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WO2008064136A2 - Composés présentant une activité au niveau des récepteurs d'acide rétinoïque - Google Patents

Composés présentant une activité au niveau des récepteurs d'acide rétinoïque Download PDF

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WO2008064136A2
WO2008064136A2 PCT/US2007/085027 US2007085027W WO2008064136A2 WO 2008064136 A2 WO2008064136 A2 WO 2008064136A2 US 2007085027 W US2007085027 W US 2007085027W WO 2008064136 A2 WO2008064136 A2 WO 2008064136A2
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optionally substituted
group
compound
straight chained
alkyl
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WO2008064136A3 (fr
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Roger Olsson
Fabrice Piu
Birgitte Winther Lund
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Acadia Pharmaceuticals Inc
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Acadia Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is in the field of pharmaceuticals, and in particular in the field of modulators of the retinoic acid receptors and treatment of diseases with these compounds.
  • Retinoids are small, lipophilic molecules that derive from the metabolism of vitamin A, a dietary vitamin. Natural and synthetic retinoid derivatives exert pleiotropic effects on cellular growth, differentiation, apoptosis, homeostasis and embryogenesis. A number of non-selective retinoids are currently marketed or undergoing clinical trials for use in dermatology and oncology. For instance, Tretinoin (all-trans-retinoic acid), Isotretinoin (13-cis retinoic acid) and Etretinate (a synthetic retinoic acid analog) are being used successfully in the treatment of acne, psoriasis, photoaging and squamous cell carcinoma. However, acute and chronic toxic side effects (skeletal abnormality, skin toxicity, triglyceride elevation, teratogenesis) are commonly observed which can lead to the discontinuation of the treatment.
  • RARs and RXRs are ligand-dependent transcription factors belonging to the steroid nuclear receptor superfamily.
  • the retinoid receptors display a modular structure: an N-terminus ligand- independent activation domain (AF-I), a DNA-binding domain (DBD) adjacent to the ligand-dependent domain (LBD) and the ligand-dependent activation domain (AF-2) contiguous to the LBD and located at the C-terminus end.
  • AF-I N-terminus ligand- independent activation domain
  • DBD DNA-binding domain
  • LBD ligand-dependent domain
  • AF-2 ligand-dependent activation domain
  • RARs and RXRs Three receptors subtypes have been reported for each of the RARs and RXRs, classified as ⁇ , ⁇ , and ⁇ . All six subtypes have reportedly distinct expression patterns in the developing embryo and in the adult, thus, are believed to exhibit specific and non-overlapping functions.
  • RAR ⁇ consists of five known isoforms generated from the use of two promoters Pl (RAR ⁇ 1 and RAR ⁇ 3) and P2 (RAR ⁇ 2 and RAR ⁇ 4).
  • RAR ⁇ 1 ' a fifth isoform
  • the isoforms only differ in the nature of their AF-I transcriptional activation domains located at the very N-terminus.
  • RAR ⁇ 1 and RAR ⁇ 3 have very similar AF-I domains. The only difference being the presence of an additional 27 amino acid insert in RAR ⁇ 3.
  • RAR ⁇ 2 on the other hand, has a unique AF-I domain, while RAR ⁇ 4 lacks such a domain as well as a portion of its DNA-binding domain (DBD).
  • DBD DNA-binding domain
  • RAR ⁇ 4 could act as a dominant negative mutant.
  • the isoforms have distinct spatial and temporal distribution.
  • RAR ⁇ 1 and RAR ⁇ 3 display a relatively restricted pattern - highly present the brain, and in limited amounts in the lung and skin.
  • RAR ⁇ 2 is more broadly expressed in the brain and heart, and at much lower levels in the liver, kidney and skeletal muscle. In humans, only the RAR ⁇ 1, 2 and 4 isoforms are expressed.
  • RAR ⁇ is expressed in the skin and lungs.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat cancer.
  • a growing body of evidence supports the hypotheses that the RAR ⁇ and/or RAR ⁇ genes are tumor suppressor genes and may have chemopreventive effects on various cancers like head and neck cancer, cervix cancer, lung cancer, skin cancer, pancreatic cancer, liver caner, mammary cancer and cancer in the digestive tract (e.g. oral cavity, stomach, esophagus and colon).
  • RAR ⁇ is expressed in normal lung cells and in cells resistant to retinoic acid but is not expressed in lung cancer cells or cells resistant to retinoic acid treatment.
  • Use of a RAR ⁇ modulating compound may restore RAR ⁇ expression and thus be efficient for lung cancer treatment.
  • RAR ⁇ and/or RAR ⁇ ligands could be used alone or in combination with existing chemo- or radiation therapy. Synergistic cytotoxicity by combination treatment of selective retinoid RAR ⁇ / ⁇ ligands with taxol (Paclitaxel) has already been demonstrated.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat a variety of neurological disorders. For instance RAR ⁇ null mice exhibit locomotor defects related to dysfunction of the mesolimbic dopamine signaling pathway. Moreover these animals lack hippocampal long-term potentiation (LTP) and long- term depression (LTD), widely studied forms of synaptic plasticity. This results in substantial performance deficits in spatial learning and memory tasks.
  • RAR ⁇ 2 is involved in neurite outgrowth from peripheral and central nervous systems.
