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WO2025214484A1 - Thyromimétique pour le traitement de l'alopécie areata - Google Patents

Thyromimétique pour le traitement de l'alopécie areata

Info

Publication number
WO2025214484A1
WO2025214484A1 PCT/CN2025/088568 CN2025088568W WO2025214484A1 WO 2025214484 A1 WO2025214484 A1 WO 2025214484A1 CN 2025088568 W CN2025088568 W CN 2025088568W WO 2025214484 A1 WO2025214484 A1 WO 2025214484A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
group
aryl
heterocycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/088568
Other languages
English (en)
Inventor
Bin Liang
Jingzi Jason WU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ascletis Pharma China Co Ltd
Original Assignee
Ascletis Pharma China Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ascletis Pharma China Co Ltd filed Critical Ascletis Pharma China Co Ltd
Publication of WO2025214484A1 publication Critical patent/WO2025214484A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/094—Esters of phosphoric acids with arylalkanols
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/36—Amides thereof
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3886—Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
    • C07F9/3891—Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
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    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
    • C07F9/4808—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof the acid moiety containing a substituent or structure which is considered as characteristic
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Definitions

  • the present invention is directed toward the use of thyromimetic compounds that are thyroid receptor ligands, pharmaceutically acceptable salts thereof, and to prodrugs of these compounds for preventing, treating, or ameliorating alopecia areata such as Androgenetic Alopecia (AGA) .
  • AGA Androgenetic Alopecia
  • Thyroid hormones are synthesized in the thyroid in response to thyroid stimulating hormone (TSH) , which is secreted by the pituitary gland in response to various stimulants (e.g., thyrotropin-releasing hormone (TRH) from the hypothalamus) .
  • Thyroid hormones are iodinated O-aryl tyrosine analogues excreted into the circulation primarily as 3, 3', 5, 5'-tetraiodothyronine (T4) .
  • T4 is rapidly deiodinated in local tissues by thyroxine 5'-deiodinase to 3, 3', 5'-triiodothyromne (T3) , which is the most potent TH.
  • T3 is metabolized to inactive metabolites via a variety of pathways, including pathways involving deiodination, glucuronidation, sulfation, deamination, and decarboxylation. Most of the circulating T4 and T3 is eliminated through the liver.
  • THs have profound physiological effects in animals and humans.
  • Hyperthyroidism is associated with increased body temperature, general nervousness, weight loss despite increased appetite, muscle weakness and fatigue, increased bone resorption and enhanced calcification, and a variety of cardiovascular changes, including increased heart rate, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure. Hypothyroidism is generally associated with the opposite effects.
  • TRs thyroid hormone receptors
  • TRs belong to the nuclear receptor superfamily, which, along with its common partner, the retinoid X receptor, form heterodimers that act as ligand-inducible transcription factors.
  • TRs have a ligand binding domain and a DNA binding domain and regulate gene expression through ligand-dependent interactions with DNA response elements (thyroid response elements, TREs) .
  • TRa and TR ⁇ are encoded by two distinct genes (TRa and TR ⁇ ) , which produce several isoforms through alternative splicing (Williams, MoI. Cell Biol.
  • TR ⁇ -1 is ubiquitously expressed in the rat with highest expression in skeletal muscle and brown fat. TR ⁇ -1 is also ubiquitously expressed with highest expression in the liver, brain and kidney. TR ⁇ -2 is expressed in the anterior pituitary gland and specific regions of the hypothalamus as well as the developing brain and inner ear. In the rat and mouse liver, TR ⁇ -1 is the predominant isoform (80%) .
  • the TR isoforms found in human and rat are highly homologous with respect to their amino acid sequences which suggest that each serves a specialized function.
  • Alopecia areata is a common problem not only in men but also in women. alopecia areata occurs for example due to physiological or pathological processes or is promoted by drugs, e.g. retinoids, chemotherapeutic agents, cholesterol, lowering agents etc., In many cases patients do not only suffer from hair loss, but there is also a lack ofhair regrowth. Both defects can lead to partial or full baldness.
  • drugs e.g. retinoids, chemotherapeutic agents, cholesterol, lowering agents etc.
