Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/008—Preparations for oily skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/06—Preparations for care of the skin for countering cellulitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
• • 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
• • 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
  • A61Q7/02—Preparations for inhibiting or slowing hair growth
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• • 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
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
  • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/74—Biological properties of particular ingredients
  • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists

Definitions

• PPARs Peroxisome Proliferator Activated Receptors
• PPARs are members of the nuclear hormone receptor super family, which are ligand- activated transcription factors regulating gene expression. Certain PPARs play roles in the regulation of cell differentiation, development and metabolism of higher organisms.
• PPAR ⁇ receptors have been associated with a number of disease states including dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
• treatment of tumor cells with ligands of PPAR ⁇ receptors can induce a decrease in cellular proliferation, cell differentiation and apoptosis, and therefore may be useful in preventing carcinogenesis.
• Intestinal anti -inflammatory activity may be dependent on binding and subsequent activation of PPAR ⁇ receptors.
• EGF receptor inhibitors may control proliferation and spread of tumors.
• compositions comprising at least one disclosed compound, or pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier.
• One embodiment provides compounds represented by formula I, and compositions comprising such compounds:
• X is d-C ⁇ alkylene, optionally substituted with one, two or three substituents selected from halogen or hydroxyl;
• R] is selected from the group consisting of Q-Coalkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 2 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
• R 3 is independently selected, for each occurrence from the group consisting of hydrogen, C]-C 6 alkoxy, C]-C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halogen, hydroxyl, and nitro;
• R 4 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
• R 5 is hydrogen or Ci-C 6 alkyl; or pharmaceutically acceptable salts or N-oxides thereof.
• Another embodiment provides compounds represented by formula II, and compositions comprising such compounds: II wherein Ri is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 2 is selected from the group consisting of hydrogen and Cj-C 6 alkyl
• R 3 is independently selected, for each occurrence from the group consisting of hydrogen, Ci-C 6 alkoxy, Ci-C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halogen, hydroxyl, and nitro;
• R 5 is d-C 6 alkyl; or pharmaceutically acceptable salts or N-oxides thereof.
• cancer e.g. colorectal cancer
• methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt or N-oxides thereof.
• compositions that include a compound represented by formula I or II and e.g., a pharmaceutically acceptable excipient.
• Figure 1 depicts the % mortality of mice receiving TNBS (trinitrobenzene sulfonic acid) versus mice receiving TNBS and N-acetyl E2 in a murine colitis model.
• TNBS trinitrobenzene sulfonic acid
• Figure 2 depicts the observed level of colonic lesions in mice receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a murine colitis model.
• Figure 3 depicts the observed level of MPO activity in mice receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a murine colitis model.
• Figure 4 depicts the observed level of colonic inflammation in mice receiving
• TNBS TNBS versus mice receiving TNBS and N-acetyl E2 in a murine colitis model.
• Figure 5 depicts effects of a disclosed compound on human keratinocytes.
• Figure 6 depicts inhibitionr of TNF alpha by H 2 O 2 and a disclosed compound.
• Figure 7 depicts inhibition on mRNA expression of IL-6 induced by the presence of IFN-gamma.
• Figure 8 depicts inhibition of a disclosed compound on the activation of NF- kB.
• Figure 9 depicts inhibition of a disclosed compound on protein expression of
• Figure 10 depicts effect of a disclosed compound on human sebocytes.
• Figure 11 depicts inhibitory capacity of a disclosed compound on sebogenesis induced by lipid type stimulus.
• Figure 12 depicts the results of a fatty acid assay (A) and squalene analysis (B) of sebogenesis inhibition.
• Figure 13 depicts treatment with linoleic acid and testosterone with lipidogenic stimulus.
• alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2- Ci 2 alkenyl, C 2 -C) 0 alkenyl, and C 2- C 6 alkenyl, respectively.
• alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc.
• alkoxy refers to an alkyl group attached to an oxygen (-O-alkyl-).
• alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein as Ci- Ci 2 alkoxy, CpCgalkoxy, and Ci-C 6 alkoxy, respectively.
• Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.
• exemplary "alkenoxy” groups include, but are not limited to vinyloxy, allyloxy, butenoxy, etc.
• alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Ci 2 alkyl, Ci-Cioalkyl, and Ci-C 6 alkyl, respectively.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2- methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l- propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3 -dimethyl- 1 -butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
