WO2000018725A1 - Cetoamides 2-substitues - Google Patents

Cetoamides 2-substitues Download PDF

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Publication number
WO2000018725A1
WO2000018725A1 PCT/US1999/022213 US9922213W WO0018725A1 WO 2000018725 A1 WO2000018725 A1 WO 2000018725A1 US 9922213 W US9922213 W US 9922213W WO 0018725 A1 WO0018725 A1 WO 0018725A1
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Prior art keywords
alkyl
group
hydrogen
nil
arylalkyl
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PCT/US1999/022213
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English (en)
Inventor
John Mcmillan Mciver
Charles Raymond Degenhardt
David Joseph Eickhoff
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The Procter & Gamble Company
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Priority to EP99969712A priority Critical patent/EP1117635A1/fr
Priority to BR9914207-4A priority patent/BR9914207A/pt
Priority to JP2000572187A priority patent/JP2002525352A/ja
Priority to AU60600/99A priority patent/AU6060099A/en
Publication of WO2000018725A1 publication Critical patent/WO2000018725A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to novel compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression.
  • HAV human immunodeficiency virus
  • Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness. Such baldness is cosmetically unappealing, and is particularly distressing to the person experiencing the hair loss.
  • hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three main stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
  • anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair.
  • catagen is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
  • telogen is often characte ⁇ zed as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells.
  • the initiation of a new anagen phase is caused by rapid cell proliferation m the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
  • Propecia ® may be more effective than Rogaine ®
  • patients using Propecia ® are experiencing limited hair growth.
  • potential side effects of Propecia ® are serious.
  • Propecia ® may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skm rash.
  • Propecia ® is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference ® . 52 th Ed. (1998), p. 1737 and The New England Journal of Medicine. Vol.
  • FK506 is a complex, macrocyclic molecule having the following structure:
  • the present inventors have discovered a novel class of compounds which arrest and / or reverse hair loss or promote hair growth but do not share the complex, macrocyclic structure of FK506.
  • the present inventors have further discovered compounds among this novel class which invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive.
  • the minimized and / or absent immunosuppressive activity of these hypert ⁇ chotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporin A and FK506.
  • the present invention relates to compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and are useful for controlling parasites and invoking immunosuppression.
  • the compounds of the present invention have the structure:
  • the present invention relates to compounds and compositions which are particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the present inventors have also surprisingly discovered that immunosuppression is not required for hair growth stimulation
  • the present inventors have further discovered compounds that are useful for treating hair loss but are su ⁇ risingly non-immunosuppressive Preferred compounds of the present invention are therefore, as defined herein, non-immunosuppressive.
  • the present compounds are also useful for treating a variety of other conditions as described herein below.
  • salt is a cationic salt formed at any acidic (e g , carboxyl) group, or an anionic salt formed at any basic (e g , ammo) group.
  • Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts.
  • Preferred anionic salts include the halides (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
  • alkenyl is an unsubstituted or substituted, straight or branched hydrocarbon chain radical having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon atoms; more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms.
  • Alkenyls have at least one olefmic double bond.
  • Non-limitmg examples of alkenyls include vinyl, allyl, and butenyl.
  • alkoxy is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
  • alkoxy radicals include -O-alkyl and -O-alkenyl.
  • An alkoxy radical may be substituted or unsubstituted.
  • alkyl is an unsubstituted or substituted, straight or branched saturated hydrocarbon chain radical having from 1 to about 15 carbon atoms; preferably from 1 to about 10 carbon atoms; more preferably from 1 to about 6 carbon atoms; and most preferably from 1 to about 4 carbon atoms
  • Preferred alkyls include, for example, methyl, ethyl, propyl, wo-propyl, and butyl
  • alkylene refers to an alkyl, alkenyl, or alkynyl which is a diradical.
  • methylene is -CH2-.
  • Alkylenes may be substituted or unsubstituted
  • aryl is an aromatic ring radical which is either carbocychc or heterocyclic.
  • Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazmyl, thiazolyl, pyrimidinyl, qumolmyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, mdolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, lmidazolyl, pyraxolyl, oxadiazolyl, mdohzmyl, indolyl, isoindolyl, pu ⁇ nyl
  • Aryls may be substituted or unsubstituted.
  • arylalkenyl is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group.
  • Arylalkenyls may be substituted or unsubstituted.
  • arylalkyl is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group.
  • Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl.
  • Arylalkyls may be substituted or unsubstituted.
  • biohydrolyzable amides are amides of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • biohydrolyzable esters are esters of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • biohydrolyzable imides are imides of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • “carbocychc ring”, “carbocycle”, or the like is a hydrocarbon ring radical.
  • Carbocychc rings are monocyclic or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
  • Polycychc rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
  • Carbocychc rings (carbocycles) may be substituted or unsubstituted
  • cycloalkyl is a saturated carbocychc or heterocychc ring radical.
  • Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be substituted or unsubstituted.
  • halo means a chloro, bromo, fluoro, or lodo atom radical, preferably bromo, chloro. or fluoro, more preferably chloro or fluoro.
  • heteroalkenyl is an alkenyl radical containing carbon atoms and one or more heteroatoms withm the alkenyl chain (e.g., -CHOCH 2 rather than pendant from like, e.g., C(O)) wherein the heteroatoms are selected from oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkenyls may be substituted or unsubstituted.
