WO2005065195A2 - Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease - Google Patents
Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease Download PDFInfo
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- WO2005065195A2 WO2005065195A2 PCT/US2004/042173 US2004042173W WO2005065195A2 WO 2005065195 A2 WO2005065195 A2 WO 2005065195A2 US 2004042173 W US2004042173 W US 2004042173W WO 2005065195 A2 WO2005065195 A2 WO 2005065195A2
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- 0 CC(C(*)C1)C1(C(*)(*)*)NC(c1c(*)c(*)cc(*)c1*)=O Chemical compound CC(C(*)C1)C1(C(*)(*)*)NC(c1c(*)c(*)cc(*)c1*)=O 0.000 description 8
- JNMRBVPZBLSNOC-UHFFFAOYSA-N CC1C(CNCc2ccccc2)C1 Chemical compound CC1C(CNCc2ccccc2)C1 JNMRBVPZBLSNOC-UHFFFAOYSA-N 0.000 description 2
- ANBDULNTXCGJFL-UHFFFAOYSA-N CN(c1nc(NCCc(cc2)ccc2F)cc(C(O)=O)c1)S(C)(=O)=O Chemical compound CN(c1nc(NCCc(cc2)ccc2F)cc(C(O)=O)c1)S(C)(=O)=O ANBDULNTXCGJFL-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- 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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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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
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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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
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- 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
- C07D409/02—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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
Definitions
- the invention is directed to compounds useful as inhibitors of the beta secretase enzyme, and useful in the treatment of diseases in which the beta secretase enzyme is involved, such as Alzheimer's Disease.
- Alzheimer's disease is characterized by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles.
- the rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein ( ⁇ A4, also referred to as A ⁇ , ⁇ -protein and ⁇ AP) which is a proteolytic product of a precursor protein of much larger size.
- the amyloid precursor protein (APP or A ⁇ PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail.
- the A ⁇ domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH 2 - and COOH-termini.
- Proteases that release APP and its fragments from the membrane are termed "secretases.”
- Most APP S is released by a putative ⁇ -secretase which cleaves within the A ⁇ protein to release ⁇ -APP s and precludes the release of intact A ⁇ .
- ⁇ -secretase A minor portion of APP S is released by a ⁇ - secretase (" ⁇ -secretase"), which cleaves near the NH 2 -terminus of APP and produces COOH-terminal fragments (CTFs) which contain the whole A ⁇ domain.
- ⁇ -secretase a ⁇ -secretase
- CTFs COOH-terminal fragments
- BACE ⁇ -secretase or ⁇ -site amyloid precursor protein-cleaving enzyme
- therapeutic agents that can inhibit ⁇ -secretase or BACE may be useful for the treatment of Alzheimer' s disease.
- the compounds of the present invention are useful for treating Alzheimer's disease by inhibiting the activity of ⁇ -secretase or BACE, thus preventing the formation of insoluble A ⁇ and arresting the production of A ⁇ .
- the present invention is directed to phenylamide and pyridylamide derivative compounds having a terminal or branched amino or hydroxyl group.
- the compounds are inhibitors of the ⁇ -secretase enzyme, and are useful in the treatment of diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's disease.
- the invention is also directed to pharmaceutical compositions comprising these compounds, and the use of these compounds and compositions in the treatment of such diseases in which the ⁇ -secretase enzyme is involved.
- Ql is selected from the group consisting of (1) -OH, and (2) -NH 2 ;
- Q2 and Q3 are independently selected from the group consisting of (1) hydrogen, and (2) halogen;
- R a is selected from the group consisting of (1) hydrogen, (2) -Ci-io alkyl, wherein said alkyl is unsubstituted or substituted with one or more fluoro, and (3) -C3-8 cycloalkyl;
- Rb is selected from the group consisting of (1) hydrogen, (2) -Ci-i ⁇ lkyl, (3) -Ci-3 alkyl-aryl, wherein said aryl is selected from the group consisting of phenyl and naphthyl, (4) -C3-8 cycloalkyl, wherein said cycloalkykl, alkyl and aryl are unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -O-Ci-l ⁇ alkyl, (5) -(CH2)n-NR c R ( i wherein Re and R are selected from the group consisting of hydrogen and Ci-io alkyl, and n is 2, 3 or 4, and (6) -(CH2)n'-0-R e wherein R e is selected from the group consisting of (a) -C ⁇ _ ⁇ o alkyl, (b) -Cfj-3 alkyl-aryl, wherein
- Rl is (1) aryl selected from the group consisting of phenyl and napthyl, or (2) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, (3) -Ci-io alkyl, and (4) -C3_8 cycloalkyl, wherein said aryl, heteroaryl, alkyl and cycloalkyl is unsubstit
- R2 is selected from the group consisting of: (1) (R4-S02)N(R7)-, wherein R4 is (a) -C ⁇ _ ⁇ o alkyl, (b) -C3-8 cycloalkyl, wherein said alkyl and cycloalkyl is unsubstituted or substituted with one or more (i) halo, ( ⁇ ) -OH, (iii) -CN, (iv) -O-Ci-10 alkyl, (v) -Ci-10 alkyl, (vi) -C3-8 cycloalkyl, (vii) aryl selected from the group consisting of phenyl and napthyl, or (viii) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, wherein said heteroaryl is unsubstituted or substituted with one or more (i) halo, (ii) -OH, (iii) -CN, (iv) -O-Ci-10 alkyl, (v) -C3-8 cycloalkyl, or (vi) -Ci
