WO2008103351A2 - Heterocyclic aspartyl protease inhibitors - Google Patents
Heterocyclic aspartyl protease inhibitors Download PDFInfo
- Publication number
- WO2008103351A2 WO2008103351A2 PCT/US2008/002182 US2008002182W WO2008103351A2 WO 2008103351 A2 WO2008103351 A2 WO 2008103351A2 US 2008002182 W US2008002182 W US 2008002182W WO 2008103351 A2 WO2008103351 A2 WO 2008103351A2
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- solvate
- tautomer
- stereoisomer
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- IUJPMBWEAKBVLI-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc(cc2)ccc2NC(c2ccc[o]2)=O)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc(cc2)ccc2NC(c2ccc[o]2)=O)C1=O IUJPMBWEAKBVLI-UHFFFAOYSA-N 0.000 description 1
- HTPBCCIUMMEFCW-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2c(C(F)(F)F)cccc2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2c(C(F)(F)F)cccc2)C1=O HTPBCCIUMMEFCW-UHFFFAOYSA-N 0.000 description 1
- OUGZMQMTANTVHT-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cc(-c(cn3)ccc3O)ccc2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cc(-c(cn3)ccc3O)ccc2)C1=O OUGZMQMTANTVHT-UHFFFAOYSA-N 0.000 description 1
- ZNMSZNUTROTNHB-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cc(F)ccc2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cc(F)ccc2)C1=O ZNMSZNUTROTNHB-UHFFFAOYSA-N 0.000 description 1
- WUHPWDUNLIERPN-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2ccc[s]2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2ccc[s]2)C1=O WUHPWDUNLIERPN-UHFFFAOYSA-N 0.000 description 1
- WRTRHEPCXSQJDD-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(-c3cc(CO)ccc3)c2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(-c3cc(CO)ccc3)c2)C1=O WRTRHEPCXSQJDD-UHFFFAOYSA-N 0.000 description 1
- XBFXIYVFRVUDOU-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(-c3ccccc3)c2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(-c3ccccc3)c2)C1=O XBFXIYVFRVUDOU-UHFFFAOYSA-N 0.000 description 1
- VKUIPBZWGSJZDX-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(C(NC3CCC3)=O)c2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(C(NC3CCC3)=O)c2)C1=O VKUIPBZWGSJZDX-UHFFFAOYSA-N 0.000 description 1
- KTQOMKKXYFKQCX-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(C(NCCOc3ccccc3)=O)c2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(C(NCCOc3ccccc3)=O)c2)C1=O KTQOMKKXYFKQCX-UHFFFAOYSA-N 0.000 description 1
- JXUNYNDLHHZXMI-UHFFFAOYSA-N N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(NC(c3ccccc3)=O)c2)C1=O Chemical compound N=C(NC1(c2ccccc2)c2ccccc2)N(Cc2cccc(NC(c3ccccc3)=O)c2)C1=O JXUNYNDLHHZXMI-UHFFFAOYSA-N 0.000 description 1
- BNEGXSGSZRFOBV-UHFFFAOYSA-N N=C(NCc1ccccc1)N(CCN1CCCCC1)C(Cc1ccccc1)=O Chemical compound N=C(NCc1ccccc1)N(CCN1CCCCC1)C(Cc1ccccc1)=O BNEGXSGSZRFOBV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
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- 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
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- 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
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
Definitions
- This invention relates to heterocyclic aspartyl protease inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human' Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes.
- renin-angiotensin system (RAS) in regulation of blood pressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 291 :381 -401 /446-57).
- the octapeptide Angiotensin-ll a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-I, which in turn was processed from angiotensinogen by the renin enzyme.
- Angiotensin-ll was also found to play roles in vascular smooth muscle cell growth, inflammation, reactive oxygen species generation and thrombosis, influence atherogenesis and vascular damage.
- AD Alzheimer's disease
- connective tissue disease connective tissue disease
- muscular dystrophy muscular dystrophy
- breast cancer a progressive neurodegenerative disease that is ultimately fatal.