  • heteroalkyl is an alkyl radical containing carbon atoms and one or more heteroatoms within the alkyl chain (e.g., -CH 2 OCH 2 rather than pendant from like, e.g., C(O)) wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • Heteroalkyls may be substituted or unsubstituted.
  • heteroaryl is an aryl radical containing carbon atoms and one or more heteroatoms within the aryl ring (e.g., -CHOCH-) rather than pendant from like, e.g., C(O)) wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • Heteroaryls may be substituted or unsubstituted.
  • heteroarylalkenyl is an arylalkenyl radical wherein the aryl group is a heteroaryl and / or the alkenyl group is a heteroalkenyl. Heteroarylalkenyls may be substituted or unsubstituted.
  • heteroarylalkyl is an arylalkyl radical wherein the aryl group is a heteroaryl and / or the alkyl group is a heteroalkyl. Heteroarylalkyls may be substituted or unsubstituted.
  • heterocyclic ring As used herein unless otherwise specified, "heterocychc ring", “heterocycle”, or the like is a ring radical comprised of carbon atoms and one or more heteroatoms in the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • Heterocycles are monocyclic or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
  • Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms Heterocychc rings (heterocycles) may be substituted or unsubstituted.
  • heterocycloalkyl is a saturated heterocycle. Heterocycloalkyls may be substituted or unsubstituted.
  • a “lower” moiety e g , "lower” alkyl is moiety having 1 to about 6, preferably 1 to about 4, carbon atoms.
  • pharmaceutically acceptable means suitable for use in a human or other mammal.
  • safe and effective amount of a compound means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the s ⁇ te(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.
  • a "spiro moiety” is a cyclic moiety sharing a carbon on another ⁇ ng, preferably the Z ring. Such spiro moiety may be carbocychc or heterocychc. Spiro moieties may be substituted or unsubstituted.
  • substituted in reference to a group, moiety, or the like, means having one or more substituent groups each independently selected from hydrogen, alkoxy, hydroxy, nitro, ammo, alkylammo, cyano, halo, carboxy, thiol, imino, and aryloxy (with additional allowed substituents on the G moiety which are selected from oxo, amido, -0-alkyl-C(0)OR 32 , and -0-alkyl-C(0)NHR 32 , wherein R 32 is selected from hydrogen and alkyl) preferably hydrogen, alkoxy, aryloxy, hydroxy, nitro, ammo, halo, and thiol, more preferably hydrogen, alkoxy, hydroxy, nitro, ammo, alkylammo, and halo, even more preferably hydrogen, halo, hydroxy, and alkoxy, and most preferably hydrogen.
  • substituent groups each independently selected from hydrogen, alkoxy, hydroxy, nitro, ammo, alky
  • unsubstituted means substitution by a hydrogen moiety.
  • a group may alternatively be consistently described as being “substituted” wherein the substitution is with a hydrogen moiety.
  • variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.
  • the compounds of the present invention have the structure:
  • (a) Z is a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered carbocycle or heterocycle wherein the heterocycle contains one or more heteroatoms selected from O, N, S, S(O), S(0 2 ), and P((O)OK);
  • V is -CU-, wherein U is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;
  • G is selected from nil, O, S, and NR ⁇ ;
  • K is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;
  • R[ is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;
  • W is selected from nil, hydrogen, and lower alkyl
  • (g) A is selected from ml and alkyl
  • X and Y are each, independently, selected from C(O), P(O), N, O, and S, wherein: (i) when X is C(O) then R 3 is nil and Y is selected from N, O, and S;
  • R 3 when X is S then R 3 is nil, Y is C(O), and R 2 is nil; (1) R 2 and R 3 are each, independently, selected from nil, hydrogen, alkyl, and arylalkyl; 0) R 4 is alkyl;
  • R 5 and R ⁇ are each, independently, selected from nil, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein R 5 and R ⁇ are bonded together to form a carbocychc or hetercychc ring;
  • R 7 , R 8 , R 9 , and R 10 are each, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, - R, 4 SR I5 , -R, 4 S(0 2 )R, 5 , -R l4 S(0)R 15 , -R 14 C(0)R 15 , -R, 4 C(0)NR 15 R 16 , -R 14 C(0)OR, 5) - Ri 4 OR 15 , -R, 4 NR, 5 R 16 , -R l4 P(0)NR 15 R 16 , -R, 4 P(0)OR, 5 R 16 , and a spiro moiety, and wherein R 7 and R
  • R 14 , and R 15 are each, independently, selected from ml, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; and
  • R, 6 and R 17 are each, independently, selected from hydrogen and alkyl.
  • the present compounds are comprised of a ⁇ ng system, Z, which is a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered carbocycle or heterocycle.
  • Z is a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered carbocycle or heterocycle.
  • the Z ⁇ ng system is a 5-, 6-, or 7-membered carbocycle or heterocycle, more preferably a 5- or 6-membered carbocycle or heterocycle.
  • the Z ring is a carbocycle.
  • V is the V substituent which is -CU-, wherein U is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, preferably hydrogen, alkyl, and arylalkyl, most preferably hydrogen.
  • the Z ring optionally contains one or more heteroatoms or heteromoieties (herein collectively described as heteroatoms for simplicity) wherein the heteroatoms are selected from oxygen (O), nitrogen (N), sulfur (S), sulfoxide (S(O)), sulfone (S(0) 2 ), and phosphonate (P((0)OK)).
