WO2012024581A2 - Composés oxystérol - Google Patents
Composés oxystérol Download PDFInfo
- Publication number
- WO2012024581A2 WO2012024581A2 PCT/US2011/048414 US2011048414W WO2012024581A2 WO 2012024581 A2 WO2012024581 A2 WO 2012024581A2 US 2011048414 W US2011048414 W US 2011048414W WO 2012024581 A2 WO2012024581 A2 WO 2012024581A2
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- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- compounds
- bone
- hydrogen
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Definitions
- the present invention is directed to novel oxysterol compounds and methods for their preparation and use as therapeutic or prophylactic agents.
- Oxysterols form a large family of oxygenated derivatives of cholesterol that are present in the circulation, and in human and animal tissues. Oxysterols that have been identified in human plasma to date include 7a-hydroxycholesterol, 24S- hydroxycholesterol. and 4u- and 4 ⁇ - hydroxycholesterol. which are present at concentrations ranging from 5-500 ng/ml. These oxysterols have a variety of half-lives in circulation ranging from 0.5-60 hours, and their levels can be altered by aging, drug interventions, and disease processes.
- Oxysterols may be formed either by autooxidation, as a secondary byproduct of lipid peroxidation, or by the action of specific monooxygenases, most of which are members of the cytochrome P450 family of enzymes. Examples of these enzymes are cholesterol 7a-hydroxylase (CYP7A 1 ) that forms 7a- hydroxycholesterol, cholesterol 25-hydroxylase that forms 25- hydro ycholesteail, cholesterol 24S-hydroxyIase (CYP46) that forms 24S- hydroxycholesterol, and others. In addition, oxysterols may be derived from the diet.
- CYP7A 1 cholesterol 7a-hydroxylase
- CYP46 cholesterol 24S-hydroxyIase
- oxysterols may be derived from the diet.
- Cytochrome P450 enzymes are also involved in the further oxidation of oxysterols and their metabolism into active or inactive metabolites that leads to their eventual removal from the system. Since certain oxysterols have potent effects on cholesterol metabolism, their involvement in that process has been widely studied in recent years.. In addition, the presence of oxysterols in atherosclerotic lesions has prompted studies of their role in the pathogenesis of this disorder.
- Oxysterols may also play a role in various physiologic processes, such as cellular differentiation, inflammation, apoptosis. and steroid production. With respect to cellular differentiation, specific oxysterols induce the differentiation of human keratinocytes in vitro, while monocyte differentiation can be induced by the oxysterol 7-ketocholcsterol. Differentiation of keratinocytes by oxysterols is mediated by the nuclear hormone receptor, liver X receptor ⁇ (LXRP). LXRa and LXR , initially identified as orphan nuclear receptors, act as receptors for oxysterols. However many of the effects of oxysterols are mediated by LXR-indcpcndent mechanisms.
- LXRP liver X receptor ⁇
- Hedgehog molecules can play roles in a variety of processes including tissue patterning, mitogencsis. morphogenesis, cellular differentiation and embryonic developments. In addition to its role in embryonic development, hedgehog signaling can play a role in postnatal development and maintenance of tissue/organ integrity and function. Hedgehog signaling can be important during skelctogenesis as well as in the development of osteoblasts in vitro and in vivo. Hedgehog signaling can inhibit adipogenesis when applied to multipotcnt mesenchymal cells. C3H- I 0T 1/2.
- Hedgehog signaling can involve a complex network of signaling molecules that includes plasma membrane proteins, kinases, phosphatases, and factors that facilitate the shuffling and distribution of hedgehog molecules.
- Production of hedgehog molecules from a subset of producing/signaling cells involves its synthesis, autoprocessing and lipid modification.
- Lipid modification of hedgehog which may be essential for its functionality, can involve the addition of a cholesterol molecule to the C-icrminal domain of the auto-cleaved hedgehog molecule and palmitoy!ation at its N- terminal domain. Additional accessory factors can help shuttle hedgehog molecules to ihe plasma membrane of the signaling cells, release them into the extracellular environment, and transport them to the responding cells.
- Multipotent mesenchymal stem cells found in the bone marrow stroma also known as bone marrow stromal cells ( MSC) have the potential to differentiate into several different cell types of the mesenchymal lineage, including osteoblasts, chondrocytes, myocytes, fibroblasts, tendon cells, and adipocytes (Caplan, Clin Plast Surg 21 :429-435. 1994; Majors et at.. J Ort op Res 1 5:546-557. 1997; Prockop, Science 276:71 -74, 1997). Regulation of stem cell fate down these various lineages is important for tissue development, homeostasis and repair (Vaananen, Ann Med 37:469- 479.
- Osteoporosis is a degenerative disease of the skeleton that generally occurs due to an alteration in bone turnover homeostasis and is characterized by fragile bones and increased susceptibility to bone fractures ( Riggs and Melton, ⁇ ' Engl J Med 327:620-627, 1992). Decreased bone synthesis due to reduced osteoblast formation and/or activity of progenitor cells, which occurs in parallel with increased adipocyte formation at the expense of osteoblasts, in addition to increased bone resorption from excessive osteoclast formation and/or activity are mechanisms leading to this degenerative disorder (Cummings and Melton, Lancet 359: 1761 - 1767, 2002).
- therapeutic molecules having pro-osteogenic and anti-adipogenic effects on MSC may help intervene with osteoporosis by enhancing bone formation through a shift in the apparent imbalance in cellular differentiation in favor of osteoblasts ( odan and Martin. Science 289: 1 508- 1514, 2000: Goltzman, Nat Rev Drug Discov 1 :784-796. 2002; Mundy, Annu Rev Med 53:337- 354, 2002).
- Oxysterols are products of cholesterol oxidation and are formed in vivo by a variety of cell types including osteoblasts (Schroepfer. Phyiol Rev 80:361 -554, 2000; Bjorkhem and Dicsfalusy. Arterioscler Ttiromb Vase Biol 22:734-742, 2002). Certain oxysterols, such as 20(S)-hydroxycholesterol (20S), alone or in combination with.
