WO2001010821A1 - Composes diceto exocycliques multivalents - Google Patents

Composes diceto exocycliques multivalents Download PDF

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Publication number
WO2001010821A1
WO2001010821A1 PCT/US2000/020567 US0020567W WO0110821A1 WO 2001010821 A1 WO2001010821 A1 WO 2001010821A1 US 0020567 W US0020567 W US 0020567W WO 0110821 A1 WO0110821 A1 WO 0110821A1
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nil
group
alkyl
independently
hydrogen
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PCT/US2000/020567
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English (en)
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Charles Raymond Degenhardt
David Joseph Eickhoff
John Mcmillan Mciver
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The Procter & Gamble Company
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Priority to AU63875/00A priority Critical patent/AU6387500A/en
Publication of WO2001010821A1 publication Critical patent/WO2001010821A1/fr

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    • 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
    • A61K8/42—Amides
    • 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
    • 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

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 are also 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 lmmunosuppression.
  • 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.
  • hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. I his 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
  • the next phase, telogen is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells.
  • telogen the initiation of a new anagen phase is caused by rapid cell proliferation in 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 also 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. 338, No. 9, February 26, 1998.
  • FK506 is a complex, macrocyclic molecule having the following structure:
  • the present inventors have discovered a novel class of multivalent compounds having an exocychc diketo moiety which arrest and / or reverse hair loss or promote hair growth but do not share the 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 hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporm 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 lmmunosuppression.
  • 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 in mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the present inventors have also surprisingly discovered that lmmunosuppression is not required for hair growth stimulation.
  • the present inventors have further discovered compounds that are useful for treating hair loss but are surprisingly 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.
  • the present inventors have surprisingly discovered that the multivalent compounds of the present mvention promote hair growth at equivalent and / or surprisingly enhanced levels. See copendmg provisional patent application serial numbers: 60/102,449 (Mclver et al.); 60/102,448 (Mclver et aU: 60/102,539 (Mclver et ah); 60/102,458 (Tiesman et aU; and 60/102,437 ( " Tiesman et al.). Without intending to be limited by theory, it is believed that the present multivalent compounds are often more active than their "single hgand" counterparts because they provide a higher concentration of pharmacophore at the receptor binding site.
  • any 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.
  • Q of structure I is independently selected from -S02- and -C(O)-. Because the definition at each occurrence of Q is independent of its definition at every other occurrence, the Q of Ji may be -S0 - even though the Q of J 2 is -C(O)-.
  • salt is a catiomc salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g , ammo) group.
  • Preferred catiomc 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 hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be approp ⁇ ate for mammalian use.
  • alkenyl is an unsubstituted or substituted 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 olefinic double bond. Non-hmitmg 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.
  • aryloxy is an oxygen radical having an aryl substituent.
  • An aryloxy radical may be substituted or unsubstituted.
  • alkyl is an unsubstituted or substituted 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 heterocychc.
  • Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazinyl, thiazolyl, py ⁇ midmyl, quinolmyl, t ⁇ azolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, mdenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, lmidazolyl, pyraxolyl, oxadiazolyl, mdohzmyl, mdolyl, isoindolyl, pu ⁇ n
  • 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 lmides are lmides 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.
  • Carbocyclic ring is a hydrocarbon ring radical.
  • Carbocyclic rings are monocychc or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocychc rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
  • Polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
  • Carbocyclic rings (carbocycles) may be substituted or unsubstituted.
  • cycloalkyl is a saturated carbocyclic or heterocychc ring radical
  • Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl Cycloalkyls may be substituted or unsubstituted.
  • heteroalkenyl is an alkenyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen Heteroalkenyls may be substituted or unsubstituted
  • heteroalkyl is an alkyl radical comprised of carbon atoms and one or more heteroatoms 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 comprised of carbon atoms and one or more heteroatoms 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 and / or the alkenyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may be substituted or unsubstituted.
  • heteroarylalkyl is an arylalkyl radical wherein the aryl group and / or the alkyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may be substituted or unsubstituted.
  • heterocyclic ring As used herein, "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 monocychc or are fused, bridged, or spiro polycyclic 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 may be substituted or unsubstituted.
  • heterocycloalkyl is a saturated heterocycle. Heterocycloalkyls may be substituted or unsubstituted.
