WO2012054315A1 - Cathepsin s inhibitor compounds - Google Patents
Cathepsin s inhibitor compounds Download PDFInfo
- Publication number
- WO2012054315A1 WO2012054315A1 PCT/US2011/056244 US2011056244W WO2012054315A1 WO 2012054315 A1 WO2012054315 A1 WO 2012054315A1 US 2011056244 W US2011056244 W US 2011056244W WO 2012054315 A1 WO2012054315 A1 WO 2012054315A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- add
- compound
- stir
- Prior art date
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002921 oxetanes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
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- 210000002254 renal artery Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000003375 selectivity assay Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- AIDBEARHLBRLMO-UHFFFAOYSA-M sodium;dodecyl sulfate;2-morpholin-4-ylethanesulfonic acid Chemical compound [Na+].OS(=O)(=O)CCN1CCOCC1.CCCCCCCCCCCCOS([O-])(=O)=O AIDBEARHLBRLMO-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 1
- YLMKRRXRBHLIPZ-GMAHTHKFSA-N tert-butyl 4-[(7s,8s)-8-[(4-fluorobenzoyl)amino]-7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-3-oxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(CC[C@H](O)[C@H]2NC(=O)C=3C=CC(F)=CC=3)C2=C1 YLMKRRXRBHLIPZ-GMAHTHKFSA-N 0.000 description 1
- PGYAZEVQYKWSGQ-GOTSBHOMSA-N tert-butyl 4-[(7s,8s)-8-[(4-fluorobenzoyl)amino]-7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(CC[C@H](O)[C@H]2NC(=O)C=3C=CC(F)=CC=3)C2=C1 PGYAZEVQYKWSGQ-GOTSBHOMSA-N 0.000 description 1
- ZZTJACWAXREGNS-RYUDHWBXSA-N tert-butyl n-[(1s,2s)-2-hydroxy-6-nitro-2,3-dihydro-1h-inden-1-yl]carbamate Chemical compound C1=C([N+]([O-])=O)C=C2[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC2=C1 ZZTJACWAXREGNS-RYUDHWBXSA-N 0.000 description 1
- AYPVOOGPVHDANQ-RYUDHWBXSA-N tert-butyl n-[(1s,2s)-6-amino-2-hydroxy-2,3-dihydro-1h-inden-1-yl]carbamate Chemical compound C1=C(N)C=C2[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC2=C1 AYPVOOGPVHDANQ-RYUDHWBXSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention is directed toward inhibitor compounds of the proteolytic enzyme cathepsin S and methods of treatment comprising administration thereof.
- the present invention is directed toward stereoisomers. More specifically, the present invention provides potent, selective and reversible stereoisomer inhibitor compounds having two chiral centers.
- Cathepsin S is a lysosomal cysteine protease. It belongs to a larger family of cathepsins, including L, B, K, V and F. Selectivity to cathepsin S may avoid undesired consequences such as side effects. Cathepsin S is produced by inflammatory cells such as dendritic cells, B lymphocytes and macrophages. It is involved in the pathology of several conditions including atherosclerosis and abdominal aortic aneurysm (AAA) (J. Clin. Invest. 1999, 104(9), 1191-1 ⁇ 91)(Am. J. Path. 2007, 170(3), 809-817).
- AAA abdominal aortic aneurysm
- the endothelial cells of the arterial wall may malfunction due to several factors that lead to plaque formation and buildup in the arterial wall including high levels of cholesterol, stress, overall health and genetics. This malfunction leads to the production and recruitment of inflammation cells from the blood that penetrate the arterial wall to protect from damage. These inflammation cells ultimately produce cathepsin S.
- An effect of cathepsin S is to degrade the extracellular matrix proteins such as elastin and collagen that make up the arterial wall.
- extracellular remodeling of the cells is ongoing to repair the damaged arterial wall, if too much proteolytic degradation of the matrix occurs, compared to deposition of matrix proteins, an imbalance may lead to instability of plaques formed within the arterial wall. Too much plaque instability could result in plaque rupture and potentially thrombotic -related events.