- Rf and Rg are selected from the group consisting of hydrogen and Ci-10 alkyl, and x is 0, 1, 2, 3 or 4 or Rf and Rg, together with the nitrogen atom to which they are attached, form the group wherein y is 1 or 2, Y 5 is -CHR21, _0- or NR21, wherein R 2 1 is selected from the group consisting of; (i) hydrogen, and (ii) Ci-io alkyl, wherein said alkyl is unsubstituted or substituted with one or more (A) halo, (B) -OH, (C) -CN, (D) -O-Ci-io alkyl, or (E) -C3_8 cycloalkyl;
- R7 is selected from the group consisting of (a) hydrogen, and (b) -Ci-io alkyl, (c) aryl selected from the group consisting of phenyl and napthyl, or (d) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl wherein said alkyl, aryl or heteroaryl is unsubstituted or substituted with one or more (i
- y' is 1 or 2
- ⁇ 6 is -CED .22, _0- or NR22
- R22 [ S selected from the group consisting of; (i) hydrogen, and (ii) Ci-io alkyl, wherein said alkyl is unsubstituted or substituted with one or more (A) halo, (B) -OH, (C) -CN, (D) -O-Ci-io alkyl, or (E) -C3_8 cycloalkyl,
- R4 and R7 are linked together to form the group wherein z is 1, 2 or 3; or
- R ⁇ is selected from the group consisting of
- o 1, 2, 3 or 4;
- R3 is selected from the group consisting of
- ⁇ 3 is CR6c or N;
- R5 is Ci-io alkyl or C ⁇ _2 perfluoroalkyl
- R6a ; R6b ; and R6c are independently selected from the group consisting of: (1) hydrogen, (2) halo, (3) -Ci_io alkyl, (4) -OH, (5) -CN, (6) -C3-8 cycloalkyl, and (7) -0-Ci_io alkyl;
- R9 and RlO are independently selected from the group consisting of (1) hydrogen, (2) -Ci-10 alkyl, and (3) -C3-8 cycloalkyl, wherem said alkyl and cycloalkyl are unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -O-Ci-io alkyl, (e) -C3-8 cycloalkyl, and (f) -NRJRk wherein RJ and R are Ci-io alkyl; or R9 and RlO are joined together with the nitrogen atom to which they are attached to form
- R23 is selected from the group consisting of
- heteroaryl is selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl
- Rl7 is hydrogen or Ci-io alkyl, wherein said Ci_io alkyl is unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -C3-8 cycloalkyl, (e) -O-Ci-io alkyl, (f) -(CH2)q-phenyl, wherein q is 1 or 2, and (g) -NR18R19, and wherein Rl°> and Rl9 are independently selected from the group consisting of i) hydrogen, or ii) Ci-io alkyl; or R18 and Rl9, together with the nitrogen atom to which they are attached, form the group wherein q' is 1 or 2, ⁇ 7 is -CHR24, -O- or NR24, wherein R24 i s selected from the group consisting of; (a) hydrogen, and (b) Ci-io alkyl, wherein said alkyl is unsub
- R26 is selected from the group consisting of (1) hydrogen, and (2) -Ci-3 alkyl;
- Rl2 is selected from the group consisting of (1) hydrogen, (2) -C i-io alkyl, wherein said alkyl is unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -C3-8 cycloalkyl, (e) -O-Ci-io alkyl, or (f) -NH 2 , (3) halo, (4) -C3_8 cycloalkyl, (5) aryl selected from the group consisting of phenyl and napthyl, and (6) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl,
- Rl3 is selected from the group consisting of (1) hydrogen, (2) Ci-10 alkyl, and (3) -C3-8 cycloalkyl; wherein said alkyl and cycloalkyl is unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -C3-8 cycloalkyl, (e) -O-Ci-io alkyl, and (f) -Cl-10 alkyl;
- Rl4 is selected from the group consisting of (1) -Cl-10 alkyl, and (2) -C3-8 cycloalkyl; wherein said alkyl and cycloalkyl is unsubstituted or substituted with one or more (a) halo, (b) -OH, (c) -CN, (d) -C3-8 cycloalkyl, (e) -O-Ci-io alkyl, or (f) -Ci-10 alkyl; (3) -(CH2) V -NR15R16, wherein v is 2, 3 or 4, and wherein Rl5 and Rl6 are independently selected from the group consisting of (a) hydrogen, or (b) C ⁇ _ ⁇ o alkyl, wherein said Cl_lo alkyl is unsubstituted or substituted with one or more (i) halo, (ii) -OH, (iii) -CN, (iv) -C3-8 cycloalkyl, or (v
- Y4 is -CHR24-, -O- or -NR24-, wherein R24 is selected from the group consisting of (i) hydrogen, and (ii) Ci-10 alkyl, wherein said alkyl is unsubstituted or substituted with one or more (A) halo, (B) -OH, (C) -CN, (D) -O-Ci-io alkyl, or (E) -C3.8 cycloalkyl,
- u is 1 or 2
- Y8 is -CHR25-, -O- or -NR25-
- R25 is selected from the group consisting of (a) hydrogen, (b) Ci-io alkyl, (c) -(CH 2 )t-phenyl, (d) -(CH2)t-heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and
- Q and Q3 are hydrogen.
- Q3 is hydrogen and Q is halogen, preferably chloro.
- Q2 is hydrogen and Q is halogen, preferably chloro.
- R a and Rb are both hydrogen.
- R is hydrogen and Rb is as defined above.
- R a is hydrogen and Rb is Ci-io alkyl, preferably C ⁇ _5 linear alkyl.
- Ql is OH
- R a is hydrogen
- Rb is -(CH2)2-NRCRd hi a preferred embodiment of the compounds of the invention
- Rl is selected from the group consisting of (1) aryl selected from the group consisting of phenyl and napthyl, or (2) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, wherein said aryl or heteroaryl is unsub
- Rl is phenyl, unsubstituted or substituted in one or two positions with halo, preferably with fluoro or chloro, and m is 1.
