EP2861222A1 - Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations - Google Patents

Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations

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Publication number
EP2861222A1
EP2861222A1 EP20130806162 EP13806162A EP2861222A1 EP 2861222 A1 EP2861222 A1 EP 2861222A1 EP 20130806162 EP20130806162 EP 20130806162 EP 13806162 A EP13806162 A EP 13806162A EP 2861222 A1 EP2861222 A1 EP 2861222A1
Authority
EP
European Patent Office
Prior art keywords
compound
pharmaceutical composition
compounds
androgen receptor
medical condition
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.)
Ceased
Application number
EP20130806162
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German (de)
English (en)
Other versions
EP2861222A4 (fr
Inventor
Charles Shih
Qian Shi
Hui-Kang Wang
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.)
Allianz Pharmascience Ltd
Original Assignee
AndroScience Corp
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
Priority claimed from US13/525,941 external-priority patent/US8710272B2/en
Application filed by AndroScience Corp filed Critical AndroScience Corp
Priority to DK16187672.7T priority Critical patent/DK3150203T3/da
Priority to EP19176039.6A priority patent/EP3549581A3/fr
Priority to EP16187672.7A priority patent/EP3150203B1/fr
Publication of EP2861222A1 publication Critical patent/EP2861222A1/fr
Publication of EP2861222A4 publication Critical patent/EP2861222A4/fr
Ceased legal-status Critical Current

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to compounds with biological activity and pharmaceutical and cosmetic formulations thereof, their derivatives and methods of use, more specifically the present invention includes compounds with at least one (substituted phenyl)-propenal moiety and their biological activity and use thereof.
  • the present invention also relates to compounds with (IE, 6E)- l,7-bis-(3,4-dimethoxyphenyl)-4,4- disubstituted-hepta-l ,6-diene-3,5-dione structural scaffold and their biological activity and uses thereof.
  • curcumin in its native form is probably not an optimal molecule for development into a therapeutic drug.
  • the present invention provides biologically active compounds having at least one (substituted phenyl)-propenal moiety.
  • a medical condition such as a human medical condition.
  • a compound having at least one (substituted phenyl) -propenal moiety is provided, the compound having the formula according to formula I:
  • R 3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl.
  • the compound has formula selected from the group consisting of monomers 1, 3, 5, 6 and 7. These monomers are provided below:
  • Monomer-7 in another aspect of the present invention a compound is provided including a (substituted phenyl )-propenal moiety having the formula according to (Ila) or (lib):
  • R 3> R 4> R 3 and R are independently selected from the group consisting of -H, -OH, and -OCII 3 ; 2) L is a CO - C8 alkylene or L is an unsaturated aikenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of -H, -OH, an aromatic ring, a cycloalkyl, -COR,, -C0 2 R u -CONR 1 R 2 , -NRiR 2 , -CX 3 , wherein Ri and R 2 are independently selected from the group consisting of -H, -CH 3 , and -C 2 H 5 ; and 4) X is a halogen atom selected from the group consisting of -F, -CI, and -Br.
  • Ila and lib are the equilibrate tautomers as a common phenomenon of diketone (see, for example, FIG. 9).
  • the compound is selected from the group consisting of II- 1, II-2, II-3, II-4 and II-5.
  • R 3 R4 R 3 t and R4 are independently selected from the group consisting of -H, -OH, and -OCH3; and 2) R
  • R 3 R 4j R 3 ; R4 : R 3 ; and R4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
  • the compound includes the formula III- 1 or III-2, which is provided as:
  • R 3; R ⁇ R4 " , R 3 >», and R4 " axe each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
  • the compound includes the formula IV- 1 :
  • each "n” is independently 1, 2, or 3; 2) R 3; R ⁇ R 3 , and R4 are independently selected from the group consisting of -H, -OH, and -OCH 3 ; 3) L-Z side chain can be no- exist, but if L-Z side chain exists, L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of -H, -OH, an aromatic ring, a cycloalkyl, -COR,, -C0 2 Ri, -CONR1 R2, -NR1R2, -CX 3; 5) Ri and R 2 are independently selected from the group consisting of -H, -CH 3 , and -C 2 H 5 ; and 6) X is a halogen atom selected from the group consisting of -F, -CI, and -Br.
  • the compound is provided according to formula V-1 or V-2:
  • the present invention also provides biologically active compounds having a structure scaffold of 4,4-disubstituted 1 ,7-bis-(3,4-dimethoxyphenyl)-hepta- 1 ,6-diene- 3,5-dione.
  • a medical conditions such as but not limited to, human medical conditions.
  • a compound having a 4,4-disubstituted 1,7- bis-(3,4-dimethoxyphenyl)-hepta-l,6-diene-3,5-dione structural scaffold is provided, the compound having the formula according to formula VI, or a compound having a structural scaffold 6,6-disubstituted 1,1 l-bis( substituted phenyl)-undeca-l, 3,8, 10- tetraene-5,7-dione as the formula according to formula VII:
  • 3 ⁇ 4 an d R 2 are mono- or di-substituted groups, such as a methoxy group (- OCH 3 ), a hydroxy] group (-OH), or an alkyl sulfonyl group, such as -OSO2C2I I5; Ri an d R 2 could be the same or different;
  • L is a carbonyl, alkylene, alkenylene, or alkynl when Z is not present;
  • X is -F, -CI, or -Br
  • Y is H when L is an alkylene, such as -CH 2 , and Z is -CONR3R 4 , R3 and R4 are each -H and a hetercyclic or a heteroaryl, or a cycloalkyl, such as a cyclopentanyl; or Y is a short alkyl (CI - 3), such as a methyl (-CH3), or -F, CI, Br.
  • CI - 3 short alkyl
  • the compound is selected from the group consisting of C4-R 3 R4.
  • the Ri, R 2, R 3, or R 4 represent a series of function groups as listed in the FIG 10.
  • a pharmaceutical formulation or cosmetic formulation including a compound including at least one
  • the pharmaceutical formulation or cosmetic formulation may provide a compound of the present invention and a pharmaceutically acceptable carrier or a cosmetically acceptable carrier.
  • the compound may include monomer 1, 3, 5, 6 or 7 alone or in combination.
  • the compound includes the formula according to formulas I, II, III, IV, V, or a combination thereof.
  • the compound may include at least one, two, three, four, five or more (substituted phenyl) -propenal moieties.