  • a “lower” moiety is moiety having 1 to about 6, preferably 1 to about 4, carbon atoms.
  • ml is used herein with reference to a group, substituent, moiety, or the like, it is meant that that group, substituent, or moiety is not present.
  • a group, substituent, or moiety is ordinarily bonded to two or more other groups, substituents, or moieties, the others are bonded together in lieu of the group, substituent, or moiety which is ml.
  • A-B-C wherein B is nil
  • C is nil
  • pharmaceutically acceptable means suitable for use in a human or other mammal, preferably 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 m the manner of this invention.
  • substituted means having one or more substituent groups each independently selected from alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, amido, alkylamino, cyano, halo, carboxy, alkoxyacyl (e.g., carboethyoxy), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., pipe ⁇ dmyl, morpholmyl, pyrrohdmyl), imino, thioxo, hydroxyalkyl, aryloxy, and arylalkyl, preferably alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, alkylamino, halo, thiol, and aryloxy, more preferably alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, alkylamino, halo
  • the compounds of the present invention have the structure:
  • each V is -CU-, wherein U is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, (b) each G is selected from the group consisting of nil, O, S, and NR ]7 ;
  • each R ⁇ is independently selected from the group consisting of nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;
  • each Z is independently a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycle optionally containing one or more additional heteroatoms selected from the group consisting of O, N, S, S(O), S(O) 2 , and P((0)OK);
  • each K is independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;
  • each W is independently selected from the group consisting of nil, hydrogen, and lower alkyl;
  • each A is independently selected from the group consisting of nil and alkyl
  • each X and Y is independently selected from the group consisting of C(O), P(O), S(0) 2 , N, O, and S, wherein:
  • each R 5 and R 6 is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein each R 5 and R 6 bonded to the same R 4 may optionally be bonded together to form a carbocyclic or heterocychc ring; (m) each R 7 , R 8 , R 9 , and R 10 is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, immo, -R
  • each R 7 and R 8 bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring;
  • each R )4 and R 15 is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; (o) each
  • the present compounds are "multivalent" meaning they have two or more groups selected from J], J 2 , J 3 , and J (collectively described as J radicals) which can potentially bind with a receptor binding site.
  • the linker, L may be any mechanism through which two or more of Jj, J 2 , J 3 , and J 4 may be covalently bonded together
  • the linker may itself, but need not, participate in binding which a receptor binding site.
  • a preferred linker will optimize, e g , physiochemical and / or pharmacokmetic properties of the compound of the present invention.
  • linker is a mechanism for covalent bonding, the ordinarily skilled artisan will recognize that the linker may be selected from a broad range of structures.
  • a simple, and preferred, linker is merely a covalent bond which links one J radical to one or more others, herein referred to as "bond”.
  • Another preferred linker is a heteroatom diradical e.g., -O- or -N(OH)-, or triradical, e.g.:
  • Preferred heteroatom diradicals and triradicals are selected from oxygen, nitrogen, and sulfur; more preferably oxygen and nitrogen; and most preferably oxygen.
  • WTierein nitrogen is the linker and J 3 and J 4 are nil, the nitrogen preferably bears a hydrogen, but may be substituted wherein the preferred substituent is alkyl.
  • linkers include radicals such as, for example, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl.
  • radicals may be substituted or unsubstituted.
  • Preferred among these examples are alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl.
  • alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl most preferably aryl.
  • Most preferred among these examples are phenyl naphthyl, and biphenyl.
  • linkers include ethers, thioethers, amines, amides, ureas, carbamates, sulfonamides, thiocarbamates, esters, thioesters, and ketones.
  • L H a radical selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl, preferably alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, more preferably alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl, and most preferably phenyl, naphthyl, and biphenyl.
  • the linker is a bis-amide linker, a retro bis- amide linker, a polyether urea linker, or a polyether linker. These linkers are described below.
  • the "attachment locations" are the points at which a J radical is linked to L.