- Rl is thienyl, unsubstituted or substituted, and m is 1.
- Rl is unsubstituted 3-thienyl, and m is 1.
- R2 is selected from the group consisting of (1) (R4-S02)N(R7)-, wherein R4 is -Ci-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more (i) halo, ( ⁇ ) -OH, (iii) -CN, (iv) -O-C1-6 alkyl, or (v) -C1-6 alkyl, R7 is selected from the group consisting of (a) hydrogen, (b) -Ci- 6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more (i) halo, ( ⁇ ) -OH, (iii) -CN, (iv) -0-Ci- 6 alkyl, (v) -Ci-6 alkyl; and
- R ⁇ is phenyl or tetrazolyl, preferably 5-tetrazolyl.
- R is (R S02)N(R7)-, wherein R4 and R7 are each C ⁇ _ 6 al yl.
- Exemplary preferred R2 groups include (R4S02)N(R7)- wherein R4 and R7 are each methyl, or (R4s ⁇ 2)N(R7)-, wherein R4 is methyl and R7 is propyl.
- R3 is (1) as described above, Y3 is
- R3 is (1) as described above, Y3 is N, R5 is C 1-2 perfluoroalkyl, and R ⁇ a and R6b are each hydrogen.
- R is (2) as described above, and R9 and RlO are each unsubstituted C ⁇ _ ⁇ o alkyl, preferably unsubstituted Ci-5 linear alkyl.
- R3 is (2) as described above, and R and RlO are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring (wherein w is 1) and R23 is -(CH2)p-phenyl or - (CH2)p-heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with chloro, and wherein p is preferably 0.
- R3 is (3) as described above, and Rl 1 is NR17 wherein Rl7 is preferably hydrogen or Cl-3 alkyl, and Rl2 is preferably hydrogen or methyl.
- R is (4) as described above, and Rl3 is hydrogen, Rl4 is -(CH2) V -NR15R16 wherein v is 2 and Rl and Rl6 are Ci-io alkyl, preferably Ci-5 alkyl, which is unsubstituted or substituted with -OH, -CN or -OCH3.
- R3 is (4) as described above, Rl3 and Rl4 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring (when Y8 is CH and s is 1), which is substituted with -(CH2)t-phenyl or -(CH2)t-heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with chloro, and wherein t is preferably 0.
- Yl is CH.
- ⁇ l is N.
- TJ formula
- Ql, Q2, Q3, Ra ; Rb R1 ; R2 t R12 ; R17 ; R26 and m are as defined above, and pharmaceutically acceptable salts thereof.
- Q2 and Q3 are hydrogen.
- Q is hydrogen and Q2 is halogen, preferably chloro.
- Ql is NH2, and R a and Rb are each hydrogen.
- Ql is NH2, R a is hydrogen and Rb is Ci-5 linear alkyl.
- Ql is OH, and R a and Rb are each hydrogen.
- Ql is OH, and R a is hydrogen and Rb is C 1-5 linear alkyl.
- Ql ,Q2, Q3, Ra, Rb ; Rl, 2, R13 ; R14 and m are as defined above, and pharmaceutically acceptable salts thereof.
- Q2 and Q3 are hydrogen, hi an alternative embodiment, Q3 is hydrogen and Q2 is halogen, preferably chloro.
- Ql is OH and R a and Rb are each hydrogen.
- Ql is NH2 and R a and Rb are each hydrogen.
- Another embodiment of the invention is directed to compounds of the formula (IV):
- R a is hydrogen and Rb is C ⁇ _ 5 linear alkyl.
- Q2 and Q are hydrogen.
- Q3 is hydrogen and Q2 is halogen, preferably chloro.
- Another embodiment of the present invention includes a compound which is selected from the title compounds of the following Examples and pharmaceutically acceptable salts thereof.
- alkyl by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., Ci- 10 alkyl means an alkyl group having from one to ten carbon atoms).
- Preferred alkyl groups for use in the invention are C .Q alkyl groups, having from one to six carbon atoms.
- Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
- alkenyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond and the number of carbon atoms designated (e.g., C2-10 alkenyl means an alkenyl group having from two to ten carbon atoms).
- Preferred alkenyl groups for use in the invention are C2-6 alkenyl groups, having from two to six carbon atoms.
- Exemplary alkenyl groups include ethenyl and propenyl.
- alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon triple bond and the number of carbon atoms designated (e.g., C2-10 alkynyl means an alkynyl group having from two to ten carbon atoms).
- Preferred alkynyl groups for use in the invention are C2-6 alkynyl groups, having from two to six carbon atoms.
- Exemplary alkenyl groups include ethynyl and propynyl.
- cycloalkyl by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., C3-8 cycloalkyl means a cycloalkyl group having from three to eight carbon atoms).
- exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- halo or “halogen” includes fluoro, chloro, bromo and iodo.
- the substituent may be bonded to a ring carbon atom of the heteroaryl group, or on a heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits substitution.
- a heteroatom i.e., a nitrogen, oxygen or sulfur
- the substituent is bonded to a ring carbon atom.
- the point of attachment may be at a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment.
- the attachment is at a ring carbon atom.
- the compounds of the instant invention have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule.
- Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
- racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
- the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
- the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
- the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
- the racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
- any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
- the compounds claimed in this invention can be prepared according to the following general procedures. Scheme 1 outlines the synthesis of amino alcohols 5 and 40 and amino azides 6. Treatment of commercially available ketone 43 with excess methyl magnesium bromide, followed by Boc deprotection gives amino alcohol 40.