  • a pharmaceutical formulation or cosmetic formulation including a compound with a structure of 4,4- disubstituted 1 ,7-bis-(substituted phenyl)-hepta-l,6-diene-3,5-dione or 6,6-disubstituted l,l l-bis(substituted phenyl)-undeca- 1 ,3,8, 10-tetraenc-5,7-dione as provided in the present application and having a desired biological activity.
  • the pharmaceutical formulation or cosmetic formulation can provide a compound of the present invention and a pharmaceutically acceptable carrier or a cosmetically acceptable carrier.
  • the compound includes the formula according to formula VI or formula VII or formula VIII, or a combination thereof.
  • a method of treating a medical condition including administering a compound including at least one (substituted phenyl)-propenal moiety having a desired or suspected of having a desired biological activity to an individual in need thereof.
  • the compound may be any disclosed herein alone or in combination.
  • the compounds of the present invention may be used to treat, prevent or ameliorate symptoms from androgen associated disorders.
  • Non-limiting examples of medical conditions that may be treated with the disclosed compounds are androgen associated inflammation including a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia; Kennedy's disease (spinal and bulbar muscular atrophy, or SBMA), polyglutamine-mediated motor neuron degeneration; cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular (liver) cancer, and pancreatic cancer; and other medical conditions described herein. Treatment of such medical conditions includes administering to an individual suffering from a medical condition describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof.
  • a method of treating a medical condition including administering a compound including 4,4-disubstituted l ,7-bis-(3,4- substituted phen l)-hepta- 1 ,6-dicne-3,5-dione or 6,6-disubstituted 1,11- bis(substituted phenyl)-undeca-l ,3,8,10-tetraene-5,7-dione structural scaffold having a desired biological activity to an individual in need thereof.
  • the compound may be any disclosed herein alone or in combination.
  • the compounds of the present invention may be used to treat, prevent or ameliorate symptoms from androgen and androgen receptor (AR) associated disorders.
  • AR androgen receptor
  • Non-limiting examples of medical conditions that can be treated with the disclosed compounds are androgen associated inflammation including a wound (the compounds assist with wound healing), acne, rheumatoid arthritis, psoriasis, rosacea, and alopecia; Kennedy's Disease, (spinal and bulbar muscular atrophy, or SBMA), polyglutamine-mediated motor neuron degeneration; cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular (liver) cancer, and pancreatic cancer; and other medical conditions described herein.
  • Treatment of such medical conditions includes administering to an individual suffering from a medical condition, including but not limited to describe herein, a therapeutically effective amount of any of the disclosed compounds, their derivatives, or pharmaceutical compositions thereof.
  • FIG. 1 depicts a structural representation of compounds ASC-J9 (l ,7-Bis-(3,4- dimethoxy-phenyl)-5-hydroxy-hepta- l ,4,6-trien-3-one) and ASC-J 15 (5-Hydroxy-7-(4- hydroxy-3-methoxy-phcnyl)-4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-hepta-4,6- dienoic acid ethyl ester), which were previously shown to have anti-androgenic activities.
  • FIG. 2A, FIG. 2B, FIG. 2C, FIG. 2D, FIG. 2E and FIG. 2F. depict a table including a nonlimiting listing of newly synthesized compounds encompassed by the present invention including at least one (substituted phenyl)-propenal moiety, with their structures, chemical formulas and molecular weights.
  • FIG. 3 depicts a table of Western Blot densitometric data showing compounds having different number of (4-hydroxy-3-methoxy-phenyl)-propenal moieties are capable of reducing Androgen Receptor (AR) expression in human prostate cancer CWR22Rvl cells.
  • FIG. 4 depicts Western Blot images showing newly provided compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing Androgen Receptor (AR) protein expression in human prostate cancer CWR22Rvl cells.
  • FIG. 5 depicts a table showing some selected ASC compounds and monomers are capable of inhibiting proliferation of human prostate cancer cells (LNCaP and
  • FIG. 6 depicts Western Blot data showing four compounds ASC-Q49, ASC- Q103, ASC-JM12, and ASC-JM4, at various concentrations, are capable of reducing endogenous AR expression in LNCaP and CWR22Rvl human prostate cancer cells.
  • FIG. 7 depicts Western Blot data showing compounds ASC-J9 and ASC-JM5 enhances AR protein degradation in the presence of a protein synthesis inhibitor, cycloheximide (CI IX), tested in LNCaP cells.
  • CI IX cycloheximide
  • FIG. 8 depicts two tables (8a and 8b) that summarize the potency of
  • FIG. 9 depicts a structural representation of compounds ASC-JM17 and ASC- Q49 as an equilibrium of enol-ketone and diketone tautomers which have anti-androgenic and anti-AR activities.
  • FIG. 10A and FIG. 10B depict a table including a nonlimiting listing of compounds encompassed by the present invention including 4,4-disubstituted 1 ,7-bis- (substituted phenyl)-hepta-l ,6-diene-3,5-dione and 6,6-disubstituted 1,1 1 -bis(substituted phenyl)-undeca-l ,3,8, 10-tetraene-5,7-dionc scaffold, with their structures, chemical formulas, and molecular weights.
  • FIG. 11 A, FIG 11B and FIG 11C depict UV spectra of ASC-Q49 diketone tautomer peak (FIG. 11 A, RT 20.6 minutes), enol tautomer peak (FIG. 11B, RT 23.7 minutes), and compound 6 (FIG. 11C, RT 21.1 minutes) from HPLC analysis.
  • FIG. 11 A, FIG 11B and FIG 11C depict UV spectra of ASC-Q49 diketone tautomer peak (FIG. 11 A, RT 20.6 minutes), enol tautomer peak (FIG. 11B, RT 23.7 minutes), and compound 6 (FIG. 11C, RT 21.1 minutes) from HPLC analysis.
  • (substituted phenyl)-propenal moiety refers to a composition including a phenyl group having attached thereto a propenal moiety (when m equals 1) and an alkoxy or hydroxy moiety, or an alkyl or substituted alkyl moiety. The substitutions may be positioned meta or para or ortho with respect to the propenal
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g. methyl, ethyl, n-propyl, 1-methylemyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
  • alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g. ethenyl, prop-l-enyl, pent- l -enyl, penta-l ,4-dienyl, and the like.
  • alkenylene refers to a straight or branched hydrocarbon chain which contains a carbon-to-carbon double bond and is represented by the formula r,H2 taxi- , wherein hydrogen may be replaced by an additional carbon-to-carbon double bond or a monovalent substituent, e.g. ethenylene, prop- 1 -enylene and the like.