- 22(S)- or 22( ?)-hydroxycholesterol can be potent inducers of osteogenic differentiation in multipotent mesenchymal cells such as M2- 10B4 (M2) marrow stromal cells and C3H 10T I/2 embryonic fibroblasts (Kha el a/.. J Bone Miner Res 19:830-840. 2004).
- M2 mesenchymal cells
- C3H 10T I/2 embryonic fibroblasts Kha el a/.. J Bone Miner Res 19:830-840. 2004.
- These oxysterols can induce osteogenic and inhibit adipogenic differentiation of MSCs through activation of the hedgehog signaling pathway, which in turn regulates the master switches that control osteogenic and adipogenic differentiation, namely Runx2 and PPARy, respectively (Richardson ct al.. J Cell Bioche 100: 1 131 - 1 145.
- Oxysterols may be able to serve as potential therapeutics for intervention with osteoporosis and other musculoskeletal disorders. Certain mechanisms may play a synergistic and or cooperative role with hedgehog signaling in mediating the effects of osteogenic oxysterols on MSC differentiation. .
- Wnls are small (39-46 kDa) lipid-modificd secreted glycoproteins that influence many aspects of embryological development, such as cell patterning, proliferation, and stem ceil fate determination (Gordon and Nusse, J Biol Chem 281 :22429-22433, 2006; Clevers. Cell 127:469-480, 2006; Willert and Jones, Genes Dev 20: 1394- 1404, 2006).
- Wnt proteins signal through Frizzled (Fz) molecules, which are a family of seven-pass transmembrane receptors that transduce the signal through either ⁇ -catenin- dependent (i.e..
- canonical ⁇ -catenin/TCF/'Lef pathway or independent (i.e., non-canonical Wnt planar cell polarity and the Wnt/calcium pathways) mechanisms.
- Activation of the ⁇ - catenin-dependent pathway requires the presence of low-density l ipoprotein receptor related protein ( LRP)5/6 (Johnson et al.. J Bone Miner Res 19: 1 749- 1 757. 2004).
- LRP low-density l ipoprotein receptor related protein
- Certain Wnts induce osteogenesis, through direct stimulation of Runx2 gene expression (Gaur ct ai, J Biol Chem 280:331 32-3 140. 2005; Westendorf et ai.
- Hedgehog and Wnt signaling act synergisttcally and/or cooperatively in regulating several physiologic and pathologic processes including osteoblast development, and hair follicle morphogenesis (Hu et ai. Development 132:49-60, 2004; Silva-Vargas et ai. Develop Cell 9: 121- 1 31 , 2005; ullor et ai. Current Biol 1 1 :769-773, 2001 ; Taipale and Beachy, Nature 41 1 :349- 354 ; 2001 ).
- the PI3-kinase/Akt pathway is involved in a variety of cellular processes including cell growth, proliferation, survival, metabolism, invasion, angiogenesis, and DNA repair.
- the PI3-kinase/Akt pathway can play a role in the survival of uncommitted osteoblast precursor cells (Debiais et ai. Experimental Cell Res 297:235- 246. 2004: Almeida ct ai. J Biol Chem 280:41342-41351 , 2005) and in the regulation of osteoblast differentiation and migration (Fujita et ai, J Cell Biol 166:85-95, 2004; Ghosh-Choudhury et ai. J Bio!
- Akt-/- mice have severely delayed bone development (Peng et ai. Genes Dev 17: 1352- 1365, 2007), and specific deletion of Akt inhibitor, Pten phosphatase, in osteoblasts results in increased bone density throughout life in mice (Liu et al.. Proc Natl Acad Sci 104: 2259-2264, 2007).
- P13-kinase/Akt activation may play a direct or synergistic role in mediating the biological effects of hedgehog signaling including cell cycle progression, neuronal and chondrogenic differentiation, and capillary morphogenesis by endothelial cells (Riobo el al. Proc Natl Acad Sci 103:4505-4510, 2006; Kenney el al.. Development 13 1 :217-228, 2003; Fu i al.. Acta Pharmacol Sinica 27:685-693, 2006; anda at al., J Biol Chem 278:8244-8249, 2003).
- Certain oxysterols can exert their osteogenic effects through a Dkk- 1 inhibitable and PI3-kinase-dependent mechanism(s). Although Dkk- 1 is able to block the oxysterol-induced osteogenic differentiation of MSC, oxysterols appear to regulate some but not al l targets of Wnt signaling.
- osteoprogenitor cells can be targeted in order to stimulate their osteogenic differentiation and bone fonning properties through the use of osteoinductive/anabolic factors.
- Certain naturally-occurring oxysterols have osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells.
- osteogenic oxysterols can activate the Wnt-related signaling pathway through a Dkk- 1 - inhibitable and ⁇ -catenin independent manner.
- Bone marrow stromal cells treated with oxysterols can demonstrate increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes.
- oxysterol effects which can occur in the absence of ⁇ -catenin accumulation or TCF/Lef activation, can be inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk-1.
- the inhibitors of P13-kinase signaling, LY 294002 and wortmanin, can inhibit oxysterol-induced osteogenic differentiation and induction of Wnt signaling target genes.
- Osteogenic oxysterols are small molecule modulators of signaling pathways in multipotent mesenchymal cel ls that regulate numerous developmental and post-developmental processes.
- osteogenic oxysterols that induce osteogenic differentiation of osteoprogenitor cells, for example bone marrow stromal cells, in vitro also stimulate osteogenic activity of cells in vivo and enhance bone healing (Aghaloo er i, J Orl op Res 25: 1488- 1497, 2007).
- oxysterol-induced osteogenesis is inhibited by the Wnt signaling inhibitor Dickkopf- 1 (Dkk- 1 ), osteogenic oxysterols selectively regulate targets of Wnt signaling, Wnt3a inhibits osteogenetic differentiation of M2- 10B4 marrow stromal cells and oxysterol-induced osteogenesis is mediated through the PI3- kinase/Akt pathway.
