Higher Education N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof
US20060014807A1 (en) * 2004-07-19 2006-01-19 Lin Leu-Fen H Neuroprotective small organic molecules, compositions and uses related thereto
US20070191378A1 (en) * 2003-08-14 2007-08-16 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor
US20070286892A1 (en) * 2006-06-13 2007-12-13 Uri Herzberg Compositions and methods for preventing or reducing postoperative ileus and gastric stasis in mammals
US20070299101A1 (en) * 2004-11-04 2007-12-27 Colletti Steven L Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
US20080008660A1 (en) * 2006-06-14 2008-01-10 Symrise Gmbh & Co. Kg Antimicrobially active compounds for treating bad breath
WO2008057862A2 (fr) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Modulateurs de récepteur de glucocorticoïde, d'activité ap-1 et/ou nf-κb, et leur utilisation
WO2009082347A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Dérivés de bis-(sulfonylamino) destinés à être utilisés en thérapie
US20090226537A1 (en) * 2005-11-30 2009-09-10 Symrise Gmbh & Co. Kg Mixtures comprising anthranilic acid amides and antidandruff agents as cosmetic and pharmaceutical compositions for alleviating itching
US7592373B2 (en) * 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663414A (en) * 1990-02-08 1997-09-02 Eisai Co., Ltd. Benzenesulfonamide derivatives
US5248825A (en) * 1990-09-20 1993-09-28 Merrell Dow Pharmaceuticals Inc. Calcium uptake inhibitors
EP0816329A1 (fr) * 1996-06-18 1998-01-07 Hoechst Aktiengesellschaft Dérivés de l'acide benzoique, procédé de leur préparation et leur usage pour le traitement de maladies
US6326510B1 (en) * 1997-02-10 2001-12-04 Centre International De Recherches Dermatologiques Bi-aromatic compounds, compositions containing them and uses
US6127392A (en) * 1997-08-05 2000-10-03 American Home Products Corporation Anthranilic acid analogs
US20020099089A1 (en) * 1999-07-27 2002-07-25 Norbert Hauel Carboxylic acid amides, pharmaceutical compositions containing these compounds, their use and preparation
US6646009B2 (en) * 2001-02-28 2003-11-11 Temple University — Of Commonwealth System of Higher Education N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof
US20070191378A1 (en) * 2003-08-14 2007-08-16 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor
US7592373B2 (en) * 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US20060014807A1 (en) * 2004-07-19 2006-01-19 Lin Leu-Fen H Neuroprotective small organic molecules, compositions and uses related thereto
US20070299101A1 (en) * 2004-11-04 2007-12-27 Colletti Steven L Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
US20090226537A1 (en) * 2005-11-30 2009-09-10 Symrise Gmbh & Co. Kg Mixtures comprising anthranilic acid amides and antidandruff agents as cosmetic and pharmaceutical compositions for alleviating itching
US20070286892A1 (en) * 2006-06-13 2007-12-13 Uri Herzberg Compositions and methods for preventing or reducing postoperative ileus and gastric stasis in mammals
US20080008660A1 (en) * 2006-06-14 2008-01-10 Symrise Gmbh & Co. Kg Antimicrobially active compounds for treating bad breath
WO2008057862A2 (fr) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Modulateurs de récepteur de glucocorticoïde, d'activité ap-1 et/ou nf-κb, et leur utilisation
WO2009082347A1 (fr) * 2007-12-20 2009-07-02 Astrazeneca Ab Dérivés de bis-(sulfonylamino) destinés à être utilisés en thérapie

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9399646B2 (en) 2010-09-16 2016-07-26 Genentech, Inc. Estrogen receptor modulators and uses thereof
US8299112B2 (en) 2010-09-16 2012-10-30 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8455534B2 (en) 2010-09-16 2013-06-04 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US11583535B2 (en) 2010-11-24 2023-02-21 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
EP3485883A1 (fr) 2010-11-24 2019-05-22 OccuRx Pty Ltd Procédés de traitement de maladies oculaires associées à l'inflammation et à la prolifération vasculaire
WO2012103583A1 (fr) * 2011-02-02 2012-08-09 Bionomics Limited Modulateurs allostériques positifs du récepteur nicotinique à l'acétylcholine α-7 et leurs utilisations
AU2012212393B2 (en) * 2011-02-02 2015-06-11 Bionomics Limited Positive allosteric modulators of the alpha 7 nicotinic acetylcholine receptor and uses thereof.
US9062013B2 (en) 2011-02-02 2015-06-23 Bionomics Limited Positive allosteric modulators of the α7 nicotinic acetylcholine receptor and uses thereof
US10195184B2 (en) 2012-01-26 2019-02-05 Angion Biomedica Corp. Antifibrotic compounds and uses thereof
US9040555B2 (en) 2012-01-26 2015-05-26 Angion Biomedica Corp. Antifibrotic compounds and uses thereof
US11504359B2 (en) 2012-01-26 2022-11-22 Angion Biomedica Corp. Antifibrotic compounds and uses thereof
CN104136436A (zh) * 2012-01-26 2014-11-05 安贞生物医学公司 抗纤维化的化合物及其用途
WO2013112959A1 (fr) * 2012-01-26 2013-08-01 Angion Biomedica Corp. Composés antifibrotiques et leurs utilisations
US9499538B2 (en) 2012-03-20 2016-11-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
JP2018516241A (ja) * 2015-04-17 2018-06-21 ダウ アグロサイエンシィズ エルエルシー 農薬の効用を有する分子ならびに関連する中間体、組成物及びプロセス
JP2018516242A (ja) * 2015-04-17 2018-06-21 ダウ アグロサイエンシィズ エルエルシー 農薬の効用を有する分子ならびに関連する中間体、組成物及びプロセス
KR102657259B1 (ko) 2015-04-17 2024-04-16 코르테바 애그리사이언스 엘엘씨 살충 유용성을 갖는 분자, 및 그와 관련된 중간체, 조성물 및 방법
KR102657257B1 (ko) 2015-04-17 2024-04-16 코르테바 애그리사이언스 엘엘씨 살충 유용성을 갖는 분자, 및 그와 관련된 중간체, 조성물 및 방법
JP6998213B2 (ja) 2015-04-17 2022-01-18 コルテバ アグリサイエンス エルエルシー 農薬の効用を有する分子ならびに関連する中間体、組成物及びプロセス
US9840481B2 (en) 2016-03-22 2017-12-12 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
US9926285B2 (en) 2016-03-22 2018-03-27 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
WO2018144620A1 (fr) * 2017-02-03 2018-08-09 Shire Human Genetic Therapies, Inc. Composés anti-fibrotiques
AU2018215089C1 (en) * 2017-02-03 2022-09-22 Certa Therapeutics Pty. Ltd. Anti-fibrotic compounds
AU2018215089B2 (en) * 2017-02-03 2022-06-23 Certa Therapeutics Pty. Ltd. Anti-fibrotic compounds
JP7185631B2 (ja) 2017-02-03 2022-12-07 サータ セラピューティクス プロプライエタリー リミテッド 抗線維化化合物
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
US11603349B2 (en) 2017-02-03 2023-03-14 Certa Therapeutics Pty Ltd Anti-fibrotic compounds
JP2020508977A (ja) * 2017-02-03 2020-03-26 サータ セラピューティクス プロプライエタリー リミテッド 抗線維化化合物
CN110546133A (zh) * 2017-02-03 2019-12-06 塞尔塔治疗有限公司 抗纤维化化合物

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