  • the optional heteroatoms are selected from the group consisting of O, N, S, S(O), and S(0) 2 .
  • the heteroatom cannot be at position 1 because the V substituent is required at position 1.
  • N is a heteroatom in the heterocycle, the additional N heteroatom must be substituted, most preferably with hydrogen or alkyl.
  • S(O), S(0)2, and P(0)OK heteroatoms are depicted below in Table 1 for cla ⁇ ty:
  • G is selected from nil, O, S, and NR, 7 , wherein NR 17 is selected from hydrogen and alkyl
  • G is selected from O, S, and NR, 7 , preferably O and NR 17 , and most preferably, G is NR .
  • the R, side chain is also directly attached to the ketoamide moiety.
  • the R, moiety is selected from is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.
  • the R, moiety is preferably substituted with at least one substituent other than hydrogen.
  • substituents oxo, amido, - 0-alkyl-C(0)OR 32 , and -0-alkyl-C(0)NHR 32 may also substitute on the R, moiety.
  • the R, moiety is preferably selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl, even more preferably aryl, arylalkyl, and heteroarylalkyl, most preferably aryl.
  • the most preferred aryl for the R, moiety is substituted aryl (most preferably substituted phenyl), particularly aryl having at least one alkoxy substituent.
  • Particularly preferred R ] moieties are shown below in Table 2.
  • At the 2-pos ⁇ t ⁇ on of the Z ring is the A-X-Y-R 4 moiety which is substituted, as described herein, by R 2 , R 3 , R 5 , and Re.
  • the A moiety of the side chain is selected from nil and alkyl. Most preferably, the A moiety is nil. Of course, wherein A is nil, X is directly attached to the Z ring
  • X and Y are each, independently, selected from C(O) (1 e , carbonyl), P(O), N, O, S, with the following limitations: (i) when X is C(O) then R 3 is nil and Y is selected from the group consisting of
  • X and Y are each, independently, selected from C(O), N, and O. More preferably, X and Y are each, independently, selected from is C(O) and N.
  • R 3 and R 2 are substituted by R 3 and R 2 , respectively.
  • R 3 and R 2 are each, independently, selected from l, hydrogen, alkyl, and arylalkyl. Wherein X is N, then R 3 is selected from hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably hydrogen. Wherein Y is N, then R 2 is selected from hydrogen, alkyl, and arylalkyl, more preferably hydrogen and alkyl, most preferably hydrogen.
  • the R 4 moiety is an alkyl moiety.
  • the preferred alkyl moieties follow the prefe ⁇ ed limitations set forth above, with the most preferred R 4 moiety being a methylene or methyne group (i.e., a C, moiety bearing only one hydrogen substituent).
  • the R 5 and R ⁇ , moieties are each directly attached to R 4 .
  • R 5 and R 6 are each, independently, selected from nil, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein R 5 and R ⁇ are bonded together to form a carbocychc or hetercyc c ring; wherein at least one of R 5 and R ⁇ , is not ml or hydrogen.
  • R 5 and R ⁇ are each, independently, selected from nil, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. More preferably, R 5 and R,; are each, independently, selected from alkyl having at least two carbon atoms, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl. Most preferably, R 5 and R ⁇ are each, independently, arylalkyl. It is often preferred that R 5 and Rg are equivalent moieties. Of course, R 5 and R, may be each, independently, substituted. Exemplary R 5 and R, ⁇ moieties are shown in Table 3 below.
  • the Z ring may be substituted at the 2-pos ⁇ t ⁇ on by an additional moiety, W.
  • the W moiety is selected from nil, hydrogen, and lower alkyl, preferably hydrogen and lower alkyl, most preferably hydrogen Wherein W is lower alkyl, W is most preferably methyl.
  • the Z nng may also have additional substituents at the other available positions, such additional substituents being defined as R 7 , R 8 , R 9 , and R ]0 .
  • R 7 , R 8 , and R 9 , and Rio are each, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, immo, -R I4 SR 15 , -R 14 S(0 2 )R t5 , -R 14 S(0)R, 5 , -R 14 C(0)R 15 , -R 14 C(0)NR 15 R 16 , - R 14 C(0)OR 15 , -R l4 OR, 5 , -R I4 NR 15 R 16 , -R, 4 P(0)NR 15 R 16 , -R l4 P(0)OR 15 R 16 , and a spiro moiety, and wherein R 7 and
  • R 7 , R 8 , and R 9 , and R1. 0 are each, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R, 4 SR 15 , -R, 4 S(0 2 )R, 5> -R 14 S(0)R 15 , -R 14 C(0)R 15 , -R 14 C(0)NR 15 R 16 , - R l4 OR 15 , -R, 4 NR, 5 R 16 , and a spiro moiety, and wherein R 7 and R 8 may be optionally bonded together to form an aromatic or saturated, carbocychc or heterocychc second ring wherein the second ring is fused to Z.
  • R 7 , R 8 , and R 9 , and R )0 are each, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R 14 SR, 5 , -R l4 S(0 2 )R l5 , -R, 4 S(0)R, 5 , -R 14 C(0)R 15 , -R 14 C(0)NR 15 R 16 , - R H OR, 5 , -R
  • R 7 , R 8 , and R 9 , and R, 0 are each, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, -R 14 C(0)R 15 , -R 14 C(0)NR, 5 R, 6 , -R, 4 OR 15 , -R 14 NR 15 R 16 , and a spiro moiety, and wherein R 7 and R 8 may be optionally bonded together to form an aromatic or saturated, carbocychc or heterocychc second ring wherein the second ring is fused to Z Most preferably, R 7 and R 8 are bonded together to form an aromatic or saturated (preferably aromatic), carbocychc or heterocychc (preferably carbocychc) second ring wherein the second ring is fused to Z.