- Dkk- 1 Dickkopf- 1
- Wnt3a inhibits osteogenetic differentiation of M2- 10B4 marrow stromal cells
- oxysterol-induced osteogenesis is mediated through the PI3- kinase/Akt pathway.
- certain oxystcrol compounds were shown to have activity as activators of hedgehog signaling, osteoinduction, antiadipogenesis and Wnt signaling.
- the present invention is directed to novel oxysterol compounds, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds in the treatment of bone disorders, obesity, cardiovascular disorders and neurological disorders.
- X is hydrogen, C
- Z is hydrogen, Cu,alkyl, aryl or heteroaryl, wherein Z is optionally substituted with one or more R 2 ;
- E is hydrogen, alkyl, hydroxyl, amino, aryl, aralkyl, heteroaryl or heteroarylalkyl, wherein E is optionally substituted with one or more R 2 ;
- Ri is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, wherein R ( is optionally substituted with one or more R ⁇ ;
- each R is, independently, deuterium, tritium, halogen, alkyl, haloalkyl,
- each R 4 , R> and R ⁇ are, independently, hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;
- each R is, independently, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;
- q is a single bond or a double bond
- a pharmaceutical composition comprising a compound having structure (I), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
- the pharmaceutical composition further comprises at least one additional agent, selected from the group consisting of parathyroid hormone, sodium fluoride, insulin-like growth factor I (I LGF-I), insulin-like growth factor 11 (ILGF-U), transforming growth factor beta (TGF- ⁇ ).
- a cytochrome P450 inhibitor an osteogenic prostanoid, BMP 2, BMP 4, BMP 7, and BMP 14.
- a method for treating a subject suffering from a bone disorder, osteoporosis, osteopontis. osteoarthritis, a bone fracture, obesity, and/or xanthoma formation comprising administering to the subject an effective amount of a compound having structure (I).
- the method comprises administering to the subject the compound at a therapeutically effective dose in an effective dosage form at.a selected interval to increase bone mass.
- the method comprises administering to the subject the compound at a therapeutically effective dose in an effective dosage form at a selected interval to ameliorate the symptoms of osteoporosis.
- a method for treating a subject suffering from a cardiovascular disorder, arteriosclerosis, myocardial infarction, peripheral vascular disease, and/or stroke comprising administering to the subject an effective amount of a compound having structure ( I).
- a method for treating a subject suffering from alopecia comprising administering to the subject an effective amount of a compound having structure (I).
- a method for treating a subject to induce bone formation comprising: harvesting mammalian mesenchymal stem cells; treating the mammalian mesenchymal cells with a compound having structure ( 1) lo induce osteoblastic differentiation of the cells; and administering the differentiated cells to the subject.
- an implant for use in a human or animal body comprising a substrate having a surface, wherein the surface of the implant comprises a compound having structure (I) in an amount sufficient to induce 'bone formation in the surrounding bone tissue.
- a method tor modulating a hedgehog (Hh) pathway mediated response, a Wnt Inhibitory Factor- 1 (Wif- 1 ) pathway mediated response, and/or a Wnt pathway mediated response in a cell or tissue is provided, the method comprising contacting the cell or tissue with an effective amount of a compound having structure (I).
- the hedgehog ( Hh) pathway mediated response is induced.
- a Wnt Inhibitory Factor- I gene is induced.
- Wnt pathway related signaling is activated.
- the hedgehog (Hh) pathway mediated response is the stimulation of osteoblastic differentiation, osteomorphogenesis. osteoinduction, osteoproliferation, and/or the inhibition of adipocyte differentiation, adipocyte morphogenesis, and/or adipocyte proliferation.
- the hedgehog (Hh) pathway mediated response is the stimulation of hair growth and/or cartilage formation.
- the hedgehog (Hh) pathway mediated response is the stimulation of angiogenesis.
- Amino refers to the -NH; radical.
- Niro refers to the -NO; radical.
- AlkyP refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (Ci-Ci ; alkyl), preferably one to eight carbon atoms (C ⁇ -C» alkyl) or one to six carbon atoms (C
- Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e. , contains one or more double and'or triple bonds), and having from one to twelve carbon atoms, e.g. , methylene, ethylene, propylene, //-butylene, ethenylene, propenylene, n-butenylene, propynylene. //-butynylene. and the like.
- the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
- alkylene chain refers to a radical of the formula -OR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
- alkylamino ** refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may he optionally substituted.
- hioalkyl refers to a radical of the formula -SR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.
- AryI refers to a hydrocarbon ring system radical comprising hydrogen.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
- Aryl radicals include, but are not limited to. aryl radicals derived from aceanthrylene. acenaphthylene, acephenanthrylene, anthracene, azulene. benzene, chrysene.
- fluorantliene fluorene, i .s-indacene, v-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- fluorantliene fluorene, i .s-indacene, v-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- aryl or the prefix "ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.
- Alkyl refers to a radical of the formula -R b -R ⁇ where R h is an alkylene chain as defined above and R ⁇ . is one or more aryl radicals as defined above. for example, benzyl, diphenylmethyi and the like. Unless staled otherwise specifically in the specification, an aralkyl group may be optionally substituted.
- Cycloalkyl or “carbocyclic ring” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
- Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimcthyl-bicyclo[2.2.1 ]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
- Cycloalkyialkyl refers to a radical of the formula -Rt > R_ where 3 ⁇ 4 is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkyialkyl group may be optionally substituted.
- fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
- the fused ring is a heter cyclyl ring or a heteroaryl ring
- any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
- Halo or "halogen” refers to bromo, chloro, fluoro or iodo.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g. , trifluoromethyl, difiuoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-di fluoroethyl, 3-bromo-2-fiuoropropyl, 1.2-dibromoethyl. and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
- Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
- heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[ 1.3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, iso azolidinyl, morpho!inyl, octahydroindolyl, octahydroisoindolyl.
- pyrrolidinyl pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl.
- thiomorpholinyl thiamo holin l. 1 -oxo-thiomorpholinyl, and I , I -dioxo-thiomorpholinyl.
- a heterocyclyl group may be optionally substituted.
- V-hetcrocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a jV-heterocyclyl group may be optionally substituted.