- Disease progression is associated with gradual loss of cognitive function related to memory, reasoning, orientation and judgment.
- Behavioral changes including confusion, depression and aggression also manifest as the disease progresses.
- the cognitive and behavioral dysfunction is believed to result from altered neuronal function and neuronal loss in the hippocampus and cerebral cortex.
- the currently available AD treatments are palliative, and while they ameliorate the cognitive and behavioral disorders, they do not prevent disease progression.
- AD extracellular ⁇ -amyloid
- a ⁇ extracellular ⁇ -amyloid
- APP amyloid precursor protein
- a ⁇ peptides result from the cleavage of APP by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , and at the C- terminus by ⁇ -secretase activity.
- APP is also cleaved by ⁇ -secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP.
- BACE-1 An aspartyl protease known as BACE-1 has been identified as the ⁇ -secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of A ⁇ peptides.
- BACE-1 An aspartyl protease known as BACE-1 has been identified as the ⁇ -secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of A ⁇ peptides.
- a ⁇ has been shown to be toxic to neuronal cells in vitro and when injected into rodent brains.
- inherited forms of early-onset AD are known in which well-defined mutations of APP or the presenilins are present. These mutations enhance the production of A ⁇ and are considered causative of AD.
- inhibition of BACE-1 should inhibit formation of A ⁇ peptides.
- inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by A ⁇ plaque deposition.
- HIV Human immunodeficiency virus
- AIDS acquired immune deficiency syndrome
- compounds such as indinavir, ritonavir and saquinavir which are inhibitors of the HIV aspartyl protease result in lowering of viral load.
- the compounds described herein would be expected to be useful for the treatment of AIDS.
- HIV-1 protease an aspartyl protease related to renin.
- HTLV-I Human T-cell leukemia virus type I
- HTLV-I Human T-cell leukemia virus type I
- HTLV-I Like other retroviruses, HTLV-I requires an aspartyl protease to process viral precursor proteins, which produce mature virions. This makes the protease an attractive target for inhibitor design.
- Plasmepsins are essential aspartyl protease enzymes of the malarial parasite.
- the present invention relates to compounds having the structural formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein
- R 1 , R 2 and R 5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, -OR 15 , -CN, -C(O)R 8 , -C(O)OR 9 , -S(O)R 10 , -S(O) 2 R 10 , -C(O)N(R 11 XR 12 ), -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ),
- R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R 10 )(R 19 ), -SH, -CN, -OR 9 , -C(O)R 8 , -C(O)OR 9 , -C(O)N(R 11 KR 12 ), -SR 19 , -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ), -N(R 11 )(R 12 ), -N(R 11 )C(O)R 8 , -N(R 11 JS(O)R 10 , -N(R 11
- M is -CH 2 -, S, -N(R 19 )- or O
- a and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when q is 2, M is optionally a double bond; and with the proviso that when R 3 , R 4 , R 6 and R 7 form said multicyclic groups
- R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR 15 , -N(R 15 )(R 16 ), -N(R 15 )C(O)R 16 , -N(R 15 )S(O)R 16 , -N(R 15 )S(O) 2 R 16 , -N(R 15 )S(O) 2 N(R 16 )(R 17 ), -N(R 15 )S(O)N(R 16 )(R 17 ), -N(R 15 )C(O)N(R 16 )(R 17 ) and -N(R 15 )C(O)OR 16 ;
- R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
- R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and -N(R 15 )(R 16 );
- R 11 , R 12 and R 13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)R 8 , -C(O)OR 9 , -S(O)R 10 , -S(O) 2 R 10 , -C(O)N(R 15 )(R 16 ), -S(O)N(R 15 XR 16 ), -S(O) 2 N(R 15 XR 16 ) and -CN;
- R 15 , R 16 and R 17 are
- R 23 numbers O to 5 substituents, m is O to 6 and n is 1 to 5;