• alkyl groups include
• Alkyl, alkenyl and alkynyl groups can, in some embodiments, be optionally be substituted with or interrupted by at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
• alkanoyl alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azid
• alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-8, or 2-6 carbon atoms, referred to herein as C 2 -Ci 2 alkynyl, C 2- C 8 alkynyl, and C 2- C 6 alkynyl, respectively.
• alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, A- propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.
• R a; R b and R c are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
• the amide can be attached to another group through the carbon, the nitrogen, R b , R c , or R 3 .
• the amide also may be cyclic, for example R b and R c , R 3 and R b , or R 3 and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10- membered ring or a 5- to 6-membered ring.
• the term "carboxamido" refers to the structure -C(O)NR b R c
• R, R', and R" can each independently be selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone and nitro.
• amine or "amino” as used herein refers to a radical of the form
• Rd, R e , and Rf are independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
• the amino can be attached to the parent molecular group through the nitrogen, R d , R e or R f .
• the amino also may be cyclic, for example any two of Rd, Re or Rf may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl.
• the term amino also includes the corresponding quaternary ammonium salt of any amino group, e.g., -[N(Rd)(Re)(Rf)]+.
• Exemplary amino groups include aminoalkyl groups, wherein at least one of R d , R e , or R f is an alkyl group.
• aryl refers to refers to a mono-, bi-, or other multi- carbocyclic, aromatic ring system. In certain embodiments, aryl refers to a monocyclic and/or bicyclic, 5 to 6 membered ring.
• the aromatic ring may be substituted at one or more ring positions with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
• substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy
• aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
• aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl.
• arylalkyl refers to an aryl group having at least one alkyl substituent, e.g. -aryl-alkyl-.
• Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms.
• phenylalkyl includes phenylC 4 alkyl, benzyl, 1 -phenyl ethyl, 2- phenylethyl, etc.
• carbonyl refers to the radical -C(O)-.
• Carboxamido refers to the radical -C(O)NRR', where R and R' may be the same or different. R and R' may be selected from, for example, alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
• carboxy refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.
• cyano refers to the radical -CN.
• cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
• cycloalkyl refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C 4-8 cycloalkyl,” derived from a cycloalkane.
• exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanes and cyclopropanes.
• Cycloalkyl groups may be substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl refers to C 3 -C 6 alkyl.
• halo or halogen or “Hal” as used herein refer to F, Cl, Br, or I.
• haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
• nitro refers to the radical -NO2-
• phenyl refers to a 6-membered carbocyclic aromatic ring.
• the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
• Phenyl can be substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
• phosphate refers to the radical -OP(O)(OR aa )2 or its anions.
• phosphanate refers to the radical - P(O)(OR aa ) 2 or its anions.
• phosphinate refers to the radical -PR aa (O)(OR aa ) or its anion, where each R aa can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl. cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
• compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
• composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• “Individual,” “patient,” or “subject” are used interchangeably and include to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
• the compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• the mammal treated in the methods of the invention is desirably a mammal in whom modulation of PPAR and/or EGF receptors is desired.
• Modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
• the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the compounds of the invention are administered in therapeutically effective amounts to treat a disease.
• a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with PPAR and/or EGF receptors.
• pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
• compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
• Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
• Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
• stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R” or "S,” depending on the configuration of substituents around the stereogenic carbon atom.
• the present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers.
• Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
• Geometric isomers can also exist in the compounds of the present invention.
• the symbol denotes a bond that may be a single, double or triple bond as described herein.