  • One aspect of the present application relates to a method for preventing, treating, or ameliorating alopecia areata , comprising administering a therapeutically effective amount of a thyromimetic compound or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein said thyromimetic compound is a compound of Formula I:
  • k is an integer from 0-4;
  • n is an integer from 0-3;
  • n is an integer from 0-2;
  • p is an integer from 0-1;
  • each R a is independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 4 alkyl, halogen, -OH, optionally substituted-O-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-S-C 1 -C 4 alkyl, -NR b R c , optionally substituted-C 2 -C 4 alkenyl, and optionally substituted-C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • each R b is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl;
  • each R c is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl, optionally substituted-C (O) -C 1 -C 4 alkyl, and -C (O) H;
  • R 1 , R 2 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted-C 1 -C alkyl, optionally substituted-S-C 1 -C 3 alkyl, optionally substituted-C 2 -C 4 alkenyl, optionally substituted-C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-O-C 1 -C 3 alkyl, hydroxy and cyano; or
  • R 8 and R 9 are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted-C 1 -C 4 alkyl, optionally substituted-S-C 1 -C 3 alkyl, optionally substituted-C 2 -C 4 alkenyl, optionally substituted-C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-O-C 1 -C 3 alkyl, hydroxy, - (CR a 2 ) aryl, - (CR a 2 ) cycloalkyl, - (CR a 2 ) heterocycloalkyl, -C (O) aryl, -C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano;
  • each R d is selected from the group consisting ofoptionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, optionally substituted- (CR b 2 ) n heterocycloalkyl and-C (O) NR f R g ;
  • each R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted- (CR a 2 ) n aryl, optionally substituted - (CR a 2 ) n cycloalkyl, and optionally substituted- (CR a 2 ) n heterocycloalkyl;
  • R f and R g are each independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted - (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocyclo alkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting ofoptionally substituted-C 1 -C 4 alkyl, -OR b , o
  • each R h is selected from the group consisting of optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocycloalkyl;
  • X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidi nedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, pho sphonic acid monoester, phosphinic acid, or a prodrug thereof; and pharmaceutic ally acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
  • Fig 1. shows the Mean Plasma Concentration-Time Profile of the compounds of present application
  • Fig. shows the Mean Plasma Concentration-Time Profile of the compounds of present application
  • Fig 4. shows the Mean Plasma Concentration-Time Profile of Compound 32 after subcutaneous injection
  • Fig. shows the Mean Plasma Concentration-Time Profile of Compound 34 after subcutaneous injection
  • Fig. 7. shows the Plasma concentration-time profiles of Compound 54 after subcutaneous injection
  • Fig 8. shows the Plasma concentration-time profiles of Compound 52 after subcutaneous injection
  • Fig 9. shows the Plasma concentration-time profiles of Compound 53 after subcutaneous injection
  • Fig. 10 shows the Plasma concentration-time profiles of Compound 29 and 30 after subcutaneous injection.
  • Fig. 11. shows the Plasma concentration-time profiles of Compound 52 after subcutaneous injection.
  • alopecia areata is an autoimmune condition affecting hair follicles causing hair loss and lack ofhair regrowth. It typically presents with discrete bald patches on the scalp but can cause hair loss from all hair-bearing areas on the body.
  • Alopecia is a Latin term meaning hair loss, and areata refers to the patchy nature of the hair loss.
  • the term alopecia areata is considered an umbrella term, which encompasses a number of variants including alopecia areata totalis or universalis, ophiasis, ophiasis inversus, and diffuse alopecia areata.
  • AGA Androgenetic Alopecia
  • T groups that have more than one atom are read from left to right wherein the left atom of the T group is connected to the phenyl group bearing the R 1 and R 2 groups, and the right atom of the T group is linked to the carbon, phosphorus, or other atom in X or E.
  • T is-O-CH 2 -or-N (H) C (O) -it means-phenyl-O-CH 2 -X and-phenyl-N (H) C (O) -X.
  • alkyl refers to a straight or branched or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-bntyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which maybe optionally substituted. Alkyl groups are C 1 -C 20 .
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl. pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • biasing represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
  • optionally substituted or “substituted” includes groups substituted by one, two, three, four, five, or six substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower-carboxamidoalkyla
  • Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
  • -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "Heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group.
  • alkylaryl- refers to an aryl group substituted with an alkyl group.
  • Lower alkylaryl- refers to such groups where alkyl is lower alkyl.
  • lower referred to herein in connection with organic radicals or compounds respectively refers to 6 carbon atoms or less. Such groups may be straight chain, branched, or cyclic.
  • cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
  • heterocyclic refers to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6 atoms, containing at least one heteroatom, in a further aspect are 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring.
  • the heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocycHc groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
  • arylamino (a) , and “aralkylamino” (b) , respectively, refer to the group-NRR'wherein respectively, (a) R is aryl and R'is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R'is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.
  • acyl refers to-C (O) R where R is alkyl, heterocycloalkyl, or aryl.
  • Carboxy esters refers to-C (O) OR where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.
  • carboxyl refers to-C (O) OH.
  • amino refers to-NRR'where R and R'a re independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R'can form a cyclic ring system.
  • halogen refers to-F, -Cl, -Br and-I.
  • alkylaminoalkylcarboxy refers to the group alkyl-NR-alk-C (O) -O-where "alk” is an alkylene group, and R is a H or lower alkyl.
  • sulphonyl or “sulfonyl” refers to-SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • sulphonate or “sulfonate” refers to-SO 2 OR, where R is-H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyi. "1-Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • alkynyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1-Alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene group contains up to and including 6 atoms. In a further aspect the alkylene group contains up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic.