  • RAR ⁇ 2-modulating compounds would be therapeutically relevant to the treatment of neurodegenerative disorders including Parkinson's and Alzheimer's diseases. Because of its involvement in cognitive function, RAR ⁇ 2 would also be relevant to the treatment of neurological disorders where cognition is altered, in particular schizophrenia. Finally, clinical data from the use of Isotretinoin has suggested an association with depression and suicide.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat a variety of hyperproliferative and inflammatory disorders. Even though RAR ⁇ expression is below detection limits in the skin, RAR ⁇ 2-modulating compounds could act indirectly through transrepression of the activating protein 1 (API) complex, a heterodimeric transcription factor composed of Fos- and Jun-related proteins. API is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis or other associated disorders, rheumatoid arthritis and in tumor metastases.
  • API activating protein 1
  • the transrepressive effects of retinoids are mediated through a mechanism unrelated to transcriptional activation, involving the RAR-dependent control of transcription factors and cofactor assembly on APl- regulated promoters.
  • Relevant therapeutic indications include acne, psoriasis, photoaging and other dermatological disorders.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may also be used to treat chronic inflammatory disorders, for example, rheumatoid arthritis.
  • retinoids through interaction with the AP-I complex suppress collagenase gene expression.
  • the fibroblast interstitial collagenase MMP-I which degrades collagen, is thought to play a critical role in the degradation of the cartilage matrix in arthritis.
  • a RAR antagonist improves clinical and histological scores of arthritis.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat eye disorders/conditions.
  • Vitamin A the precursor of natural retinoids
  • RAR ⁇ mRNA transcripts are detectable in corneal stroma cells, conjunctival fibroblasts and corneal epithelial cells.
  • RAR ⁇ expression is predominantly confined to the periocular mesenchyme and ciliary body.
  • retinoic acid further induces the expression of RAR ⁇ in corneal and conjunctival fibroblasts. Knockout of RAR ⁇ indicates that RAR ⁇ is the main RAR subtype involved in modulation of retinal cell populations. In chicken, retinoic acid through its actions on RAR ⁇ is associated with form- deprivation myopia.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat pulmonary disorders/conditions.
  • Retinoic acid suppresses growth of vascular smooth muscle cells (SMCs) from the systemic and pulmonary circulation and inhibits migration of airway smooth muscle cells.
  • SMCs vascular smooth muscle cells
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used in treatment of e.g. asthma.
  • endogenous retinoids have been implicated in alveologenesis, and exogenous retinoic acid can reverse or partially reverse emphysema and associated pulmonary diseases.
  • compounds modulating RAR ⁇ and/or RAR ⁇ may exert the same effects.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may also be used for stimulating tropo-elasting gene expression in human lung fibroblasts.
  • RAR ⁇ and/or RAR ⁇ modulating compounds may be used to treat dermatological disorders/conditions.
  • RAR modulators especially RAR ⁇
  • the high level of RAR ⁇ and/or RAR ⁇ in the skin may indicate an ability, for a ligand of either of the two receptors, to exert a therapeutic effect on such dermatological disorders/conditions.
  • R 1 , R2, R3, are each independently selected from the group consisting of hydrogen, -OH, -COOH, halogen, optionally substituted C 1 - Cio straight chained or branched alkyl, optionally substituted C 2 -C 1 0 straight chained or branched alkenyl, optionally substituted C 2 -C 1 0 straight chained or branched alkynyl, optionally substituted C 3 -C 9 cycloalkyl, optionally substituted C 3 -C 9 cycloalkylalkyl, optionally substituted C 5 -C 7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroaralkyl;
  • X is C or N + ;
  • Y is a counter ion and is absent when X is C; and n is an integer from 1 to 5, such as n is 1, 2, 3, 4, or 5, and pharmaceutical composition comprising the same.
  • Also disclosed herein is a method of treating, or alleviating the symptoms of, a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I.
  • the disease may be selected from the group consisting of cancer, hyperproliferative disorder, inflammatory disorder, neurological disorder, neurodegenerative disorder, eye disorder, eye condition, depression, pulmonary disorders/conditions, and dermatological disorders/conditions.
  • DETAILED DESCRIPTION OF THE INVENTION [0014]
  • R 1 , R 2 , R3, are each independently selected from the group consisting of hydrogen, - OH, -COOH, halogen, optionally substituted C 1 -C 10 straight chained or branched alkyl, optionally substituted C 2 -C 10 straight chained or branched alkenyl, optionally substituted C 2 -C 10 straight chained or branched alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C5-C7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroaralkyl;
  • X is C or N + ;
  • Y is a counter ion and is absent when X is C; and n is an integer from 1 to 5, such as n is 1, 2, 3, 4, or 5.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring atom) and heteroalicyclic (bonded through a ring atom), and where n is 0 or 1.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring atom) and heteroalicyclic (bonded through a ring atom), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
  • Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified.
  • the procedures and specific groups used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein in its entirety.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • subsitutent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (hetereoalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamid
  • C m -C n in which "m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, or of the aryl can contain from “m” to "n", inclusive, carbon atoms.
  • a "Ci-C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, CH 3 CH(CH 3 )-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, and (CH 3 ) 3 CH-. If no "m” and "n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (all carbon) group.
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • an alkyl group of this invention may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, oxo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR a R b , protected hydroxyl, protected
  • substituted alkyl groups include, without limitation, 2- oxo-prop-1-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, m-trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6- hydroxyhexyl, 2,4-dichlorobutyl, 2-aminopropyl, 1 -chloroethyl, 2-chloroethyl, 1- bromoethyl, 2-chloroethyl, 1 -fluoroethyl, 2-fluoroethyl, 1-iodoethyl,
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • alkenyl group of this invention may be unsubstituted or substituted.