- HeterocyclylalkyP refers to a radical of the formula - h c where R h is an alkylcne chain as defined above and R is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl. the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
- Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
- the heteroaryl radical may be a monocyclic, bicyclic. tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl.
- bcnzindolyl benzodioxolyl.
- benzofuranyl benzooxazolyl, benzolhiazolyl, benzothiadiazolyl, benzo[ >][ l ,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl.
- benzodioxinyl benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl.
- benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4.6]imidazo[ 1.2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl. dibenzothiophenyl, furanyl. furanonyl, isothiazolyl, imidazolyl. indazolyl. indolyl, indazolyl. isoindolyl. indolinyl. isoindolinyl, isoquinolyl, indolizinyl. iso azolyl. naphthyridinyl, oxadiazolyl.
- * '/V-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an .'V-heteroaryl group may be optionally substituted.
- Heteroarylalkyl refers to a radical of the formula -RbRi where Rb is an alkylene chain as defined above and Rr is a heteroaryl radical as defined above. Unless stated othenvise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
- substituted used herein means any of the above groups (i.e.. lkyl. alkylene, alko y, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl. heterocyc lyl.
- a non-hydrogen atom such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines.
- a halogen atom such as F, CI, Br, and I
- an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups
- a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups
- a nitrogen atom in groups such as amines, amides, alkylamines.
- "'Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heieroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines. oximes.
- R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyi, aryl, aralkyl, cycloalkyl, cycloalkylalkyl. haloalky , heterocyclyl. /V-heterocyclyl. heterocyclylalkyl. heteroaryl. ⁇ '-heteroaryl and/or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano. hydroxyl, imino. nitro, oxo, thioxo, halo, alkyl.
- Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
- prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
- a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
- Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs ( 1985), pp. 7-9, 21 -24 (Elsevier, Amsterdam)).
- prodrugs are provided in Higuchi, T.. et al.. A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press. 1987.
- prodaig is also meant to include any covalcntly bonded camei-s, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
- Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
- Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
- the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of structure (I) being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
- isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as : H, U "C, l 3 C. I C, , 3 N, I J N. ,5 0. 17 0, l s O. I P.
- radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
- Certain isotopically-labelled compounds of structure (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
- the radioactive isotopes tritium, i.e. ⁇ , and carbon-14, i.e. U C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the an or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
- the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds.
- Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes.
- the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof.
- Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
- Solid compound and “stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- Subject and “Mammal” include humans and both domestic animals such as laboratory animals and household pets (e.g.. cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
- Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or othenvise undesirable, and which are formed with inorganic acids such as. but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to. acetic acid, 2.2-dichIoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonie acid, benzoic acid. 4-acetamidobenzoic acid, camphoric acid, camphor- 10-su!
- fonic acid capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1.2-disulfonic acid, ethanesulfonic acid.
- 2-oxo-glutaric acid glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandclic acid, methanesulfonic acid, mucic acid, naphthalene- 1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, l -hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, / oluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary.
- substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine. diethylamine, triethylamine, cripropylamine, diethanolamine, ethanolaminc. deanol, 2-dimcthylaminocthano .
- Particularly preferred organic bases are isopropylamine, diethylamine, cthanolamine, trimethylamine, dicyclohexylamine. choline and caffeine.
- solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
- the solvent may be water, in which case the solvate may be a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may exist as a hydrate, including a monohydrate. dihydrate, hcmihydrate, sesquihydrate, trihydrate, letrahydrate and the like, as well as the corresponding solvated forms.
- the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
- a "pharmaceutical composition'' refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g.. humans.
- a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
- Effective amount refers to that amount of a compound of the invention which, when administered to a subject, preferably a human, is sufficient to effect treatment, as defined below, of a condition of interest in the subject, preferably a human.
- the amount of a compound of the invention which constitutes a '"therapeutically effective amount will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
- treating '* or “treatment” covers the treatment of the disease or condition of interest in a subject, preferably a human, having the disease or condition of interest, and includes:
- disease relieving the symptoms resulting from the disease or condition. i.e., relieving pain without addressing the underlying disease or condition.
- condition may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
- the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers.
- diasiereomers, and other stcreoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( ?)- or (S)- or, as (D)- or (L)- for amino acids.
- the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
- Optically active (+) and (-), (R)- and (5)-, or (D)- and ( L)- isomers may be prepared using chiral synlhons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
- stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
- the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
- tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
- the present invention includes tautomers of any said compounds.
- the oxysterol compounds presented herein can be useful in creating new therapeutic formulations for induction of bone formation, treatment of osteoporosis, and for other indications. These oxysterol compounds can have a lower cost of synthesis/production as well as better safety and activity profiles than conventional compounds presently used to induce bone formation and treat osteoporosis. Such applications can be based on the ability of these oxysterol compounds to induce the hedgehog signaling pathway. Certain oxysterol compounds can target pluripotent cells to induce their lineage specific differentiation into various cell types, for example, osteoblasts, due to the induction of hedgehog signaling in these cells. Mesenchymal stem cells treated with these compounds can show induced expression of markers of osteoblast differentiation.
- oxysterol compounds have been synthesized and tested in vitro for activation of hedgehog signaling pathway in pluripotent mesenchymal cells and induction of markers of osteogenic differentiation. Certain oxysterol compounds can inhibit adipogenic differentiation of similar cells and/or can induce Wnt related signaling.
- the oxysterol compounds presented herein can be used in therapeutic formulations for various indications including but not limited to induction of local bone formation, treatment of osteoporosis, and anti-obesity applications.
- Other indications that are applicable based on the hedgehog pathway activating property of these molecules are 1 ) cardiovascular diseases including, but not limited to, arteriosclerosis, angina pectoris, myocardial infarction, and stroke.
- ⁇ oxysterol compound according to the invention can have an activity, that is. can induce a biological response, when contacted with a human or animal cell.
- the cell can be a mesenchymal stem cell or a bone marrow stromal cell. This activity or response can be correlated with stimulating osteoblastic differentiation, inhibiting adipocyte differentiation, stimulating cartilage formation, stimulating hair growth, and/or stimulating angiogenesis.
