JP2010510309A - Compounds useful for the treatment of neurodegenerative disorders - Google Patents

Abstract

  The present invention provides compounds that are useful for treating or reducing the severity of neurodegenerative disorders. The invention also provides a method of treating or reducing the severity of such a disorder comprising administering to a patient a compound of the invention or composition thereof. The method is useful, for example, for treating Alzheimer's disease or reducing its severity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a US patent application Ser. No. 11/434, filed May 16, 2006, claiming priority of US Provisional Application No. 60 / 681,662, filed May 17, 2005. No. 726, a continuation-in-part application (these are incorporated herein by reference).

  The present invention relates to pharmaceutically active compounds useful for treating or reducing the severity of neurodegenerative disorders.

  The central role of long forms of amyloid β peptide, specifically Aβ (1-42), in Alzheimer's disease has been established by various histopathological, genetic, and biochemical studies. Selkoe, DJ, Physiol. Rev. 2001, 81: 741-766, Alzheimer's disease: genes, proteins, and therapy, and Youngkin SG, J Physiol Paris. 1998, 92: 289-92, The role of A beta 42 in Alzheimer's disease. Specifically, Aβ (1-42) deposition in the brain has been found to be an early invariant feature of all forms of Alzheimer's disease. In fact, this occurs before Alzheimer's disease can be diagnosed and before Aβ (1-40), the shorter major form of A-β, is deposited. Parvathy S et al., Arch Neurol. 2001, 58: 2025-32, Correlation between Abetax-40-, Abetax-42-, and Abetax-43-containing amyloid packets and cognitive deline. Another involvement of Aβ (1-42) in the pathogenesis of the disease is that mutations in the presenilin (γ-secretase) gene with early-onset familial Alzheimer's disease uniformly increase Aβ (1-42) levels. Derived from the observation that it brings. Ishii K et al., Neurosci Lett. 1997, 228: 17-20, Increased A beta 42 (43)-place deposition in early-onset family Alzheimer's disease in the height of the population. That. Further mutations in the amyloid precursor protein APP increase total Aβ, and in some cases only Aβ (1-42). Kosaka T et al., Neurology, 48: 741-5, The beta APP717 Alzheimer's mutation in the properties of plasma amidid-beta protein ending at A bet. Various APP mutations can affect the type, amount, and location of deposited AP, but the predominant early deposited species in the brain parenchyma has been found to be long Aβ (Mann) . Mann DM et al., Am J Pathol. 1996, 148: 1257-66, Predominant deposition of amyloid-beta 42 (43)

  In the early deposit of Aβ, if the majority of the deposited protein is in the form of amorphous or scattered plaque, Aβ is substantially all long. Gravina SA et al., J Biol Chem, 270: 7013-6, Amyloid beta protein (A beta) in Alzheimer's disease brain. Biochemical and immunochemical analysis with antibodies specific for endending at A beta 40 or A beta 42 (43); Iwatsubo T et al., Am Jol. 1996, 149: 1833-30, Full-length amyloid-beta (1-42 (43)) and amino-terminally modified and transduced amyloid-beta 42 (43) deposit in diff Acer A, N USA. 1993, 90: 10836-40, beta-Amyloid- (1-42) is a major component of cerebral amyloidal deposit deposits: reference for implications for the pathology of Alzheimer. These initial depositions of Aβ (1-42) can then result in subsequent deposition of both long and short forms of Aβ. Tamoka A et al., Biochem Biophys Res Commun. 1994, 205: 834-42, Biochemical evidence for the long-tail form (A beta 1-42 / 43) of amyloid beta protein as a seed molecular in cerebral deposit.