  • alkoxy refers to the radical having the formula -OR wherein R is an alkyl, haloalkyl or cycloalkyl.
  • An “optionally substituted alkoxy” refers to the radical having the formula -OR wherein R is an optionally substituted alkyl as described herein.
  • alkynl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g. ethynyl, prop-l-ynyl, but- 1 -ynyl, pent-1 - ynyl, pent-3-ynyl and the like.
  • aryl refers to a radical of carbocyclic ring system wherein at least one of the rings is aromatic.
  • the aryl may be fully aromatic or may contain an aromatic ring in combination with a non-aromatic ring.
  • a "biaryl system” is a compound that includes at least two aryl groups.
  • cycloalkyl refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • di-ketone bridge refers to a straight or branched hydrocarbon chain including two ketones or an enol positioned in close proximity to a ketone respectively.
  • the "di-ketone bridge” or “ketone-enol bridge” is positioned between at least two aryl moieties.
  • hydroxyalkyl refers to a straight or branched hydroxy substituted hydrocarbon chain radical having from one to ten carbon atoms, e.g. - CH 2 OH, -(CH 2 ) 2 OH and the like.
  • DHT dihydrotestosterone
  • Androgen stimulates or controls the development and maintenance of masculine characteristics and other physiological functions in vertebrates by binding to androgen receptors, which in turn binds to the androgen/ AR-controlled genes (DNA) and activates or modulates the gene.
  • AR refers to the intracellular receptor that specifically binds androgens, including testosterone and DHT. AR includes all mammalian isoforms, splice variants and polymorphisms of the androgen receptor.
  • estradiol the main endogenous estrogen
  • ER the intracellular receptor specific for estradiol (the main endogenous estrogen). When bound to a hormone, it acts as a transcription factor (it regulates the reading of DNA and production of proteins).
  • ER includes ERa and ERfi.
  • ER includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
  • glucocorticoid receptor refers to the intracellular receptor that has a high affinity to Cortisol and other glucocorticoids.
  • GR includes all mammalian isoforms, splice variants, and polymorphisms of the nuclear receptor.
  • progesterone receptor or "PR” as used herein refers to the intracellular steroid receptor that specifically binds progesterone. PR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
  • PPAR peroxisome proliferator activated receptor
  • PPARa increases transcription of target genes by binding to a specific nucleotide sequence in the gene's promoter.
  • RXR retinoid X receptor
  • PPARy is activated by prostaglandins and leukotrienes and regulates the gene expression of proteins involved in the storage of fatty acids.
  • PARP is weakly activated by fatty acids, prostaglandins, and leukotrienes. Its physiological ligand has not been identified.
  • retinoic acid receptor or “RAR” as used herein refers to the intracellular receptor known to bind many retinoid forms.
  • RAR includes all family members, which include RARa, RARp and RARy.
  • RAR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
  • retinoid x receptor or “RXR” as used herein refers to the intracellular receptor that specifically binds 9-cis-Retinoic acid.
  • RXR includes all mammalian isoforms, splice variants and polymorphisms of the nuclear receptor.
  • steroid receptor or "steroid nuclear receptor” as used herein refers to intracellular receptors that bind to and regulate the transcription of DNA under the regulation of steroid hormones. Receptors for the different hormones have strong structural and functional similarities which point to an evolution from a common ancestral gene and therefore are considered a gene superfamily.
  • Representative receptors which belong to this gene superfamily include the DNA binding and regulatory proteins controlled by the steroid hormones estradiol (ER), glucocorticoid (GR), androgen (AR), progesterone (PR), mineralocorticoid (MR), the nonsteroid hormones triiodothyronine (T3R) and dihydroxyvitamin D3 (VDR), and two classes of retinoid (all-trans retinoic acid and 9-cis retinoic acid) receptors (RARs and RXRs respectively). More than 32. genes encoding at least 75 proteins with different DNA specificity, regulation, or hormone affinity have been identified as part of this gene superfamily.
  • Steps of this superfamily are being reported frequently and are herein intended to be incorporated by reference in their entirety as published in peer reviewed scientific literature or as provided in sequence databases such as GenBank, whether DNA, RNA or polypeptide sequence, and S WISSPROT. Using new biotechnology, molecular biologists and biochemists have identified protein receptors for which the ligands have not yet been identified, thus giving birth to a class of "orphan receptors". "Steroid receptor" includes all mammalian splice variants and isoforms of the steroid receptors.
  • extended release refers to dosage form that provides for the delayed, slowed over a period of time, continuous, discontinuous, or sustained release of a compound or composition.
  • pharmaceutically acceptable refers to approved or approvable by a regulatory agency of the Federal or a state government for use in animals, and more particularly in humans.
  • pharmaceutically acceptable carrier refers to an approved or approvable diluent, adjuvant, excipient or carrier with which a compound is administered.
  • prodrug refers to a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • the prodrug includes a cleavable ester, which upon cleavage, releases the active form.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered to a patient for treating a disease or disorder, is sufficient to affect such treatment for the disease or disorder.
  • the “therapeutically effective amount” will vary depending on the compound, the disease or disorder and its severity and the age and weight of the patient to be treated.
  • the “therapeutically effective amount” may include a series of administrations that eventually causes a desired effect whether or not the initial administration is effective.
  • derivative refers to variations on a core structure or pharmacophore that yields a desired effect. Derivatives may include substitutions along the phenyl ring, the propenal region of the molecule or along a side chain. Thus derivatives encompassed herein include compounds formed from or include at least one disclosed compound, such as those identified in formulas I, II, III, IV, or V. It may be desirable to form derivatives of the particular compounds to modulate solubility, efficacy, aggregation and the like.
  • the inventors of the present invention have found that compounds described herein, including those with at least one (substituted phenyl)-propenal moiety show promise for the treatment or prevention of medical conditions. Moreover compounds disclosed herein are believed to possess activities, such as reducing the proliferation of cells that are believed to have or suspected of having a cancerous profile. Additionally, compounds disclosed herein demonstrate the ability to selectively modulate populations of steroid receptors. Thus it is an object of the present invention to provide compounds having biological activities useful in the treatment or prevention of disease in mammals, such as humans.
  • compositions disclosed herein may be provided or administered as compounds themselves or may be adapted with a suitable carrier to effect the desired treatment.
  • the compounds disclosed herein as a pharmaceutical may be provided in combination with a
  • the compounds may be provided in combination with a cosmetically acceptable carrier.