- inhibition of cathepsin S provides a means for treating atherosclerosis.
- AAA is the tenth leading cause of death in men greater than 55 years old.
- cathepsin S provides an option for addressing this unmet medical need.
- Cathepsin S is implicated in autoimmune disorders which may include rheumatoid arthritis, lupus and psoriasis, through its intracellular trafficking involvement in the initiation of an immune response (Immunity, 2001, 15, 909-9 ⁇ 9)(Eur. J. Immunol. 2005, 35, 2552-2562).
- cathepsin S cleaves lip 10 (plO) in B lymphocyte and dendritic cells to generate CLIP (class-II associated Ii-peptide). This allows loading of a peptide fragment, e.g., self-antigen, and subsequent presentation of the class II Major Histocompatability Complex (MHC) molecules on the cell surface of the antigen presenting cells.
- MHC Major Histocompatability Complex
- autoimmune response results thereby generating an autoimmune response.
- inhibition of cathepsin S blocks plO processing and surface presentation of T cell antigens, thereby providing a means for treating autoimmune related disorders such as rheumatoid arthritis, psoriasis, and lupus.
- Z is -CH 2 -, -CH 2 CH 2 -, -OCH 2 -, -CH 2 CH 2 CH 2 -, or -OCH 2 CH 2 -;
- R 1 is H, F, or CI
- R 2 is H, methyl, ethyl, propyl, or isopropyl
- An aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
- Another aspect of the present invention provides methods for treatment of AAA by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- a further aspect of the present invention provides methods for treatment of X18795
- AAA in a mammal such as a human, dog, cat, cow, horse, sheep, or monkey by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- a further aspect of the present invention provides methods for treatment of AAA in a human whose aortic diameter is greater than the normal diameter of approximately 3 cm but less than approximately 5 cm and surgical or endovascular repair is not required, by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- Yet a further aspect of the present invention provides methods for treatment of AAA in a human whose aortic diameter is greater than approximately 5 cm but surgical or endovascular repair is not a treatment option by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- Another aspect of the present invention provides methods for treatment of plaque instability in a mammal such as a human, dog, cat, cow, horse, sheep, or monkey by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- a further aspect of the present invention provides methods for treatment of atherosclerosis in a mammal such as a human, dog, cat, cow, horse, sheep, or monkey by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- Yet another aspect of the present invention provides methods for treatment of autoimmune disorders in a mammal such as a human, dog, cat, cow, horse, sheep, or monkey in need thereof by administering a therapeutically effective amount of a X18795
- a further aspect of the present invention provides methods for treatment of psoriasis, rheumatoid arthritis, or lupus in a human by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention.
- a further aspect of the present invention provides a compound or
- Another aspect of the present invention provides a compound or pharmaceutically acceptable salt thereof for use in therapy.
- Another aspect of the present invention provides a compound or pharmaceutically acceptable salt thereof for use in the treatment of abdominal aortic aneurysm, plaque instability, atherosclerosis, or autoimmune disorders such as rheumatoid arthritis, psoriasis, and lupus.
- Yet another aspect of the present invention is the use of a compound or pharmaceutically acceptable thereof for the manufacture of a medicament for the treatment of abdominal aortic aneurysm, plaque instability, atherosclerosis, or autoimmune disorders such as rheumatoid arthritis, psoriasis, and lupus.
- Another aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present invention in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more other therapeutic agents.
- Yet another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abdominal aortic aneurysm, plaque instability, atherosclerosis, rheumatoid arthritis, psoriasis, and lupus.
- Yet another aspect of the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abdominal aortic aneurysm, plaque instability, atherosclerosis, rheumatoid arthritis, psoriasis, and lupus.
- Embodiments of the inhibitor compounds and methods for treatment comprising administration thereof in the present invention include any combination of Ri, R2 and Z X18795
- an embodiment of the present invention is directed toward a compound of Formula (I) or pharmaceutically acceptable salt thereof where Ri is H or F. More specifically, an embodiment of the present invention is directed toward a compound of Formula (I) or pharmaceutically acceptable salt thereof where Ri is F.