  In transgenic animals expressing Aβ, deposition was accompanied by elevated levels of Aβ (1-42), but the pattern of deposition was that Aβ (1-42) was deposited early, followed by Aβ (1-40). ) Is similar to the pattern seen in human disease. Rockenstein E et al., J Neurosci Res. 2001, 66: 573-82, Early formation of maturity amyloid-beta protein deposits in a mutant APP transgenetic model dependents on lens of bers; Refer to Amyloid deposits in transgenic messicating human beta-amyloid precursor protein the the like characteristics as this in Alzheimer's. Similar deposition patterns and timing are seen in Down syndrome patients with increased Aβ expression and accelerated deposition. Iwatsubo T et al., Ann Neurol. 1995, 37: 294-9, Amyloid beta protein (A beta) deposition: A beta 42 (43) Precedes A beta 40 in Down syndrome.

  Thus, selective reduction of Aβ (1-42) reduces the potential to form all forms of Aβ amyloid, delays or stops the formation of new deposits of Aβ, It has emerged as a disease-specific method for inhibiting the formation of Aβ, thereby delaying or stopping the progression of neurodegeneration.

  As described herein, the present invention provides compounds that are useful for treating or reducing the severity of neurodegenerative disorders. The present invention also provides a method of treating or reducing the severity of such disorders comprising administering to a patient a compound of the present invention or composition thereof. The method is useful, for example, for treating Alzheimer's disease or reducing its severity.

Is a diagram showing the ¹ H NMR spectrum of the fraction sat14-9 and satl4-10 chromatography. It is a diagram showing the ¹ H NMR spectrum of the fraction sat14-11 and sat14-12 chromatography. FIG. 2 shows ¹ H NMR spectra of chromatographic fractions satl5-1 and at15-2. Is a diagram showing the ¹ H NMR spectrum of the fraction sat15-4 and sat15-5 chromatography. FIG. 4 is an enlarged view of C15 reverse phase HPLC chromatogram separation of sat15-5 (where the numbers 1-5 correspond to the time windows of fractions sat16-1 to sat16-9). Is a diagram showing the ¹ H NMR spectrum of the fraction sat16-3 corresponding to compound 6 98% pure. It is a flowchart figure which shows the outline | summary of the isolation protocol 2. FIG. 5 shows an HPLC trace of a black cohosh extract after semi-preparative HPLC. FIG. 5 shows an HPLC trace of Compound 6 showing a small deacyl peak. FIG. 5 shows an HPLC trace of Compound 6. 2 is a diagram showing a mass spectrum of deacyl-compound 6. FIG. FIG. 2 shows ¹ H NMR of deacyl-compound 6. FIG. 5 shows an HPLC trace of Compound 6. ¹ is a diagram showing ¹ H NMR (CD ₃ OD) of Compound 6. FIG. 4 is a diagram showing a mass spectrum of compound 6. FIG. FIG. 5 shows an HPLC trace of compound 6 isolated according to protocol 2 and detected at 205 nm. FIG. 5 shows an HPLC trace of compound 6 isolated according to protocol 2 and detected at 230 nm. It is a figure which shows HPLC of the compound 6 detected by ELSD. FIG. 5 shows a ¹ H NMR spectrum of compound 6 isolated according to protocol 2. FIG. 5 shows a mass spectrum of compound 6 isolated according to protocol 2. The effect of compound 6 on the relative amounts of amyloid β (1-40), (1-42), (1-37), (1-38), and (1-39) as determined by IP-MS FIG. Amyloid β (1-40), (1-42), (1-37), (1-38), and (1-38) in wild-type and 717-mutant cells of compound 6, as determined by IP-MS It is a figure which shows the effect which it has on the quantity of 39).