  • Pharmaceutically acceptable carriers and cosmetically acceptable carriers may be the same, may be derived from one another and the like as known in the pharmaceutical and cosmetic industries, or may be different such as but not limited to variations depending on desired route of administration.
  • Compounds may be tested for solubility, activity and dipole moment before or after the preparation as a pharmaceutical or cosmetic and may be tested alone or in combination with other compounds disclosed herein for synergistic effects.
  • the present invention includes one or more compound and derivatives thereof, including those with hydrophilic or hydrophobic additions, substitutions or subtractions.
  • a compound having at least one (substituted phenyl) -propenal moiety is provided.
  • compounds having a (substituted phenyl)-propenal moiety have biological activity including anti- androgen/anti-AR biological activity.
  • the (substituted phenyl )-propenal moiety has the formula according to formula I:
  • R 3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen; and 2) X is selected from the group consisting of hydroxy, alkoxy, ethyl propionate, ethyl methyl carbonate, and carbonyl alkyl.
  • compounds having at least one (substituted phenyl)-propenal moiety are capable of decreasing the presence of the androgen receptor or inducing degradation of the androgen receptor.
  • compounds having at least one (substituted phenyl)-propenal moiety are capable of decreasing the presence of the androgen receptor or inducing degradation of the androgen receptor.
  • compounds having at least one (substituted phenyl)-propenal moiety are capable of decreasing the presence of the androgen receptor or inducing degradation of the androgen receptor.
  • the compound includes a (substituted phenyl)-propenal compound or a pharmaceutically acceptable salt thereof, selected from monomer 1 , 3, 5, 6 or 7, alone or in combination, the monomers being provided below:
  • derivatives of the above referenced monomers having biological activity are also provided.
  • the derivatives may have substitutions at one or more positions to increase one or more characteristic such as activity, solubility and the like.
  • Such derivatives may modulate the dipole moment of a compound and may result in a composition that is more or less hydrophobic or hydrophilic.
  • a compound including a (substituted phenyl)-propenal moiety having the formula according to (Ila) or (lib):
  • R 3i R ⁇ R3 _ and R4 are independently selected from the group consisting of -H, -OH, and -OCH 3 ; 2) L is a CO - C8 alkylene or L is an unsaturated alkenylene or alkynl when Z is nothing; 3) Z is selected from the group consisting of -H, -OH, an aromatic ring, a cycloalkyl, -COR -C0 2 R,. -CONR 1 R 2 .
  • -NRiR 2 , -CX 3 wherein R, and R 2 are independently selected from the group consisting of -H, -CH 3 , and -C 2 H 5 ; 4) X is halogen atom selected from the group consisting of -F. -CI, and -Br; and further wherein the formula Ila and lib are the equilibrate tautomers as a common phenomenon of diketone.
  • the compound is selected from the group consisting of II- 1 , II-2, II- , II-4 and 11-5.
  • R 3j R 4- R 3 _ and R 4 are independently selected from the group consisting of -H, -OH, and -OCH 3 ; and 2) R ⁇ and R 2 are independently selected from the group consisting of -H, -C3 ⁇ 4, -C2H 5 , a substituted aryl and a substituted benzyl group.
  • a compound is provided according to formula III: wherein R 3 R4 R3 R4 R3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
  • R 3 R4 R3 R4 R3 and R 4 are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
  • Nonlimiting examples include those with the formula I I I- l or 111-2:
  • R 3 R4 Ry R ⁇ R 3 > R 4 ", R 3 -, and R "' are each independently selected from the group consisting of alkoxy, hydroxy, and hydrogen.
  • the compound has the formula IV- 1 :
  • a compound is provided according to formula V: wherein 1) each "n” is independently 1 , 2, or 3 ; 2) R 3 R 4> R 3 , and R4 are independently selected from the group consisting of -H, -OH, and -OCH 3 ; 3) L-Z side chain can be no- exist, but if L-Z side chain exists, L is a C0-C8 alkylene, or an unsaturated alkenylene or alkynl when Z is nothing; 4) Z is selected from the group consisting of -H, -OH, an aromatic ring, a cycloalkyl, -COR h -C0 2 Ri, -CONR,R 2 , -NRiR 2 , -CX 3; 5) R t and R 2 are independently selected from the group consisting of -H, -CH 3 , and -C 2 H 5 ; and 6) X is a halogen atom selected from the group consisting of -F,
  • the compounds have the formula according to V- 1 or V-2.
  • the following are representatives of the compounds with formula V-1 and V-2:
  • Synthesis of the disclosed compounds may be performed using standard practices known in the organic synthesis arts using known solvents. Synthesized compounds may be tested for desired activity such as degradation of a steroid receptor, such as the androgen receptor, the ability to prevent or inhibit proliferation of cancer cell lines, the reduction of tumor size in grafted animal studies and the like. Compounds identified as hits or leads may be further adapted using the synthesis methods and techniques disclosed herein. Thus, variations on the provided synthetic methods will be readily apparent to those skilled in the art and are deemed to be within the scope of the present invention.
  • Example 1 demonstrates a variety of synthesis schemes for the provided monomers as well as derivatives thereof, which are also encompassed herein.
  • derivatives are provided as a combination of monomers or portions thereof to form a biphenyl, triphenyl, or quadrophenyl ring system or more.
  • a biphenyl ring system was utilized for testing and comparison to other proposed treatments; however compounds having a single
  • Another important structural feature of this type of compounds is the enol-ketone bridge between the two phenyl groups, existing in equilibrium with its diketone form, which results in the unique molecular intrinsic fluorescence, i.e., the high density of the compound's color.
  • This molecular property affects, in certain degree, pharmaceutical formulation, such as solubility and stability in solvents.
  • medicinal chemistry and organic synthesis strategies were used by introducing a second function group, such as a fluoro or methyl group, at C4 position, in addition to the prior mono substitution, to break the extensive molecular conjugation and stabilize the molecule to a distinct diketon form.
  • the innovations presented in this invention provide a more user friendly (i.e., less coloring) topical therapeutics for skin disorders such as acne, alopecia, wound healing and other diseases, disorders and conditions discussed herein and as applicable to the present invention.
  • the innovative findings presented in this invention can greatly increase the usefulness of the compounds as drugs (ie. increase the drugability) and thus benefit the therapeutic drug development.
  • the reduction in intrinsic color of the compounds also increased the potential of development of these further series of compounds into topical drugs that could avoid the potential skin discoloration and make them more user friendly.
  • the present invention includes the disclosed compounds themselves, as well as their salts and their prodrugs, if applicable.