- a bioactive composition for example, a pharmaceutical composition including a pharmaceutically acceptable carrier and an oxysterol compound according to the invention can have an activity, that is, can induce a biological response, when administered to a mammalian cell, for example, a cell in vitro or a cell in a human or an animal.
- This activity or response can be correlated with stimulating osteoblastic differentiation, stimulating osteoinduction, inhibiting adipocyte differentiation, stimulating cartilage formation, stimulating hair growth, and/or stimulating angiogenesis.
- Such an activity or response can arise from stimulation of the hedgehog pathway.
- an activity or response of an oxysterol compound according to the invention can be characterized by one or more of the following when the oxysterol compound is administered to a cell, a human, a mammal, or an animal: osteocalcin, Gli 1 , Patched, bone sialoprotein, Axin2, Cyclin Dl, Nkd2, and/or VVif-I mRNA expression above that observed for a control; adipocyte growth less than that observed for a control (the oxysterol compound according to the invention and any control compound each administered with Troglitazone); Gli induced reporter activity above that observed for a control, TCF/Lef reporter activity above that observed for a control; and/or "l5 Ca "r incorporation and/or alkaline phosphatase activity above that observed for a control.
- the control can be, for example, an untreated cell, in vitro or in a human or animal, such as a mammal.
- the control can be a cell to which a control compound has been administered.
- a control compound can be a vehicle, a pharmaceutically acceptable carrier, a naturally occurring or synthetic oxysterol, and/or another compound.
- a biological response may be identified via a cell-level laboratory assay, such as an assay discussed herein, including measurements of various types of protein expression and other activity. According to the invention, these biological responses are considered to be "correlated with" desirable tissue-level pharmaceutical effects identified herein, such as stimulating osteoblastic differentiation, inhibiting adipocyte differentiation, stimulating cartilage formation, stimulating hair growth, and/or stimulating angiogenesis.
- "Above that observed” and “less than that observed” refers to a statistically significant difference, for example, with p ⁇ 0.05.
- An oxysterol compound can be used to activate the hedgehog pathway in order to target any cell, organ, or tissue in humans and'or animals for an indication that would benefit from the activation of the hedgehog pathway.
- An oxysterol compound can be used to induce systemic bone formation to treat a disorder such as osteoporosis, to induce local bone formation to treat conditions such as nonunion fractures, and bone defects of any sort, such as calvarial bone or ja bone defects in dental applications/implants, and to induce spinal fusion.
- An oxysterol compound can be used alone or in combination with one or more bone morphogenetic paiteins and other osteoinductive and osteoinductive molecules.
- a combination of di fferent oxysterol compounds can be used.
- An oxysterol compound can be used to inhibit systemic fat formation to treat a condition such as obesity, and can be used to inhibit local fat formation to treat a condition such as a xanthoma.
- An oxysterol compound can be used to induce the formation of cartilage, for example, by activating the hedgehog pathway, when used alone or in combination with other inducers of chondrocyte differentiation.
- the used of an oxysterol compound to induce the formation of cartilage can be used to treat a condition such as osteoarthritis or in the repair of normal wear and tear of joints.
- An oxysterol compound can be used to treat a cardiovascular condition, for example, a condition that may benefit from increased hedgehog pathway activity resulting in protective effects on cells of all origin, including neural and vascular, in indications such as. but not limited to, stroke, myocardial infarction, arteriosclerosis, and peripheral vascular disease.
- An oxysterol compound can be used to induce new blood vessel formation and/or angiogenesis, for example, by activating the hedgehog pathway.
- An oxysterol compound can be used to induce hair growth to treat alopecia.
- An oxysterol compound can be used to induce Wif- 1 (Wnt Inhibitory Factor- 1 ) in any cell type of human or animal origin.
- An oxysterol compound can be used to activate Wnt pathway related signaling in any cell type of human or animal origin.
- X is hydrogen, C
- Z is hydrogen, C
- E is hydrogen, alkyl, hydroxyl, amino, aryl, aralkyl, heteroaryl or heteroarylalkyl, wherein E is optionally substituted with one or more R;;
- R i is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, helerocyclylalkyi, heteroaryl or heteroarylalkyl, wherein Ri is optionally substituted with one or more R?;
- each j is, independently, deuterium, tritium, halogen, alkyl, haloalkyl, -OR,, -C -Nj, -NR 5 R restroom, -SR , -SOR . -SO;R4, -NR5SO2R4, aryl or heteroaryl;
- R5 and R ⁇ are. independently, hydrogen, alkyl. cycloalkyl, aryl, heterocyclyl or heteroaryl;
- each R 7 is. independently, alkyl, cycloalkyl. aryl. heterocyclyl or heteroaryl: and
- q is a single bond or a ' double bond
- X is C
- X is methyl.
- Z is hydrogen
- E is hydrogen
- is alkyl optionally substituted with one or more R:.
- i is alkyl.
- is C
- q is a double bond.
- any embodiment of the compounds of structure (I), as set forth above, and any specific substituent set forth herein for a X, Z, E. Ri, R;, R ⁇ , RA. R Rt» R? or q group in the compounds of structure (I), as set. forth above, may be independently combined with other embodiments and/or substituents of compounds of structure (I) to form embodiments of the inventions not specifically set forth above.
- substitutcnts or variables is listed for any particular group in a particular embodiment and/or claim, it is understood that each individual substituent or variable may be deleted from the particular embodiment and/or claim and that the remaining list of substituents and variables will be considered to be within the scope of the invention.
- compositions of the present invention comprise a compound of structure (I) and a pharmaceutically acceptable carrier, diluent or excipient.
- the compound of structure ( 1) is present in the composition in an amount which is effective to treat a particular disease or condition of interest, and preferably with acceptable toxicity to the patient.
- the activity of compounds of structure (I) can be determined by one skilled in the art. for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels. microspheres, and aerosols.
- compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavaiiable upon administration of the composition to a patient.
- Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
- compositions to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
- a pharmaceutical composition of the invention may be in the form of a solid or liquid.