- enantiopure amino esters 1 Starting from commercially available enantiopure amino esters 1, the amine is Boc protected and the ester hydrolyzed to give acid 2. Alternatively, commercially available enantiopure amino acids may be Boc protected using Schotten-Baumann conditions. EDC coupling of 2 with Weinreb' s amine generates the Weinreb amide 3. Treatment of the Weinreb amide with organometallic reagents gives ketones 4. The ketones are then reduced to give a diastereomeric mixture of alcohols 5a. The individual diastereomers of 5a are either treated directly with HCl to give amino alcohol 5b or treated with hydrazoic acid under Mitsunobu conditions to generate the desired azide.
- the alcohol can be mesylated and displaced with sodium azide. Removal of the Boc group with HCl gives the amino azide 6.
- the Weinreb amide is reduced with lithium aluminum hydride and then treated with an organometallic to give alcohols with opposite anti diastereoselection. Boc removal as before provides the final amines of formula type 5b.
- Scheme 3 outlines the synthesis of tr ⁇ s-methyl cyclopropylmethylamine 14.
- the benzyl amide is generated via EDC coupling. Cyclopropanation using diazomethane and palladium acetate gives the trans-cyclopropane amide 13.
- Reduction with borane delivers the desired amine 14, which is used as an amine coupling partner in Scheme 4 below.
- Further elaboration of 14 via amide coupling, borane reduction and hydrogenation of the benzyl group gives substituted amines of type 40 which are also used as coupling partners in Scheme 4.
- reductive animation of 14 and aldehyde followed by hydrogenation generates amines of type 42.
- Scheme 4 demonstrates a general route to acids of type 19, 20, 21.
- the sulfonamide is coupled to methyl dichloroisonicotinate 15 using palladium catalyzed conditions.
- Ester 16 is then coupled to an amine (which, as an example, can include either 10 or 14) using different palladium catalyzed conditions to give 17.
- R 2 is a benzyl group
- hydrogenation effectively removes the benzyl group to give 18.
- Saponification of the ester gives acid 19.
- alkylation of 18 using KHMDS and an alkyl halide introduces a second alkyl group prior to saponifaction to give dialkyl aminopyridine acids of type 19.
- Scheme 5 demonstrates the preparation of acids of type 20a from dimethyl 5-aminoisophthalate via sulfonylation followed by alkylation, hydrolysis, amide coupling and hydrolysis.
- final example compounds of type 20b can be prepared through incorporation of the R group as the final step following a sequence from dimethyl-5-bromoisophthalate involving first mono hydrolysis, followed by amide coupling, hydrolysis, a second amide coupling and a fnal Pd(0) catalyzed cross-coupling with an appropriate amide.
- Acid of type 21 is prepared from dimethyl 5-iodoisophthalate via Pd (0) coupling, hydrolysis, amide coupling and a final hydrolysis.
- final example compounds of the invention of type 22 and 23 can be prepared through installation of the R2 biaryl as the final step following a sequence involving first monohydrolysis, followed by amide coupling, hydrolysis, a second amide coupling and a final Suzuki Pd(0) catalyzed cross-coupling.
- Acid of type 27 may be prepared via first alkylation of phenol 24 followed by conversion of the methyl ester to a bromomethyl functionality to give access to intermediate 25.
- the cyano-cycloalkyl group is introduced via TMS-CN and the necessary dibromoalkane. Subsequent cyclopropanation followed by hydrolysis provides desired acid 27.
- the preparation of acid 31 relies on similar methodology regarding the R7 -bearing side chain and a Curtius rearrangement for the introduction of R NS02R4.
- Scheme 7 illustrates two alternative preparations of acid of type 33.
- the first preparation relies on conversion of the methyl ester to an aldehyde and a Wittig coupling to install the R8-bearing alkene.
- the second preparation is based on an indenium/palladium coupling strategy.
- Scheme 8 depicts a final assembly of examples of type 36 and 38.
- Amide coupling of acids of type ' A-H' with amines of type 5b gives compounds of the general formula 36.
- Amide coupling of acids of type ' A-H' with amines of type 6 gives the azide 37, which after hydrogenation with palladium on carbon generates amines of the general formula 38.
- treatment with N-chlorosuccinimide or SelectFluorTM gives the 3-chloro or fluoro pyridine derivative 43 preferentially.
- substantially pure means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N -dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- the present invention is directed to the use of the compounds disclosed herein as inhibitors of ⁇ - secretase enzyme activity or ⁇ -site amyloid precursor protein-cleaving enzyme ("BACE") activity, in a patient or subject such as a mammal in need of such inhibition, comprising the administration of an effective amount of the compound.
- BACE ⁇ -secretase enzyme
- ⁇ -site amyloid precursor protein- cleaving enzyme and “BACE” are used interchangeably in this specification, hi addition to humans, a variety of other mammals can be treated according to the method of the present invention.
- the present invention is further directed to a method for the manufacture of a medicament or a composition for inhibiting ⁇ -secretase enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
- the compounds of the present invention have utility in treating, ameliorating, controlling or reducing the risk of Alzheimer' s disease.
- the compounds may be useful for the prevention of dementia of the Alzheimer' s type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer' s type.
- the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ - secretase.
- diseases include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
- the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom inhibition of ⁇ -secretase enzyme activity is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which inhibition of ⁇ -secretase enzyme activity or treatment of the above noted disorders is desired.
- the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone.
- the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention.
- Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention.
- the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention.
- the combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
- combinations of the compounds of the present invention with other drugs in either unit dose or kit form include combinations with: anti-Alzheimer's agents, for example other beta- secretase inhibitors or gamma-secretase inhibitors; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonists; neuronal nicotinic agonists
- composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- compositions in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Other pharmaceutical compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
- compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be formulated according to the known art, or may be administered in the form of suppositories for rectal administration of the drug.