  • the salts or prodrugs should retain a portion of the desired biological activity of the parent compound or be provided in a form that the body or subject can convert to a biologically active form.
  • the salts for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, tartrate, trifluoroacetate, and acetate.
  • a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation.
  • Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as
  • Nonlimiting examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the compounds derivatives described above.
  • the compounds of the present invention may be formulated for administration for the prevention or treatment of a variety of medical conditions.
  • Pharmaceutical formulations may include at least one of the disclosed compounds or pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
  • Suitable carriers for use with the compounds of the present invention include diluents, excipients, or carrier materials, selected according to the intended form of administration and consistent with conventional pharmaceutical or cosmetic practice.
  • suitable carriers include, but are not limited to, water, physiological saline, phosphate-buffered saline, a physiologically compatible buffer, saline buffered with a physiologically compatible salt, a water-in-oil emulsion, and an oil-in-water emulsion, an alcohol, dimethylsulfoxide, dextrose, mannitol, lactose, glycerin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like, and mixtures thereof.
  • Suitable carriers can also include appropriate pharmaceutically acceptable antioxidants or reducing agents, preservatives, suspending agents, solubilizers, stabilizers, chelating agents, complexing agents, viscomodulators, disintegrating agents, binders, flavoring agents, coloring agents, odorants, opacifiers, wetting agents, pH buffering agents, and mixtures thereof, as is consistent with conventional pharmaceutical practice ("Remington: The Science and Practice of Pharmacy", 20th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000).
  • Suitable routes of administration may include oral, intestinal, parenteral, transmucosal, transdermal, intramuscular, subcutaneous, rectal, intramedullary, intrathecal, intravenous, intraventricular, intraatrial, intraaortai, intraarterial, or intraperitoneal administration.
  • compositions of the present invention can be administered to the subject by a medical device, such as, but not limited to, implantable devices, biodegradable implants, patches, and pumps.
  • a medical device such as, but not limited to, implantable devices, biodegradable implants, patches, and pumps.
  • the compositions may be formulated to include a dissolvable or nondissolvable matrix or medium (for example, a coating, membrane, film, impregnated matrix, polymer, sponge, gel, or porous layer on or within the medical device) to permit the release of the active compound or compounds over a specified period of time.
  • compositions of the present invention can be formulated and provided in any formulation suitable to the intended form of administration and consistent with conventional pharmaceutical practice ("Remington: The Science and Practice of Pharmacy", 20 th edition, Gennaro (ed.) and Gennaro, Lippincott, Williams & Wilkins, 2000).
  • suitable formulations include tablets, capsules, syrups, elixirs, ointments, creams, lotions, sprays, aerosols, inhalants, solids, powders, particulates, gels, suppositories, concentrates, emulsions, liposomes, microspheres, dissolvable matrices, sterile solutions, suspensions, or injectables, and the like.
  • injectables can be prepared in conventional forms either as liquid solutions or suspensions, as concentrates or solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • the present invention includes methods of treating, ameliorating symptoms from or preventing the progression of a variety of medical conditions using the disclosed compounds and compositions, including pharmaceutical and cosmetic formulations.
  • the medical conditions may, at least in part, be modulated by a steroid receptor.
  • Steroid receptors of particular interest may include but are not limited to androgen receptor (AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptors (RARs and RXRs), and orphan steroid hormone receptors.
  • Compositions or compounds of the present invention may target a specific receptor, such as the androgen receptor or may target particular receptors within the steroid receptor superfamily.
  • the methods of the present invention may prevent, treat or ameliorate symptoms from cancers such as but not limited to prostate cancer, liver cancer, bladder cancer, cervical cancer, lung cancer and breast cancer, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, endometrial cancer, ovarian cancer, central nervous system cancer, and the like.
  • cell lines having a profile of a cancerous cell such as cell lines prepared from cancer cells, may be utilized.
  • activities of compounds of the present invention are evaluated for the ability to inhibit cancer cell growth or proliferation, optionally stimulated with a stimulator, such as DHT.
  • a stimulator such as DHT.
  • Compounds disclosed herein were specifically shown to reduce growth or proliferation of prostate cancer cells.
  • the compounds their derivatives, pharmaceutical compositions and the like are used to prevent, treat or ameliorate symptoms from neurological and neuromuscular disorders such as Kennedy Disease.
  • Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease is a gender- specific motor neuron disease that affects 1 in every 40,000 males (reviewed by Katsuno et al, 2004).
  • SBMA patients have a mutated androgen receptor containing an expanded polyglutamine tract. The expanded polyglutamine androgen receptor forms aggregates that interfere with cell functioning and is the factor that causes the proximal muscle atrophy associated with SBMA.
  • the methods of the present invention may include relieving the stress caused by aggregate formation by reducing the amount of the mutant AR to a level that could be more easily policed by the cells' native housekeeping machinery.
  • the methods of the present invention may including selectively degrading the androgen receptor and thus may be used as a therapy for SBMA.
  • the disclosed compounds that can enhance androgen receptor degradation may suppress the steady-state level of the receptor thus, attenuating the severity of aggregate formation in patients.
  • Compounds and compositions of present invention may prevent, treat or ameliorate symptoms from androgen related hair disorders.
  • androgenetic alopecia or "male pattern baldness” is hair loss caused by androgen activity on the androgen receptors in follicles and adjacent cells.
  • hirsutism is excessive growth of thick dark hair in locations where hair growth in women usually is minimal or absent.
  • Such male-pattern growth of terminal body hair usually occurs in androgen-stimulated locations, such as the face, chest, and areolae.
  • Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention.
  • Compounds and compositions of the present invention may treat inflammation (e.g., rheumatoid arthritis), acne, alopecia, and may accelerate wound healing.
  • Acne is caused by andro gen-induced AR activation of sebaceous glands and may therefore be treated by administering a compound capable of preventing or decreasing AR activation.
  • Compounds of the present invention are believed to induce degradation of the androgen receptor and thus would provide an effective treatment against such medical conditions.
  • Androgenetic alopecia and other hair growth disorders are known to cause by the activation of androgen receptors (AR) in hair follicles by endogenous androgen.
  • Certain inflammation conditions and wound healing are also believed to be associated with the androgen receptor in response to androgen.
  • Methods of the present invention may include administering a compound, pharmaceutical or cosmetic formulation to an individual in need of such treatment or prevention. Topical application of such formulations may be of particular interest.