- the carrierfs) are particulate, so that the compositions are, for example, in tablet or powder form.
- the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
- the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
- the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
- a solid composition will typically contain one or more inert diluents or edible carriers.
- binders such as carboxymethylcellu!ose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; exciptents such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate. Primogel.
- lubricants such as magnesium stearate or Sterotex
- glidants such as colloidal silicon diox ide
- sweetening agents such as sucrose or saccharin
- a flavoring agent such as peppermint, methyl salicylate or orange flavoring
- a coloring agent such as peppermint, methyl salicylate or orange flavoring
- the pharmaceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
- a liquid carrier such as polyethylene glycol or oil.
- the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
- the liquid may be for oral administration or for delivery by injection, as two examples.
- preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
- a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
- the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline. Ringer ' s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serv e as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Physiological saline is a
- a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.
- the pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
- the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil. diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.
- the pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
- the composition for rectal administration may contain an ⁇ oleaginous base as a suitable nonirritating excipient.
- bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
- the pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
- the composition may include materials that form a coating shell around the active ingredients.
- the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
- the active ingredients may be encased in a gelatin capsule.
- the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound.
- Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
- the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
- aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.
- the present invention contemplates an implant for use in an animal (e.g., human) body, comprising a surface, a matrix, and a compound or pharmaceutical composition of the invention, in an amount sufficient to induce bone formation in the surrounding bone tissue.
- a compound or pharmaceutical composition of the invention can be adsorbed or coated on the surface of the implant and/or absorbed into the matrix of the implant.
- Implants comprising a compound or pharmaceutical composition of the invention, and other molecules, e.g. , collagen, PLG A. can be dried, e.g. , frcezc-dricd. and introduced to the animal body.
- the implant may be formed into the shape of, e.g., a pin, screw, plate, prosthetic joint, or in the shape of bone or, portion thereof requiring repair.
- specific bones that can be repaired using the implants contemplated herein include, without limitation, the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, incus, stapes, malleus, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, sacrum, sternum, ribs, clavicle, scapula, humerus, ulna, radius, carpal bones, metacaipal bones, phalanges, ileum, ischium, pubis, pelvis, femur, patella, tibia, fibula, calcaneus, talus, and metatarsal bones.
- Implants of the invention can be used to treat bone defects resulting from injury, brought about during the course of surgery, infection, malignancy, or developmental malformation.
- inventive implants can also be used in orthopedic, neurosurgical, cosmetic, and oral and maxillofacial surgical procedures such as the repair of simple and compound fractures and non-unions, external and internal fixations, joint reconstructions such as arthrodesis, general arthroplasty, cup arthroplasty of the hip.
- femoral and humeral head replacement femoral head surface replacement and total joint replacement, repairs of the vertebral column including spinal fusion and internal fixation, tumor surgery (e.g., deficit filling), discectomy, laminectomy, excision of spinal cord tumors, anterior cervical and thoracic operations, repair of spinal injuries, scoliosis, lordosis and kyphosis treatments, intennaxillary fixation of fractures, mentoplasty, temporomandibular joint replacement, alveolar ridge augmentation and reconstruction, inlay bone grafts, implant placement and revision, sinus lifts, etc.
- tumor surgery e.g., deficit filling
- discectomy laminectomy
- excision of spinal cord tumors e.g., anterior cervical and thoracic operations
- repair of spinal injuries e.g., scoliosis, lordosis and kyphosis treatments
- intennaxillary fixation of fractures mentoplasty, temporomandib
- the implant is a rigid, substantially solid implant.
- the implant is a malleable, substantially porous implant, e.g., a sponge.
- the rigidity or malleability of an implant can be influenced, in part, by the porousity of the implant matrix.
- at least 10% of the pores are between about 10 micrometers and about 500 micrometers at their widest points.
- at least 20% of the pores are between about 50 micrometers and about 150 micrometers at their widest points.
- at least 30% of the pores are between about 30 micrometers and about 70 micrometers at their widest points.
- At least 50% of the pores are between about 10 micrometers and about 500 micrometers at their widest points. In some embodiments, at least 90% of the pores are between about 50 micrometers and about 150 micrometers at their widest points. In some embodiments, at least 95% of the pores are between about 100 micrometers and about 250 micrometers at their widest points. In some embodiments, 100% of the pores are between about 10 micrometers and about 300 micrometers at their widest points.
- the implant having a porosity of at least about
- the pore may support ingrowth of cells, formation or remodeling of bone, cartilage and/or vascular tissue.
- Implants may comprise natural and/or synthetic material.
- an implant may comprise poly (alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylaclide (PLA), polyglycolide ( PG). polyethylene glycol ( PEG) conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE), polyaspirins, polyphosphagenes, collagen, hydrolyzed collagen, gelatin, hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch, pre-gelatinized starch, hyaluronic acid, chitosan.
- D.L-lactidc. or L-lactide. -caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol ( PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates. poly (N-isopropylacrylamide), PEO-PPO-PEO (pluronics).
- potoxamer 407 PEG- PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate).
- SAIB sucrose acetate isobutyrate.
- implants comprise a resorbable ceramic (e.g., hydroxyapatite. tncaicium phosphate, bioglasses. calcium sulfate, etc.) tyrosine-derived polycarbonate poly (DTE-co-DT carbonate), in which the pendant group via the tyrosine--an amino acid— is either an ethyl ester (DTE) or free carboxylate ( DT) or combinations thereof.
- a resorbable ceramic e.g., hydroxyapatite. tncaicium phosphate, bioglasses. calcium sulfate, etc.
- DTE-co-DT carbonate tyrosine-derived polycarbonate poly
- an implant comprises a collagen sponge.
- Exemplary collagens include human or non-human (bovine, ovine, and/or porcine), as well as recombinant collagen or combinations thereof.
- suitable collagen include, but are not limited to, human collagen type I, human collagen type II, human collagen type III. human collagen type IV, human collagen type V, human collagen type VI. human collagen type VII, human collagen type VIII, human collagen type IX, human collagen type X. human collagen type XI. human collagen type XII, human collagen type XIII, human collagen type XIV.