  • polyether urea linker An example of a polyether urea linker is:
  • polyether linkers examples are:
  • linkers are selected from bond, aryl, alkyl, biaryl ether (i.e , aryl-O-aryl), biaryl methyl (i.e , aryl-CH 2 -aryl), -0-, -S-, and -NH-, more preferably bond, lower alkyl, aryl, biaryl ether, -0-, and-NH-, even more preferably bond, aryl, biaryl ether, and -0-, with the most preferable among these being phenyl, naphthyl, biphenyl, biphenyl ether, biphenyl methyl, methyl, and -0-.
  • R is not nil, L is most preferably selected from bond, alkyl, aryl, -0-, -S-, and -NH-.
  • Rj is nil, L is most preferably selected from phenyl, naphthyl, and biphenyl.
  • the compounds of the present invention have two or more radicals selected from J 1 ; J 2 , J 3 , and J 4 .
  • J] and J 2 are each, independently, a radical of structure I.
  • J 3 and J 4 are each, independently, selected from nil and a radical of structure I.
  • J 2 , J 3 , and J 4 are each, independently, a radical of structure I.
  • J 1 ; J 2 , and J 3 are each, independently, a radical of structure I, and J 4 is nil.
  • Ji and J 2 are each, independently, a radical of structure I, and J 3 and J 4 are each nil.
  • Each Z ring system is, independently, saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9- membered heterocycles.
  • each Z ring system is, independently, a 5-, 6-, or 7- membered heterocycle, more preferably, independently, a 5- or 6-membered heterocycle.
  • Z is saturated.
  • each ring system is the V substituents, each of which is, independently, -CU-, wherein each U is independently selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, preferably hydrogen, alkyl, and arylalkyl, and most preferably hydrogen (of course, each C of -CU- is a carbon atom).
  • Each Z ring may independently and optionally contain one or more heteroatoms or heteromoieties (herein collectively described as heteroatoms for simplicity) wherein the heteroatoms are independently selected from oxygen (O), nitrogen (N), sulfur (S), sulfoxide (S(O)), sulfone (S(0) 2 ), and phosphonate (P((0)OK)).
  • heteroatoms are independently selected from the group consisting of O, N, S, S(O), and S(0) 2 , but more preferably each of the Z rings do not contain any heteroatoms.
  • N is a heteroatom within the Z ring
  • the N heteroatom will be substituted, most preferably with hydrogen, alkyl, or oxo; and / or the linker L is covalently bonded to this heteroatom or the substituent thereon.
  • the S(O), S(0) 2 , and P(0)OK heteroatoms are depicted below in Table 1 to exemplify. Table 1
  • G is selected from nil, O, S, and NR , wherein NR 17 is selected from hydrogen and alkyl.
  • G is selected from O, S, and NR ⁇ 7 , preferably O and NR ⁇ , and most preferably, G is NR ]7 .
  • R 17 is selected from hydrogen and alkyl, most preferably R ]7 is hydrogen.
  • G is ml
  • the respective V is directly attached to the respective diketo moiety.
  • each Ri moiety is attached to the diketo (-C(O)C(O)-) moiety
  • R moiety is independently selected from nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.
  • a R] moiety is nil, the linker (L) is bonded directly to the respective diketo moiety.
  • L is bonded to Jj through the diketo moiety of J]
  • any or each (more preferably each) R) moiety is nil
  • L is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl.
  • Each R) moiety may be independently substituted with at least one substituent other than hydrogen.
  • substituents -0-alkyl-C(0)OR 32 , and -0-alkyl-C(0)NHR 32 , wherein R 32 is selected from hydrogen and alkyl may also substitute on any of the Ri moieties.
  • Each Ri moiety is preferably independently selected from ml, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl, even more preferably nil, aryl, arylalkyl, and heteroarylalkyl, most preferably aryl Preferred aryls are substituted or unsubstituted phenyl and biphenyl.
  • the most preferred aryl for each Ri moiety is substituted aryl (most preferably substituted phenyl), particularly aryl having at least one alkoxy substituent.
  • Particularly preferred R, moieties are shown below m Table 2.
  • each Z ring is, independently, the A-X-Y-T-R side chain which is substituted, as described herein, by R 2 , R 3 , R 5 , and R ⁇ .
  • Each A moiety of the side chains is, independently, selected from nil and alkyl. Most preferably, each A moiety is nil. Of course, wherein A is nil, the respective X moiety is directly attached to the respective Z ring. For example, wherein the A moiety of Ji is nil, then the X moiety of J] is directly attached to the Z ring of J].