• the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
• Substituents around a carbon-carbon double bond are designated as being in the "Z” or "E” configuration wherein the terms “Z” and "E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
• Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
• the arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.”
• the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
• the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
• the compound is amorphous.
• the compound is a polymorph.
• the compound is in a crystalline form.
• the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 U, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Certain isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
• Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-C 8 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N-(
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C i-C 6 )alkanoyloxym ethyl, l -((Ci-C 6 )alkanoyloxy)ethyl, 1 -methyl- 1 -((C] -C 6 )alkanoyloxy)ethyl (Ci-C 6 )alkoxycarbonyloxymethyl, N-(C]-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, ⁇ -amino(Ci-C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino
• a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ - aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C r C 4 ) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy(Ci-C 6 )alkyl, amino(C]-C 4 )alkyl or mono
• compositions that include a compound represented by formula I and e.g., a pharmaceutically acceptable carrier.
• X is Ci-C 3 alkylene, optionally substituted with one, two or three substituents selected from halogen or hydroxyl;
• Ri is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 2 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
• R 3 is independently selected, for each occurence from the group consisting of hydrogen, Ci-C 6 alkoxy, C]-C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halogen, hydroxyl, and nitro;
• R 4 is selected from the group consisting of hydrogen and C]-C 6 alkyl
• R 5 is C)-C 6 alkyl; or pharmaceutically acceptable salts or N-oxides thereof.
• Ri can be Ci-C ⁇ alkyl, such as methyl
• R 2 can be hydrogen.
• R 3 can be selected from the group consisting of hydrogen, Ci-C 6 alkyl, halogen, and hydroxyl. hi a further embodiment, R 3 can be hydrogen.
• R 4 and R 5 can each be Ci-C ⁇ alkyl.
• R 4 may be hydrogen and R 5 may be methyl.
• X may be (CH 2 ),, , wherein n is 1 or 2, such as 1.
• -NR 2 -CORi can be in the meta position relative to X as shown in formula III.
• -NR 2 -CORi can be in the para position relative to X as shown in formula IV.
• compositions that include a compound represented by formula II and e.g., a pharmaceutically acceptable carrier.
• Ri is selected from the group consisting of Ci-C ⁇ alkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 2 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
• R 3 is independently selected, for each occurence from the group consisting of hydrogen, CpC ⁇ alkoxy, Ci-C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halogen, hydroxyl, and nitro;
• R 5 is hydrogen or Ci-C 6 alkyl; or pharmaceutically acceptable salts or N-oxides thereof.
• Compounds of Formula V are also contemplated as shown below, as well as compositions that include a compound represented by formula V and e.g., a pharmaceutically acceptable carrier.
• Ri is selected from the group consisting of C)-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 3 is independently selected, for each occurence from the group consisting of hydrogen, Q-Qalkoxy, Ci-C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halogen, hydroxyl, and nitro;
• R 4 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
• R 5 is hydrogen or C ( -C 6 alkyl
• A is a fused five or six membered heterocycle; or pharmaceutically acceptable salts or N-oxides thereof.
• R 1 can be Ci-Qalkyl, such as methyl.
• Ri and R 3 can each be Ci-C ⁇ alkyl, such as methyl.
• R 2 can be hydrogen.
• a compound can be represented by
• Ri is selected from the group consisting of CpQalkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, and C 2 -C 6 alkynyl;
• R 4 and R 8 are each independently selected from the group consisting of hydrogen and C,-C 6 alkyl; or pharmaceutically acceptable salts or N-oxides thereof.
• Contemplated compounds, and pharmaceutical compositions, comprising at least one compound may be selected from the group consisting of: N-acetyl-(R)-(-)-3-(4- aminophenyl)-2-methoxypropionic acid (Compound A) , N-acetyl-(S)-(-)-3-(4-aminophenyl)- 2-methoxypropionic acid (Compound B), racemic N-acetyl-(S)-(-)-3-(4-aminophenyl)-2- methoxypropionic acid (compound AB);
• compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
• parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
• the disclosure further provides, in some embodiments, methods of modulating activity of one or more PPAR and/or EGF receptors comprising exposing said receptor to a compound of the invention.
• methods of modulating activity of one or more PPAR and/or EGF receptors comprising exposing said receptor to a compound of the invention.
• methods of treating a disease associated with expression or activity of one or more PPAR and/or EGF receptors in a patient comprising administering to the patient a therapeutically effective amount of a compound of the invention.