- Collagen further may comprise hetero- and homo-trimers of any of the above-recited collagen types.
- the collagen comprises hetero- or homo-trimers of human collagen type I, human collagen type II, human collagen type III, or combinations thereof.
- Implants may comprise particles of bone-derived materials.
- the bone- derived material may include one or more of non-dcmincralized bone particles, demineralized bone particles, lightly demineralized bone particles, and/or deorganified bone particles.
- Implants may be seeded with harvested bone cells and/or bone tissue, such as for example, conical bone, autogenous bone, allogenic bones and/or xenogenic bone.
- the implant may be seeded with harvested cartilage cells and/or cartilage tissue (e.g., autogenous, allogenic, and/or xenogenic cartilage tissue).
- the implant can be wetted with the graft bone tissue/cells, usually with bone tissue/cells aspirated from the patient, at a ratio of about 3: 1 , 2: 1 , 1 : 1 , 1 :3 or 1 :2 by volume.
- the implant provides a malleable, non- water soluble carrier that permits accurate placement and retention at the implantation site.
- the implant may contain an inorganic material, such as an inorganic ceramic and/or bone substitute material.
- inorganic materials or bone substitute materials include but are not limited to aragonite, dahlitc, calcite, amorphous calcium carbonate, vaterite, weddellite, whewellite, struvite, urate, fcrrihydrate, francolite, monohydrocalcite, magnetite, goethite, dentin, calcium carbonate, calcium sulfate, calcium phosphosilicate, sodium phosphate, calcium aluminate.
- the invention may include implants for use in theiziman body, comprising a substrate liaving a surface, wherein at least the surface of the implant includes at least one compound or pharmaceutical composition of the invention in an amount sufficient to induce bone formation in the surrounding bone tissue and/or enhance bone repair.
- the implant may include mammalian cells capable of osteoblastic differentiation, or osteoblastic mammalian cells, or a combination thereof for inducing bone formation and/or enhancing bone repair in combination with one or more compound or pharmaceutical composition of the invention.
- the implant comprises a dose of a compound of the invention that is suitable for inducing bone formation in the surrounding bone tissue and/or enhance bone repair.
- the implant comprises a dose of a compound of the invention of about 1000 mg to about 100 mg, about 900 mg to about 200 mg, about 800 mg to about 300 mg, about 800 mg to about 400 mg, about 800 mg to about 500 mg, about 800 mg to about 600 mg, about 700 mg to about 300 mg, about 700 mg to about 400 mg, about 700 mg to about 500 mg, or about 600 mg to about 400 mg, or any intervening range of oxysterol dose.
- the implant comprises a dose of a compound of the invention of about 800 mg to about 500 mg.
- the implant comprises a dose of a compound of the invention of about 1000 mg, about 900 mg, about 850 mg. about 800 mg, about 750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about 500 mg, about 400 mg, or about 300 mg.
- compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
- a pharmaceutical composition intended to lie administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
- a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
- Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
- the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination: the severity of the panicular disorder or condition; and the subject undergoing therapy.
- Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
- Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.
- a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
- the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e.. concurrently, or at separately staggered times, i.e.. sequentially; combination therapy is understood to include all these regimens.
- the functional groups i ' intermediate compounds may need to be protected by suitable protecting groups.
- suitable protecting groups include trialkylsilyl or diarylalkylsilyl (for example, i-butyldimethylsilyl, /-butyldiphenylsilyl or trimethylsilyl), letrahydropyranyl, benzyl, and the like.
- Suitable protecting groups for amino, amidino and guanidino include /-butoxycarbonyl, benzyloxycarbonyi, and the like.
- Suitable protecting groups for mercapto include -C(0)- " (where R" is alkyl, aryl or arylalkyl). /?-methoxybenzyl. trityl and the like.
- Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M.
- the protecting group may also be a polymer resin such as a Wang resin. Rink resin or a 2-chlorotrityl-chloride resin.
- starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, inc.. Maybridge. Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention.
- reagents of the formula (XV) are useful intermediates for the synthesis of compounds of the formula ( XVII) via reduction with an appropriate reducing reagent such as aBH4.
- DIBALH, LiAIH(OtBu)j, or L- selectride in a suitable solvent such as MeOH.
- EtOH, toluene, CH ⁇ C , or THF at temperatures below room temperature afford compounds of the formula (XVI).
- compounds of the formula (XV) are reduced to compounds of the formula (XVI) using NaBH in MeOH. Removal of the hydroxyl protecting group then provides compounds of the formula (XVII). deprotection
- reagents of the formula (XV) are useful intermediates for " the synthesis of compounds of the formula (XX) via the nucleophilic addition of a suitable organolithium or Grignard reagent to the ketone of (XV) in an appropriate solvent such as E O, THF, DME, MTBE, or dioxane and deprotection using general conditions known to one skilled in the an.
- an appropriate solvent such as E O, THF, DME, MTBE, or dioxane and deprotection using general conditions known to one skilled in the an.
- compounds of the fomiula (XV) are exposed to Grignard reagents in THF to afford compounds of the formula (XIX).
- Compounds of the formula (XIX) are then subjected to removal of the hydroxyl protecting group affording compounds of the formula (XX).
- reagents of the formula (XXI) are useful intermediates for the synthesis of compounds of the formula (XXIV) via reduction with an appropriate reducing agent such as NaBH t , DIBALH, LiAlH(OtBu) ⁇ , or L-selectride in a suitable solvent such as eOH. EtOH. toluene. or THF at temperatures below room termperature and removal of the protecting group.
- an appropriate reducing agent such as NaBH t , DIBALH, LiAlH(OtBu) ⁇ , or L-selectride in a suitable solvent such as eOH. EtOH. toluene. or THF at temperatures below room termperature and removal of the protecting group.
- compounds of the formula (XXI) are exposed to LiAIH(OtBu).? in THF to afford compounds of the fomiula ( XXI Il ). Removal of the hydroxyl protecting group then provides compounds of the formula (XXIV).