  • PCOS polycystic ovary syndrome
  • Cushing's syndrome congenital adrenal hyperplasia
  • non-classical adrenal hyperplasia ovary or adrenal tumor
  • iatrogenic androgen excess a malignant ovary syndrome
  • hyperandrogenic symptoms can also be detected in human immunodeficiency virus (HlV)-infected women showing lipodystrophy syndrome (Hadigan et al., 2000). It has been suggested that hyperandrogenism may be involved in lipid aberrations observed in the latter group of patients.
  • HlV human immunodeficiency virus
  • the methods of the present invention include the treatment of a variety of medical conditions as disclosed herein or are believed to be associated at least in part with a steroid or steroid associated disorder.
  • the methods of treatment include administering a compound, pharmaceutical formulation or cosmetic formulation of the present invention to an individual or subject in need thereof.
  • Subjects may be treated with a therapeutically effective dosage.
  • a therapeutically effective dosage may vary somewhat from compound to compound, patient to patient, and will depend on the condition of the patient and route of delivery. As general guidance, a dosage from about 0.1 to about 50 mg/kg may have therapeutic efficacy, while still higher dosages potentially being employed.
  • compounds composed of a single (substituted phenyl) propenal core structural unit were prepared through standard and advanced organic syntheses. In some embodiments, compounds consisting of two or more
  • (substituted phenyl) propenal core structural moieties were prepared by a condensation of substituted benzaldehydes and 2,4-pentanedion or 3 -substituted 2,4-pentanedions by the method known in the literature. Pedersen et al. (Liebigs Ann. Chem., 1557-1569, 1985). The desired substituents on the biphenyl ring and on the C4 of conjugation bridge were synthesized either before or after the condensation. The length of conjugation bridge between the two phenyl moieties could be varied from 5 carbons to 1 1 carbons through synthetic strategies. Properly adding and removing protecting groups allow ultimate synthesis of the disclosed derivatives. In addition, various synthetic steps may be performed in an alternate sequence in order to give the desired compounds.
  • Derivative phosphate prodrugs were further prepared by reacting compounds having compounds a (substituted phenyl)-propenal moiety with phosphorous oxychloride in an appropriate solvent, e.g., dichioromethane, in the presence of an organic base, e.g., triethylamine.
  • Tartrate of disclosed compounds as water-soluble salts were synthesized by reacting compounds having a (substituted phenyl)-propenal moiety with tartaric acid in water.
  • Preparative thin layer chromatography (PTLC) on silica gel plates were also used for separation and purification.
  • Precoated silica gel plates were used for thin layer chromatography (TLC) analysis.
  • ASC-J9 was synthesized as starting material by reaction of 3,4-dimethoxybenzaldehyde with 2,4-pentanedione based on a published method (Pedersen et al., Liebigs Ann.
  • the monomers structurally with a (3,4-dimethoxy or 3-methoxy, 4-hydroxy substituted phenyl)-propenal moiety, a basic structure of the currently provided compounds, have been synthesized by reaction of 3 -( 3 ⁇ 4 ' -Dimethoxy-pheny I )-acry 1 i c acid with corresponding reagents (monomers 1 , 3), or reaction of 3,4-dimethoxybenzaldehyde or 3 -methoxy-4 -hydroxy benzaldehyde with ethyl levulinate (monomers 5 and 6).
  • Monomor-7 was synthesized starting from 3-(3,4-dimethoxypheny)propane through two steps. More specifically, the synthesis methods for the monomers are described as below and illustrated in Scheme 1.
  • Monomer 1 3-(3',4'-Dimethoxy-phenyl)-acrylic acid methyl ester, was synthesized by reaction of 3 -( 3 ⁇ 4 ' -Dimcthoxy-phenyl )-acry 1 i c acid with methanol in the presence of acetic chloride. After re fluxing for 2.5 h, the reaction mixture was concentrated by evaporation to 1/3 and the white solid was filtered and dried in vacuo to get the desired product in 76% yield as a white crystalline solid, mp.74-75 °C.
  • Monomer 3 a mixed anhydride, was prepared by reaction of 3-(3',4'-Dimethoxy- phenyl)-acrylic acid in toluene/'CTTCb (1 : 1) in the presence of Et 3 N, The solution was cooled to 0 °C, ethyl chloroformate (1 .5 eq.) was added dropwise. After stirring at 0 °C for 2 h, the precipitate was filtered out. The filtrate was concentrated to get a relatively pure white solid, which was purified by a fast filtration through a thin silica gel pad and eluted with hexanes: ethyl acetate (1 :0 to 4: 1) to afford the desired product as a white solid in quantity.
  • Monomer 5 i.e., 6-(3 ⁇ 4 , -Dimethoxy-phenyl)-4-oxo-hex-5-enoic acid ethyl ester
  • ethyl levulinate 1 eq.
  • boron oxide 0.7 eq
  • tributyl borate and 3,4-dimethoxy- benzaldehyde both 1 eq.
  • Monomer 7, i.e., 7-(3,4-Dimethoxy-phenyl)-hept-6-enc-2,5-dione was made by 3- (3,4-dimethoxypheny)propane through 2 steps.
  • 3,4-dimethoxycinnamaldehyde was made as described in the synthesis of Ql 10 (Scheme 13) in 60% yield. Dissolving the resulting compound (1 eq.) in dry EtOH, 3-butene-2-one (1 eq.) was added.
  • TABS tetrabutylammonium bisulfate
  • Compounds QIOO, Ql 01, JM1 , JM6, and JM7 were made with an unsaturated side chain at C4 position of ASC-J9 intending to enhance anti-prostate cancer activity.
  • Compound QIOO was synthesized by reaction of ASC-J9 with 3-bromo-propyne in CH 2 C1 2 at 60 °C over night in the presence of K 2 C0 3 .
  • Compound Q101 was made by reaction of ASC-J9 with bromopropene in DMF at 100 °C for 2 h in the presence of K 2 C0 3 and KI (Scheme 8). The crude compounds were purified by silica gel flash column chromatography eluted by hexanes and EtOAc mixture to get the desired products.
  • Compound JM6 was synthesized by reaction of ASC-J9 (60 mg) with
  • reaction mixture was washed with brine and extracted the CH 2 C1 2 , dried over Na 2 S0 4 and purified by silica gel flash column chromatography to give a mixture of C3-octanyl substituted 2,4-pentadione and O-octyl substituted 2,4-pentadione.
  • Reaction of the mixture with 3, 4-methoxybenzaldehyde through the method mentioned above afforded the compound Q104.
  • Compounds JM4, JM20, Ql 16 structurally share the property of a (substituted)- triaryl systerm [three (substituted phenyl) propenal conjugation].