  • acyloxy refers to the ester group-0-C (O) R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • aminoalkyl- refers to the group NR 2 -alk-wherein “alk” is an alkylene group and R is selected from-H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alkylaminoalkyl- refers to the group alkyl-NR-alk-wherein each "alk” is an independently selected alkylene, and R is H or lower alkyl.
  • Lower alkylaminoalkyl- refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively.
  • arylaminoalkyl- refers to the group aryl-NR-alk-wherein
  • alk is an alkylene group and R is-H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • the alkylene group is lower alkylene.
  • alkylaminoaryl- refers to the group alkyl-NR-aryl-wherein
  • aryl is a divalent group and R is-H, alkyl, aralkyl, or heterocycloalkyl.
  • R is-H, alkyl, aralkyl, or heterocycloalkyl.
  • the alkyl group is lower alkyl.
  • alkoxyaryl- refers to an aryl group substituted with an alkyloxy group.
  • the alkyl group is lower alkyl.
  • aralkyloxyalkyl- refers to the group aryl-alk-O-alk-wherein “alk” is an alkylene group. "Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • alkoxy- or "alkyloxy-” refers to the group alkyl-O-.
  • alkoxyalkyl- or “alkyloxyalkyl-” refer to the group alkyl-O-alk-wherein “alk” is an alkylene group. In “lower alkoxyalkyl-, " each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkylthio- refers to the group alkyl-S-.
  • alkylthioalkyl- refers to the group alkyl-S-alk-wherein
  • alk is an alkylene group.
  • each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • aryloxycarbonyloxy- refers to aryl-O-C (O) -O-.
  • R and R 1 include-H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • R and R 1 include-H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C (O) -NR-.
  • R and R 1 include-H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alk is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alk is alkylene, R 1 and R include-H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • hydroxyalkyl refers to an alkyl group substituted with one-OH.
  • haloalkyl refers to an alkyl group substituted with halo.
  • cyano refers to-C ⁇ N.
  • nitro refers to-NO 2 .
  • acylalkyl refers to an alkyl-C (O) -alk-, where "alk” is alkylene.
  • aminocarboxamidoalkyl- refers to the group
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • perhalo refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group.
  • Suitable perhaloalkyl groups include -CF 3 and-CFCI 2 .
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion.
  • the co-crystals of the present invention comprise a co-crystal former H-bonded to a compound of the present invention.
  • the co-crystal former may be H-bonded directly to the compound of the present invention or may be H-bonded to an additional molecule which is bound to the compound of the present invention.
  • the additional molecule may be H-bonded to the compound of the present invention or bound ionically to the compound of the present invention.
  • the additional molecule could also be a second API.
  • Solvates of compounds of the present invention that do not further comprise a co-crystal former are not "co-crystals" according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention as a co-crystal.
  • the co-crystals may also be a co-crystal between a co-crystal former and a salt of a compound of the present invention, but the compound of the present invention and the co-crystal former are constructed or bonded together through hydrogen bonds.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
  • hydrogen-bonding is the dominant interaction in the formation of the co-crystal, (and a required interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other.
  • Crystalline material comprised of solid compound of the present invention and one or more liquid solvents (at room temperature) are included in the present invention as “solvates.
  • solvates A "hydrate” is where the solvent is water.
  • Other forms of the present invention include, but are not limited to, anhydrous forms and de-solvated solvates.
  • ratio of the compound of the present invention to co-crystal former or solvent may be specified as stoichiometric or non-stoichiometric. 1: 1, 1.5: 1, 1: 1.5, 2: 1, 1: 2, and 1: 3 ratios of APLco-crystal former/solvent are examples of stoichiometric ratios.
  • binding means the specific association of the compound of interest to the thyroid hormone receptor.
  • One method of measuring binding in this invention is the ability of the compound to inhibit the association of 125 I-T3 with a mixture of thyroid hormone receptors using nuclear extracts or purified or partially purified thyroid hormone receptor (for example, alpha or beta) in a heterologous assay.
  • energy expenditure means basal or resting metabolic rate as defined by Schoeller et al, JAppl Physiol. 53 (4) : 955-9 (1982) . Increases in the resting metabolic rate can also be measured using increases in O 2 consumption and/or CO 2 efflux and/or increases in organ or body temperature.
  • terapéuticaally effective amount means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
  • salts of compounds of Formula I and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base include acetic acid, adipic acid, benzenesulfonic acid, (+) -7, 7-dimethyl-2-oxobicyclo [2.2.1] heptane-l-methanesulfonic acid, citric acid, 1, 2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid,
  • Effective amount refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease.
  • the effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • terapéuticaally effective amount means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
  • Prevently effective amount usually refers to the amount of a drug dose or intervention measure that can effectively prevent the occurrence of a disease or control the risk of a disease.