- the compounds of the present invention may also be administered by inhalation, by way of inhalation devices known to those skilled in the art, or by a transdermal patch.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- administering should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful fonn and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
- oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
- injectable dosage forms such as IV, IM, or IP, and the like
- transdermal dosage forms including creams, jellies, powders, or patches
- buccal dosage forms inhalation powders, sprays, suspensions, and the like
- rectal suppositories rectal suppositories.
- an effective amount or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- treatment refers to the treatment of the mentioned conditions, particularly in a patient who demonstrates symptoms of the disease or disorder.
- treatment means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
- controlling includes preventing, treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
- the compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person adminstering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
- Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
- compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person adminstering the drug to the patient.
- kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
- the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 80 mg, 100 mg, 150 mg, 300 mg and 500 mg.
- Pharmaceutical compositions of the present invention may be provided in a formulation comprising about 0.5 mg to 1000 mg active ingredient; more preferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient.
- Specific pharmaceutical compositions useful for treatment may comprise about 1 mg, 5 mg, 10 mg, 30 mg, 80 mg, 100 mg, 150 mg, 300 mg and 500 mg of active ingredient.
- FRET Assay A homogeneous end point fluorescence resonance energy transfer (FRET) assay is employed with the substrate ([TAMRA-5-CO-EEISEVNLDAEF-NHQSY] QFRET), which is cleaved by BACE 1 to release the fluorescence from TAMRA.
- the Km of the substrate is not determined due to the limit of solubility of the substrate.
- a typical reaction contains approximately 30 nM enzyme, 1.25 ⁇ M of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 ⁇ l.
- the reaction is proceeded for 30 min and the liberation of TAMRA fragment is measured in a 96-well plate LJL Analyst AD using an excitation wavelength of 530 nm and an emission wavelength of 580 nm. Under these conditions, less than 10% of substrate is processed by BACE 1.
- the enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system.
- solutions of inhibitor in DMSO four concentrations of the inhibitors are prepared: lmM, 100 ⁇ M, 10 ⁇ M, 1 ⁇ M) are included in the reactions mixture (final DMSO concentration is 0.8%). All experiments are conducted at room temperature using the standard reaction conditions described above.
- HPLC assay A homogeneous end point HPLC assay is employed with the substrate (coumarin- CO-REVNFEVEFR), which is cleaved by BACE 1 to release the N-terminal fragment attached with coumarin.
- the Km of the substrate is greater than 100 ⁇ M and can not be determined due to the limit of solubility of the substrate.
- a typical reaction contains approximately 2 nM enzyme, 1.0 ⁇ M of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 ⁇ l.
- the reaction is proceeded for 30 min and the reaction is stopped by the addition of 25 ⁇ L of 1 M Tris-HCl, pH 8.0.
- the resulting reaction mixture is loaded on the HPLC and the product is separated from substrate with 5 min linear gradient. Under these conditions, less than 10% of substrate is processed by BACE 1.
- the enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system.
- the errors in reproducing the dissociation constants are typically less than two-fold.
- the compounds of the following examples had activity in inhibiting the beta- secretase enzyme in the aforementioned assays, generally with an IC50 from about 1 nM to 100 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the beta- secretase enzyme activity.
- Step A Ketone preparation To a solution of N-Boc-phenylalanine-Weinreb amide (2.19 g, 7.10 mmol) in 50 mL Et 2 0 cooled to
- nBuLi (15.5 mL, 24.86 mmol, 1.6 M in hexane) dropwise, via syringe. After stirring at -78 °C for 3 h, an additional 10 mL nBuLi was added and the reaction mixture was stirred at -78 °C for 1 h.
- reaction mixture was partitioned between water and EtOAc, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo, combined with a previous 440 mg tert-butyl (lS)-l-benzyl-2-oxohexylcarbamate probe reaction, and purified by flash chromatography (300 g silica, 0 -> 30% EtOAc/hexanes, then repeat on mix: 165 g silica, 10 ->
- reaction mixture was stirred at room temperature for 8 h, combined with a previous 250 mg tert-butyl (lS,2R)-l-benzyl-2-hydroxyhexylcarbamate probe reaction, concentrated in vacuo, and purified by flash chromatography (120 g silica, 0 -> 50% EtOAc/hexanes) to afford tert-butyl (1S,2R)-1- benzyl-2-hydroxyhexylcarbamate and tert-butyl (lS,2S)-2-azido-l-benzylhexylcarbamate as a white solid.
- step B involving Michael addition using dimethyl amine (vida infra).
- Step A To a solution of N-Boc-phenylalanine-Weinreb amide (10.0 g, 32.4 mmol) in 200 mL THF cooled to -40 °C was added vinyl magnesium bromide (97.0 mL, 97.0 mmol, 1.0 M in THF) dropwise. After stirring at -40 to -20°C for 5 h.
- Step B In a flask containing tert-butyl (lS)-l-benzyl-2-oxobut-3-enylcarbamate (0.75 g, 2.72 mmol) in MeOH (lOmL) was added dimethyl amine (2.73 mL, 2.0 M MeOH, 5.45 mmol). The mixture was stirred at rt for lh. The mixture was concentrated to dryness to give tert-butyl (lS)-l-benzyl-4-(dimethylamino)- 2-oxobutylcarbamate which was used in the next reaction without further purification.
- Step C In a 50mL flask containing ketone (825mg, 2.57 mmol) from step B in 25mL of EtOH at room temperature was added NaBH (92mg, 2.57 mmol) in two portions. The mixture was stirred overnight and lmL of H 2 0 added. The reaction was concentrated to dryness and partitioned between EtOAc and H 2 0. The layers were separated and the aqueous layer extracted once again. The combined organic layers were washed with brine, dried over Na 4 S0 and concentrated to dryness to give crude tert-butyl (lS,2RS)-l-benzyl-4-(dimethylamino)-2-hydroxybutylcarbamate. * H NMR indicated a mixture of alpha and beta diastereomers. The crude material was deprotected in step D below without further purification.