1. General description of the compounds of the invention:
According to one embodiment, the present invention provides a compound of formula I:

またはその医薬上許容される塩
［式中、
環Ａ、環Ｂ、環Ｃ、環Ｄ、および環Ｅは、各々独立して、飽和、部分不飽和、または芳香族であり、
Ｇは、Ｓ、ＣＨ_２、ＮＲ、またはＯであり、
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、Ｎ（Ｒ）_２、または適宜保護されたアミノ基であるか、あるいはＲ^１とＲ^２が一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜７員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｒは、各々独立して、水素、所望により置換されたＣ_１〜６脂肪族基、あるいは所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環であり、
ここで、同じ窒素原子上の２つのＲが前記窒素原子と所望により一緒になって、窒素、酸素、または硫黄から独立して選択された１〜４個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環を形成し、
ｎは０〜２であり、
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適宜保護されたアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され、
ｍは０〜２であり、
Ｒ^５は、Ｔ−Ｃ（Ｒ’）_３、Ｔ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適宜保護されたアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であるか、あるいは
Ｒ^５がＴ−Ｃ（Ｒ’）_３またはＴ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３である場合、Ｒ^６とＲ^５のＲ’基とは所望により一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｔは、各々独立して、原子価結合、あるいは所望により置換された直鎖または分枝状の飽和または不飽和のＣ_１〜６アルキリデン鎖であり、ここで、Ｔのメチレン単位は２個まで、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−によって所望によりかつ独立に置換され、
Ｒ’およびＲ”は、各々独立して、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され、
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり、
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択され、あるいはＲ^１とＲ^２とは一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜７員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｑは、原子価結合、あるいは所望により置換された直鎖または分枝状の飽和または不飽和のＣ_１〜６アルキリデン鎖であり、ここで、Ｑのメチレン単位は２個まで、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−によって所望によりかつ独立に置換され、
Ｒ^１０は、Ｒ、適宜保護されたヒドロキシル基、適宜保護されたチオール基、適宜保護されたアミノ基、所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する３〜８員の飽和単環式環、部分不飽和単環式環、またはアリール単環式環、所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する８〜１０員の飽和二環式環、部分不飽和二環式環、またはアリール二環式環、検出可能な部分、ポリマー残基、ペプチド、あるいは糖含有または糖様部分である］
を提供する。

Or a pharmaceutically acceptable salt thereof [wherein
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
Are R ¹ and R ² each independently a halogen, R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, N (R) ₂ , or an appropriately protected amino group? Or R ¹ and R ^{2 taken} together to form a 3-7 membered saturated, partially unsaturated ring, or aryl having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forming a ring,
Each R independently represents 0 to 4 heteroatoms independently selected from hydrogen, optionally substituted C _1-6 aliphatic groups, or optionally substituted nitrogen, oxygen, or sulfur; A 3- to 8-membered saturated, partially unsaturated, or aryl ring having
Wherein two R on the same nitrogen atom are optionally combined with the nitrogen atom to have a 3-8 membered having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forming a saturated, partially unsaturated or aryl ring;
n is 0-2,
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O ( Selected from CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2,
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ , or R ⁵ is TC (R ′) ₃ or TC When (R ′) ₂ C (R ″) ₃ , R ⁶ and R ⁵ groups of R ⁵ are optionally combined together with 0 to 2 independently selected from nitrogen, oxygen, or sulfur Forming a 3-8 membered saturated, partially unsaturated, or aryl ring having
Each T is independently a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-6 alkylidene chain, wherein T has up to 2 methylene units Optionally and independently substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2-
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ,
R ⁹ and R ⁹ ′ are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen, or sulfur Forming a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from
Q is a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-6 alkylidene chain, wherein Q has up to two methylene units, —O—, Optionally and independently substituted by -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2-
R ¹⁰ is 0 to 4 independently selected from R, optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally substituted nitrogen, oxygen, or sulfur. Independently selected from 3-8 membered saturated monocyclic ring, partially unsaturated monocyclic ring, or aryl monocyclic ring, optionally substituted, nitrogen, oxygen, or sulfur 8-10 membered saturated bicyclic ring having 0-4 heteroatoms, partially unsaturated bicyclic ring, or aryl bicyclic ring, detectable moiety, polymer residue, peptide, or sugar-containing or Sugar-like part]
I will provide a.