- Another embodiment of the present invention is a compound of Formula (I) or pharmaceutically acceptable salt thereof where R 2 is methyl or ethyl.
- an embodiment of the present invention is a compound of Formula (I) or pharmaceutically acceptable salt thereof where R 2 is methyl.
- Yet another embodiment of the present invention is directed to a compound of Formula (I) or a pharmaceutically acceptable salt thereof where Z is -CH 2 -, -CH2CH2-, -OCH 2 -, -CH 2 CH 2 CH 2 -, or -OCH 2 CH 2 -.
- an embodiment of the present invention is a compound of Formula (I) or pharmaceutically acceptable salt thereof where Z is -CH 2 CH 2 - or -OCH 2 -.
- Further embodiments of the present invention consist of a combination where Ri is H or F, R 2 is methyl or ethyl, and Z is -CH 2 CH 2 - or -OCH 2 -.
- More preferred compounds of the present invention are:
- abdominal aortic aneurysm shall mean a localized dilation or bulge of the abdominal aorta in a mammal causing the size of at least a segment of the abdominal aorta to exceed the size of an otherwise considered normal state.
- the abdominal aorta may be measured and compared in terms of any measurement dimension including but not limited to luminal diameter, luminal perimeter, and luminal area.
- the means for measurement and diagnosis may be through the use of ultrasound, CT scan, or other imaging techniques.
- AAA is present in a human when the aortic diameter is greater than its normal diameter, approximately 3 cm.
- aortic diameter is however more than approximately 5 cm, then immediate surgical or endovascular repair (stent or graft) is the standard of care to prevent rupture and potential fatality. If however such treatment is unavailable or not an option due to any reason, e.g., age, then this population may also be treated using the present invention.
- the term "in need thereof as used herein shall mean having or being diagnosed with a condition, e.g., atherosclerosis, AAA, autoimmune disorder such as psoriasis, lupus or rheumatoid arthritis, that requires treatment.
- a condition e.g., atherosclerosis, AAA, autoimmune disorder such as psoriasis, lupus or rheumatoid arthritis, that requires treatment.
- mammal as used herein shall mean a human or nonhuman mammal such as a dog, cat, cow, horse, sheep, or monkey.
- pharmaceutically acceptable salt thereof refers to salts of the compounds of the present invention. Examples and methods for their preparation are well within the knowledge of those skilled in the art. See, for example, Stahl et ah,
- terapéuticaally effective amount refers to the amount or dose of a compound of Formula (I) or composition comprising a compound of Formula (I) to X18795
- a therapeutically effective amount can be readily determined by the attending physician, as one skilled in the art, by considering a number of factors known to a person skilled in the art such as, for example, weight, height, age, general health of the patient, severity of the condition, mode of administration, dosing regimen, etc.
- treatment shall mean slowing the rate or progression of a disease state. It may also include halting the disease state. The term may further include not only halting the disease but also reducing any disease state that already has occurred.
- treatment may mean slowing of the expansion rate of an abdominal aortic aneurysm. It may also include stopping the expansion of the abdominal aortic aneurysm. Furthermore, it may include reducing any expansion that has already occurred.
- the compounds of the present invention are preferably formulated as
- the compounds of Formula I, or salts thereof may be prepared by a variety of procedures known in the art, as well as those described in the Schemes, Preparations, and Examples below.
- the specific synthetic steps for each of the routes described may be combined in different ways to prepare compounds of Formula I, or pharmaceutically acceptable salts thereof.
- R or S configuration of compounds of the invention may be determined by standard techniques such as X-ray analysis and correlation with chiral-HPLC retention time.
- the naming of the following Preparations and Examples is generally done using the IUPAC naming feature in Symyx Isentris® version 3.2.3.