  • each side chain is dependent upon the structure of the Y moiety of the same side chain and vice versa.
  • each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and
  • Each X and Y is, independently, substituted by R 3 and R 2 , respectively.
  • Each R 3 and R 2 is, independently, selected from nil, hydrogen, alkyl, and arylalkyl Wherein X is O or S, then the R 3 attached thereto is nil Wherein Y is O or S, then the R 2 attached thereto is nil.
  • X is P(O), then the R 3 attached thereto is nil, and wherein Y is P(O) then the R 2 attached thereto is nil.
  • X is N, then the R 3 attached thereto is selected from hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably hydrogen.
  • Y is N, then the R 2 attached thereto is selected from hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably hydrogen.
  • Each T moiety is selected from ml, N, N(R 18 ), and O, preferably nil, N, and O; with the proviso that wherein when Y is selected from the group consisting of N, O, and S, then T is nil
  • the substituent R 18 is selected from alkyl and arylalkyl, preferably alkyl. Wherein a T moiety is nil, the respective Y and R 4 moieties are directly covalently attached to each other. Regardless of the identity of Y, T is most preferably nil.
  • Each R 4 moiety is, independently, alkyl
  • the preferred alkyls for each R follow the preferred limitations set forth above, with the most preferred R ⁇ being a methylene or methyne group (1 e , a C
  • Each of the R 5 and Re moieties are directly attached to the respective R 4 .
  • Each R 5 and R 6 is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, or wherein each R 5 and R 6 bonded to the same ( may be optionally bonded together to form a carbocyclic or heterocychc ring.
  • each R 5 and R « is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. More preferably, each R 5 and R ⁇ is, independently, selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl. Most preferably, each R 5 and R 6 is, independently, arylalkyl. It is often preferred that the R 5 and R ⁇ , moieties which are bonded to the same are equivalent moieties Of course, each R 5 and R 6 may be, independently, substituted. Exemplary R 5 and Re moieties are shown m Table 3 below.
  • Each of the Z rings may be substituted at the 2-pos ⁇ t ⁇ on by an additional moiety, W.
  • W moiety is, independently, selected from nil, hydrogen, and lower alkyl, preferably hydrogen and lower alkyl, most preferably hydrogen.
  • the most preferable lower alkyl for W is methyl.
  • R 7 , R 8 , R 9 , and R 10 substituents are each, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, lmmo, -R] 4 SR ⁇ 5 , - R 14 S(0 2 )R 15 , -R 14 S(0)R 15 , -R 14 C(0)R I5 , -R 14 C(0)NR, 5 R 16 , -R 14 C(0)OR 15 , -R ⁇ 4 OR 15 , -R NR 15 R 16 , -R ⁇ 4 P(0)NRi5Ri6, -Ri4P(0)ORi 5 Ri 6 , and a spiro moiety, and wherein each R 7 and R 8
  • At least one R 7 , R 8 , R 9 , and Rio is not ml or hydrogen.
  • Each R, 4 and R, 5 is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl.
  • R 16 is selected from hydrogen and alkyl.
  • each R 7 , R 8 , R 9 , and R 10 is, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R 14 SR 15 , -R 14 S(0 2 )R 15 , -R 14 S(0)R 15 , -R 14 C(0)R 15 ,
  • each R 7 and R 8 bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring.
  • each R 7 , R 8 , R 9 , and R ]0 is, independently, selected from ml, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R 14 SR ⁇ 5 , -R 14 S(0 2 )R,5, -R, 4 S(0)R 15 , -R I4 C(0)R,5, -R 14 C(0)NR 15 R, 6 , -R ⁇ 4 OR 15 , -R 14 NR 15 R 16 , and a spiro moiety, and wherein each R 7 and R 8 bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring.
  • each R 7 , R 8 , R 9 , and R ]0 is, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, - R, 4 C(0)R, 5 . -R 14 C(0)NR 15 R 16 , -R )4 OR 15 -R ⁇ 4 OR 15 (particularly -0-CH 2 -phenyl; wherein R, 4 is ml and Ri 5 is arylalkyl (in this case, benzyl),
  • each R 7 and R 8 bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring.