- Step D A scintillation vial containing tert-butyl (lS,2RS)-l-benzyl-4-(dimethylamino)-2- hydroxybutylcarbamate (250mg, 0.78 mmol) in EtOAc was cooled to 0 °C. HCl (g) was gently bubbled into the mixture for ca. lmin. The vial was sealed with a cap and allowed to warm to rt. After 30min.
- Step A Epoxide opening tert-Butyl[(lS)-l-oxiran-2-yl-2-phenylethyl]carbamate (l.Og, 3.8 mmol), potassium fluoride hydrogen fluoride (0.59g, 7.6 mmol) and N,N,N-tributylbutan-l-aminium fluoride dihydrofluoride (0.06g, 0.19 mmol) in chlorobenzene (2.0 mL) was heated to 120 °C for 16 hours. The reaction was cooled to ambient temperature, diluted with methylene chloride, filtered through celite and evaporated in vacuo.
- Step A Coupling In a 100-mL flask acrylic acid (0.17 g, 2.4 mmol), ⁇ -benzyl-l-(2-trans-methylcyclopropyl)methanamine (0.5 g, 2.4 mmol) and DIPEA (0.64 g, 4.9 mmol) were dissolved in 20 mL of dichloromethane. To this solution at room temperature EDC (0.68 g, 3.5 mmol) was added as a solid portionwise and stirred 15 hours. The reaction was partitioned between IM HCl and methylene chloride. The organics were dried over sodium sulfate, filtered, concentrated in vacuo and carried into next reaction crude.
- N 1 -benzyl-N 3 ,N 3 -dimethyl-N 1 -[(2-methylcyclopropyl)-methyl]- ⁇ -alaninamide (0.47 g, 1.7 mmol) was dissolved in 10 mL anhydrous THF.
- BH 3 -THF 5.1 mmol, 5.1 mL of a IM solution in THF.
- the reaction was equipped with a reflux condenser and heated to reflux for 16 hours.
- the reaction was cooled to 0 °C and quenched with methanol followed by concentrated HCl (5 mL). The resulting mixture was heated to reflux for 16 hours.
- Step A Grignard Addition
- a solution of Boc-3-amino-4-phenyl-2-butanone (0.5g, 1.9 mmol) in 100 mL methylene chloride was cooled to -78 °C and treated with methyl magnesium bromide (1.39mL of a 3.0M solution, 4.2 mmol).
- the reaction was warmed to ambient temperature and stirred for 14 hours.
- the reaction was charged with additional methyl magnesium bromide (1.39mL of a 3.0 M solution, 4.2 mmol) and stirred at ambient temperature for 5 hours.
- the reaction was quenched with ammonium chloride solution and partitioned between water and ethyl acetate.
- Step A Reductive Amination A solution of N-benzyl-l-(2-trans-methylcyclopropyl)methanamine hydrochloride (5.0g. 23.6 mmol ' ) and formaldehyde (19.0g, 640 mmol) in 60 mL dichloroethane and 30 mL methanol was treated with sodium triacetoxyborohydride (lO.Og. 47.3 mmol). The reaction was stirred at ambient temperature for 1 hour.
- Step A Epoxide opening hi a flask charged with NaH (60% dispersion, 0.26 g, 34.1 mmol) in EtOH at 0 °C was added tert- Butyl[(lS)-l-oxiran-2-yl-2-phenylethyl]carbamate (3.0g, 11.3 mmol) and the reaction allowed to warm to rt and stir overnight. Aqueous NH C1 (3-5 mL) was added slowly, the reaction stirred for 30 min. and then concentrated to dryness. The crude product was partitioned between EtOAc and water. The organic layer was isolated and washed with brine and dried over Na 2 S0 .
- Step B Mesy late formation To a lOOmL flask containing a CH 2 C1 2 (60 mL) solution of tert-butyl [(lS,2S)-l-benzyl-3-ethoxy-2- hydroxypropyljcarbamate (3.0 g, 9.7 mmol) and mesyl chloride (0.75 mL, 9.7 mmol) was added TEA (1.48 mL, 10.6 mmol) dropwise at rt. The resulting mixture was stirred for 30 min. and then poured onto water.
- Step A employed DMF as solvent and 3 equiv of phenol as nucleophile.
- Step A employed DMF as solvent and 3 equiv of alcohol as nucleophile.
- Step B Rh(I) catalyzed Michael addition A 20 mL Personal chemistry microwave vial charged with 3-chlorophenyl boronic acid (1.13 g, 7.26 mmol), vinyl ketone from step A (1.00 g, 3.63 mmol), r c-BINAP (203 mg, 0.33 mmol) and Rh(acac) 2 (CH 2 CH 2 ) z (56 mg, 0.22 mmol) were sealed and put under an argon atmosphere. To this mixture 16.0 mL degassed dioxane was added. After 15 min. 4.0 mL H 2 0 was added and the contents heated in microwave at 110 °C for 120 min.
- Step C-E Reduction, Mitsunobu HN 3 inversion and Boc removal
- Crotonaldehyde (23.64 mL, 285.35 mmol), triethyl orthoformate (57.02 mL, 342.42 mmol) and ammonium nitrate (2.28 g, 28.54 mmol) were combined in 60 mL EtOH. After 22 h at ambient temperature, the reaction was diluted with EtOAc (60 mL) and washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (40 mL), dried over Na 2 S0 , filtered and concentrated in vacuo to give 36.5 g (89%) of l,l-diethoxybut-2-ene.