- R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO 2 , halo, heteroaryl, HO- alkyoxyalkyl, -CF 3 , -CN, alkyl-CN, -C(O)R 19 , -C(O)OH, -C(O)OR 19 , -C(O)NHR 20 , -C(O)NH 2 , -C(O)NH 2 -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 19 , -S(O) 2 R 20 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alky
- R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
- R 20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyclo
- R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one
- R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, -NO 2 , halo, -CF 3 , -CN, alkyl-CN, -C(O)R 28 , -C(O)OH, -C(O)OR 28 , -C(O)NHR 29 , -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 28 , -S(O) 2 R 29 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O) 2 NH 2 , -S(O) 2 NHR 28 , -S(O) 2 NH(aryl), -S(
- R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl
- R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; provided that when W is -C(O)- and U is a bond, R 1 is not optionally substituted phenyl, and that when U is -C(O)- and W is a bond, R 5 is not optionally substituted phenyl; provided that neither R 1 nor R 5 is -C(O)-alkyl-azetidinone or alkyl di-substituted with (-COOR 15 or -C(O)N(R 15 )(R 16 )) and (-N(R 15 )(R 16 ), -N(R 15 )C(O)R 16 , -N(R 15 )S(O)R 16 , -N(R 15 )S(O) 2 R 16 , -N(R 15 )S(O) 2 N(R 16 )(R 17 ), -N(R
- R 3 and R 4 are alkyl
- R 21 is halo, -CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R 3 and R 4 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group, and R 1 is
- R 21a is not H, -C(O) 2 R 15 , wherein R 15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R 22 , wherein R 22 is selected from the group consisting of phenyl, phenyl substituted with alkyl,
- R 22 is selected from the group consisting of H, methoxy, nitro, oxo, -OH, halo and alkyl,
- the invention in another aspect, relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.
- the invention comprises the method of inhibiting aspartyl protease comprising administering at least one compound of formula I to a patient in need of such treatment.
- the invention comprises: the method of treating a cardiovascular disease such as hypertension, renal failure, or a disease modulated by renin inhibition; the method of treating Human Immunodeficiency Virus; the method of treating a cognitive or neurodegenerative disease such as Alzheimer's Disease; the method of inhibiting plasmepins I and Il for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of Plasmodium falciparnum, for the treatment of fungal infections.
- Said method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment.
- the invention comprises the method of treating Alzheimer's disease comprising administering at least one compound of formula I to a patient in need of such treatment.
- the invention comprises the method of treating Alzheimer's disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and a cholinesterase inhibitor or a muscarinic mi agonist or m 2 antagonist.
- the invention relates to a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, in which one container comprises a compound of formula I in a pharmaceutically acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic mi agonist or m 2 antagonist in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's disease.
- U is preferably a bond or -C(R 6 )(R 7 )-.
- U is preferably -C(O)-.
- R 1 is the same as the definition of R 5 , when X is -N(R 5 )-, compounds of formula I wherein W is a bond and U is a bond, -S(O)-, -S(O) 2 -, -C(O)-, -O-, -C(R 6 )(R 7 )- or -N(R 5 )- are equivalent to compounds of formula I wherein U is a bond and W is a bond, -S(O)-, -S(O) 2 -, -C(O)-, -O-, -C(R 6 XR 7 )- or -N(R 5 )-.
- More preferred compounds of the invention are those of formula IB wherein U is a bond or those of formula IB wherein U is -C(R 6 )(R 7 )-.
- R 3 , R 4 , R 6 and R 7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R 10 )(R 19 ), -SH, -CN, -OR 9 , -C(O)R 8 , -C(O)OR 9 , -C(O)N(R 11 XR 12 ), -SR 19 , -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ), -N(R 11 )(R 12 ), -N(R 11 )C(O)R 8 , -N(R 11 )
- R 3 , R 4 , R 6 and R 7 are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.