  • R 7 and R 8 are bonded together to form an aromatic or saturated, carbocychc or heterocychc second ⁇ ng wherein the second ring is fused to Z, the second ⁇ ng may, of course, be substituted or unsubstituted.
  • a preferred second ring is phenyl.
  • R 18 , R 19 , and R 2 o are each, independently, selected from hydrogen, aryloxy, hydroxy, nitro, amino, halo, and thiol.
  • R 32 is selected from the group consisting of hydrogen and alkyl.
  • R 35 is selected from hydrogen and -OR 36 , wherein R 36 is selected hydrogen and alkyl.
  • R 30 an R 35 are eac , in epen ent y, se ecte rom -OR 32 an OCH 2 C(0)OR 32 , wherein R 32 is selected from hydrogen and alkyl.
  • the present compounds are hair growth actives, the more preferred among these being non-immunosuppressive.
  • the compounds (test compounds) of the present invention may be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term "non-immunosuppressive" being defined according to the method disclosed herein).
  • the Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle (“anagen").
  • telogen there are three principal phases of the hair growth cycle: anagen, catagen, and telogen It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth promoters are evaluated.
  • the Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
  • the length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays).
  • Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly
  • Table 9 A typical study design is shown in Table 9 below:
  • mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib).
  • a pipettor and tip are used to deliver 400 ⁇ L to each mouse's back.
  • the 400 ⁇ L application is applied slowly while moving hair on the mouse to allow the application to reach the skm.
  • the immunosuppression assay herein predicts the immunosuppressive activity of a compound of the present invention
  • the assay is performed as follows:
  • Spleens are excised from euthanized (CO, asphyxiation) adult male C3H mice ranging in age from seven to sixteen weeks old (live mice commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN). The spleens are placed immediately in cold Hanks Balanced Salt Solution (HBSS, commercially available from Gibco-BRL, Gaithersburg, MD) The spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris.
  • HBSS Hanks Balanced Salt Solution
  • the resulting cell suspension is underlayed with an equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and centrifuged at 400 x g for approximately forty minutes at 20 °C in order to collect the splenocytes
  • the splenocytes are collected from the interface using a disposable pipet and are washed twice with HBSS, followed by centrifugation at 100 x g for ten mm at 20 °C.
  • Splenocytes are resuspended m five to ten mL of cell culture media consisting of phenol red- free RPMI 1640 (culture media commercially available from Gibco-BRL) containing 10% heat-inactivated fetal bovine serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 ⁇ g/mL), L-glutamme (2 mM), 2-mercaptoethanol (10 "5 M), and N-2-hydroxyethylp ⁇ peraz ⁇ ne-N'-2-ethanesulfon ⁇ c acid (HEPES) (10 mM) The cells are counted and checked for viability using, for example, trypan blue.
  • DMSO methyl sulfoxide
  • the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubihzed in Microscmt 20 (Packard), and counted on a TopCount microplate scintillation and luminescence plate counter (Packard) Activity is measured as a percentage of control activity in the absence of test compound and plotted versus test compound concentration. The data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated.
  • test compounds are considered non-immunosuppressive if, by using this method, the ratio of (cyclosporin A IC 50 /test compound IC 50 ) x 100 is less than or equal to 0.02, i e , a non-immunosuppressive test compound has ⁇ 2% of the immunosuppressive activity of cyclosporin A.
  • MTT 3-[4,5-d ⁇ methyl-th ⁇ azoyl-2-yl]2,5-d ⁇ phenyl- tetrazohum bromide
  • MTT 3-[4,5-d ⁇ methyl-th ⁇ azoyl-2-yl]2,5-d ⁇ phenyl- tetrazohum bromide
  • the assay is carried out in serum-free, phenol red-free RPMI 1640 and the dye is solubihzed in 100 ⁇ L/well DMSO and read at an OD of 540 nm with a background correction at 650 nm on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).
  • the present compounds are also useful, for example, to increase the antiprohferative activity of a drug and / or prevent and / or treat multi-drug resistance
  • the present compounds may be assayed for this property as described in U.S. Patent No. 5,744,485, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued April 28, 1998, U.S. Patent No. 5,726,184, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued March 10, 1998, U.S. Patent No. 5,620,971, Armistead et al.. assigned to Vertex Pharmaceuticals Inc., issued Ap ⁇ l 15, 1997, and U.S. Patent No. 5,543,423, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued August 6, 1996.
  • the compounds of the present invention are prepared according to methods which are well-known to those skilled in the art.
  • the starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available as a starting material. It is recognized that the skilled artisan the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed in standard texts such as J. March, Advanced Organic Chemistry. John Wiley & Sons, 1992.
  • the compounds of the present invention may have one or more chiral center
  • one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture).
  • the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography .
  • one optical isomer including a diastereomer and enantiomer, or a stereoisomer
  • both optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
  • Oxazohne la (9.36 g, 26.8 mmol) is dissolved in dioxane (100 mL) at room temperature. 3N HCl (200 mL) is added and the resulting solution is heated at reflux for 18 hours. The solution is cooled to ambient temperature then poured onto water (200 mL) and extracted with ethyl ether (3 x 150 mL). The combined ethyl ether extracts are washed successively with water (75 mL), and brine (75 mL) then dried over MgS0 4 , filtered, and concentrated in vacuo to afford the desired product.