  • the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • substituted alkenyl groups include, without limitation, styrenyl, 3-chloro-propen-l-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl and 1-cyano-buten- 3-yl.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • cycloalkyl refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of this invention may range from C 3 to C9. A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above with regard to substitution of an alkyl group.
  • the "cycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein).
  • a cycloalkenyl group of this invention may unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • the "cycloalkenyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms).
  • the ring that is connected to the rest of the molecule is a cycloalkenyl as defined above.
  • the other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • acyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl and benzoyl.
  • Presently preferred acyl groups are acetyl and benzoyl.
  • An acyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • Example of substituted acyl groups include, without limitation, 4-phenylbutyroyl, 3- phenylbutyroyl, 3-phenylpropanoyl, 2-cyclohexanylacetyl, cyclohexanecarbonyl, 2- furanoyl and 3-dimethylaminobenzoyl.
  • aromatic refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine).
  • carbocyclic aryl e.g., phenyl
  • heterocyclic aryl groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic refers to a compound which contains one or more covalently closed ring structures, wherein the atoms forming the backbone of the ring are all carbon atoms.
  • heteroaryl refers to an aromatic group, which contains at least one heterocyclic ring, which may be optionally substituted.
  • aryl refers to a carbocyclic (all carbon) ring that has a fully delocalized pi-electron system.
  • the "aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the aryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system.
  • aryl groups include, without limitation, benzene, naphthalene and azulene.
  • heteroaryl refers to a ring that has a fully delocalized pi-electron system and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring.
  • the "heteroaryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heteroaryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi- electron system.
  • heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • heterocycloalkyl refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the ring may also contain one or more double bonds provided that they do not form a fully delocalized pi- electron system in the rings.
  • Heteroalicyclyl groups of this invention may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido.
  • the "heterocycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a heterocycloalkyl as defined above.
  • the other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • arylalkyl or “aralkyl,” which are used synonymously and interchangeably, refer to an aryl group covalently bonded to an alkyl group, as defined herein.
  • a "phenylalkyl” is a species of an aralkyl group, and refers to a phenyl ring covalently bonded to an alkyl group as defined herein. Examples, without limitation, of phenylalkyl groups include, without limitation, benzyl, 2-phenylethyl, 1-phenylpropyl, 4-phenylhexyl, 3-phenylamyl and 3-phenyl-2- methylpropyl.
  • phenylalkyl groups are those wherein the phenyl group is covalently bonded to one of the presently preferred alkyl groups.
  • a phenyl alkyl group of this invention may be unsubstituted or substituted.
  • substituted phenylalkyl groups include, without limitation, 2-phenyl-l-chloroethyl, 2- (4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy phenyl)hexyl, 2-(5-cyano-3- methoxyphenyl)pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3-aminobenzyl, 6-(4- methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethylphenyl)-3-
  • heteroarylalkyl or “heteroaralkyl,” which are used synonymously and interchangeably, and “heteroalicyclylalkyl” refer to a heteroaryl or a heteroalicyclyl group, respectively, covalently bonded to an alkyl group, as defined herein.
  • examples of such groups include, without limitation, 2- pyridylethyl, 3-pyridylpropyl, 4-furylhexyl, 3-piperazylamyl and 3-morpholinylbutyl.
  • Presently preferred heteroarylalkyl and heteroalicyclylalkyl groups are those in which a presently preferred heteroaryl or heteroalicyclyl group is covalently bonded to a presently preferred alkyl group as disclosed herein.
  • phenyl refers to a 6-member aryl group.
  • a phenyl group may be unsubstituted or substituted.
  • the substituent(s) is/are one or more, preferably one or two, group(s) independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, -NR a R b wherein R a and R b are as defined above but in addition R a may be an amino protecting group as defined herein, carboxamide, protected carboxamide, N-alkylcarboxamide, protected N- alkylcarboxamide, N,N-dialkylcarboxamide, trifluoromethyl, N-alkylsulfonylamino, N-(phenylsulfonyl)amino and pheny
  • substituted phenyl groups include, without limitation, 2, 3 or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 and A- fluorophenyl, 2, 3 or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof, 2, 3 or 4-nitrophenyl; 2, 3 or 4-cyanophenyl; 2, 3 or A- methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4-(iso-propyl)phenyl, 2, 3 or A- ethylphenyl, 2, 3 or 4-(n-propyl)phenyl, 2,6-dimethoxyphenyl, 2, 3 or A- methoxyphenyl, 2, 3 or 4-ethoxyphenyl
  • phenylalkoxy refers to a “phenylalkyl-O-" group with “phenyl” and “alkyl” as defined herein.
  • a phenylalkoxy group of this invention may be substituted or unsubstituted on the phenyl ring, in the alkyl group or both.
  • phenylalkoxy groups include, without limitation, 2-(4- hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2R)-3-phenyl-2-amino- propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and 2,2-dimethyl-3 -phenyl- 1-propoxy.
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. Presently preferred halogens are chloro and fluoro.
  • amino protecting group refers to a group commonly employed to keep (i.e., to "block” or “protect”) an amino group from reacting with a reagent while it reacts with an intended target functional group of a molecule.
  • a "protected carboxamide” refers to a carboxamide in which the nitrogen is substituted with an amino protecting group.