  • each R 7 and R 8 bonded to the same Z ring is bonded together to form an aromatic or saturated, carbocyclic or heterocychc ⁇ ng which is fused to said same Z ring.
  • R 7 and R 8 are bonded together to form an aromatic or saturated, carbocyclic or heterocychc second ring wherein the second ring is fused to Z, the second ring may, of course, be substituted or unsubstituted.
  • a preferred second ring is phenyl, optionally substituted.
  • a more preferred second ring is unsubstituted phenyl.
  • J J 2 , J 3 , and J may be equivalent or different radicals.
  • the J radicals of the compound are equivalent, particularly due to efficiency of synthesis and / or optimization of the binding moiety.
  • the J radicals may be attached through L at any atom ("attachment locations") on each of the radicals.
  • Preferred attachment locations include R, of each of J], J 2 , J 3 , and J .
  • Rj is the attachment location with respect to J 1; the R) of Jj is directly covalently bonded to L.
  • Other preferred attachment locations include any of R 5 , Rg, R 7 , R g , R 9 , and R ⁇ 0 , preferably R 5 and R ⁇
  • the more preferred attachment locations for each of J], J 2 , J 3 , and J 4 are R,, R 5 , and Re, most preferably R] (or wherein R t is nil, the respective diketo moiety)
  • Non-limiting examples of compounds linked through each R 7 or through each Z ring in the above manners include:
  • L is -0-L H -0-, and L H is preferably selected from alkyl, aryl, heteroalkyl, and heteroaryl;
  • each R 7 and R 8 are bonded together to form an aromatic or saturated, carbocyclic or heterocychc second ring wherein the second ring is fused to Z, wherein the second ring is optionally substituted, and the linker L is attached through the second ring or any optional substituents thereon is as follows:
  • Preferred compounds of the present invention are disclosed below in Tables 4 - 16.
  • each R 5 is independently selected from the group consisting of hydrogen and 3-phenylpropyl
  • each R 6 is independently selected from the group consisting of phenyl and 3-phenylpropyl.
  • G is nil
  • L is aryl (preferably phenyl or biphenyl).
  • each R] is not nil, L is -0-.
  • each R] is independently selected from the group consisting of ml, phenyl, 4- methylphenyl, and 3,4-dimethoxyphenyl; each R 5 is independently selected from the group consisting of hydrogen and 3-phenylpropyl; and each Re is independently selected from the group consisting of phenyl and 3-phenylpropyl.
  • each G is nil
  • L is aryl (preferably phenyl or biphenyl).
  • each R, is not nil, L is -0-.
  • each Rj is independently selected from the group consisting of nil, 4-methylphenyl, 2- thienyl, 2,4,6-trnsopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-d ⁇ methoxyphenyl, 3,4,5-tr ⁇ methoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- d ⁇ methylammo)naphthyl, 4-methoxyphenyl, 5 -methylphenyl, 4- ⁇ odophenyl, 2,4,6- t ⁇ methylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-n ⁇ trophenyl, 3-n ⁇ trophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-tr ⁇ methoxy)phenyl,
  • each Ri is independently selected from the group consisting of nil, 4-methylphenyl, 2- thienyl, 2,4,6-tr ⁇ sopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-d ⁇ methoxyphenyl, 3,4,5-tr ⁇ methoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- d ⁇ methylammo)naphthyl, 4-methoxyphenyl, 5 -methylphenyl, 4- ⁇ odophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-mtrophenyl, 3-n ⁇ trophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-tr ⁇ methoxy)phenyl, and 3,4
  • each R 6 is independently selected from the group consisting of hydrogen and 3-phenylpropyl; and each R 5 is independently selected from the group consisting of phenyl and 3-phenylpropyl.