  • Carboxylic acid lb (1.0 g, 3.37 mmol) is dissolved in dicloromethane (50 mL) at room temperature under inert atmosphere, trans- 1 ,2-D ⁇ ammocyclohexane (0.77 g, 6.75 mmol) is added followed by ⁇ -Pr,NEt (0.6 mL., 3.4 mmol) and PyBOP (1.9 g, 3.7 mmol).
  • the reaction mixture is stirred at ambient temperature for 18 hours then poured onto ethyl acetate (300 mL) and washed successively with 0.1 N HCl (150 mL), saturated sodium bicarbonate solution (75 mL), and b ⁇ ne (50mL).
  • the organic solution is dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the crude product by preparative chromatography over silica gel affords the desired product.
  • reaction mixture is stirred for 18 hours at room temperature then poured onto water (50 mL) and extracted with dichloromethane (3 x 40 mL). The combined organic extracts are washed successively with 0.1 N HCl (40 mL), and saturated sodium bicarbonate solution (40 mL) then dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the crude product by preparative chromatography over silica gel affords the desired product Id.
  • reaction mixture is stirred at ambient temperature for 18 hours then poured onto ethyl acetate (600 mL) and washed successively with 0.1 N HCl (300 mL), brine (lOOmL), saturated sodium bicarbonate solution (150 mL), and brme (lOOmL).
  • the organic solution is dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the crude product by preparative chromatography over silica gel affords the desired amide 3a.
  • reaction mixture is stirred for 18 hours at room temperature then poured onto ethyl acetate (300 mL) and washed successively with 0.1 N HCl (150 mL), brine (50mL), saturated sodium bicarbonate solution (150 mL), and brine (50 mL).
  • the organic solution is dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the crude product by preparative chromatography over silica gel affords the desired amide 3b.
  • 5- Phenylpentanoic acid (6.0 g, 33.7 mmol) is dissolved in dichloromethane (500 mL) at room temperature under inert atmosphere.
  • N,N'-D ⁇ methyl-trans-l,2-d ⁇ ammocyclohexane (9.6 g, 67.5 mmol) is added followed by ⁇ -Pr 2 NEt (5.9 mL, 33.9 mmol) and PyBOP (19.3 g, 37.1 mmol).
  • N,N' -Dimethyl -trans- 1 ,2-D ⁇ ammocyclohexane, l-N-5-phenylpentano ⁇ c acid amide, 2-N- (phenylglyoxyl) amide The amide 6a (0.55 g, 1.83 mmol) is dissolved in anhydrous dichloromethane (30 mL) at room temperature. Phenylglyoxylic acid (0.42 g, 2.8 mmol) is added in one portion followed by ⁇ -Pr 2 NEt (0.75 mL, 4.3 mmol) and PyBOP (1.44 g, 2.77 mmol) m succession.
  • N,N'-D ⁇ methyl-tra «5-l,2-D ⁇ am ⁇ nocyclohexane, l-N-5-phenylpentano ⁇ c acid amide, 2-N-(2- furyl)glyoxyhc acid amide.
  • N,N'-D ⁇ methyl-tra «s-l ,2-D ⁇ am ⁇ nocyclohexane, 5-phenylpentano ⁇ c acid amide 6a (10.0 g, 33.1 mmol) is dissolved in anhydrous dichloromethane (600 mL) at room temperature.
  • Phenylglyoxylic acid (5.5 g, 49.7 mmol) is added in one portion followed by l- Pr 2 NEt (13.5 mL, 77.8 mmol) and PyBOP (25.8 g, 49.6 mmol) in succession.
  • the reaction is stirred for 18 hours at room temperature, then poured onto ice-cold 0.1N HCl (600 mL) and extracted with dichloromethane (800 mL). The layers are separated and the organic layer washed with saturated NaHC0 3 solution (600 mL) and brine (300 mL). Purification of the crude product by preparative chromatography over silica gel affords the desired product 7a.
  • the compounds herein may be used for the treatment of such conditions as, for example, treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness. While certain of the present compounds may exhibit immunosuppressive activity, the preferred compounds of the present invention are, as defined herein, non-immunosuppressive.
  • the compounds of the present invention may be used to treat a variety of clinical conditions which include, but are not limited to, multi- drug resistance (particularly for use in cancer chemotherapy), neurological disorders and neurodegenerative diseases, cardiac injury associated with ischemia/reperfusion injury, and treatment of fungal, microbial, viral (especially HIV), malarial or other parasitic diseases or conditions.
  • the present compounds may also be useful as inhibitors of multi-drug transporter proteins to enhance, for example, pharmacokmetics and bioavailabihty. Certain compounds of the present invention may exhibit immunomodulatory properties.
  • autoimmune diseases include, but are not limited to, Behcet's disease, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthema gravis, insulin-dependent diabetes melhtus, and Graves' disease.
  • the present compounds may have utility for the treatment of certain inflammatory and allergic disease states, including urticaria, allergic contact dermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatory bowel disease, and asthma.
  • the present compounds may also be useful in the treatment of cardiac hypertrophy in congestive heart failure.