  • amino protecting groups include, without limitation, formyl ("For"), trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl groups, t-butoxycarbonyl ("Boc”), 2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc”), 2-phenylpropyl-2-oxycarbonyl ("Poc”), 2-(4-xenyl)isopropoxycarbonyl, 1 , 1 -diphenylethyl- 1 -oxycarbonyl, 1 , 1 -diphenylpropyl- 1 -oxycarbonyl, 2-(3 ,5 - dimethoxyphenyl)propyl-2-oxycarbonyl (“Ddz”), 2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1 -methylcycl
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • amino-protecting groups are Boc, Cbz and Fmoc. Descriptions of these and other amino-protecting groups may be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 7, M.
  • carboxy protecting group refers to a labile ester commonly used to block or protect a carboxylic acid while reactions are carried out on other functional groups on the compound.
  • carboxy protecting groups include, without limitation, t-butyl, 4-nitrobenzyl, 4- methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t- butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, -(trimethylsilyl)ethyl, -(di(n- butyl)methylsily
  • the ester employed is not critical so long as it is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • carboxy -protecting groups are found in E. Haslam, "Protective Groups in Organic Chemistry,” J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N. Y., 1991, Chapter 5.
  • a "hydroxyl protecting group” refers to a readily cleavable group that replaces the hydrogen of the hydroxyl group, such as, without limitation, tetrahydropyranyl, 2-methoxypropyl, 1-ethoxy ethyl, methoxymethyl, 2- methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'- dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t- butyl)dimethylsilyl, and 2,2,2-trichloroethoxycarbonyl.
  • hydroxyl protecting groups are not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • Further examples of hydroxy- protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry,” J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapters 2 and 3.
  • alkylthio refers to an "alkyl-S-" group, with alkyl as defined above.
  • alkylthio group include, without limitation, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and t-butylthio.
  • alkylsulfinyl refers to an "alkyl-SO-" group, with alkyl as defined above.
  • alkylsulfinyl groups include, without limitation, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl and sec-butylsulfinyl.
  • alkylsulfonyl refers to an "alkyl-SO 2 -" group.
  • alkylsulfonyl groups include, without limitation, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and t- butylsulfonyl.
  • phenylthio refers to a "phenyl-S-,” “phenyl-SO-,” and “phenyl-SO 2 -” group, phenyl as defined herein.
  • alkylaminocarbonyl groups include, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl.
  • substituted alkylaminocarbonyl include, without limitation, methoxymethyl- aminocarbonyl, 2-chloroethylaminocarbonyl, 2-oxopropylaminocarbonyl and A- phenylbutylaminocarbonyl.
  • substituted phenylaminocarbonyl groups include, without limitation, 2- chlorophenyl-aminocarbonyl, 3-chlorophenylaminocarbonyl, 2- nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and A- methoxyphenylaminocarbonyl.
  • alkylaminothiocarbonyl groups include, without limitation, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl and butylaminothiocarbonyl.
  • alkyl-substituted alkylaminothiocarbonyl groups include, without limitation, methoxymethylaminothiocarbonyl, 2- chloroethylaminothiocarbonyl, 2-oxopropylaminothiocarbonyl and A- phenylbutylaminothiocarbonyl.
  • phenylaminothiocarbonyl groups include, without limitation, 2- chlorophenylaminothiocarbonyl, 3-chlorophenyl-aminothiocarbonyl, 2- nitrophenylaminothiocarbonyl, 4-biphenylaminothiocarbonyl and A- methoxyphenylaminothiocarbonyl.
  • hydroxyl refers to an "-OH” group.
  • cyano refers to a "-C ⁇ N” group.
  • nitro refers to an "-NO 2 " group.
  • a "C-carboxy” group refers to a “-C(O)OR” group with R as defined above.
  • acetyl refers to a CH 3 C(O)- group.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfinyl” group refers to an "-S(O)-R” group with R as defined above.
  • S-sulfonamido refers to a "-SO 2 NR" group with R as defined above.
  • N-sulfonamido refers to a "RSO 2 NH-" group with R as defined above.
  • a "trihalomethanesulfonamido" group refers to an "X 3 CSO 2 NR-" group with X as halogen and R as defined above.
  • An "O-carbamyl” group refers to a "-OC(O)-NR" group with R as defined above.
  • N-carbamyl refers to an "ROC(O)NH-" group with R as defined above.
  • a "C-amido” group refers to a "-C(O)-NR a R b group with R a and R b as defined above.
  • N-amido refers to a RC(O)NH- group with R as defined above.
  • haloalkyl refers to an alkyl group where one or more of the hydrogen atoms are replaced by halogen.
  • groups include but are not limited to , chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2- fluoromethyl, 2-fluoroisobutyl.
  • perhaloalkyl refers to an alkyl group in which all the hydrogen atoms are replaced by halogen atoms.
  • an “ester” refers to a “-C(O)OR a " group with R a as defined herein.
  • an “amide” refers to a “-C(O)NR a R b " group with R a and R as defined herein.
  • substituents are not specified (e.g. haloalkyl) there may be one or more substituents presents.
  • haloalkyl may include one or more of the same or differents halogens.
  • C 1 -C 3 alkoxy phenyl may include one or more of the same of different alkoxygroups containing one, two or three atoms.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999). Compounds containing any such converted hydroxyl, amino and/or carboxylic acid groups are within the scope of this invention.
  • an “ether” refers to a "-C-O-C-" group wherein either or both carbons may independently be part of an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroalicyclyl group.
  • halogenated ether refers to an ether in which the groups to either side of the oxygen are both alkyl substituted with halogen.
  • amino acid refers to any one of the twenty naturally-occurring L-amino acids, to their non-natural D-enantiomers, to non- naturally occurring amino acids such as, without limitation, norleucine ("NIe”), norvaline (“Nva”), L- or D-naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and to other amino acids well-known in the peptide art such as those described in M.