• One embodiment of the invention provides a method of treating tumors of the esophagus, stomach, pancreas, colon, prostate, breast, uterus, kidneys, and lungs comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
• a method for delaying clinical manifestation of a colorectal tumor, or a solid tumor (e.g., a breast, prostate, lung or hepatocellular carcinoma) in a patient, for example, a patient at risk of colorectal cancer comprising administering to the patient an effective amount of a compound disclosed herein.
• Administering such a compound may be on e.g., at least a daily basis.
• the delay of clinical manifestation of a colorectal tumor in a patient as a consequence of administering a compound disclosed here may be at least e.g., 6 months, 1 year, 18 months or even 2 years or more as compared to a patient who is not administered a compound such as one disclosed herein.
• Another embodiment of the invention provides a method of treating or ameliorating chronic inflammation, such as Crohn's disease or ulcerative colitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
• Methods of treating dermatological conditions are also provided, such as the treatment of at least one of: acne vulgaris, comedo-type acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne, solar acne, acne medicamentosa or occupational acne, ichthyosis, Darrier's disease, keratosis palmaris or plantaris, cutaneous, mucosal or ungual psoriasis, skin disorders due to exposure to UV radiation, of skin aging, photoinduced or chronological or actinic pigmentations and keratoses, acne hyperseborrhoea, simple seborrhoea or seborrhoeic dermatitis, cicatrization disorders or stretch marks.
• Methods of treating atopic dermatitis is also contemplated.
• the composition may be administered orally or topically.
• continuous sebum production can increase in acne patients; and application of a sebum inhibitor, such as disclosed herein, may be useful in the treatment of acne, seborrhea or alopecia.
• chronic inflammation of hair follicles can be an indication of e.g., androgenic alopecia.
• An inhibitor of such inflammation such as disclosed herein can be useful in e.g., the treatment of hair loss.
• Provided herein are methods of treating fine lines, wrinkles or surface irregularities of the skin, or protecting from and/or ameliorating free radical damage to the skin, comprising topically administering an effective amount of a composition comprising a compound of the invention.
• a method of treating hair loss in a patient suffering from unwanted hair loss comprising administering an effective amount of a composition comprising a disclosed compound.
• Methods of treating alopecia areata, androgenetic alopecia and/or telogenic defluvium are contemplated.
• methods of treating a vascular or cardiac disorder comprising identifying a patient suffering from or at risk of developing said disorder and administering to said patient an effective amount of a disclosed compound as defined above.
• a cardiac disorder being treated may be chosen from chronic coronary ischemia, arteriosclerosis, congestive heart failure, ischemic or reperfusion related injury, angina, atherosclerosis, myocardial infarction, stroke and myocardial hypertrophy.
• a method of treating an autoimmune disorder wherein the autoimmune disorder may be chosen from, for example, Addison's disease, chronic thyroiditis, dermatomyositis, Grave's disease, multiple sclerosis, systemic lupus erythematosis, psoriasis, or rheumatoid arthritis.
• autoimmune disorder may be chosen from, for example, Addison's disease, chronic thyroiditis, dermatomyositis, Grave's disease, multiple sclerosis, systemic lupus erythematosis, psoriasis, or rheumatoid arthritis.
• Other contemplated indications include mucosal disorders such as aphtae (mouth ulcers) and/or gingivitis.
• treatment of ocular disorders is also contemplated such as diabetic retinopathy or age-related macular degeneration.
• the compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
• the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• a therapeutically effective amount of active component will be in the range of from about 0.1 mg/kg to about 100 mg/kg, optionally from about 1 mg/kg to about 100 mg/kg, optionally from about 1 mg/kg to 10 mg/kg.
• the amount administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compounds, formulation of compounds, the presence and types of excipients in the formulation, and the route of administration.
• the initial dosage administered may be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
• Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study designed to run from 0.5 mg/kg to 20 mg/kg.
• Dosing frequency can vary, depending on factors such as route of administration, dosage amount and the disease condition being treated. Exemplary dosing frequencies are once per day, once per week and once every two weeks.
• Contemplated formulations or compositions comprise a disclosed compound and typically include a compound a pharmaceutically acceptable carrier.
• Contemplated compositions may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations or enemas or suppositories. For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments.
• compositions may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
• any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
• Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
• Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
• Compositions of the present invention may also be administered as a bolus, electuary, or paste.
• the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• Formulations and compositions may include micronized crystals of the disclosed compounds. Micronization may be performed on crystals of the compounds alone, or on a mixture of crystals and a part or whole of pharmaceutical excipients or carriers. Mean particle size of micronized crystals of a disclosed compound may be for example about 5 to about 200 microns, or about 10 to about 110 microns.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
• Tablets, and other solid dosage forms such as film coated tablets or sugar coated tablets, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
• Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
• suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
• Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
• Dosage forms for transdermal or topical administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
• the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
• a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
• Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
• an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
• the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
• Aerosols generally are prepared from isotonic solutions.
• compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate and cyclodextrins.
• Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• the efficacy of treatment with the subject compositions may be determined in a number of fashions known to those of skill in the art.
• compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
• processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Except where indicated otherwise, the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, unless otherwise noted, two or more steps or actions may be conducted simultaneously.
• the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, compounds of the invention may be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
• Example 1 Preparation of N-acetyl-rR-V(-V3-(4-aminophenyl)-2-methoxypropionic acid (N- Acetyl E2); Compound A
• Colitis in C57bI6 mice is induced by administering TNBS (150 mg/kg) by oral gavage on day -3. Stool samples were taken 8 hours after adminstration. At day 0-5, N- acetylated E2 (3OmM) was administrated by oral gavage. On day 5, micewere analyzed to obtain a mortality macroscopic score (Wallace, Gastroenterology 96: 29-36, 1989).
• a spectrophotometric test was carried out.
• the human primary keratinocytes isolated from skin biopsies, were plated in wells of a 24-well plate in suitable medium with addition of antibiotics, calcium, and specific growth factors.
• the cells were exposed to the presence of Compound A, at various concentrations (0.1-1-2 mM), for 24 and 48 h in suitable medium with addition of antibiotics, calcium, but no growth factors. This culture condition was done for all the subsequent experiments.
• the MTT test was done. The results are indicated in Figure 5. Compound A in all concentrations used did not show any effect on cellular vitality.
• Compound A proved able to inhibit the expression of the mRNA of TNF- ⁇ induced by H 2 O 2 at the two higher doses (0.1 mM; 0.5 mM).
• the higher dose demonstrated a complete inhibition of the proinflammatory cytokine with an effect similar to troglitazone (Tg).
• Tg troglitazone
• Example 6 Inhibition of mRNA expression of IL-6 induced by presence of IFN- ⁇ .
• the cells were treated with IFN- ⁇ (30 ng/ml) in presence of compound A (N-Acetylged) at the three concentrations (0.01-0.1-0.5 mM) for 6 h.
• the cells were lysed in a lysis buffer and subjected to isolation and subsequent retrotranscription of the RNA
• the results reveal the ability of Compound A to inhibit the expression of the inflammatory cytokine induced by presence of IFN- ⁇ which does not appear to be dose-dependent.
• Example 7 Inhibitory capacity on the activation of nuclear factor NF -kB induced by presence
• the keratinocytes were plated in wells of a 12-well plate. At 80% confluence, the cells were treated with H 2 O 2 (300 ⁇ M) in presence of compound A at the three concentrations (0.01-0.1-0.5 mM) for 1 h. At the end of the treatment, the cells were fixed in paraformaldehyde, permeabilized in methanol and then incubated in presence of the specific antibody of subunit p65. Compound A revealed an inhibitory effect on the activation and subsequent translocation of NF-kB in dose-dependent manner (Figure 8).
• LPS lipopolysaccharide
• a spectrophotometric test was carried out.
• the sebocytes were plated in wells of a 24- well plate in suitable medium with addition of antibiotics, calcium and EGF.
• the cells were exposed to the presence of compound A , in various concentrations (0.1-0.5-1-2 mM), for 24 and 48 h.
• the MTT test was performed.
• Compound A in all concentrations used demonstrated no effects on cell vitality.
• Example 11 Evaluation of the inhibitory capacity on sebogenesis induced by stimuli of lipid type (Linoleic acid. Testosterone): evaluation of fatty acids and squalene.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Birds (AREA)
• Gerontology & Geriatric Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cosmetics (AREA)