- AcOH refers to acetic acid
- BCA bicinchoninic acid
- b.i.d refers to two times a day
- brine refers to saturated aqueous NaCl solution
- cat. refers to a catalytic amount
- CD74 refers to the invariant chain (Ii);
- CDI refers to ⁇ , ⁇ -carbonyldiimidazole;
- DMAP refers to 4-dimethylaminopyridine;
- DMSO refers to dimethyl sulfoxide;
- DTT dithiothreitol;
- EDTA refers to ethylenediaminetetraacetic acid;
- EtOH refers to ethanol
- hr refers to hour(s)
- IC5 0 refers to the concentration of an agent which produces 50% of the maximal inhibitory response possible for that agent or, alternatively, to the concentration of an agent which produces 50% displacement of ligand binding to the receptor
- IMAC Immobilized Metal Affinity
- IP A refers to isopropyl alcohol
- LC ES/MS liquid chromatography electrospray mass spectrometry
- MCPBA meta- chloroperoxybenzoic acid
- MeOH refers to methanol
- min. refers to minute(s)
- NMP N-bromosuccinimide
- NMP N-methylpyrrolidine
- ⁇ / ⁇ refers to not available
- plO refers to a fragment of the invariant chain CD74
- PBS refers to phosphate buffered saline
- PWBC refers to peripheral white blood cells
- PvFU refers to relative fluorescence units
- SFC refers to supercritical fluid chromatography
- STAB refers to sodium triacetoxyborohydride
- SDS sodium dodecyl sulfate
- THF tetrahydrofuran
- Formation of intermediate (3) can be carried out in accordance with reactions as depicted in Scheme 1.
- Step A 6-bromo-2H-chromene is treated with NBS to form a bromohydrin (1).
- Preferred conditions use a solvent mixture of DMSO/water at about 0 - 50 °C, but more preferably at room temperature.
- Step B the bromohydrin (1) is treated with ammonium hydroxide to provide the amino alcohol (2).
- the bromohydrin is reacted with ammonium hydroxide in a solvent mixture of THF and EtOH at room temperature to 60 °C for 4 to 24 hr.
- Step C the racemic amino alcohol is resolved into its 3R, 4S and 3S, 4R enantiomers to provide the chiral amino alcohol (3).
- Methods for resolution are commonly known to those skilled in the art and include crystallization as a salt of a chiral acid, or separation of the enantiomers by chiral chromatography.
- 6-Bromo-2H-chromene is commercially available or can be prepared by methods commonly known in the art. For example 6-bromo-4-chromanone can be reduced to the alcohol and subsequently eliminated to obtain 6-bromo-2H-chromene. X18795
- Step A a cyclic alkene of formula (4) is oxidized with MCPBA to obtain an epoxide of formula (5).
- the reaction is performed in a biphasic mixture of a halogenated solvent, such as dichloromethane and an aqueous base, such as aqueous sodium bicarbonate.
- a halogenated solvent such as dichloromethane
- an aqueous base such as aqueous sodium bicarbonate.
- the MCPBA is added in portions at -10 to 10 °C and the reaction allowed to warm to room temperature with stirring for 1 to 8 hr. Additional MCPBA is added if needed.
- Step B an epoxide of formula (5) is treated with ammonia to form a racemic amino alcohol of formula (6).
- Preferred conditions use a sealed vessel with an inert solvent, such as THF, with the addition of ammonia in MeOH.
- the reaction is heated at 50 to 100 °C for 1 to 4 days, adding additional ammonia if necessary.
- Step C a racemic amino alcohol (6) is resolved to a chiral amino alcohol of formula (7) as previously described in Scheme 1, Step C.
- the racemic material (6) can be carried through to final products and the enantiomers separated by chiral chromatography.
- X18795 1- amino-7-bromo-tetralin-2-ol
- Step A the amino indane (9) is obtained from the nitro indane (8) by hydrogenation over 5% palladium on carbon according to procedures contained in the literature for the 1R,2R enantiomer (US 7,326,731 B2).
- Step B the amino indane (9) is converted to the iodo indane (10) using a
- the diazonium salt is formed in situ in a solvent such as acetonitrile using -toluenesulfonic acid and an aqueous solution of sodium nitrite.
- the diazonium salt is subsequently treated with an aqueous solution of potassium iodide at a temperature of 0 to 30 °C for 0.5 to 6 h to provide the iodoindane (10).