  • “Amelioratly effective amount” refers to the minimum dose or level of a drug, therapeutic method, or intervention that can produce a positive improvement effect on a disease in the medical field.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of the compound) .
  • Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose.
  • Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose.
  • patient means an animal.
  • animal includes birds and mammals.
  • a mammal includes a dog, cat, cow, horse, goat, sheep, pig or human.
  • the animal is a human.
  • the animal is a male.
  • the animal is a female.
  • prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction (s) , enzyme catalyzed chemical reaction (s) , and/or metabolic chemical reaction (s) , or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g., HO-, HS-, HOOC-, R 2 N-, associated with the drug, that cleave in vivo.
  • Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters ofhydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of the present invention fall within this scope. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems” pp.
  • Prodrugs of carboxylic acid-containing thyromimetics are convertible by solvolysis or under physiological conditions to the free carboxylic acids.
  • Examples of prodrugs include carboxylic acid esters, and are preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, aryl esters, mono-or di-substituted lower alkyl esters, e.g., the ⁇ - (amino, mono-or di-lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl esters, and the ⁇ - (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl esters, such as the pivaloyloxy-methyl ester.
  • Prodrugs of phosphorus-containing thyromimetics breakdown chemically or enzymatically to a phosphonic acid or phosphinic acid group or a monoester thereof in vivo.
  • the term includes, but is not limited to, the following groups and combinations of these groups:
  • acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al, Biochem. Pharm, 35: 3193-3198 (1989) ) .
  • alkyloxycarbonyloxymethyl esters as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R', and R" are independently-H, alkyl, aryl, alkylaryl, and heterocycloalkyl have been studied in the area of ⁇ -lactam antibiotics (Nishimura et al., J. Antibiotics 40 (l) : 8l-90 (1987) ; for a review see Ferres, H., Drugs of Today, 19: 499 (1983) ) . More recently Cathy, M. S. et al.
  • surrogates of carboxylic acid refers to groups that possess near equal molecular shapes and volumes as carboxylic acid and which exhibit similar physical and biological properties.
  • examples of surrogates of carboxylic acid include, but are not limited to, tetrazole, 6-azauracil, acylsulphonamides, sulfonic acids, thiazolidinedione, hydroxamic acid, oxamic acid, malonamic acid, and carboxylic acid amides.
  • phosphorus-containing thyromimetics e.g., phosphoric acid-, phosphonic acid monoester-, and phosphinic acid-containing compounds
  • phosphonic acid, phosphonic acid monoester, and phosphinic acid are not considered to be surrogates of carboxylic acid in these compounds.
  • the term "enhanced oral bioavailability" refers to an increase of at least 50%of the absorption of the dose of the parent drug, unless otherwise specified. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100%, that is a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following systemic administration of the compound administered orally.
  • a compound of the present invention for the manufacture of a medicament for decreasing the alopecia areata or for the prevention, , treatment or amelioration of a alopecia areata such as Androgenetic Alopecia (AGA) .
  • AGA Androgenetic Alopecia
  • compounds used in the present methods are compounds that selectively distribute to the liver.
  • the compounds have at least 10 fold, 25 fold, 50 fold, 75 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold 6000 fold, 7000 fold, 8000 fold, 9000 fold, 10,000 fold, 20,000 fold, 30,000 fold, 40,000 fold or 50,000 fold greater selectivity.
  • the selectivity for the liver is compared to the heart.
  • the selectivity for the liver is compared to the pituitary.
  • the selectivity for the liver is compared to the kidney.
  • compounds used in the present methods are compounds of the present invention that bind at least one thyroid hormone receptor with an Ki of ⁇ 100 nM, ⁇ 90nM, ⁇ 80nM, ⁇ 70nM, ⁇ 60nM, ⁇ 50nM, ⁇ 40nM, ⁇ 30nM, ⁇ 20nM, ⁇ 10nM, ⁇ 5nM, ⁇ 1nM, or ⁇ 0.5 nM relative to T3.
  • said thyroid hormone receptor is TRa.
  • said thyroid hormone receptor is TR ⁇ .
  • thyroid hormone receptor with an Ki of>100 nM, >90nM, >80nM, >70nM, >60nM, >50nM, >40nM, >30nM, > 20nM, >10nM, >5nM, ⁇ 1nM, or>0.5 nM relative to T3, but in each case ⁇ 150nM.
  • said thyroid hormone receptor is TRa.
  • said thyroid hormone receptor is TR ⁇ .
  • said thyroid hormone receptor is TR ⁇ l.
  • said thyroid hormone receptor is TR ⁇ 2.
  • said thyroid hormone receptor is TR ⁇ 2.
  • Novel methods described herein describe the use of thyromimetic compounds that bind to TRs.
  • compounds described below include compounds of Formula I-BC.