- Step B diisopropyl (4S,5S)-2-[(lE)-prop-l-enyl]-l,3-dioxolane-4,5-dicarboxylate
- (2E)-l,l-diethoxybut-2-ene 32.20 g, 223.27 mmol
- (-)-diisopropyl D-tartrate 64.64 mL, 245.60 mmol
- pyridinium tosylate (2.24 g, 8.93 mmol) in 100 mL benzene was heated to 95 °C to distill off the solvent and EtOH produced. After 7 h at 95 °C, the reaction was cooled to rt and concentrated in vacuo.
- Step C diisopropyl (4S,5S)-2-[(lS,2S)-2-methylcyclopropyl]-l,3-dioxolane-4,5-dicarboxylate
- IM diethylzinc was added in 60 mL hexanes (42.96 mL, 42.96 mmol).
- Diiodomethane (6.92 mL, 85.92 mmol) was added dropwise with vigorous stirring. After 1 h at -20 °C, the reaction was refrigerated at -5 °C. After 17 h at -5 °C, the reaction was stirred at 0 °C for an additional 5 h and then quenched with cold saturated ammonium chloride solution (100 mL) and extracted with Et 2 0 (100 mL x 3). The combined organics were washed w/ aqueous sodium thiosulfate (100 mL) and brine (100 mL), filtered, dried over Na 2 S0 , filtered again and concentrated in vacuo.
- Step D 2-methyl-N- ⁇ (lE)-[(lS,2S)-2-methylcyclopropyl]methylidene ⁇ propane-2-sulfinamide
- ⁇ -toluenesulfonic acid 0.071 g, 0.38 mmol
- Step E 2-methyl-N- ⁇ (lS)-l-[(lS,2S)-2-methylcyclopropyl]ethyl ⁇ propane-2-sulfmamide
- 2-methyl-N- ⁇ (lE)-[(lS,2S)-2-methylcyclo ⁇ ropyl]methylidene ⁇ propane-2- sulfinamide (0.300 g, 1.60 mmol) in 5 mL CH 2 Cl 2 as added 3M methylmagnesium bromide in Et 2 0 (1.07 mL, 3.20 mmol).
- Et 2 0 1.07 mL, 3.20 mmol
- Methyl 2,6-dichloroisonicotinate (5.0g, 24.3 mmol), methyl(methylsulfonyl)amine (3.18g, 29.12 mmol), potassium phosphate (7.22g, 34.0 mmol), Xantphos (0.87g, 1.50 mmol) and tris(dibenzylideneacetone)dipalladium (0.68g, 0.51 mmol) were added to a dry, argon flushed flask.
- Step A and B Cross-coupling and Saponification.
- Step C Amide coupling. hi a 500 mL flask containing 2'-cyano-5-(methoxycarbonyl)-l,l'-biphenyl-3-carboxylic acid (3.0 g, 10.6 mmol) from step B, N-methyl-butylamine (1.39g, 16.0 mmol), HOAt (1.45 g, 10.6 mmol) in CH 2 C1 2 was added EDC-HC1 (3.06 g, 16.0 mmol) at rt. After stirring overnight the reaction was poured onto 0.1 ⁇ HCl, extracted with CH 2 C1 2 (3x75mL) and the combined extracts washed with brine, dried over ⁇ a 2 S0 and concentrated in vacuo.
- Step A To a stirred solution of dimethyl 5-hydroxyisophthalate (8.6 g, 41.1 mmol) in 200 mL of acetone was added K 2 C0 3 (5.7 g, 41.1 mmol) and trans-crotyl bromide (5.5 g, 41.1 mmol). The resulting mixture was stirred at reflux for 16 h. The solids were removed by filtration and the filtrate was evaporated to near dryness. The resulting residue was dissolved in 200 mL of ether and washed 3 x 20 mL of IN HCl then brine. The organic extracts were dried over MgS0 and evaporated to give aryl ether A.
- Step B A 0°C solution containing 9.4 g (35.6 mmol) of the isophthalate from step A in 300 mL of a 1: 1 mixture of THF and MeOH was treated with 35.6 mL (35.6 mmol) of IN ⁇ aOH. The ice bath was allowed to stir to ambient temperature over 16 h. The reaction mixture was concentrated to ca. 1/8 volume before it was acidified with 25 mL of 3N HCl. The solids that precipitated were redissolved in 300 mL of EtOAc and washed with brine (2 x 25 mL).
- Step E To a solution of the benzyl carbamate (3.6 g, 10.0 mmol) from step D and 1.5 g of 10 % Pd/C in EtOAc (100 mL) was stirred at room temperature under a balloon of hydrogen gas for 5 h. The mixture was filtered through a pad of Celite, concentrated, and purified on silica gel (50 % EtOAc / Hexanes) to afford the desired aniline.
- Step F To a 0°C solution of the aniline from step E (940 mg, 4.0 mmol) in 30 mL of CH 2 C1 2 and 5 mL of pyridine was added methanesulfonyl chloride (0.40 mL, 4.0 mmol).
- Step G The sulfonamide from step F (1.25 g, 4.0 mmol) in DMF (20 mL) was treated with 95 % sodium hydride (106 mg, 4.4 mmol) and excess methyl iodide (3 mL).
- Step A Amide formation A solution of acid intermediate A (35 mg, 0.112 mmol), amine intermediate I (28mg, 0.134 mmol), N,N- diisopropylethylamine (36mg, 0.28 mmol), and HOAT (15mg, 0.112 mmol) in methylene chloride (1.5 mL) was treated with EDC (32mg, 0.168 mmol). After stirring 2 hours at ambient temperature the solution was partitioned between water/methylene chloride. The organics were washed with IN HCl followed by brine.