- U is a bond or -C(O)-;
- W is a bond or -C(O)-;
- X is -N(R 5 )-;
- R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
- R 2 is H;
- R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
- R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
- R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;
- R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
- R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
- R 15 R 16 and R 17 is H, R 18 -alkyl, alkyl or
- R ⁇ 2'1 1 i,s alkyl, aryl, halo, -OR i1 1 5 0 , -NO 2 , -C(O)R 15 , -CH 2 -N(R >1 1 5 0 ⁇ )C(O)N(R i1 1 6 0 ⁇ )(/rR-,1 1 7' ⁇ ) or
- R 18 is -OR 20
- R 20 Is aryl
- R 23 is alkyl
- R 3 , R 4 , R 6 and R 7 are preferred compounds.
- U is a bond or -C(O)-
- W is a bond or -C(O)-
- X is -N(R 5 )-
- R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
- R 2 is H
- R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
- R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
- R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 - cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;
- R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
- R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl;
- R 15 , R 16 and R 17 is H, cycloalkyl, cycloalkylalkyl, R 18 -alkyl, alkyl, aryl, R 18 -aryl,
- R 18 -arylalkyl, arylalkyl, n is 1 or 2; m is O oM ;
- R 18 is -OR 20 or halo;
- R 20 is aryl or halo substituted aryl;
- R 21 is alkyl, aryl, heteroaryl, R 22 -alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyl, -N(R 15 )(R 16 ), -OR 15 , -NO 2 , -C(O)R 15 , -N(R 15 )C(O)R 16 , -N(R 15 )S(O) 2 R 16 , -CH 2 -N(R 15 )C(O)N(R 16 )(R 17 ), -N(R 15 )C(O)N(R 16 )(R 17 ) or -CH(R 15 KR 16 ); R 22 is -OR 15 or halo and
- R ⁇ »2"3 is H or alkyl.
- carbons of formula I may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
- alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
- “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
- suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n- pentyl, heptyl, nonyl and decyl.
- R 21 -substituted alkyl groups include fluoromethyl, trifluoromethyl and cyclopropylmethyl .
- “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
- Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
- Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
- Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
- suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
- Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
- Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
- Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
- “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
- suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. •
- Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
- the aryl group can be optionally substituted with one or more substituents (e.g., R 18 , R 21 ' R 22 , etc.) which may be the same or different, and are as defined herein or two substituents on adjacent carbons can be linked together to form .
- substituents e.g., R 18 , R 21 ' R 22 , etc.
- suitable aryl groups include phenyl and naphthyl.
- Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to eight of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
- the "heteroaryl” can be optionally substituted by one or more R 21 substituents which may be the same or different, and are as defined herein.
- the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
- a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
- suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl
- Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
- the cycloalkyl can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above.
- suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- Non- limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following
- Cycloalkylether means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
- Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond.
- the cycloalkenyl ring can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above.
- Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
- suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
- Non- limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
- Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
- Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
- the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
- the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
- the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
- Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1 ,2,3,4- tetrahydropyridine, 1 ,2-dihydropyridyl, 1 ,4-dihydropyridyl, 1 ,2,3,6- tetrahydropyridine, 1 ,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, and the like.
- suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like.
- Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
- suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.
- Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
- Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
- Heterocyclyl (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
- Preferred heterocyclyls contain about 5 to about 6 ring atoms.
- the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
- the heterocyclyl can be optionally substituted by one or more R 21 substituents which may be the same or different, and are as defined herein.
- the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S 1 S- dioxide.
- suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3- dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
- Arylcycloalkyl means a group derived from a fused aryl and cycloalkyl as defined herein.
- Preferred arylcycloalkyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms.
- the arylcycloalkyl can be optionally substituted by 1-5 R 21 substituents.
- suitable arylcycloalkyls include indanyl and 1,2,3,4-tetrahydronaphthyl and the like.
- the bond to the parent moiety is through a non-aromatic carbon atom.
- Arylheterocycloalkyl means a group derived from a fused aryl and heterocycloalkyl as defined herein.
- Preferred arylcycloalkyls are those wherein aryl is phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms.