  • the compounds of the present invention can he used in the methods described herein.
  • the compounds useful in the invention are thyromimetic compounds that bind to and activate thyroid receptors in the liver.
  • the present invention relates to compounds of Formula I-IX, including stereoisomers and mixtures of stereoisomers thereof, pharmaceutically acceptable salts thereof, co-crystals thereof, and prodrugs (including stereoisomers and mixtures of stereoisomers thereof) thereof, and pharmaceutically acceptable salts and co-crystals of the prodrugs.
  • compositions comprising a crystalline form a compound of the present invention may contain only one crystalline form of said compound or more than one crystalline form.
  • the composition may contain two or more different polymorphs.
  • the polymorphs may be two different polymorphs of the free form, two or more polymorphs of different co-crystal forms, two or more polymorphs of different salt forms, a combination of one or more polymorphs of one or more co-crystal forms and one or more polymorphs of the free form, a combination of one or more polymorphs of one or more salt forms and one or more polymorphs of the free form, or a combination of one or more polymorphs of one or more co-crystal forms and one or more polymorphs of one or more salt forms.
  • Pharmaceutically acceptable base addition salts of the compounds herein are included in the present invention.
  • Pharmaceutically acceptable base addition salts refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to: sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine
  • Pharmaceutically acceptable acid addition salts of the compounds herein having a base functional group are also included in the present invention.
  • Pharmaceutically acceptable acid addition salts refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic acid or an organic acid to the free base.
  • Salts derived from inorganic acids include, but are not limited to: acistrate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate. bromide, fumarate, pamoate, glucuronate, hydroiodide, iodide, sulfate, xinofoate and chloride salts.
  • the compounds of the present invention may be pure or substantially pure or have a purity of at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or a purity at least 99.5%.
  • the compounds may also be part of a pharmaceutically acceptable composition.
  • the compounds may also be part of a biological material or sample.
  • included in the present invention are cells and tissues comprising a compound of the present invention.
  • the cells or tissues can be in vivo, ex vivo or in vitro. Examples include liver or liver cells (e.g., hepatocytes) , blood, gastric fluid (simulated or actual) , intestinal fluid (simulated or actual) and urine.
  • the invention relates to a method for preventing, treating, or ameliorating alopecia areata, comprising administering a therapeutically effective amount of a thyromimetic compound or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein said thyromimetic compound is a compound of Formula I:
  • k is an integer from 0-4;
  • n is an integer from 0-3;
  • n is an integer from 0-2;
  • each R a is independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 4 alkyl, halogen, -OH, optionally substituted-O-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-S-C 1 -C 4 alkyl, -NR b R c , optionally substituted-C 2 -C 4 alkenyl, and optionally substituted-C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • each R b is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl;
  • each R c is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl, optionally substituted-C (O) -C 1 -C 4 alkyl, and -C (O) H;
  • each R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted- (CR a 2 ) n aryl, optionally substituted - (CR a 2 ) n cycloalkyl, and optionally substituted- (CR a 2 ) n heterocycloalkyl;
  • R f and R g are each independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted - (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocyclo alkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting ofoptionally substituted-C 1 -C 4 alkyl, -OR b , o
  • each R h is selected from the group consisting of optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocycloalkyl;
  • X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidi nedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, pho sphonic acid monoester, phosphinic acid, or a prodrug thereof; and pharmaceutic ally acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
  • the invention relates to the use of a compound of Form ula III:
  • k is an integer from 0-4;
  • n is an integer from 0-3;
  • n is an integer from 0-2;
  • p is an integer from 0-1;
  • each R a is independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 4 alkyl, halogen, -OH, optionally substituted-O-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-S-C 1 -C 4 alkyl, -NR b R c , optionally substituted-C 2 -C 4 alkenyl, and optionally substituted-C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • each R b is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl;
  • each R c is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl, optionally substituted-C (O) -C 1 -C 4 alkyl, and -C (O) H;
  • R 1 and R 2 are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted-C 1 -C 4 alkyl, optionally substituted-S-Ci-C 3 alkyl, optionally substituted-C 2 -C 4 alkenyl, optionally substituted-C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-O-C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
  • each R d is selected from the group consisting ofoptionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, optionally substituted- (CR b 2 ) n heterocycloalkyl and-C (O) NR f R g ;
  • each R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted- (CR a 2 ) n aryl, optionally substituted - (CR a 2 ) n cycloalkyl, and optionally substituted- (CR a 2 ) n heterocycloalkyl;
  • R f and R g are each independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted - (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocyclo alkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting ofoptionally substituted-C 1 -C 4 alkyl, -OR b , o
  • each R h is selected from the group consisting of optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocycloalkyl;
  • X is carboxylic acid or esters thereof, carboxylic acid amide, sulfonic acid, tetrazole, hydroxamic acid, oxamic acid, malonamic acid, 6-azauracil, thiazolidinedione, acylsulfonamide, other carboxylic acid surrogates, phosphonic acid, phosphonic acid monoester, phosphinic acid, or a prodrug thereof.