- Step C the boc protected iodoindane (10) is taken to the iodo amino indane
- Preferred conditions use HCl in dioxane at 0 to 25 °C for 0.5 to 4 h.
- rert-butyl-N-[(l S,2S)-6-amino-2-hydroxy-indan-l-yl]carbamate (8) can be prepared by methods known in the art. For example, racemic-trans- l-amino-6- X18795
- -12- nitroindan-2-ol can be obtained in six steps from indene (Adv. Synth. Catal. 2005, 347, 255-265).
- the racemic material is resolved and isolated as the 1R,2R and 1S,2S salts of (+)-L-mandelic acid.
- the 1S,2S salt is freed to lS,2S-£raws-l-amino-6-nitroindan-2-ol and the amine subsequently protected as the tert-butyl carbamate to obtain material in greater than 97% ee as analyzed by chiral HPLC.
- Step A the amino alcohol of formula (12) (either chiral or racemic) is acylated to obtain an amide of formula (13).
- Various acylation methods are well known in the art using either a carboxylic acid or an acid chloride. Preferred conditions use an appropriate benzoyl chloride in a solvent mixture of THF and aqueous sodium bicarbonate at a temperature of 0 to 25 °C for 1 to 8 hr. If the starting amino alcohol is used as the salt of a chiral acid, sufficient base is used to generate the free amine.
- Step B the bromo or iodo amide of formula (13) is coupled with a protected 2- oxo-piperazine using copper (I) iodide and a ligand, such as sym-dimethylethylene diamine to provide an oxopiperazine of formula (14).
- the reaction is preferably performed in a sealed vessel, under an inert atmosphere, in the presence of an inorganic base such as potassium carbonate.
- the reaction is run in an inert solvent, such as NMP at a temperature of 80 to 150 °C.
- Step C the oxopiperazine is selectively reduced in the presence of the benzamide to provide the piperazine of formula (15).
- the reaction is accomplished using a reducing agent such as borane-dimethyl sulfide complex in an inert solvent such as THF at a temperature of 0 to 40 °C for one to four hours. Additional borane-dimethyl sulfide complex may be used to drive the reaction to completion.
- Step D the piperazine is reacted directly with the iodo or bromo amide (13) using N-tert-butoxycarbonylpiperazine in a coupling reaction.
- the reaction proceeds in the presence of a Pd catalyst, such as allylpalladium(II) chloride dimer and a ligand such as tri-tert-butylphosphonium tetrafluoroborate.
- a base is used, such as sodium tert-butoxide in an inert solvent such as DMSO at temperature of 20 to 120 °C for 0.5 to 8 hr. to provide the piperazine of formula (15).
- Step E the boc protecting group is removed to give the unprotected piperazine of formula (16).
- Acidic conditions for removal of boc groups, such as HC1 in dioxane, are well known in the art.
- Step F the unprotected amine (16) is reacted in a reductive amination with 3-oxetanone to provide an oxetanyl piperazine of formula (17).
- a reducing agent such as sodium triacetoxy borohydride
- an inert solvent such as acetonitrile
- reaction can be accomplished using a reducing agent such as sodium cyanoborohydride, in a solvent mixture such as MeOH and glacial acetic acid, in the presence of molecular sieves.
- a reducing agent such as sodium cyanoborohydride
- solvent mixture such as MeOH and glacial acetic acid
- Step G the alcohol of the oxetanyl piperazine (17) is converted to the carbamate of Formula I.
- carbamate of Formula I there are various means available to the skilled artisan for synthesizing carbamates such as triphosgene/amine, 4-nitrophenyl chloroformate/amine, CDI/amine or directly with an appropriately substituted isocyanate.
- the alcohol (17) in an aprotic solvent such as dichloromethane, dioxane, or preferably THF, in the presence of an organic base, such as DMAP or preferably 4-pyrrolidinopyridine, is treated with methyl isocyanate.
- the reaction is run in a sealed vessel at 20 to 70 °C for about 2 to 16 hr.
- the trichloroacetyl group is cleaved using neutral AI2O 3 or an organic acid such as -toluene sulfonic acid.