- the arylheterocycloalkyl can be optionally substituted by 1-5 R 21 substituents.
- suitable arylheterocycloalkyls include
- heteroarylalkyl means a heteroaryl-, cycloalkyl- or heterocycloalkyl-alkyl- group in which the heteroaryl, cycloalkyl, heterocycloalkyl and alkyl are as previously described. Preferred groups contain a lower alkyl group.
- the bond to the parent moiety is through the alkyl.
- acyl means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)- or cycloalkyl-C(O)- group in which the various groups are as previously described.
- the bond to the parent moiety is through the carbonyl.
- Preferred acyls contain a lower alkyl.
- suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.
- Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
- suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
- the bond to the parent moiety is through the ether oxygen.
- Alkyoxyalkyl means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl.
- Arylalkenyl means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more R 27 substituents. The bond to the parent moiety is through a non- aromatic carbon atom.
- Arylalkynyl means a group derived from a aryl and alkynyl as defined herein. Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more R substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
- Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.
- a variable appears more than once in a group e.g., R 8 in -N(R 8 ) 2
- a variable appears more than once in the structure of formula I e.g., R 15 may appear in both R 1 and R 3
- the variables can be the same or different.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- the wavy line 'vwx, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
- Lines drawn into the ring systems such as, for example: indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
- R 21 and R 22 are, for example, -N(R 15 )C(O)N(R 16 )(R 17 ) and R 15 and R
- purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
- purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
- any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
- protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
- variable e.g., aryl, heterocycle, R 2 , etc.
- its definition on each occurrence is independent of its definition at every other occurrence.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- Prodrugs and solvates of the compounds of the invention are also contemplated herein.
- the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof.
- prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S.
- a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 -Ci2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbony
- a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC 6 )alkanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C 6 )alkanoyloxy)ethyl, (C 1 - C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Cr C ⁇ jalkanoyl, ⁇ -amino(CrC 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)alkanoyloxymethyl, 1-((Ci- C 6
- a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Ci O )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (C r C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (d-C ⁇ Jalkyl, carboxy (CrC 6 )alkyl, amino(Ci-C 4 )alkyl or mono-N — or di-
- One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
- “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
- One or more compounds of the invention may optionally be converted to a solvate.
- Preparation of solvates is generally known.
- M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
- Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(D, article 12 (2004); and A. L. Bingham et al, Chem. Comm ⁇ n., 603-604 (2001).
- a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
- Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
- Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting aspartyl protease and/or inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient.
- the compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
- salts when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
- Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
- Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge ef a/, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D. C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.
- Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-
- Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
- organic bases for example, organic amines
- organic bases for example, organic amines
- benzathines diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-
- Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
- lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
- long chain halides
- esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci -4 alkyl, or C- ⁇ alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphoric acid
- the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
- the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Moshei ⁇ s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Moshei ⁇ s acid chloride
- the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
- All stereoisomers for example, geometric isomers, optical isomers and the like
- of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
- those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyi and 3-pyridyl).
- Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
- the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
- Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
- lsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
- Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
- the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can beheterocyclic aspartyl protease inhibitors.
- pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
- the bulk composition and each individual dosage unit can contain fixed amounts of the afore- said "more than one pharmaceutically active agents".
- the bulk composition is material that has not yet been formed into individual dosage units.
- An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
- the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
- MP-TsOH resin Microporous Toluene sulfonic acid resin
- PS-trisamine tris-(2-aminoethyl)aminomethyl polystyrene
- PS-NCO Microporous Toluene sulfonic acid resin
- the compounds in the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below.
- the tables contain the compounds with observed m/e values from mass spectroscopy and/or NMR data. These compounds can be obtained with synthetic methods similar to these listed in the last column using appropriate reagents.
- Polystyrene isocyanate resin 45 mg, 3 eq
- polystyrene trisamine resin 40 mg, 6 eq
- a 1 :1 mixture of CH 3 CNTHF 0.5 ml_
- the mixture was agitated for 6 h.