  • One of the purposes to synthesize these compounds is to study the effect of multi- phenyl propenal moiety on anti-AR and anti-prostate cancer activities.
  • Compound JM4 were synthesized from a condensation of 3,4-dimethyoxybenzaldehyde with triacetylmethane as shown in Scheme 11.
  • Compounds JM20 and Q 1 16 were synthesized with the same method described as
  • reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Ql 10 as a red solid.
  • EXAMPLE 2 DETECTING BIOLOGICAL EFFECTS OF COMPOUNDS HAVING AT LEAST ONE (3,4-AL OXY OR HYDROXY SUBSTITUTED PHENYL)-PROPENAL MOIETY ON HUMAN ANDROGEN RECEPTOR (AR) AND ANDROGEN/AR- MEDIATED ACTIVITY
  • ASC compounds and monomers were tested for their activity to block androgen/ AR-induced functions.
  • a cell growth assay using human prostate cancer cells, either LNCaP or CWR22Rvl was applied in the studies. Functional AR proteins are expressed in both cancer cell lines; whereas the growth of LNCaP cells is DHT dependant, but the growth of CWR22Rvl cells, derived from a relapsed hormone- refractory tumor, was not.
  • Western Blot analysis were performed by testing monomers, and some representative new compounds in prostate cancer cells to demonstrate that compounds with at least one (4-hydroxy-3-methoxy-phenyl)-propenal moiety are capable of reducing AR protein expression levels and inhibiting cancer cell growth in vitro.
  • the MTT cell proliferation assay was applied in the present invention to detect the capability of compounds to suppress or inhibit prostate cancer cells growth.
  • the MTT assay which is a method widely used to detect proliferation of culture cells and is relied upon the conversion of a colorless substrate to reduced tetrazolium by a mitochondrial dehydrogenase (possessed by all viable cells), and has been demonstrated previously (Su et ah, 1999) to assess the growth of various tissue-cultured cells. Briefly, 1 x 10 LNCaP or CWR22Rvl cells suspended in complete medium were plated into each well of a 96-well Microtest III tissue culture plate (Falcon, NJ).
  • the medium was replaced with RPMI-1640 medium containing 10% charcoal/dextran- deprived FBS (hormone-deprived fetal bovine serum). Testing compounds were added to the medium at indicated concentrations with or without 1 nM DHT and cells were cultured for 5 days in an incubator (at 37 °C). MTT substrate solution (5 mg/ml in PBS) in 1/10 of volume was added to the cells in each well at 2 hours before harvesting. After 2 hour incubation, the plates were centrifuged (10 min at 1,000 rpni) and the supernatant from each well was carefully removed.
  • a 100 ⁇ of lysis buffer (50% dimethyl formamide, 5% sodium dodecyl sulphate, 0.35 M acetic acid, and 50 mM HC1) was added to each well to lyse the cells and dissolved tetrazolium in each well.
  • the relative quantity of enzyme activity from each well was measured based on absorbance read at a wavelength of 450 nm using a Bio-RAD BenchMark microplate reader. Data derived from the MTT assay were also verified by the actual cell count and cell morphology on a separate plate set up in parallel. Data from this parallel plate demonstrated a positive relationship between the quantity of enzyme activity and the number of viable cells in the well.
  • a widely used Western Blotting analysis was employed to measure AR protein expression level.
  • representative ASC compounds were tested in Western blot assay to evaluate their activity in reducing AR expression; and the assays were carried out in either the presence or absence of dihydrotestosterone (DHT, 1 nM). After cells were incubated with testing compounds for the designated time, they were harvested and lysed according to Western Blot techniques known in the biochemical arts. Details of Western Blotting analysis method have been published previously (Su et al., 1999).
  • cells were harvested either in 2x sodium dodecyl sul phate/po ly aery 1 am i dc gel electrophoresis (SDS/PAGE) loading buffer or in Radio-Immunoprecipitation Assay (RIP A) lysis buffer strengthened with 10 of benzamidine, 10 ⁇ «/ ⁇ 1 of trypsin inhibitor, and 1 mM of phenylmethylsulfonyl fluoride.
  • a sample of total protein (approximately 40 ⁇ ig) from each cell lysate was separated by electrophoresis on a SDS/PAGE gel. After separation by electrophoresis, the proteins were transferred from the gel to a nitrocellulose membrane following the standard procedures.
  • the membrane was then incubated with 10% non-fat milk in phosphate- buffered saline supplemented with 0.1 % Tween-20 (PBST) for 1 hour and then followed with an overnight incubation with a primary human AR-specific antibody (purchased from BD-PharMingen) at 4°C. After incubation, the membrane was rinsed with PBST buffer three times; 10 min each time; an alkaline phosphatase-conjugated secondary antibody was then added and incubated for 1 hour at room temperature. After second antibody incubation, membrane was again rinsed with PBST, and AR protein signal in the membrane was visualized by adding alkaline phosphatase substrates,
  • AR protein "degradation" in prostate cancer cells was measured by using cycloheximide (a protein synthesis inhibitor) chasing assay method. Briefly, LNCaP cells were incubated with testing ASC compound at the designated concentrations for 24 hours. Subsequently, cycloheximide was added to the cells at a concentration of 15 to block new protein synthesis. After incubation, cells were harvested at designated time periods and the resultant change in AR protein levels were analysed using Western Blot analysis as described above.
  • Compound 28 was synthesized by methylation of Q1230 with methyl iodide in acetone using potassium carbonate as descripted above (Scheme 1). Demethylation of 28 with boron tri bromide (3 eq.) in methylene chloride and purification through combiflash column chromatograph yielded the Compound 29. Treatment of 29 with ethanesulfonyl chloride (3 eq.) in the presence of triethyl amine afforded the Compound 31.
  • Compound 25 was made by conversion of compound 23 through the method of making 24 from 22.
  • Compound 27 was synthesized starting from 4-hydroxy-3-methoxybenzaldehyde through general MOM protection (chloro-methoxy methane) and condensation reactions to make Q15M. Fluoridation of Q15M, the resulting compound (0.06 mM) was subjected a de -protection reaction with zinc bromide (ZnBr) (1.5 eq.) and propylthiol (3 eq.) in methylene chloride at rt for 30 min. During which time, a red solution was generated. Methylene chloride was added and the solution was stirred in an ice bath for 10 min. Sat. NaHC0 3 (0.3-0.5 mL) was added and the mixture was stirred in cold for 15 min. After filtration through celite, extraction with CH 2 CI 2, (x2), and purification through combi flash column chromatograph, the desired product was obtained.