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Priority Applications (5)
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AU2004311749A AU2004311749A1 (en) | 2003-12-19 | 2004-12-15 | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
US10/582,856 US7550481B2 (en) | 2003-12-19 | 2004-12-15 | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
EP04814367.1A EP1697308B1 (en) | 2003-12-19 | 2004-12-15 | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease |
CA002548849A CA2548849A1 (en) | 2003-12-19 | 2004-12-15 | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease |
JP2006545405A JP2007517781A (en) | 2003-12-19 | 2004-12-15 | Phenylamide and pyridylamide β-secretase inhibitors for the treatment of Alzheimer's disease |
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JP (1) | JP2007517781A (en) |
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AU (1) | AU2004311749A1 (en) |
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Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6161794A (en) * | 1993-01-17 | 1994-08-15 | Schering Corporation | Peptides having anti-hiv activity |
JP2002037731A (en) * | 2000-05-19 | 2002-02-06 | Takeda Chem Ind Ltd | beta-SECRETASE INHIBITOR |
PE20020276A1 (en) | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | SUBSTITUTE AMINE COMPOUNDS AS ß-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER |
EP1186305A1 (en) | 2000-09-07 | 2002-03-13 | Schering Aktiengesellschaft | New brominated compounds as contrast media for X-ray mammography |
US20060100196A1 (en) | 2001-09-24 | 2006-05-11 | Andrea Gailunas | Substituted amines for the treatment of alzheimer's disease |
AR039555A1 (en) * | 2001-11-08 | 2005-02-23 | Upjohn Co | N, N'-SUBSTITUTED DERIVATIVES OF 1,3-DIAMINO-2-HYDROXIPROPANE |
AR037460A1 (en) * | 2001-11-30 | 2004-11-10 | Smithkline Beecham Plc | HYDROXYETHYLENE COMPOUND, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT, USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND PROCEDURE FOR PREPARATION |
US7160905B2 (en) * | 2001-11-30 | 2007-01-09 | Smithkline Beecham P.L.C. | Hydroxyethylene compounds with Asp2 inhibitory activity |
EP1458745A2 (en) | 2002-01-04 | 2004-09-22 | Elan Pharmaceuticals, Inc. | SUBSTITUTED AMINO CARBOXAMIDES FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
MXPA04008317A (en) | 2002-02-27 | 2005-06-08 | Upjohn Co | Substituted hydroxyethylamines. |
US7132568B2 (en) | 2002-06-17 | 2006-11-07 | Sunesis Pharmaceuticals, Inc. | Aspartyl protease inhibitors |
CA2498269A1 (en) | 2002-09-10 | 2004-03-25 | Pharmacia & Upjohn Company Llc | Substituted aminoethers for the treatment of alzheimer's disease |
ATE443043T1 (en) | 2002-11-12 | 2009-10-15 | Merck & Co Inc | PHENYLCARBOXAMIDE AS A BETA-SECRETASE INHIBITOR FOR THE TREATMENT OF ALZHEIMER'S |
GB0228410D0 (en) * | 2002-12-05 | 2003-01-08 | Glaxo Group Ltd | Novel Compounds |
CA2512111A1 (en) | 2003-01-07 | 2004-07-29 | Merck And Co., Inc. | Macrocyclic beta-secretase inhibitors for treatment of alzheimer's disease |
GB0305918D0 (en) | 2003-03-14 | 2003-04-23 | Glaxo Group Ltd | Novel compounds |
WO2005005374A1 (en) | 2003-06-16 | 2005-01-20 | Sunesis Pharmaceuticals, Inc. | Aspartyl protease inhibitors |
JP2007516207A (en) | 2003-06-30 | 2007-06-21 | メルク エンド カムパニー インコーポレーテッド | N-alkylphenylcarboxamide β-secretase inhibitors for the treatment of Alzheimer's disease |
CA2530006A1 (en) | 2003-07-01 | 2005-01-20 | Merck & Co., Inc. | Phenylcarboxylate beta-secretase inhibitors for the treatment of alzheimer's disease |
CN1835936A (en) | 2003-08-14 | 2006-09-20 | 默克公司 | Macrocyclic beta-secretase inhibitors for the treatment of alzheimer's disease |
CA2540452A1 (en) | 2003-10-03 | 2005-04-14 | Merck & Co., Inc. | Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer's disease |
JP4576386B2 (en) | 2003-11-24 | 2010-11-04 | メルク・シャープ・エンド・ドーム・コーポレイション | Benzyl ether and benzylamino β-secretase inhibitors for the treatment of Alzheimer's disease |
-
2004
- 2004-12-15 EP EP04814367.1A patent/EP1697308B1/en active Active
- 2004-12-15 US US10/582,856 patent/US7550481B2/en active Active
- 2004-12-15 WO PCT/US2004/042173 patent/WO2005065195A2/en active Application Filing
- 2004-12-15 JP JP2006545405A patent/JP2007517781A/en active Pending
- 2004-12-15 CA CA002548849A patent/CA2548849A1/en not_active Abandoned
- 2004-12-15 CN CNB2004800380630A patent/CN100537523C/en not_active Expired - Fee Related
- 2004-12-15 AU AU2004311749A patent/AU2004311749A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of EP1697308A4 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1697308A2 (en) | 2006-09-06 |
EP1697308B1 (en) | 2014-03-19 |
WO2005065195A3 (en) | 2006-04-06 |
US20070142634A1 (en) | 2007-06-21 |
CN1898199A (en) | 2007-01-17 |
US7550481B2 (en) | 2009-06-23 |
EP1697308A4 (en) | 2007-08-22 |
CA2548849A1 (en) | 2005-07-21 |
JP2007517781A (en) | 2007-07-05 |
AU2004311749A1 (en) | 2005-07-21 |
CN100537523C (en) | 2009-09-09 |
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