  • the present compounds may also be useful combination with a matrix metalloproteinase inhibitor for treatment of various conditions including, for example, tissue destructive diseases mediated by excessive metalloproteinase activity, cancer, and multi-drug resistance, as well as all of the conditions previously mentioned herein above.
  • matrix metalloproteinase inhibitors useful in such combination include those described in U.S. Patent Application Serial No. 60/024,765, Pikul et al.. assigned to The Procter & Gamble Co., filed August 28, 1996, U.S. Patent Application Serial No. 60/024,842, Natchus et al. assigned to The Procter & Gamble Co., filed August 28, 1996, U.S. Patent Application Serial No.
  • the compounds of the present invention are formulated into pharmaceutical compositions for use m treatment or prophylaxis of conditions such as the foregoing Standard pharmaceutical formulation techniques are used, such as those disclosed m Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA. (1990).
  • m treatment or prophylaxis of conditions such as the foregoing Standard pharmaceutical formulation techniques are used, such as those disclosed m Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA. (1990).
  • from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound of the present invention is administered per day for systemic administration.
  • dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors
  • the specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent
  • the dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
  • compositions of the subject invention contain a pharmaceutically-acceptable carrier ("carrier").
  • carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, m a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations.
  • Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal, being treated
  • the carrier can itself be inert or it can possess pharmaceutical benefits of its own.
  • compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is especially preferred.
  • a variety of pharmaceutically-acceptable carriers well-known m the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface- active agents, and encapsulating substances
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound of the present invention.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stea ⁇ c acid and magnesium stearate, calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma, polyols such as propylene glycol, glycerine, sorbitol, manmtol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tabletmg agents, stabilizers, antioxidants, preservatives; pyrogen-free water
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, algmic acid, phosphate buffer solutions, emulsifiers, isotonic salme, and pyrogen-free water.
  • Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, py ⁇ ohdone, ethanol, and sesame oil.
  • the pharmaceutically-acceptable carrier, in compositions for parenteral administration comprises at least about 90% by weight of the total composition.
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound of the present invention. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in the art Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, manmtol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stea ⁇ c acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance.
  • inert diluents such as calcium carbonate, sodium carbonate, manmtol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • dismtegrants such as starch, alginic acid and croscarmelose
  • lubricants such
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
  • Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium algmate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract m the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvmylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions useful for attaining systemic delivery of the subject compounds include subhngual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and manmtol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.
  • soluble filler substances such as sucrose, sorbitol and manmtol
  • binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.
  • Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • the compounds of the present invention may also be topically administered.
  • the carrier of the topical composition preferably aids penetration of the present compounds into the skm to reach the environment of the hair follicle
  • Topical compositions of the present invention may be in any form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave- on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skm patches, and the like.
  • Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like
  • emollients for example, emollients, solvents, humectants, thickeners and powders
  • solvents for example, ethanol, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, glymer, sulfate, glymer, glymer, glymer, sulfate, glycerin, glycerin, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate,
  • Emollients such as stearyl alcohol, glyceryl mono ⁇ cmoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane- 1,3-d ⁇ ol, mink oil, cetyl alcohol, zso-propyl isostearate, stea ⁇ c acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, d ⁇ - «-butyl sebacate, iso- propyl my ⁇ state, zs ⁇ -propyl palmitate, zso-propyl stearate, butyl stearate, polythylene glycol, t ⁇ ethylene glycol, lanolm, sesame oil, coconut oil,
  • the compounds of the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large umlamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylam e or phosphatidylchohnes
  • a preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al , "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospo ⁇ n A: I. An in vitro Study Using Hairless Mouse Skm", S T P Pharma Sciences. Vol. 3, pp.
  • the compounds of the present invention may also be administered by iontophoresis. See, e.g.. www.unipr.it/arpa/dipfarm/erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm. Res.. Vol.
  • compositions of the present invention may also optionally comprise an activity enhancer.
  • the activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention.
  • Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.
  • Additional hair growth stimulants can be chosen from a wide variety of molecules which can function m different ways to enhance the hair growth effects of a compound of the present invention. These optional other hair growth stimulants, when present, are typically employed in the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5% by weight of the composition.
  • Vasodilators such as potassium channel agonists including, for example, mmoxidil and mmoxidil derivatives such as aminexil and such as those described in U.S. Patent 3,382,247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S.
  • antiandrogens include, but are not limited 5- ⁇ -reductase inhibitors such as finasteride and those described m U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and in Nane et al., Cancer Research 58. "Effects of Some Novel Inhibitors of C17,20-Lyase and 5 ⁇ -Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer," as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S.
  • Another suitable class of optional hair growth stimulants are lmmunosuppressants or non-immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described m U.S. Provisional Patent Application No. 60/122,925, Fulmer et al.. filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/147,279, Degenhardt et al. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,313, Degenhardt et al. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,280, Degenhardt et al.
  • optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, t ⁇ clocarbon, t ⁇ closan, zinc py ⁇ thione, ltraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (herein incorporated by reference), clmacycm hydrochlo ⁇ de, benzoyl peroxide, benzyl peroxide and minocychn.
  • Anti-inflammato ⁇ es can also be incorporated into the compositions herein as an optional hair growth stimulant.
  • glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone
  • nonsteroidal anti-mflammato ⁇ es including cyclooxygenase or hpoxygenase inhibitors such as those desc ⁇ bed m U.S. Patent 5,756,092, and benzydamine, salicylic acid, and those compounds described in EPA 0,770,399, published May 2, 1997, WO 94/06434, published March 31, 1994, and FR 2,268,523, published November 21, 1975, all of which are herein incorporated by reference.
  • thyroid hormones and derivatives and analogs thereof are thyroid hormones and derivatives and analogs thereof.
  • suitable thyroid hormones for use herein may include triiodothyrionme.
  • thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,022, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,023, Zhang et al, filed June 1, 1999, U.S. Provisional Patent Application No.
  • Prostagland agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein.
  • suitable prostaglandins agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO 95/1 1003, Stjernschantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
  • Suitable retmoids may include isotretinoin, acitretin, and tazarotene.
  • Another class of optional hair growth stimulants for use herein are t ⁇ terpenes such as, for example, those disclosed in Bradbury et al, U.S. Patent Application Serial No. 09/353,408, “Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al, U.S. Patent Application Serial No. 09/353,409, "Compositions Which Contain T ⁇ terpenes for Regulating Hair Growth", filed July 15, 1999, each incorporated by reference in their entirety.
  • optional hair growth stimulants for use herein include flavmoids, ascomycm derivatives and analogs, histamme antagonists such as diphenhydramme hydrochlo ⁇ de, other t ⁇ terpenes such as oleanohc acid and ursohc acid and those described in U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S. Patent 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S.
  • Patent 5,631,282 U.S Patent 5,679,705, JP 08193094, saponms such as those described in EP 0.558,509 to Bonte et al, published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997 (both of which are herein incorporated by reference in their entirety), proteoglycanase or glycosammoglycanase inhibitors such as those described in U.S. Patents 5,015,470, issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S.
  • Patent 4,987,150 to Kurono et al issued January 22, 1991; JP 290811 to Ohba et al, published October 15, 1992; JP 05-286,835 to Tanaka et al, published November 2, 1993, FR 2,723,313 to Greff, published August 2, 1994, U. S. Patent 5,015,470 to Gibson, issued May 14, 1991, U.S. Patent 5,559,092, issued September 24, 1996, U.S. Patent 5,536,751, issued July 16, 1996, U.S.
  • Patent 5,714,515 issued February 3, 1998, EPA 0,319,991, published June 14, 1989, EPA 0,357,630, published October 6, 1988, EPA 0,573,253, published December 8, 1993, JP 61- 260010, published November 18, 1986, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,053, 410, issued October 1, 1991, and U.S. Patent 4,761,401, issued August 2, 1988, all of which are herein incorporated by reference.
  • Non-hmitmg examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-d ⁇ ol, POE(2) ethyl ether, d ⁇ (2-hydroxypropyl) ether, pentan-2,4-d ⁇ ol, acetone, POE(2) methyl ether, 2-hydroxypropiomc acid, 2-hydroxyoctano ⁇ c acid, propan-1-ol, 1,4-d ⁇ oxane, tetrahydrofuran, butan-l,4-d ⁇ ol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropy
  • compositions can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • compositions may further include additional drugs or excipients as appropriate for the indication.
  • composition and method examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention.
  • a compound of the present invention other than the one mentioned may be substituted in the example with similar results.
  • a tablet for oral administration according to the present invention comprising:
  • Example B A composition for topical administration according to the present invention is made, comprising:
  • the above composition is daily administered topically to the subject.
  • a composition for topical administration according to the present invention is made according to the method of Dowton et al, "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using the compound of Example 4 m lieu of cyclosporin A and using the Novasome 1 for the non-ionic liposomal formulation.
  • a human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.
  • a shampoo according to the present invention comprising:

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Abstract

La présente invention concerne de nouveaux composés et de nouvelles compositions qui sont particulièrement utiles pour le traitement de la chute de cheveux chez les mammifères, et qui visent notamment à freiner et /ou à stopper la chute de cheveux et à activer leur croissance. Ces composés et compositions peuvent également contribuer à combattre divers troubles comme la multirésistance médicamenteuse, le virus de l'immmunodéficience humaine (VIH), les affections cardiaques ou certains troubles neurologiques. Par ailleurs, ils peuvent être un moyen de lutter contre les parasites et de stimuler l'immunosuppression.