- a preferred method for synthesis of the carbamate of Formula I makes use of CDI in an inert solvent such as THF at 0 to 25 °C for 4 - 20 hr. to form the imidazole N-carboxylic ester in situ.
- Subsequent reaction with an appropriate amine (H 2 NR 2 ) provides the carbamate of Formula I.
- tert-Butyl N-[(l S,2S)-2-hydroxy-6-iodo-indan- 1 -yl]carbamate Cool a suspension of tert-bu yl N-[(lS,2S)-6-amino-2-hydroxy-indan-l- yljcarbamate (25.0 g, 94.6 mmol) in acetonitrile (800 mL) in an ice bath for 30 min and add -toluenesulfonic acid monohydrate (53.97 g, 283.7 mmol) in one portion.
- Exemplified compounds of the present invention are tested in the following in vitro and in vivo assays.
- Test compounds are prepared in DMSO to make up a lOmM stock solution.
- the stock solution is serially diluted in DMSO to obtain a ten-point dilution curve with a final compound concentration range la in a 96-well round-bottom plate before conducting the in vitro enzymatic assay.
- Compounds are further diluted lb in assay buffer (used for entire assay) described immediately hereafter:
- Human cathepsins K and V 100 mM sodium acetate (pH 5.5) containing 100 mM NaCl, 2.5 mM DTT and 2.5 mM EDTA plus 0.01% TRITON® X-100
- Ten ⁇ of each dilution is added to each well of row A through H of a corresponding low protein binding half area black plate (Costar 3694).
- Amount lc of substrate, benzyloxycarbonyl-L-leucyl-L-arginine-4-methyl-coumaryl-7-amide (Peptide Institute), prepared in assay buffer, is added to each well of the plate for a final concentration Id.
- Amount le of the respective enzyme, described immediately hereafter, prepared in assay buffer is added to each well of the plate containing substrate and test compound resulting in a final concentration If to initiate the reaction.
- Mouse cathepsin S Briefly, mouse cathepsin S is cloned in baculovirus using a mCathepsin S-pAN51(T760) construct containing a histidine tag. IMAC is then employed to purify the active protein.
- Human cathepsin F Briefly, human recombinant cathepsin F enzyme is prepared in house as follows. Procathepsin F is cloned in 293E cells using the CathepsinF- pAN60 (T-2188) construct containing a histidine tag. IMAC is then employed to purify the protein. The procathepsin F is digested using pepsin and repurified using Mono S column chromatography resulting in purified activated cathepsin F. The mixture is briefly shaken at low speed on a plate mixer.
- the RFU of the mixture is recorded using an Envision 2103 Multilabel Reader at excitation wavelength 355 nm and emission wavelength 460 nm for 0.1 sec after an incubation time lg at room temperature.
- RFU are plotted versus inhibitor concentration and a curve is fitted with a four-parameter logistic equation to obtain IC5 0 values using Activity Base (ver. 7.3.2.1).
- Activity Base ver. 7.3.2.1
- a Packard Fusion Alpha Microplate Reader 0.5 sec
- exemplified compounds display IC5 0 S in the human cathepsin S and mouse cathepsin S enzyme inhibitor assay of less than 800 nM and 400 nM, respectively.
- the compounds of Examples 1 and 2 display IC5 0 S in the human cathepsin S enzyme inhibitor assay of about 6.4 nM and 10.2 nM respectively, and in the mouse cathepsin S enzyme inhibitor assay of about 1.7 nM and 3.9 nM, respectively, thus demonstrating that certain compounds within the scope of the present invention are potent inhibitors of human and mouse cathepsin S.
- the compound of Example 1 displays IC5 0 S of about >167 ⁇ , 5.2 ⁇ , >100 ⁇ , and 33 ⁇ , respectively, and Example 2 of about >167 ⁇ , 94 ⁇ , >100 ⁇ , and >100 ⁇ , respectively.
- human cathepsin F the compound of Example 1 displays no inhibition up to 30 ⁇ .
- AAA animal efficacy model using CaC3 ⁇ 4 induction to study the effect of cathepsin S inhibitors on AAA is modified as described below.