  • each R] is independently selected from the group consisting of 4-methylphenyl, 2- thienyl, 2,4,6-trnsopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-d ⁇ methoxyphenyl, 3,4,5-t ⁇ methoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- d ⁇ methylam ⁇ no)naphthyl, 4-methoxyphenyl, 5 -methylphenyl, 4- ⁇ odophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-n ⁇ trophenyl, 3-n ⁇ trophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-tr ⁇ methoxy)phenyl, and 3,4- dimer
  • each R is independently selected from the group consisting of 4-methylphenyl, 2- thienyl, 2,4,6-trnsopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-d ⁇ methoxyphenyl, 3,4,5-tr ⁇ methoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- d ⁇ methylammo)naphthyl, 4-methoxyphenyl, 5 -methylphenyl, 4- ⁇ odophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-n ⁇ trophenyl, 3-n ⁇ trophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-tr ⁇ methoxy)phenyl, and 3,4- dimerth
  • J 3 and J 4 are each nil, L is biphenyl, R, of J] is ml,
  • J 3 and J 4 are each nil, L is phenyl, R ⁇ of Ji is nil,
  • J 3 and J 4 are each nil, L is phenyl, R] of J t is biphenyl, R, of J 2 is biphenyl, Re of Ji is heteroarylalkyl, R 5 of J] is heteroalkyl substituted with oxo, R 6 of J 2 is heteroarylalkyl, and R 5 of J 2 is heteroalkyl substituted with oxo:
  • J 3 and J 4 are each nil, Ri of Ji is phenyl, R] of J is phenyl, and L is bond:
  • J 3 and J 4 are each nil, Ri of Ji is phenyl, Rj of J 2 is phenyl, and L is oxygen:
  • L is -O-phenyl-O-
  • Ri of Ji is biphenyl
  • R] of J is biphenyl
  • J 3 is nil
  • J 4 is nil:
  • L is -0-C(0)-phenyl-C(0)-0-
  • Rj of Ji is biphenyl
  • Ri of J 2 is biphenyl
  • J 3 is nil
  • J is nil:
  • the present compounds are useful for treating hair loss, 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 a hair growth promoter is applied.
  • the Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
  • a vehicle control group Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound of the present invention.
  • 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.
  • a typical study design is shown in Table 19 below:
  • the vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO).
  • 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 skin.
  • the lmmunosuppression assay herein predicts the immunosuppressive activity of a compound of the present mvention.
  • the assay is performed as follows:
  • Spleens are excised from euthanized (C0 2 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 cent ⁇ fugation 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-mactivated fetal bovme serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 ⁇ g/mL), L-glutamme (2 mM), 2-mercaptoethanol (10 5 M), and N-2-hydroxyethylp ⁇ perazme-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.
  • GF/C filter plates commercially available from Packard, Downers Grove, IL
  • solubihzed in Microscmt 20 Packard
  • 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 (cyclosporm 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 cyclosporm 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 m 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 April 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 m 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.
  • the compounds of the present invention may have one or more chiral center.
  • one optical isomer including diastereomers and enantiomers
  • another optical starting materials for example by chiral starting materials, catalysts or solvents
  • 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.
  • Example 1 la la. 4,4'-Biphenylglyoxylic acid 4,4'-d ⁇ acetylb ⁇ phenyl (5 g, 21 mmol, Ald ⁇ ch Chemical Co., Milwaukee, WI) is dissolved in anhydrous pyridme (65 mL) at ambient temperature.
  • Selenium dioxide (9.3 g, 83.9 mmol) is added in one portion and the resulting mixture is carefully heated to reflux After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyridme, and concentrated under reduced pressure.
  • the reaction is stirred for 19 hours at room temperature, then poured onto ice-cold 0.1N HCl (600 mL) and extracted with ethyl acetate (600 mL). The layers are separated and the organic layer washed successively with brine (100 mL), saturated NaHC0 3 solution (300 mL), and brine (2 x 200 mL). The organic solution is dried over MgS0 4 , filtered, and concentrated in vacuo. Purification of the product by chromatography over silica gel affords the desired amide Id.
  • c ⁇ -2-Amino-l-cyclohexanecarboxylic acid, l,7-diphenyl-4-heptylamide The amide Id (7.54 g, 15.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (120 mL) is added dropwise over a 5 minute period. After 2 hours the mixture is cooled in an ice-bath and saturated K 2 C0 3 solution is added until the pH is approximately 8. The mixture is transferred to a separator funnel containing dichloromethane (200 mL) and water (200 mL) and shaken. The organic layer is separated and washed with water (200 mL) before drying over MgS0 4 . The mixture is filtered and concentrated in vacuo to afford the desired amine le.