Priority Applications (30)

Applications Claiming Priority (6)

Related Child Applications (2)

Publications (2)

Family

ID=42562114

Family Applications (2)

Family Applications After (1)

Country Status (25)

Cited By (11)

Families Citing this family (7)

Citations (1)

Family Cites Families (109)

• 2010
  • 2010-02-16 AU AU2010213093A patent/AU2010213093B2/en active Active
  • 2010-02-16 UA UAA201111055A patent/UA109525C2/ru unknown
  • 2010-02-16 SI SI201031492T patent/SI2396081T1/sl unknown
  • 2010-02-16 NZ NZ595076A patent/NZ595076A/xx unknown
  • 2010-02-16 AU AU2010213095A patent/AU2010213095B2/en not_active Ceased
  • 2010-02-16 PL PL10708105T patent/PL2396081T3/pl unknown
  • 2010-02-16 WO PCT/EP2010/000935 patent/WO2010091892A2/en not_active Ceased
  • 2010-02-16 LT LTEP14170446.0T patent/LT2805746T/lt unknown
  • 2010-02-16 DK DK10708105.1T patent/DK2396081T3/en active
  • 2010-02-16 EA EA201171062A patent/EA020198B1/ru not_active IP Right Cessation
  • 2010-02-16 MX MX2014008192A patent/MX381002B/es unknown
  • 2010-02-16 DK DK14170446.0T patent/DK2805746T3/da active
  • 2010-02-16 KR KR1020117021457A patent/KR101776337B1/ko not_active Expired - Fee Related
  • 2010-02-16 ES ES10708489T patent/ES2429143T3/es active Active
  • 2010-02-16 BR BRPI1008752-4A patent/BRPI1008752B1/pt active IP Right Grant
  • 2010-02-16 EA EA201171063A patent/EA020856B1/ru not_active IP Right Cessation
  • 2010-02-16 JP JP2011549494A patent/JP5645851B2/ja not_active Expired - Fee Related
  • 2010-02-16 US US13/201,790 patent/US8796334B2/en not_active Expired - Fee Related
  • 2010-02-16 EP EP14170446.0A patent/EP2805746B1/en active Active
  • 2010-02-16 EP EP10708489.9A patent/EP2396082B1/en not_active Not-in-force
  • 2010-02-16 HU HUE10708105A patent/HUE032999T2/hu unknown
  • 2010-02-16 EP EP20172608.0A patent/EP3744398A1/en active Pending
  • 2010-02-16 HR HRP20170936TT patent/HRP20170936T1/hr unknown
  • 2010-02-16 CN CN201080007816.7A patent/CN102316931B/zh active Active
  • 2010-02-16 UA UAA201111058A patent/UA105037C2/uk unknown
  • 2010-02-16 EP EP10708105.1A patent/EP2396081B1/en active Active
  • 2010-02-16 MX MX2011008602A patent/MX2011008602A/es active IP Right Grant
  • 2010-02-16 ES ES14170446T patent/ES2806691T3/es active Active
  • 2010-02-16 CA CA2752626A patent/CA2752626C/en not_active Expired - Fee Related
  • 2010-02-16 HU HUE14170446A patent/HUE050267T2/hu unknown
  • 2010-02-16 ES ES10708105.1T patent/ES2630044T3/es active Active