  • NIe norleucine
  • Nva norvaline
  • Orn ornithine
  • homoarginine homoarginine
  • contemplated herein is a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer.
  • substantially free it is meant that the composition comprises less than 10%, or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer. If the particular compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers.
  • compositions comprising all four diastereomers includes compositions comprising all four diastereomers, compositions comprising the racemic mixture of R,R and S,S isomers, compositions comprising the racemic mixture of R,S and S,R isomers, compositions comprising the R,R enantiomer substantially free of the other diastereomers, compositions comprising the S, S enantiomer substantially free of the other diastereomers, compositions comprising the R, S enantiomer substantially free of the other diastereomers, and compositions comprising the S,R enantiomer substantially free of the other diastereomers.
  • Ri is selected from the group consisting of optionally substituted C 1 -C 10 straight chained or branched alkyl, optionally substituted C 3 -C 9 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In other embodiments, Ri is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.
  • the aryl and the heteroaryl of Ri are optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, C-amido, N-amido, C-carboxy, protected C-carboxy, O-carboxy, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, perhaloalkyl, and amino.
  • substituents selected from the group consisting of alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, C-amido, N-amido, C-carboxy, protected C-
  • the aryl and the heteroaryl of Ri are optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, aryloxy, cyano, halogen, and amino.
  • the aryl and the heteroaryl of Ri are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, iodo, haloalkyl, and perhaloalkyl.
  • the aryl is phenyl
  • Ri is selected from the group consisting of phenyl, 4-cholorophenyl, 3-cholorophenyl, and 2-cholorophenyl.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 straight chained or branched alkyl, optionally substituted C 2 -C 10 straight chained or branched alkenyl, optionally substituted C 2 -C 10 straight chained or branched alkynyl, optionally substituted C 3 -C 9 cycloalkyl, and optionally substituted C5-C7 cycloalkenyl.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-Ci 0 straight chained or branched alkyl.
  • R 2 is hydrogen.
  • R3 is selected from the group consisting of optionally substituted Ci-Ci 0 straight chained or branched alkyl, optionally substituted C 2 -C 10 straight chained or branched alkenyl, optionally substituted C 2 -C 10 straight chained or branched alkynyl, optionally substituted C 3 -C 9 cycloalkyl, optionally substituted C5-C7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroaralkyl.
  • R3 is selected from the group consisting of optionally substituted Ci-Ci 0 straight chained or branched alkyl, optionally substituted C3-C9 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroaralkyl. In further embodiments, R 3 is selected from the group consisting of optionally substituted aralkyl, and optionally substituted heteroaralkyl.
  • the aralkyl or heteroaralkyl of R3 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, C-amido, N-amido, C-carboxy, protected C-carboxy, O-carboxy, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, perhaloalkyl, and amino.
  • the substituent is selected from the group consisting of alkyl, hydroxy, halogen, carbonyl, C-carboxy, protected C-carboxy, and amino.
  • the aralkyl or heteroaralkyl of R3 is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, C-carboxy, and protected C-carboxy.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
  • the C-carboxy is protected by an alkyl group, which in some embodiments, is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
  • R3 is selected from the group consisting of benzyl, 4- chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-cyanobenzyl, 2,4- dicholorbenzyl, 2,6-dicholorbenzyl, and 4-methylcarboxybenzyl.
  • X is N + .
  • Y is selected from the group consisting of halide, acetate, tartrate, phosphate, sulfonate, tetrafluoroborate.
  • the halide is selected from the group consisting of fluoride, chloride, bromide, and iodide.
  • Y is selected from the group consisting of chloride, bromide, and acetate.
  • the compound of Formula I or II is not one of the following compounds:
  • the compound of Formula I or II is not one of the following compounds: where Y is a counter ion.
  • L is an alkyl spacer optionally substituted with one or more substituents
  • Ri and R 3 are each independently optionally substituted aryl or optionally substituted heteroaryl;
  • R 2 is selected from the group consisting of hydrogen, -OH, -COOH, halogen, optionally substituted C 1 -C 10 straight chained or branched alkyl, optionally substituted C 2 -C 10 straight chained or branched alkenyl, optionally substituted C 2 -C 10 straight chained or branched alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C5-C7 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroaralkyl;
  • Y is a counter ion; and n is an integer from 1 to 5, such as n is 1, 2, 3, 4, or 5.
  • Ri is optionally substituted phenyl.
  • R3 is optionally substituted phenyl.
  • L is -CH 2 -.
  • a method of modulating the activity of a RAR ⁇ or RAR ⁇ receptor subtypes comprising contacting a RAR ⁇ or RAR ⁇ receptor with at least one compound of Formula I or II.
  • the modulating is performed in vivo, whereas in other embodiments, the modulating is performed in vitro.
  • the compound of Formula I or II modulates the activity of an RAR ⁇ isoform. In other embodiments, the compound of Formula I or II modulates the activity of an RAR ⁇ isoform.
  • a modulator is defined as a compound that is an agonist, a partial agonist, an inverse agonist or an antagonist of one or more RAR ⁇ and/or RAR ⁇ receptors.
  • a modulator may increase the activity of the RAR ⁇ or RAR ⁇ receptor subtype, or may decrease the activity of the RAR ⁇ or RAR ⁇ receptor subtype.
  • an "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • An "antagonist” is defined as a compound, which blocks the action of an agonist on a receptor.