- -Z-NH-C(O)R 16 - is equivalent to R 1 substituted by R 21 , or R 1 Subsitituted by alkyl-R 22 , wherein R 21 and R 22 are -N(R 15 )C(O)R 16 and R 15 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene- alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene- cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)
- R 1 Subsitituted by alkyl-R 22 , wherein R 21 and R 22 are -N(R 16 )-C(O)-NHR 15 and R 16 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene- arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene- heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)
- the following compounds were prepared using similar methods:
- the following compounds were prepared using similar methods:
- the reaction mixture was stirred at room temperature overnight before it was partitioned between ether and saturated NaHCO 3 water solution.
- the aqueous phase was extracted with ether 2 times.
- the combined organic phase was washed with brine 2 times, and dried over anhydrous NaSO 4 .
- the reaction mixture was stirred at room temperature overnight under N 2 before the solid was filtered, and the solvent was evaporated. The residue was dissolved in 100 ml ether, washed with water 2X and dried over anhydrous MgSO 4 .
- BA1 prepared according to a literature procedure (Terao, Y; Kotaki, H; Imai, N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7), 1985, 2762-2766) was converted to BA2 using a procedure described by Coldham, I; Crapnell, K.M; Fernandez, J-C; Moseley J. D. and Rabot, R. (Journal of Organic Chemistry, 67 (17), 2002, 6185-6187).
- BA3 was generated from BA2 using a literature procedure described by Winkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.; Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056).
- Analytical data for compound BA3 MS m/e: 262.1 , 264.1 (M+H).
- 1 H NMR(CDCI 3 ) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).
- BQ1 was prepared according to Method AZ.
- NBS N-bromosuccinimide
- Method CB The following compounds were synthesized using methods similar to Method E and/or AX.
- Compound CC6 was generated from CC5 using a similar procedure in Method E. Crude compound CC6 was purified by flash chromatography (gradient 0-10% EtOAc in hexane). Two isomers were isolated during purification isomer A which eluted first followed by isomer B.
- ISOMER A 1 H-NMR (CDCI 3 ) ⁇ 7.26-7.37, m, 5H; 5.57, s, 1H; 5.38, s, 1H; 5.02, q, 2H; 4.08, br s, 1 H; 3.67, s, 3H; 3.08, d, 1 H; 2.58, d, 1 H; 1.80-1.92, m, 1 H; 1.60-1.75, m, 3H; 1.32-1.44, m, 3H; 0.83, s, 9H; 0.35-0.45, m, 4H; 0.01 , s, 6H.
- ISOMER B 1 H-NMR (CDCI 3 ) ⁇ 7.286-7.36, m, 5H; 5.56, s, 1H; 5.39, s, 1H; 5.06, q, 2H; 4.15, br s, 1H; 3.71 , s, 3H; 3.06, d, 1H; 2.70, d, 1 H, 1.60-1.90, m, 4H; 1.33-1.48, m, 3H; 0.87, s, 9H; 0.37-0.51 , m, 4H; 0.03, s, 6H. Yield 26% isomer A and 22% isomer B.
- Step 1 terf-Butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate
- Step 2 te/t-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate
- Step 4 4-(3-(3,4-Difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine
- Compound CK3 was obtained from CK2 using method BK, step 3.
- CK3 (1.18 g, 2.83 mmol) in THF (15 ml_) and 2 N LiOH (4 mL, 8 mmol) was stirred overnight at RT. The mixture was quenched with 6 N HCI (2 mL, 12 mmol) and then partitioned between water and EtOAc. The dried EtOAc layer was concentrated in vacuo and the residue subjected to reverse-phase HPLC (gradient from 10% ⁇ 95% CH 3 CN/H 2 O with 0.1 % HCO 2 H, 30 mL/min flow rate on a preparative C18 reverse-phase column) to afford CK4.