PCT/US1999/022213 1998-09-30 1999-09-24 Cetoamides 2-substitues WO2000018725A1 (fr)

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EP99969712A EP1117635A1 (fr) 1998-09-30 1999-09-24 Cetoamides 2-substitues
BR9914207-4A BR9914207A (pt) 1998-09-30 1999-09-24 Ceto-amidas 2-substituìdas
JP2000572187A JP2002525352A (ja) 1998-09-30 1999-09-24 ２−置換ケトアミド
AU60600/99A AU6060099A (en) 1998-09-30 1999-09-24 2-substituted ketoamides

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US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7749999B2 (en) 2003-09-11 2010-07-06 Itherx Pharmaceuticals, Inc. Alpha-ketoamides and derivatives thereof
CN102627654A (zh) * 2012-05-08 2012-08-08 山东大学 含异山梨醇结构单元的hiv-1蛋白酶抑制剂及其制备方法与应用
US8410088B2 (en) 2011-04-13 2013-04-02 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US8691507B2 (en) 2010-09-10 2014-04-08 Epizyme, Inc. Inhibitors of human EZH2 and methods of use thereof
US9006242B2 (en) 2012-10-15 2015-04-14 Epizyme, Inc. Substituted benzene compounds
US9175331B2 (en) 2010-09-10 2015-11-03 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
US9376422B2 (en) 2011-04-13 2016-06-28 Epizyme, Inc. Dihidropyridin-2-one benzamine compounds
US9394283B2 (en) 2012-04-13 2016-07-19 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
US10040782B2 (en) 2013-10-16 2018-08-07 Epizyme, Inc. Hydrochloride salt form for EZH2 inhibition
US11326212B2 (en) 2010-06-23 2022-05-10 British Columbia Cancer Agency Branch Biomarkers for non-hodgkin lymphomas and uses thereof
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

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EP0940390A1 (fr) * 1998-03-03 1999-09-08 Shiseido Company Limited Dérivé de (6-(méthyl substitué)-3-cyclohexényl) formamide, agent favorisant la croissance des cheveux et composition pour la peau à usage externe

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WO1993004679A1 (fr) * 1991-09-05 1993-03-18 Abbott Laboratories Immunomodulateurs macrocycliques
WO1996015101A1 (fr) * 1994-11-16 1996-05-23 Vertex Pharmaceuticals Incorporated Nouveaux derives d'acides amines presentant une meilleure activite contre la resistance a plusieurs medicaments
WO1997036869A1 (fr) * 1996-03-29 1997-10-09 Vertex Pharmaceuticals Incorporated Derives d'acide n-(2 oxoacetyle ou sulfonyle)-pyrrolidine/piperidine-2-carboxylique presentant une meilleure action dans les cas de resistance multiple aux anti-cancereux
EP0940390A1 (fr) * 1998-03-03 1999-09-08 Shiseido Company Limited Dérivé de (6-(méthyl substitué)-3-cyclohexényl) formamide, agent favorisant la croissance des cheveux et composition pour la peau à usage externe

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7749999B2 (en) 2003-09-11 2010-07-06 Itherx Pharmaceuticals, Inc. Alpha-ketoamides and derivatives thereof
US7897599B2 (en) 2003-09-11 2011-03-01 iTherX Pharmaceuticals Inc. Cytokine inhibitors
US7919617B2 (en) 2003-09-11 2011-04-05 iTherX Pharmaceuticals Inc. Cytokine inhibitors
US11326212B2 (en) 2010-06-23 2022-05-10 British Columbia Cancer Agency Branch Biomarkers for non-hodgkin lymphomas and uses thereof
US8691507B2 (en) 2010-09-10 2014-04-08 Epizyme, Inc. Inhibitors of human EZH2 and methods of use thereof
US9175331B2 (en) 2010-09-10 2015-11-03 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
US9333217B2 (en) 2010-09-10 2016-05-10 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
US8895245B2 (en) 2010-09-10 2014-11-25 Epizyme, Inc. Inhibitors of human EZH2 and methods of use thereof
US9949999B2 (en) 2010-09-10 2018-04-24 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
US9334527B2 (en) 2010-09-10 2016-05-10 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
US8410088B2 (en) 2011-04-13 2013-04-02 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US10155002B2 (en) 2011-04-13 2018-12-18 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US9090562B2 (en) 2011-04-13 2015-07-28 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US8765732B2 (en) 2011-04-13 2014-07-01 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US9376422B2 (en) 2011-04-13 2016-06-28 Epizyme, Inc. Dihidropyridin-2-one benzamine compounds
US10420775B2 (en) 2011-04-13 2019-09-24 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US9522152B2 (en) 2011-04-13 2016-12-20 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US11052093B2 (en) 2011-04-13 2021-07-06 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US9549931B2 (en) 2011-04-13 2017-01-24 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US9855275B2 (en) 2011-04-13 2018-01-02 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US9394283B2 (en) 2012-04-13 2016-07-19 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
US9872862B2 (en) 2012-04-13 2018-01-23 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
US10821113B2 (en) 2012-04-13 2020-11-03 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
US10245269B2 (en) 2012-04-13 2019-04-02 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
US11491163B2 (en) 2012-04-13 2022-11-08 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor
CN102627654A (zh) * 2012-05-08 2012-08-08 山东大学 含异山梨醇结构单元的hiv-1蛋白酶抑制剂及其制备方法与应用
US9006242B2 (en) 2012-10-15 2015-04-14 Epizyme, Inc. Substituted benzene compounds
US10098888B2 (en) 2012-10-15 2018-10-16 Epizyme, Inc. Substituted benzene compounds
US10092572B2 (en) 2012-10-15 2018-10-09 Epizyme, Inc. Substituted benzene compounds
US9532992B2 (en) 2012-10-15 2017-01-03 Epizyme, Inc. Substituted benzene compounds
US9089575B2 (en) 2012-10-15 2015-07-28 Epizyme, Inc. Substituted benzene compounds
US11642348B2 (en) 2012-10-15 2023-05-09 Epizyme, Inc. Substituted benzene compounds
US10710987B2 (en) 2013-10-16 2020-07-14 Epizyme, Inc. Hydrochloride salt form for EZH2 inhibition
US10040782B2 (en) 2013-10-16 2018-08-07 Epizyme, Inc. Hydrochloride salt form for EZH2 inhibition
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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AU6060099A (en) 2000-04-17
EP1117635A1 (fr) 2001-07-25
CN1332722A (zh) 2002-01-23
JP2002525352A (ja) 2002-08-13

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