  • a "partial agonist” is defined as an agonist that displays limited, or less than complete, activity such that it fails to activate a receptor in vitro, functioning as an antagonist in vivo.
  • An "inverse agonist” is defined as a compound that decreases the basal activity of a receptor.
  • the administered compound modulates the activity of a RAR ⁇ or RAR ⁇ receptor subtypes.
  • the compound of Formula I or II is administered in conjunction with at least one chemotherapeutic agent and/or radiation therapy.
  • the cancer is associated with malignant tumors.
  • the cancer is selected from the group consisting of breast carcinoma and cancers of the skin, head, neck, lung, esophagus, mammary gland, liver, pancreas, cervix and digestive tract (e.g. oral cavity, esophagus, stomach, small intestine, including duodenum, jejunum, and ileum, and colon).
  • the term "subject” refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment.
  • the mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.
  • terapéuticaally effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human and includes alleviation of the symptoms of the disease being treated.
  • a method of treating, or alleviating the symptoms of, hyperproliferative and inflammatory disorders comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ or RAR ⁇ receptor subtypes.
  • the inflammatory disorder is a chronic inflammatory disorder.
  • the inflammatory disorder is rheumatoid arthritis
  • a method of treating or alleviating symptoms of a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ or RAR ⁇ receptor subtypes.
  • the neurological disorder is selected from the group consisting of performance deficits in spatial learning and memory tasks and age-related memory deficit.
  • the neurological disorder is a disorder wherein cognition is altered.
  • the neurological disorder is schizophrenia.
  • a method treating or alleviating symptoms of a neurodegenerative disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ or RAR ⁇ receptor subtypes.
  • the neurodegenerative disorder is Parkinson's disease or Alzheimer's disease.
  • the neurodegenerative disorder relates to a method for the treatment of neurodegenerative disorders where nerve regeneration is necessary after, e.g. a spinal cord injury, after a stroke, after damage to the cardiac musles, after damage caused to myelin in multiple sclerosis and damage to islet cells in diabetes.
  • a method treating or alleviating symptoms of a hyperproliferative or inflammatory disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ and/or RAR ⁇ receptor subtypes.
  • the inflammatory disorder is a chronic inflammatory disorder.
  • the inflammatory disorder is psoriasis or other associated disorders or rheumatoid arthritis.
  • a method for treating or alleviating symptoms of an eye disorder or an eye condition comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ and/or RAR ⁇ receptor subtypes.
  • a method for treating or alleviating symptoms of depression comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ and/or RAR ⁇ receptor subtypes.
  • a method for treating or alleviating symptoms of pulmonary disorders/conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ and/or RAR ⁇ receptor subtypes.
  • a method for treating or alleviating symptoms of dermatological disorders/conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or II, described above.
  • the administered compound modulates the activity of a RAR ⁇ and/or RAR ⁇ receptor subtypes.
  • the dermatological disorder is selected from the group consisting of cystic acne, acne vulgaris and other related acneiform diseases, cutanous disordes of keratinization (e.g.
  • a method of identifying a compound that is an agonist, inverse agonist, or antagonist of one or more RAR ⁇ receptors and/or RAR ⁇ receptors comprising contacting RAR ⁇ receptor and/or RAR ⁇ receptor with at least one test compound of Formula I or II and determining any change in activity of the one or more RAR ⁇ receptors and/or RAR ⁇ receptors so as to identify the test compound as an agonist, inverse agonist, or antagonist of one or more RAR ⁇ receptors and/or RAR ⁇ receptors.
  • the RAR ⁇ receptor and/or RAR ⁇ receptor is expressed in a cell.
  • the cell is a cultured cell.
  • the cultured cells overexpress the RAR ⁇ receptor and/or RAR ⁇ receptor.
  • the identified agonist, inverse agonist or antagonist is selective for the RAR ⁇ receptor and/or RAR ⁇ receptor.
  • the R-SAT test method disclosed in Example 42, may be used. When using this test, a compound is considered to have activity if the pECso is > 5.0 and the %Eff is > 25.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula I or II, and a physiologically acceptable component such as a carrier, a diluent, a salt or an excipient, or a combination thereof.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of a subject.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above. [00136]
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds disclosed herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in abs ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in abs ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may be used.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • the dose about the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • human dosages for treatment of at least some condition have been established.
  • the methods disclosed herein will use those same dosages, or dosages that are between about 0.1% and 500%, or between about 25% and 250%, or between 50% and 100% of the established human dosage.
  • a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the ring closing reaction between an ⁇ -aminoketone and an imino ether followed by an N-alkylation can provide compounds of Formula I or II.
  • the ring closing reaction is preferably carried out in a microwave, preferably at a temperature of about 130 0 C and for about 15min.
  • Ethanol is preferably used as solvent.
  • the N- alkylation is preferably carried out in a microwave, at a temperature about 160 0 C and for about 15min. In one embodiment, the reaction is carried out with acetonitrile as solvent.
  • the final product is isolated by conventional means, preferably purified by re-crystallization.
  • Rl, R2 and R3 have the definitions as described herein.
  • Y is defined as a leaving group e.g. a halide.
  • X is defined as a counterion e.g. a halide, acetate or phosphate, n is an integer from 1-5. X can in some cases be identical with
  • the cyclic imidazoles are formed in one step using microwave irradiation (Scheme 5).