  • T is selected from the group consisting of- (CR a 2 ) n C (R b 2 ) O-, - (CR a 2 ) n C (R b 2 ) N (R b ) -, - (CR a 2 ) n C (R b 2 ) S-, -C (O) (CR a 2 ) p C (R b 2 ) O-, -C (O) (CR a 2 ) p C (R b 2 ) N (R b ) -, -C (O) (CR a 2 ) p C (R b 2 ) S-, - (CR a 2 ) p C (O) C (R b 2 ) O-, - (CR a 2 ) p C (O) C (R b 2 ) N (R b ) -, and- (CR a 2 ) p C (O) C (R b 2 ) S-,
  • k is an integer from 0-4;
  • n is an integer from 0-3;
  • n is an integer from 0-2;
  • p is an integer from 0-1;
  • each R a is independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 4 alkyl, halogen, -OH, optionally substituted-O-C 1 -C 4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-S-C 1 -C 4 alkyl, -NR b R c , optionally substituted-C 2 -C 4 alkenyl, and optionally substituted-C 2 -C 4 alkynyl; with the proviso that when one R a is attached to C through an O, S, or N atom, then the other R a attached to the same C is a hydrogen, or attached via a carbon atom;
  • each R b is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl;
  • each R b is independently selected from the group consisting ofhydrogen and optionally substituted-C 1 -C 4 alkyl, optionally substituted-C (O) -C 1 -C 4 alkyl, and -C (O) H;
  • R 1 , R 2 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted-C 1 -C 4 alkyl, optionally substituted -S-C 1 -C 3 alkyl, optionally substituted-C 2 -C 4 alkenyl, optionally substituted -C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted -O-C 1 -C 3 alkyl, and cyano; with the proviso that at least one of R 1 and R 2 is not hydrogen;
  • R 8 and R 9 are each independently selected from the group consisting ofhydrogen, halogen, optionally substituted-C 1 -C 4 alkyl, optionally substituted-S-C 1 -C 3 alkyl, optionally substituted-C 2 -C 4 alkenyl, optionally substituted-C 2 -C 4 alkynyl, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, optionally substituted-O-C r C 3 alkyl, hydroxy, - (CR a 2 ) aryl, - (CR a 2 ) cycloalkyl, - (CR a 2 ) heterocycloalkyl, -C (O) aryl, -C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) alkyl and cyano; or
  • each R d is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted - (CR b 2 ) n cycloalkyl, optionally substituted- (CR b 2 ) n heterocycloalkyl, and-C (O) NR f R g ;
  • each R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted -C 2 -C 12 alkynyl, optionally substituted- (CR a 2 ) n aryl, optionally substituted - (CR a 2 ) n cycIoalkyl, and optionally substituted- (CR a 2 ) n heterocycloalkyl;
  • R f and R g are each independently selected from the group consisting ofhydrogen, optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted - (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR C , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting ofoptionally substituted-C 1 -C 4 alkyl, -OR b , o
  • each R h is selected from the group consisting of optionally substituted-C 1 -C 12 alkyl, optionally substituted-C 2 -C 12 alkenyl, optionally substituted-C 2 -Q 2 alkynyl, optionally substituted- (CR b 2 ) n aryl, optionally substituted- (CR b 2 ) n cycloalkyl, and optionally substituted- (CR b 2 ) n heterocycloalkyl; or
  • R 3 and R 5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations not including the unsaturation on the ring to which R 3 and R 5 are attached, including O to 2 heteroatoms independently selected from-O-, and-S-, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
  • X is P (O) (YR 11 ) Y”
  • Y is selected from the group consisting of-O-, and-NR V -;
  • R 11 attached to-O- is independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted-alkylaryl, -C (R Z ) 2 OC (O) NR Z 2 , -NR z -C (O) -R y , -C (R z ) 2 -OC (O) R y , -C (R 2 ) 2 -O-C (O) OR y , -C (R z ) 2 OC (O) SR y , -alkyl-S-C (O) R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-alkylhydroxy;
  • R 11 attached to-NR V - is independently selected from the group consisting of-H, - [C (R z ) 2 ] q -C (O) OR y , -C (R x ) 2 C (O) OR y , - [C (R z ) 2 ] q -C (O) SR y , and-cycloalkylene-C (O) OR y ;
  • q is an integer 2 or 3;
  • each R z is selected from the group consisting of R y and-H;
  • each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • each R x is independently selected from the group consisting of-H, and alkyl, or together R x and R x form a cycloalkyl group;
  • each R v is selected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
  • X is P (O) (YR 11 ) (Y’R 11 ) or P (O) (YR 11 ) Y”;
  • Y and Y’ axe each independently selected from the group consisting of-O-, and -NR v -;
  • R 11 attached to-O- is independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted-alkylaryl, -C (R Z ) 2 OC (O) NR z 2 , -NR z -C (O) -R y , -C (R z ) 2 -OC (O) R y , -C (R z ) 2 -O-C (O) 0R y , -C (R z ) 2 OC (O) SR y , -alkyl-S-C (O) R y , -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-