- Example 1 City, Indiana
- Example 2 divided into six groups for Example 1 and five groups for Example 2 with each group containing 12 mice are used.
- Groups 1-5 for Examples 1 and 2 are administered respectively a vehicle solution 1% NATROSOL®
- Group 6 (in the study of Example 1) representing a sham group (0.9% saline applied to the aorta instead of CaCi 2 and dosed with vehicle) is included to establish a baseline. The first dose is given one day prior to surgery (p.m.) and the second dose is given the morning of surgery. Animals do not receive a p.m. dose on the day of surgery. B.i.d. dosing (a.m. and p.m.) is continued the day after surgery for 28 days.
- mice received analgesia (BUPRENEX®, 0.1 mg/kg) subcutaneously 10 min. pre-operatively and 3 hr. post-operatively. Mice are anesthetized by inhalation of 2% isoflurane and a laparotomy is performed.
- the abdominal aorta is exposed by retracting the bowel laterally with a surgical retractor and leaving the bowel in the abdominal cavity.
- the abdominal aorta from the level of the renal arteries to the iliac bifurcation is isolated from the inferior vena cava and surrounding connective tissues using micro-surgical techniques.
- the region of interest of the abdominal aorta is wrapped with a premeasured sterile cotton gauze soaked in 0.25 M aqueous CaCl 2 solution.
- 0.9% saline is substituted for CaCl 2 .
- the gauze is removed and a second CaCi 2 soaked gauze (or 0.9% saline soaked gauze in sham animals) is applied.
- the gauze is removed, the aorta is rinsed with 0.9% saline and the abdomen is closed.
- the animals are returned to general housing where they are housed individually with ad lib access to standard rodent diet (Purina 2014) and water.
- the aortic luminal perimeter, area and diameter of the aortic segments that were wrapped with gauze are determined by ultrasound (Biosound Ultrasound - 7.5 MHz) and statistically analyzed with JMP® 7 software (Cary, North Carolina). Percentage reductions of AAA determined by measurement of the aortic luminal perimeter (which represents in this instance a more accurate measurement of the abdominal aorta due to the irregular geometry associated with the aortic segment being measured) are shown below in Table 1 and are represented as means ⁇ standard deviation. For Example 1, vehicle group is compared to sham group, and testing compound is compared to vehicle. For Example 2, testing compound is compared to vehicle.
- the compounds of Examples 1 and 2 reduce the aortic luminal perimeter in a dose-dependent manner, and therefore demonstrate that certain compounds within the scope of the invention reduce AAA.
- NATROSOL® hydroxyethylcellulose
- TWEEN® 80 polysorbate 80
- Antifoam-1510 Dow Corning
- 3 mg/kg of test compound in vehicle solution by oral gavage 3 mg/kg of test compound in vehicle solution by oral gavage.
- whole blood 300-500 ⁇
- the step of removing red blood cells is performed by adding one mL Flow Cytometry Lysing SolutionTM (Santa Cruz Biotechnology, Inc.), keeping at room temperature for 10 min., centrifuging at 4000 rpm for 5 min. and then discarding the supernatant. This step is repeated once to remove the red blood cells completely.
- the PWBC pellet is resuspended with 50 ⁇ ⁇ CytoBusterTM Reagent (Novagen) and sonicated at high power for 5-10 sec.
- the protein concentrations are determined using a BCA assay (Anal. Biochem. 1988, 175, 231-237/
- the p 10 amount is determined using a Western blot.
- Samples 0.5 ⁇ g/ ⁇ l protein concentration
- 20 ⁇ /well of samples ⁇ g/well
- Gels are run at 120 V for 60 min. with the NUPAGE® MES SDS running buffer (Invitrogen).
- Proteins are transferred to 0.2 ⁇ nitrocellulose (BIO-RAD) at 100 V for 30 min. with NUPAGE® Transfer Buffer (Invitrogen) and 20% methanol (EMD).
- Blot is briefly rinsed with PBS and blocked in 10 mL in ODYSSEY® Blocking Buffer (LI-COR Biosciences) at room temperature for 60 min.