- reagents of the formula (XXI) are useful intermediates for the synthesis of compounds of the formula (XXVI) via the nucleophilic addition of a suitable organolithiuni or Grignard reagent to the ketone of ( XXI) in an appropriate solvent such as Et;0, THF, DME, MTBE, or dioxane followed by removal of the protecting group.
- compounds of the formula (XXI) are exposed to Grignard reagents in THF to afford compounds of the fonnula (XXV).
- Compounds of the formula (XXV) are then subjected to removal of the hydroxyl protecting group affording compounds of the formula (XXVI).
- compounds of the formula (XXI) are useful reagents for the synthesis of compounds of the formula (XXXI) via enolization and substitution. Substitution is achieved using an appropriate base such as LDA, LHiMDS, or KHMDS under conditions known by those trained in the art to afford compounds of the formula (XXXI). In the preferred embodiment, enolization is achieved using LHMDS in THF at temperatures below room temperature affording compounds of the formula (XXXI). Reagents of the formula (XXXI) are useful intermediates for the synthesis of compounds of the formula ( XXXII) via ketone reduction and removal of the protecting group.
- Ketone reduction is achieved using an appropriate nucleophilic hydride reagent such as LiAIFL;, LiAlH(OtBu)3. or DI BA LH in a suitable solvent such as CH ⁇ C , Et;0, THF, DME, benzene, or toluene.
- ketone reduction is achieved using LiAIH(OtBu) 3 in THF afford compounds of the formula (XXXI). Removal of the protecting group then affords compounds of the formula (XXXI I).
- compounds of the formula ( ⁇ ) are useful reagents for the synthesis of compounds of the formula (XXXVI) via hvdroboration and oxidation.
- Panection is achieved using an appropriate base such as DMAP under conditions known by those trained in the art to afford compounds of the formula (XXXIV).
- protection is achieved using DMAP in pyridine at temperatures affording compounds of the formula ( XXXIV).
- Reagents of the formula ( XXXIV) are useful intermediates for the synthesis of compounds of the formula (XXXV) via hvdroboration and oxidation.
- Hydroboration is achieved using a source of borane such as BH3.THF in a suitable solvent such as CHjCI;. Et;0, THF, DME, benzene, or toluene, followed by oxidation with hydrogen peroxide. Removal of the protecting group then affords compounds of the formula (XXXVI).
- NMR spectra were recorded on 500 MHz model spectrometers.
- the format of the ⁇ NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).
- Mass spectra were obtained on an Agilent series 1200 MSD using electrospray ionization (ESI ) in either positive or negative modes as indicated. Calculated mass corresponds to the exact mass.
- ESI electrospray ionization
- Thin-layer chromatography was performed on Merck silica gel 60 F;5 2.5 cm x 7.5 cm 250 ⁇ or 5.0 cm x 10 cm 250 ⁇ pre-coated silica gel plates.
- Preparative thin-layer chromatography was performed using EM Science silica gel 60 F:s4 20 cm x 20 cm 0.5 mm pre-coated with a 20 cm x 4 cm concentrating zone.
- Step B (3S.7R.8S.9S.10R.13S.14S.1 7S)-1 7-((S)-2-hvdroxyoctan-2-yl)- 10.13-dimethyl- 2.3.4.7.8.9.10.1 1.12.13.14.15.16.1 7-tetradecahvdro- 1 H-cyclopentaf abhenanthrene-3.7- diol
- Example 2 was prepared and purified using methods analogous to those described in Step B of Example 1 .
- SHH- Light2 reporter cell line contains a concatemer of 8 Gli response elements upstream of a minimal promoter driving the expression of firefly lucifcrasc.
- SHH-Light2 cells were plated at 1 ,000 cells well in 384 well plates with 20 uL'vvell of DMEM/ 10% FCS. 24 hrs after plating, cells were treated 20 uiywell of test compound in DMEM/0.5% FCS. Triplicate wells were used for each treatment.
- C3H 10T I 2 cell line This multipotential cell line is a model of mesenchymal stem cells, and can be differentiated into cells of the mesenchymal lineage, including, osteoblasts, chondrocytes, myoblasts and adipocytes.
- C3H 10T I/2 cells were plated in 24 well plates and cultured to confluence in EMEM/10% FCS. After teaching confluence, duplicate wells of cells were treated 3 times per week for 2 weeks with test compound in fresh EMEM/10% FCS.
- Total RNA . was prepared using the Qiagen RNeasy Plus kit, and cDNA was created from total RNA using Invitrogen Superscript III kit.
- Quantitative RT-PCR was performed on cDNA samples using ⁇ 1 Taqman assays, with the ⁇ method, to measure the expression levels of osteoblast genes, BGLAP and IBSP. Results were normalized to GAPDH and expressed relative to cells treated with the D.VISO solvent control.
- the compounds of Examples 1 -2 show at least a 2-fold activation of osteocalcin at 10 ⁇ .
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Abstract
La présente invention concerne des composés destinés à être utilisés dans le traitement de troubles osseux, de l'obésité, de troubles cardiovasculaires et de troubles neurologiques. Les composés ont la structure suivante (I) comprenant les stéréoisomères, les sels pharmaceutiquement acceptables et les promédicaments de ceux-ci, dans laquelle X, Z, E, R1 et q sont tels que définis ici. L'invention concerne également des procédés associés à la préparation et à l'utilisation de tels composés, ainsi que des compositions pharmaceutiques comprenant de tels composés.
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WO2013169399A1 (fr) * | 2012-05-07 | 2013-11-14 | The Regents Of The University Of California | Oxy133, un analogue de l'oxystérol, induisant l'ostéo-genèse et la signalisation hedgehog et inhibant l'adipogenèse |
WO2014179756A1 (fr) * | 2013-05-02 | 2014-11-06 | The Regents Of The University Of California | Agents de ciblage osseux à base d'oxystérol ostéogène à sélectivité osseuse |
US9526737B2 (en) | 2007-12-03 | 2016-12-27 | The Regents Of The University Of California | Oxysterols for activation of hedgehog signaling, osteoinduction, antiadipogenesis, and Wnt signaling |
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