  • R P-CI, 0-CH 3 , m-CH 3 , P-CH 3 , p-CN 0,0-Cl, o, m-CI, o,p-CI
  • HPLC/MS analyses were performed on a Waters/Micromass ZQ2000 LC/MS instrument with a Xterra® MS Ci 8 3.5 ⁇ m, 30x4.6 mm ID column with a guard column cartridge system and a 996 Photodiode Array Detector; eluent: A: 10 mM aq. NH 4 OAc; B: 10 mM aq. NH 4 OAc CH 3 CN-H 2 O (95:5); 5 min. gradient starting at 30% B (initial hold for 0.5 min.), over 5 min. to 90% B, hold for 0.5 min., over 0.5 min. to 30% B, hold for 2.5 min. The flow rate was 1 mL/min.
  • Example 2 General procedure for the synthesis of 7 member quaternary imidazoles (Procedure B) [00183] The benzylhalide (0.30 mmol), triethylamine (33 ⁇ L, 0.47 mmol) and 3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[l,2-a]azepine (0.24 mmol) in 1 mL dry acetonitrile were microwave irradiated at 160 0 C for 15 min. The reaction mixture was evaporated to dryness. The residue was dissolved in H 2 O and loaded on a hydromatrix. The hydromatrix was washed with Et 2 O and the filtrate was extracted with CH 2 Cl 2 .
  • the CH 2 Cl 2 phase was evaporated to dryness and dissolved in H 2 O.
  • the water phase was washed 3 times with Et 2 O (limited amounts of brine was added to the water phase), and extracted 3 times with CH 2 Cl 2 .
  • the organic phase was dried over Na 2 SO 4 , filtrated and evaporated to dryness.
  • This product was added to a solution of hexametylenetetramine (2.12 g, 15 mmol) in 70 mL CHCl 3 and was stirred at 50 0 C for 1 h and 15 min. The mixture was cooled to r.t. and the white precipitate was collected by filtration and washed with CHCI3. The resulting quaternary salt was suspended in a mixture of 95% EtOH (20 mL) and cone. HCl (7.5 mL) and heated at 50 0 C for 3 h. The mixture was cooled to 0 0 C and the resulting white solid was collected by filtration.
  • Example 11 3-(4-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-imidazori,2-a1azepine
  • 2-Amino-l-(4-chloro-phenyl)-ethanone; hydrochloride (268 mg, 1.30 mmol) and 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (158 mg, 1.24 mmol) were subjected to general procedure A and gave the title compound (293 mg, 96%).
  • Example 14 3 -(4-Chloro-phenyl)-5 ,6,7, 8 ,9 , 10-hexahydro-imidazo [ 1 ,2-ai azocine
  • the reaction mixture was microwave irradiated at 100 0 C for 5 min, evaporated to dryness, dissolved in 4 mL EtOH and 0.3 mL cone. HCl and then microwave irradiated at 120 0 C for 15 min.
  • the product was evaporated to dryness and column chromatographed on silica (heptane/EtOAc 1: 1) which gave the title compound (102 mg, 32%).
  • Example 15 3 -(3 -Chloro-phenyl)-5 ,6,7, 8 ,9 , 10-hexahydro-imidazo [ 1 ,2-ai azocine
  • the reaction mixture was microwave irradiated at 100 0 C for 5 min, evaporated to dryness, dissolved in 4 mL EtOH and 0.3 mL cone. HCl and then microwave irradiated at 120 0 C for 15 min.
  • the product was evaporated to dryness and column chromatographed on silica (heptane/EtOAc 1 : 1) which gave the title compound (59 mg, 18%).
  • the reaction mixture was microwave irradiated at 100 0 C for 5 min, evaporated to dryness, dissolved in 4 mL EtOH and 0.3 mL cone. HCl and then microwave irradiated at 120 0 C for 15 min.
  • the product was evaporated to dryness and column chromatographed on silica (heptane/EtOAc 1: 1) which gave the title compound (82 mg, 29%).
  • Example 17 l-(4-Chloro-benzyl)-3-phenyl-6J,8,9-tetrahydro-5H-imidazori,2- alazepin-l-ium; chloride (compound 1)
  • Example 18 1 -(2-Methyl-benzyl)-3-phenyl-6 J,8,9-tetrahydro-5H-imidazor 12- a "
  • Example 19 l-(3-Methyl-benzyl)-3-phenyl-6J,8,9-tetrahydro-5H-imidazori,2- alazepin-l-ium; chloride (compound 3)
  • Example 20 l-(4-Methyl-benzyl)-3-phenyl-6J,8,9-tetrahydro-5H-imidazori,2- a]azepin-l-ium; chloride (compound 4)
  • Example 21 l-(4-Cvano-benzyl)-3-phenyl-6 J,8,9-tetrahydro-5H-imidazori 2- a "
  • Example 22 l-(2,6-Dichloro-benzyl)-3-phenyl-6J,8,9-tetrahydro-5H-imidazori,2- a "
  • Example 25 3-(4-Chloro-phenyl)-l-(2,4-dichloro-benzyl)-5,6,7,8-tetrahvdro- imidazo
  • Example 26 3-(3-Chloro-phenyl)-l-(2,4-dichloro-benzyl)-5,6,7,8-tetrahvdro- imidazori,2-a1pyridin-l-ium; chloride (compound 9)
  • Example 30 l-(2 ⁇ -dichloro-benzyl)-3-phenyl-6J,8,9-tetrahvdro-5H-imidazori,2- aiazepin-1-ium; acetate (compound 7)
  • Example 32 3 -(3 -chloro-phenyl)- 1 -(4-methoxycarbonyl-benzyl)-5 ,6,7,8-tetrahydro- imidazori.2-a1pyridin-l-ium; acetate (compound 12)
  • Example 36 1 -(4-methoxycarbonyl-benzyl)-3-phenyl-6,7,8,9-tetrahvdro-5H- imidazori,2-a1azepin-l-ium; acetate (compound 18)
  • R-SAT ® The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT ® ), was used to investigate the pharmacological properties of known and novel RAR ⁇ agonists and antagonists and novel RAR ⁇ agonists and antagonists.