  • MOM protection chloro-methoxy methane
  • the indicated compound induced AR protein expression in cancer cells as assayed and determined by Western blotting at 24 or 48 hr post- incubation. The dose of each compound, which induces 50% reduction of AR expression are shown.
  • Table 2 Biological activity of Compounds and Derivatives having (IE, 6E)-l,7-bis- (3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-l ,6-diene-3,5-dione OR (IE, 10E)-l,ll-bis(substituted phenyl)- 6,6-disubstituted undeca-1 , 3,8,10- tetraene-5,7-dione structural scaffold

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Abstract

La présente invention concerne des composés, des produits pharmaceutiques et des produits cosmétiques ayant au moins une fraction propénal (substitué par phényle). Les composés et les compositions de la présente invention sont utiles dans le traitement ou la prévention d'états pathologiques comprenant les états associés à l'androgène, l'inflammation associée à l'androgène, une plaie (les composés aident à la cicatrisation des plaies), l'acné, la polyarthrite rhumatoïde, le psoriasis, la rosacée et l'alopécie ; la maladie de Kennedy (atrophie musculaire spinale et bulbaire, ou SBMA), la dégénération de motoneurones médiée par la polyglutamine ; les cancers tels que le cancer de la prostate, le cancer de la vessie, le cancer du sein, le cancer des ovaires, le cancer hépatocellulaire (du foie) et le cancer pancréatique ; et d'autres états pathologiques décrits selon l'invention. Le traitement de tels états pathologiques comprend l'administration à un individu souffrant d'un état pathologique décrit selon l'invention, d'une quantité thérapeutiquement efficace de l'un quelconque des composés selon l'invention, leurs dérivés ou des compositions pharmaceutiques à base de ceux-ci.
EP13806162.7A 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations Ceased EP2861222A4 (fr)

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DK16187672.7T DK3150203T3 (da) 2012-06-18 2013-06-17 Forbindelser med (1e,6e)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstitueret-hepa-1,6-dien-3,5-di-on strukturel scaffold, deres biologiske aktivitet og anvendelser deraf
EP19176039.6A EP3549581A3 (fr) 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations
EP16187672.7A EP3150203B1 (fr) 2012-06-18 2013-06-17 Composés avec (1e, 6e) -1,7-bis- (3,4- diméthoxyphényl) -4,4-distribué-hepa-1,6-diene-3,5-di-one, échafaudage structural, leur activité biologique et leurs utilisations

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US13/525,941 US8710272B2 (en) 2007-01-08 2012-06-18 Compounds with (1 E, 6E)-1,7-bis-(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity, and uses thereof
PCT/US2013/046138 WO2013192091A1 (fr) 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations

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EP16187672.7A Division EP3150203B1 (fr) 2012-06-18 2013-06-17 Composés avec (1e, 6e) -1,7-bis- (3,4- diméthoxyphényl) -4,4-distribué-hepa-1,6-diene-3,5-di-one, échafaudage structural, leur activité biologique et leurs utilisations
EP19176039.6A Division EP3549581A3 (fr) 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations

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EP16187672.7A Active EP3150203B1 (fr) 2012-06-18 2013-06-17 Composés avec (1e, 6e) -1,7-bis- (3,4- diméthoxyphényl) -4,4-distribué-hepa-1,6-diene-3,5-di-one, échafaudage structural, leur activité biologique et leurs utilisations
EP13806162.7A Ceased EP2861222A4 (fr) 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations
EP19176039.6A Withdrawn EP3549581A3 (fr) 2012-06-18 2013-06-17 Composés ayant un échafaudage structural (1e, 6e)-1,7-bis-(3,4-diméthoxyphényl)-4,4-disubstitué-hepta-1,6-diène-3,5-dione, leur activité biologique et leurs utilisations

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US11712418B2 (en) 2017-05-26 2023-08-01 Bruin Biosciences, Inc. Chemoembolization agents
CN107226783B (zh) * 2017-06-20 2019-07-23 武汉工程大学 一种溶酶体靶向荧光探针及其制备方法
EP3508855A1 (fr) * 2018-01-05 2019-07-10 Allianz Pharmascience Ltd Procédé de sélection de patients et kit
GB2572259B (en) * 2018-03-23 2022-03-30 Merry Life Biomedical Company Ltd Uses of curcumin derivative
JP2020125285A (ja) * 2019-01-04 2020-08-20 アリアンツ ファーマサイエンス リミテッド 神経変性性障害の治療方法
JP2020117489A (ja) * 2019-01-04 2020-08-06 アリアンツ ファーマサイエンス リミテッド 脳癌の治療方法
CN110183320B (zh) * 2019-04-15 2021-06-11 四川大学 一类多烯二酮类抗肿瘤化合物

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US812408A (en) 1905-08-19 1906-02-13 Roy Ernest Dickerson Educational device for teaching spherics.
US7355081B2 (en) * 2002-04-17 2008-04-08 The University Of North Carolina At Chapel Hill Curcumin analogues and uses thereof
US6790979B2 (en) * 2002-04-17 2004-09-14 University Of North Carolina At Chapel Hill Curcumin analogues and uses thereof
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EP2861222A4 (fr) 2015-08-05
ES2775173T3 (es) 2020-07-24
CA2876957A1 (fr) 2013-12-27
JP2018135386A (ja) 2018-08-30
JP6392752B2 (ja) 2018-09-19
CN110279680A (zh) 2019-09-27
JP2015520233A (ja) 2015-07-16
NZ703167A (en) 2016-09-30
DK3150203T3 (da) 2020-04-14
KR20150023012A (ko) 2015-03-04
EP3150203B1 (fr) 2020-02-19
EP3549581A3 (fr) 2020-02-19
SG11201408387YA (en) 2015-01-29
CA2876957C (fr) 2021-02-16
MX2014015936A (es) 2016-06-24
AU2013277423A1 (en) 2015-01-22
HK1211211A1 (en) 2016-05-20
CN104755076A (zh) 2015-07-01
EP3549581A2 (fr) 2019-10-09
KR102171469B1 (ko) 2020-10-30
AU2013277423B2 (en) 2018-08-09
WO2013192091A1 (fr) 2013-12-27
IN2015MN00131A (fr) 2015-10-16
EP3150203A1 (fr) 2017-04-05
CN106220507A (zh) 2016-12-14

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