  • 2010-02-16 MX MX2011008601A patent/MX2011008601A/es active IP Right Grant
  • 2010-02-16 US US13/201,786 patent/US8754127B2/en active Active
  • 2010-02-16 CA CA2752623A patent/CA2752623C/en active Active
  • 2010-02-16 AR ARP100100447A patent/AR080596A1/es active IP Right Grant
  • 2010-02-16 KR KR1020117021458A patent/KR101800901B1/ko active Active
  • 2010-02-16 CN CN201080007823.7A patent/CN102316932B/zh not_active Expired - Fee Related
  • 2010-02-16 PT PT141704460T patent/PT2805746T/pt unknown
  • 2010-02-16 PT PT107084899T patent/PT2396082E/pt unknown
  • 2010-02-16 BR BRPI1011226-0A patent/BRPI1011226B1/pt not_active IP Right Cessation
  • 2010-02-16 CN CN201410526159.7A patent/CN104666288B/zh active Active
  • 2010-02-16 PT PT107081051T patent/PT2396081T/pt unknown
  • 2010-02-16 LT LTEP10708105.1T patent/LT2396081T/lt unknown
  • 2010-02-16 JP JP2011549492A patent/JP5715070B2/ja active Active
  • 2010-02-16 WO PCT/EP2010/000939 patent/WO2010091894A2/en not_active Ceased
  • 2010-02-16 SI SI201032023T patent/SI2805746T1/sl unknown
  • 2010-02-16 NZ NZ595080A patent/NZ595080A/xx not_active IP Right Cessation
• 2011
  • 2011-08-15 IL IL214664A patent/IL214664A/en active IP Right Grant
  • 2011-08-15 IL IL214665A patent/IL214665A/en active IP Right Grant
  • 2011-08-25 ZA ZA2011/06256A patent/ZA201106256B/en unknown
• 2014
  • 2014-04-17 US US14/255,255 patent/US9511041B2/en active Active
  • 2014-06-25 US US14/314,738 patent/US20150148418A1/en not_active Abandoned
  • 2014-08-04 JP JP2014158397A patent/JP5820030B2/ja active Active
• 2015
  • 2015-04-01 JP JP2015074798A patent/JP2015155427A/ja active Pending
  • 2015-12-15 US US14/969,939 patent/US9901557B2/en not_active Expired - Fee Related
• 2016
  • 2016-10-28 US US15/337,707 patent/US10137101B2/en active Active
• 2017
  • 2017-06-28 CY CY20171100678T patent/CY1119225T1/el unknown
• 2018
  • 2018-01-16 US US15/872,436 patent/US10398667B2/en not_active Expired - Fee Related
  • 2018-10-02 US US16/149,524 patent/US20190269637A1/en not_active Abandoned
• 2019
  • 2019-07-18 US US16/515,532 patent/US10959970B2/en not_active Expired - Fee Related
• 2020
  • 2020-01-03 US US16/733,349 patent/US20200383942A1/en not_active Abandoned
  • 2020-07-29 HR HRP20201184TT patent/HRP20201184T1/hr unknown
  • 2020-07-29 CY CY20201100702T patent/CY1123213T1/el unknown
• 2021
  • 2021-12-01 US US17/539,447 patent/US20220354809A1/en not_active Abandoned

Patent Citations (1)

Also Published As

Similar Documents

Legal Events