  • R-SAT ® is disclosed, for example, in U.S. Patent Nos. 5,707,798, 5,912,132, and 5,955,281, Piu, F., Gauthier, N. K., and Wang, F., (Beta Arrestin 2 modulates the activity of Nuclear Receptor RAR beta 2 through activation of ERK2 kinase) Oncogene 2006, 12:25(2):218-29, Burstein, E.

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Abstract

L'invention concerne un composé représenté par la formule (I) et une composition pharmaceutique comportant celui-ci. Sont également décrits par les présentes des procédés conçus pour traiter ou pour soulager les symptômes d'une maladie nécessitant l'administration à un sujet en besoin de celle-ci d'une quantité thérapeutique efficace d'un composé représenté par la formule (I). La maladie peut être sélectionnée dans le groupe constitué par le cancer, un trouble hyperprolifératif, un trouble inflammatoire, un trouble neurologique, une maladie neurodégénérative, un trouble de la vue, une affection de l'œil, la dépression, des troubles/affections pulmonaires, des troubles/affections dermatologiques, et la stérilité.
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WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
EP2329817A1 (fr) * 2009-09-04 2011-06-08 Ernst-Moritz-Arndt-Universität Greifswald Antagonistes du récepteur de l'acide rétinoïque, inhibiteurs de miR-10a et inhibiteurs des répresseurs HOXB1 et/ou HOXB3 pour le traitement du cancer du pancréas
WO2012085582A1 (fr) 2010-12-23 2012-06-28 Astrazeneca Ab Composé
WO2012085583A1 (fr) 2010-12-23 2012-06-28 Astrazeneca Ab Nouveau composé
WO2013192301A1 (fr) * 2012-06-22 2013-12-27 The Board Of Trustees Of The Leland Stanford Junior University Composés imidazo bicycliques imminium en tant qu'agents anti-tumoraux
WO2015109231A1 (fr) 2014-01-17 2015-07-23 Cornell University Méthodes de traitement d'états pathologiques apparentés à un syndrome métabolique à l'aide d'agonistes du récepteur de l'acide rétinoïque
US20160289228A1 (en) * 2013-12-09 2016-10-06 Ucb Biopharma Sprl Tetrahydroimidazopyridine Derivatives as Modulators of TNF Activity
US9512407B2 (en) 2009-09-07 2016-12-06 Genome Research Limited Cells and methods for obtaining them
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US6521814B1 (en) * 1997-12-22 2003-02-18 Institut National De La Santa Et De La Recherche Medicale Use of ligands for treatment of diseases responsive to retinoids
KR20010053282A (ko) * 1998-07-01 2001-06-25 다케다 야쿠힌 고교 가부시키가이샤 레티노이드-관련 수용체 기능 조절제
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WO2011012897A1 (fr) 2009-07-31 2011-02-03 Astrazeneca Ab Nouvelle combinaison pour le traitement de l'asthme
WO2011026912A3 (fr) * 2009-09-04 2011-08-25 Ernst-Moritz-Arndt-Universität Greifswald Inhibiteurs de mir-10a et inhibiteurs de répresseurs de hoxb1 et/ou hoxb3 dans le blocage d'un comportement métastasique d'un cancer pancréatique
EP2329817A1 (fr) * 2009-09-04 2011-06-08 Ernst-Moritz-Arndt-Universität Greifswald Antagonistes du récepteur de l'acide rétinoïque, inhibiteurs de miR-10a et inhibiteurs des répresseurs HOXB1 et/ou HOXB3 pour le traitement du cancer du pancréas
US9512407B2 (en) 2009-09-07 2016-12-06 Genome Research Limited Cells and methods for obtaining them
WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
WO2012085582A1 (fr) 2010-12-23 2012-06-28 Astrazeneca Ab Composé
WO2012085583A1 (fr) 2010-12-23 2012-06-28 Astrazeneca Ab Nouveau composé
WO2013192301A1 (fr) * 2012-06-22 2013-12-27 The Board Of Trustees Of The Leland Stanford Junior University Composés imidazo bicycliques imminium en tant qu'agents anti-tumoraux
US9611276B2 (en) 2012-06-22 2017-04-04 The Board Of Trustees Of The Leland Stanford Junior University Imidazo bicyclic iminium compounds as antitumor agents
US20160289228A1 (en) * 2013-12-09 2016-10-06 Ucb Biopharma Sprl Tetrahydroimidazopyridine Derivatives as Modulators of TNF Activity
US9969728B2 (en) * 2013-12-09 2018-05-15 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
WO2015109231A1 (fr) 2014-01-17 2015-07-23 Cornell University Méthodes de traitement d'états pathologiques apparentés à un syndrome métabolique à l'aide d'agonistes du récepteur de l'acide rétinoïque
US11160769B2 (en) 2014-01-17 2021-11-02 Cornell University Methods of treating metabolic syndrome related conditions using retinoic acid receptor agonists
EP3563683A1 (fr) 2014-03-10 2019-11-06 Cornell University Polythérapie pour le cancer de la tête et du cou

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