  • R 11 attached to-NR V - is independently selected from the group consisting of -H,- [C (R z ) 2 ] q -C (O) OR y 5 -C (R x ) 2 C (O) OR y 5 - [C (R z ) 2 ] q -C (O) SR y , and -cycloalkylene-C (O) OR y ;
  • V, W, and W’ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or
  • V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
  • V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; or
  • V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen and substituted with one substiruent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus; or
  • Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
  • W and W’ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
  • q is an integer 2 or 3;
  • each R z is selected from the group consisting of R y and-H;
  • each R y is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • each R x is independently selected from the group consisting of-H, and alkyl, or together R x and R x form a cycloalkyl group;
  • each R v is selected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
  • V, Z, W, W’ are not all-H
  • each of R 13 and R 14 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl, or R 13 and R 14 are combined with the atoms to which they are attached to form a C 3-10 cycloalkyl or a heterocyclyl;
  • R 15 is selected from the group consisting of H, C 1-30 alkyl, C 5-10 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, and C 6-10 aryl-C 1-8 alkyl, wherein R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 12 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • said compound is selected from the group consisting of:
  • said compound is selected from the group consisting of:
  • said compound is selected from the group consisting of:
  • the thyromimetic compound is compound 29, which structure is as follow:
  • the alopecia areata is selected from hair loss, lack ofhair regrowth and androgenetic alopecia.
  • the alopecia areata is androgenetic alopecia (AGA) .
  • the androgenetic alopecia is selected from male pattern baldness, female pattern baldness and chemotherapy-induced hair loss.
  • the subject is a human being.
  • the thyromimetic compound is applied topically on the skin of a mammal.
  • the thyromimetic compound is administered in the form of a pharmaceutical composition.
  • the invention relates to a method for preventing, treating, or ameliorating alopecia areata comprising administering a effective amount of a pharmaceutical composition to a subject in need thereof,
  • composition comprises:
  • the alopecia areata is selected from hair loss, lack ofhair regrowth and androgenetic alopecia, wherein androgenetic alopecia is selected from male pattern baldness, female pattern baldness and chemotherapy-induced hair loss.
  • the pharmaceutical composition comprises 0.0001 to about 10 wt. %of compound 29, based on the total weight of the pharmaceutical composition.
  • the pharmaceutically acceptable excipient is selected from the group consisting of solvents, gelling agents, buffers, surfactants, detergents, oils, alcohols, emulsifiers, solubilizers, humectants, fillers and bioadhesives.
  • the invention relates to non-therapeutic use of compound 29 in the treatment and/or prevention of hair loss in mammals.
  • Pentan-3-ol (28 g, 318 mmol) was added to a solution of Int A-1 (60 g, 317 mmol) , Imidazole (21 g, 323 mmol) , HATU (180 g, 473 mmol) and TEA (64 g, 633 mmol) in DMF/DCM (500ml/500ml) , and stirred overnight at RT. The reaction was concentrated in vacuo to remove the DCM. The residue was added into water and stirred for 1 h. The mixture was filtrated to obtain a solid. The solid was dried to obtain Int A-2 (80.0g, yield 97.3%) .
  • the Int A-2 (50 g, 193 mmol) was dissolved into the solution of HCl in dioxane (4 M, 500 ml) at 0-5°C, and stirred for 1 h. The reaction was concentrated in vacuo to obtain a solid. The solid was added into DCM (500 ml) and saturated sodium carbonate solution (500 ml) , and stirred for 15 mins. The organic layer was separated and concentrated in vacuo to obtain Int A (27.0 g, yield 87.9%) .
  • Potassium carbonate (3.30 g, 23.85 mmol) was added to a solution of 4- [ (4- (methoxymethoxy) -3- (propan-2-yl) phenyl) methyl] -3, 5-dimethylphenol (5 g, 15.90 mmol) , and diethyl [ (4-methylbenzenesulfonyl) oxy] methanephosphonate (5.12 g, 15.9 mmol) in acetonitrile (30 ml) , and stirred for 4 h at 80-85°C. After cooling, water and ethyl acetate were added to the mixture.
  • TMSBr (3.30 g, 21.6 mmol) was add dropwise to a solution of diethyl [ (4- [ (4- (methoxymethoxy) -3- (propan-2-yl) phenyl) methyl] -3, 5-dimethylphenoxy) met hyl] phosphonate (5 g, 10.76 mmol) in dichloromethane (25 ml) and stirred for 4 h at 10-15°C. Water was added dropwise to the mixture. The organic layer was separated and concentrated under reduced pressure to obtain compound A (3.6g, yield 92%) .