  • 1,3,5-Triglyoxylbenzene 1,3,5-T ⁇ acetylbenzene (5 g, 19.2 mmol; ACROS Organics, Pittsburgh, PA) is dissolved m anhydrous pyridme (65 mL) at ambient temperature.
  • Selenium dioxide 13 1 g, 118.1 mmol is added in one portion and the resulting mixture is carefully heated to reflux. After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyridme, and concentrated under reduced pressure.
  • 1,3-Phenylglyoxylic acid 1,3-D ⁇ acetylbenzene (3.41 g, 21 mmol, Ald ⁇ ch Chemical Co., Milwaukee, WI) is dissolved m anhydrous pyridme (65 mL) at ambient temperature.
  • Selenium dioxide (9.3 g, 83.9 mmol) is added in one portion and the resulting mixture is carefully heated to reflux. After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyridme, and concentrated under reduced pressure. The residue is slurried in ethyl acetate (100 mL) and 1 N HCl (100 mL) until dissolution is complete.
  • the compounds herein may be used for the treatment of such conditions as, for example, treating hair loss in 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.
  • 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 lmmunomodulatory 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 m congestive heart failure
  • the present compounds may also be useful in 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 No. 5,830,915, Pikul et al., assigned to The Procter & Gamble Co., filed August 26, 1997; U S. Patent Application Serial No. 08/918,317, Natchus et al., assigned to The Procter & Gamble Co., filed August 26, 1997; U.S Patent Application Serial No.
  • the compounds of the present invention are formulated into pharmaceutical compositions for use in treatment or prophylaxis of conditions such as the foregoing.
  • Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. (1990).
  • a compound of the present invention is administered per day for systemic administration. It is understood that these 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, in 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 in 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 mvention.
  • 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; alg ic 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, lsotonic salme, and pyrogen-free water.
  • Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrohdone, 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-mducmg 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.
  • 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 in 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 sublmgual, 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, microcrystalhne 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 mvention may be m 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 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.
  • carrier materials 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.
  • compositions suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
  • Emollients such as stearyl alcohol, glyceryl mono ⁇ cinoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane-l,3-d ⁇ ol, mink oil, cetyl alcohol, rso-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, di-n-butyl sebacate, isopropyl my ⁇ state, zso-propyl palmitate, zso-propyl stearate, butyl stearate, polythylene glycol, triethylene glycol, lanolm, sesame oil, coconut oil, arachis oil,
  • the compounds of the present invention may also be administered in the form of hposome delivery systems, such as small unilamellar vesicles, large umlamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholmes.
  • 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 Cyclosporm A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences. Vol. 3, pp.
  • the compounds of the present invention may also be administered by iontophoresis. See, e.g., www.umpr.it/arpa/dipfarm/erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugs", Pharm. Res., Vol. 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol 70, pp.
  • compositions of the present invention may also optionally comp ⁇ se 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 mvention.
  • 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 in 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, minoxidil and minoxidil derivatives such as ammexil and such as those described m 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. Patent 5,760,043, issued June 2, 1998, U.S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, (all of which are herein incorporated by reference), and cromakahn and diazoxide can be used as an additional hair growth stimulant in the compositions herein.
  • minoxidil and minoxidil derivatives such as ammexil and such as those described m
  • minoxidil and minoxidil derivatives such as ammexil and such as those described m
  • minoxidil and minoxidil derivatives such as
  • antiandrogens include, but are not limited 5- ⁇ -reductase inhibitors such as fineste ⁇ de and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and m 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.
  • 5- ⁇ -reductase inhibitors such as fineste ⁇ de and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and m Nane et al., Cancer Research 58, "Effects of Some Novel Inhibitors of C17,20-Lyase and 5 ⁇ -Reductase in vitro and in vivo
  • Another suitable class of optional hair growth stimulants are immunosuppressants or non-immunosuppressants such as 1) cyclosporm and cyclosporm analogs including those described in U.S. Provisional Patent Application No.
  • Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zmc pyrithione, ltraconazole, asiatic acid, hmokitiol, mipirocm and those described m EPA 0,680,745 (herein incorporated by reference), chnacycm hydrochlonde, benzoyl peroxide, benzyl peroxide and minocyclm.
  • antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zmc pyrithione, ltraconazole, asiatic acid, hmokitiol, mipirocm and those described m EPA 0,680,745 (herein incorporated by reference), chnacycm hydrochlonde, benzoyl peroxide, benzyl peroxide and minocyclm.
  • Anti-mflammato ⁇ es can also be incorporated into the compositions herein as an optional hair growth stimulant.
  • suitable anti-mflammatories may include glucocorticoids such as hydrocortisone, mometasone furoate and predmsolone, nonsteroidal anti-inflammato ⁇ es including cyclooxygenase or hpoxygenase inhibitors such as those described in U.S. Patent 5,756,092, and benzydamme, salicylic acid, and those compounds described m 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 m U.S. Provisional Patent Application No. 60/136,996, Zhang et al., “Method of Treating Hair Loss", filed June 1, 1999, U.S. Provisional Patent Application No 60/137,024, Zhang et al., "Method of Treating Hair Loss Using Biphenyl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No.
  • Prostaglandin agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein.
  • suitable prostaglandms agonists or antagonists include latanoprost and those described m WO 98/33497, Johnstone, published August 6, 1998, WO 95/1 1003, Stje ⁇ ischantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
  • Suitable retinoids may include isotretinoin, acitretm, and tazarotene.
  • 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 flavinoids, 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, sapomns 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 glycosaminoglycanase 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-limitmg 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-hydroxyprop ⁇ on ⁇ c 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-isopropyl
  • kits comprising a compound and / or composition of the present invention and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss in mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth.
  • the kit may comprise a compound and / or composition of the present invention and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.
  • 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 is made,
  • composition for topical administration comprising:
  • a human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, 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 Cyclosporm A: I. An in vitro Study Using Hairless Mouse Skin", S.T P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclosporm 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.
  • Example D A shampoo according to the present invention is made, comprising

Abstract

L'invention concerne des composés et des compositions convenant particulièrement au traitement de la perte de poils chez des mammifères, qui consiste à arrêter et/ou à inverser la perte de poils et à stimuler la croissance des poils. Ces composés et ces compositions peuvent également servir à lutter contre une variété de troubles, notamment la résistance aux antibiotiques, le virus de l'immunodéficience humaine (VIH), les affections cardiaques et certains troubles neurologiques. Par ailleurs, ils peuvent servir à lutter contre les parasites et à provoquer l'immunosuppression. Ces composés présentent la structure (A), dans laquelle L représente un lieur par lequel J1, J2, J3 et J4 sont attachés; où J1 et J2 représentent chacun, indépendamment, des radicaux représentés par la structure (I); et J3 et J4 sont chacun, indépendamment, choisis dans le groupe constitué de zéro et de radicaux représentés par la structure (I), laquelle se présente de la manière suivante.
PCT/US2000/020567 1999-08-05 2000-07-28 Composes diceto exocycliques multivalents WO2001010821A1 (fr)

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AU63875/00A AU6387500A (en) 1999-08-05 2000-07-28 Multivalent exocyclic diketo compounds

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US60/147,313 1999-08-05

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Cited By (1)

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US7749999B2 (en) 2003-09-11 2010-07-06 Itherx Pharmaceuticals, Inc. Alpha-ketoamides and derivatives thereof

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US5543423A (en) * 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity
WO1999062486A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings Inc. Compositions pour la croissance des cheveux a base de n-oxydes de ketones, de thioesters, d'amides ou d'esters heterocycliques, et utilisation de ces compositions
WO2000018358A2 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Methode de traitement de la chute des cheveux au moyen de cetoamides
WO2000018733A1 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Cetoamides heterocycliques 2-substitues destinees au traitement de la chute de cheveux chez les mammiferes

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US5543423A (en) * 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity
WO1999062486A1 (fr) * 1998-06-03 1999-12-09 Gpi Nil Holdings Inc. Compositions pour la croissance des cheveux a base de n-oxydes de ketones, de thioesters, d'amides ou d'esters heterocycliques, et utilisation de ces compositions
WO2000018358A2 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Methode de traitement de la chute des cheveux au moyen de cetoamides
WO2000018733A1 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Cetoamides heterocycliques 2-substitues destinees au traitement de la chute de cheveux chez les mammiferes

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Publication number Priority date Publication date Assignee Title
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

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