- reverse-phase HPLC gradient from 10% ⁇ 95% CH 3 CN/H 2 O with 0.1 % HCO 2 H, 30 mL/min flow rate on a preparative C18 reverse-phase column
- CL2 was obtained from CL1 (3-chlorophenyl boronic acid) following method AW. Method CL, Step 2;
- Trimethylsilyldiazomethane (2 M hexanes, 2.5 mL, 5.0 mmol) was added to a solution of LDA (freshly prepared from DIPA and "BuLi) in THF at -78° C. After 30 min at -78° C, a solution of aldehyde CL2 (900 mg, 4.13 mmol) in THF (5 mL) was added and the reaction slowly warmed to RT over 3 h. The reaction was quenched with water, then extracted with Et 2 O (2x 100 mL). The combined organic layers were washed with brine (1x), dried over MgSO 4 , filtered, and evaporated under vacuum.
- LDA freshly prepared from DIPA and "BuLi
- methanol 20 ml_
- 10% Pd/C 200 mg
- the mixture was hydrogenated by a hydrogen balloon for 3 hour 40 min at stirring.
- the tube was sealed, and evacuated and back-filled with N 2 (5X). The mixture was then exposed to microwave irradiation (110 0 C, 30 min). The resulting mixture was filtered with copious MeOH washes.
- step 3 CP4 is used to prepare the title compound (CP5).
- methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-amino-1-(4-chloro)phenyl]ethylphosphonate (CQ1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.
- step 3 CR3 is used to prepare the title compound.
- methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-(4-methoxy)phenylmethylamino-2-(4-bromo)phenyl]ethylphosphonate (CS1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provide the title compound.
- step 3 CS2 is used to prepare the title compound.
- step 3 is used to prepare the title compound.
- methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl (2-amino-1-phenyl)ethylphosphonate (CU1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.
- step 3 CU2 is used to prepare the title compound.
- step 3 Using a route similar to that described in Method A, step 3, CV3 is used to prepare the title compound.
Abstract
Description
Claims
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
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SI200831653A SI2097387T1 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
CN200880013100.0A CN101715442B (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
ES08714220.4T ES2582367T3 (en) | 2007-02-23 | 2008-02-20 | Aspartyl protease heterocyclic inhibitors |
MX2009009063A MX2009009063A (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors. |
DK08714220.4T DK2097387T3 (en) | 2007-02-23 | 2008-02-20 | HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS |
BRPI0807547-6A2A BRPI0807547A2 (en) | 2007-02-23 | 2008-02-20 | HYPERCYCLIC ASPARTIL PROTEASE INHIBITORS |
NZ579301A NZ579301A (en) | 2007-02-23 | 2008-02-20 | 2-Imino-3,6-dimethyl-5,6-diphenyl-tetrahydropyrimidin-4-one derivatives for treatment of Alzheimer's disease |
MEP-2016-142A ME02528B (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
AU2008219071A AU2008219071B2 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
JP2009550601A JP5340177B2 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
RU2009135277/04A RU2496774C2 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
CA2678958A CA2678958C (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
RS20160558A RS54979B1 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
LTEP08714220.4T LT2097387T (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
EP08714220.4A EP2097387B1 (en) | 2007-02-23 | 2008-02-20 | Heterocyclic aspartyl protease inhibitors |
ZA2009/05837A ZA200905837B (en) | 2007-02-23 | 2009-08-21 | Heterocyclic aspartyl protease inhibitors |
IL200561A IL200561A (en) | 2007-02-23 | 2009-08-23 | Heterocyclic aspartyl protease inhibitors or tautomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same and use thereof |
HK09108902.1A HK1130792A1 (en) | 2007-02-23 | 2009-09-28 | Heterocyclic aspartyl protease inhibitors |
HRP20160876TT HRP20160876T1 (en) | 2007-02-23 | 2016-07-14 | Heterocyclic aspartyl protease inhibitors |
CY20161100753T CY1117946T1 (en) | 2007-02-23 | 2016-07-29 | Heterocyclic Asparaginyl Protease Suspensions |
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