  • Oxalyl chloride (8.6 g, 67.7 mmol) was added dropwisely to a solution of Int F (10 g, 22.7 mmol) and DMF (166 mg, 2.27 mmol) in DCM (100 ml) and stirred for 2 h at RT.
  • the reaction mixture was concentrated to dryness to afford an oil.
  • the oil was dissolved into DCM (100 ml) , followed by addition of pentan-3-yl L-alaninate (18.05 g, 113.5 mmol) and stirred for 2 h at RT.
  • the compound 25 was purified by chiral column (Welch XT C18150 mm*21.2 mm, 5 um) to afford compound 28, (1.5 g, yield) and compound 29 (1.2 g, yield) .
  • n-Docosanol (1.90g, 5.83mmol) , Et 3 N (3.5g, 35mmol) and DMAP (2mg) was added into dichloromethane (50ml) at 0°C and stirred 1hour. Then a solution of compound A (2.0g, 3.88mmol, 10ml) was added into the mixture solution, and stirred for 2 hours at 0°C. Water (50ml) was added into the mixture, and an organic layer was extracted. The organic layer was concentrated in vacuo to obtain an oil, which was purified by flash column chromatography (DCM/MeOH 10: 1) to produce Compound 57, 1.2g, yield: 35.6%.
  • X log of Activator concentration
  • Y %Activity
  • the compound of formula I is a prodrug of protide, which would be metabolize into an active moiety compound A or analogues.
  • Dosing Information Formulation concentration: 10mg/kg; Formulation concentration: 20mg/ml.
  • Dosing Information Formulation concentration: 10mg/kg; Formulation concentration: 20mg/ml.
  • mice were depilated on the back in a central area measuring 2.5 cm ⁇ 2.5 cm. Mice with pink skin color, no dark pigmentation, and no residual hair were selected for model induction. The model was induced by subcutaneous injection of 100 ⁇ L of testosterone propionate solution (80 mg/kg) . Seven days after model induction, mice without dark pigmentation and residual hair were grouped into the following categories: blank control group (no model induction after depilation) , blank vehicle group (administer the blank solvent after model induction) , and drug administration group. Drug administration (topical application to the depilated area, once daily) began and lasted for 4 weeks.
  • the disclosed compounds are capable of significantly promoting hair growth.

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Abstract

Est divulguée une méthode de prévention, de traitement ou d'amélioration de l'alopécie areata, comprenant l'administration d'une quantité thérapeutiquement efficace d'un composé thyromimétique ou d'un sel pharmaceutiquement acceptable de celui-ci à un sujet en ayant besoin, ledit composé thyromimétique étant un composé de formule I, R1, R2, R3, R4, R5, R6, R7, R8, R9, G, T et X étant tels que définis dans la description.
PCT/CN2025/088568 2024-04-12 2025-04-11 Thyromimétique pour le traitement de l'alopécie areata Pending WO2025214484A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072813A1 (fr) * 1999-06-01 2000-12-07 The University Of Texas Southwestern Medical Center Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane
US20030007941A1 (en) * 2001-05-31 2003-01-09 Peter Cornelius Method of treating hair loss using thyromimetic compounds
US6525094B1 (en) * 1999-06-01 2003-02-25 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylether derivatives
US6646005B1 (en) * 1999-06-01 2003-11-11 The University Of Texas Southwestern Medical Center Method of treating hair loss using sulfonyl thyromimetic compounds
US20090232879A1 (en) * 2005-05-26 2009-09-17 Metabasis Therapeutics, Inc. Thyromimetics for the Treatment of Fatty Liver Diseases
US20240294561A1 (en) * 2023-02-07 2024-09-05 Gannex, Llc Prodrugs of Thyroid Hormone Analogs, Methods of Making and Methods of Using Thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072813A1 (fr) * 1999-06-01 2000-12-07 The University Of Texas Southwestern Medical Center Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane
US6525094B1 (en) * 1999-06-01 2003-02-25 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylether derivatives
US6646005B1 (en) * 1999-06-01 2003-11-11 The University Of Texas Southwestern Medical Center Method of treating hair loss using sulfonyl thyromimetic compounds
US20030007941A1 (en) * 2001-05-31 2003-01-09 Peter Cornelius Method of treating hair loss using thyromimetic compounds
US20090232879A1 (en) * 2005-05-26 2009-09-17 Metabasis Therapeutics, Inc. Thyromimetics for the Treatment of Fatty Liver Diseases
US20240294561A1 (en) * 2023-02-07 2024-09-05 Gannex, Llc Prodrugs of Thyroid Hormone Analogs, Methods of Making and Methods of Using Thereof

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