- ODYSSEY® Blocking Buffer LI-COR Biosciences
- the blot is incubated with primary antibody against mouse CD74 (1 ⁇ g/ml of rat anti-CD74 antibody)(BD Bioscience) in blocking buffer at 4 °C overnight.
- the blot is incubated with rabbit anti-beta tubulin pAb (0.2 ⁇ g/ml)(Abcam) in blocking buffer at 4 °C overnight.
- the blot is washed with washing buffer (DPBS from HyClone) with 0.01% polysorbate 20 four times for 10 min. each.
- blot is then incubated with secondary antibody at room temperature for 60 min.
- ALEXA FLUOR® 680 goat anti rat IgG (1 :5000 dilution)(Invitrogen) is used.
- the blot is again washed as described above and placed in PBS for scanning. X18795
- the images are captured by scanning on an ODYSSEY® Infrared Imager (LI-COR Biosciences).
- the plO amount is analyzed with ODYSSEY® software and normalized with the tubulin amount.
- the data are statistically analyzed with JMP® 7 software (Cary, North Carolina). Relative plO accumulations (fold increase) to the vehicle are shown in Table 3. Values are represented as means ⁇ standard deviation.
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Abstract
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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CN2011800507006A CN103153989A (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds |
EA201370052A EA201370052A1 (en) | 2010-10-19 | 2011-10-14 | COMPOUNDS INHIBITORS KATEPSIN S |
KR1020137009844A KR20130093120A (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds |
JP2013534962A JP2013540154A (en) | 2010-10-19 | 2011-10-14 | Cathepsin S inhibitory compound |
MX2013004421A MX2013004421A (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds. |
BR112013009670A BR112013009670A2 (en) | 2010-10-19 | 2011-10-14 | cathepsin inhibiting compounds s |
CA2816033A CA2816033C (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds |
EP11776639.4A EP2630141A1 (en) | 2010-10-19 | 2011-10-14 | Cathepsin s inhibitor compounds |
AU2011318316A AU2011318316A1 (en) | 2010-10-19 | 2011-10-14 | Cathepsin S inhibitor compounds |
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EP3617195A4 (en) * | 2017-04-27 | 2020-12-16 | Mochida Pharmaceutical Co., Ltd. | Novel tetrahydronaphthyl urea derivatives |
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WO2002040462A2 (en) * | 2000-11-17 | 2002-05-23 | Medivir Uk Limited | Cysteine protease inhibitors |
WO2005039496A2 (en) * | 2003-10-21 | 2005-05-06 | Irm Llc | Inhibitors of cathepsin s |
US7326731B2 (en) | 2001-09-21 | 2008-02-05 | Eli Lilly And Company | Muscarinic agonists |
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WO2002042278A2 (en) | 2000-11-21 | 2002-05-30 | Vertex Pharmaceuticals Incorporated | Imidazole and benzimidazole caspase inhibitors and uses thereof |
GB0418353D0 (en) * | 2004-08-17 | 2004-09-22 | Novartis Ag | Organic compounds |
WO2008130322A1 (en) | 2007-04-23 | 2008-10-30 | Astrazeneca Ab | Novel 5-heterocyclyl-chromane derivatives for the treatment of pain |
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WO2002040462A2 (en) * | 2000-11-17 | 2002-05-23 | Medivir Uk Limited | Cysteine protease inhibitors |
US7326731B2 (en) | 2001-09-21 | 2008-02-05 | Eli Lilly And Company | Muscarinic agonists |
WO2005039496A2 (en) * | 2003-10-21 | 2005-05-06 | Irm Llc | Inhibitors of cathepsin s |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3617195A4 (en) * | 2017-04-27 | 2020-12-16 | Mochida Pharmaceutical Co., Ltd. | Novel tetrahydronaphthyl urea derivatives |
US10927079B2 (en) | 2017-04-27 | 2021-02-23 | Mochida Pharmaceutical Co., Ltd. | Intermediate compound of novel tetrahydronaphthyl urea derivative |
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