  According to another embodiment, the present invention provides a compound of formula I:

またはその医薬上許容される塩
［式中、
環Ａ、環Ｂ、環Ｃ、環Ｄ、および環Ｅは、各々独立して、飽和、部分不飽和、または芳香族であり、
Ｇは、Ｓ、ＣＨ_２、ＮＲ、またはＯであり、
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、Ｎ（Ｒ）_２、または適宜保護されたアミノ基であるか、あるいはＲ^１とＲ^２が一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜７員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｒは、各々独立して、水素、所望により置換されたＣ_１〜６脂肪族基、あるいは所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環であり、
ここで、同じ窒素原子上の２つのＲが前記窒素原子と所望により一緒になって、窒素、酸素、または硫黄から独立して選択された１〜４個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環を形成し、
ｎは０〜２であり、
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適宜保護されたアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され、
ｍは０〜２であり、
Ｒ^５は、Ｔ−Ｃ（Ｒ’）_３、Ｔ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３、Ｒ、ＯＲ、適宜保護されたヒドロキシル基、ＳＲ、適宜保護されたチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適宜保護されたアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であるか、あるいは
Ｒ^５がＴ−Ｃ（Ｒ’）_３またはＴ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３である場合、Ｒ^６とＲ^５のＲ’基とは所望により一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜８員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｔは、各々独立して、原子価結合、あるいは所望により置換された直鎖または分枝状の飽和または不飽和のＣ_１〜６アルキリデン鎖であり、ここで、Ｔのメチレン単位は２個まで、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−によって所望によりかつ独立に置換され、
Ｒ’およびＲ”は、各々独立して、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され、
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり、
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択され、あるいはＲ^１とＲ^２が一緒になって、窒素、酸素、または硫黄から独立して選択された０〜２個のヘテロ原子を有する３〜７員の飽和環、部分不飽和環、またはアリール環を形成し、
Ｑは、原子価結合、あるいは所望により置換された直鎖または分枝状の飽和または不飽和のＣ_１〜６アルキリデン鎖であり、ここで、Ｑのメチレン単位は２個まで、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−によって所望によりかつ独立に置換されており、
Ｒ^１０は、Ｒ、適宜保護されたヒドロキシル基、適宜保護されたチオール基、適宜保護されたアミノ基；所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する３〜８員の飽和単環式環、部分不飽和単環式環、またはアリール単環式環、所望により置換された、窒素、酸素、または硫黄から独立して選択された０〜４個のヘテロ原子を有する８〜１０員の飽和二環式環、部分不飽和二環式環、またはアリール二環式環、検出可能な部分、ポリマー残基、ペプチド、あるいは糖含有または糖様部分である。
ただし、前記化合物が

Or a pharmaceutically acceptable salt thereof [wherein
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
Are R ¹ and R ² each independently a halogen, R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, N (R) ₂ , or an appropriately protected amino group? Or R ¹ and R ^{2 taken} together to form a 3-7 membered saturated, partially unsaturated ring, or aryl having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forming a ring,
Each R independently represents 0 to 4 heteroatoms independently selected from hydrogen, optionally substituted C _1-6 aliphatic groups, or optionally substituted nitrogen, oxygen, or sulfur; A 3- to 8-membered saturated, partially unsaturated, or aryl ring having
Wherein two R on the same nitrogen atom are optionally combined with the nitrogen atom to have a 3-8 membered having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forming a saturated, partially unsaturated or aryl ring;
n is 0-2,
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O ( Selected from CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2,
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ , or R ⁵ is TC (R ′) ₃ or TC When (R ′) ₂ C (R ″) ₃ , R ⁶ and R ⁵ groups of R ⁵ are optionally combined together with 0 to 2 independently selected from nitrogen, oxygen, or sulfur Forming a 3-8 membered saturated, partially unsaturated, or aryl ring having
Each T is independently a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-6 alkylidene chain, wherein T has up to 2 methylene units Optionally and independently substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2-
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ,
R ⁹ and R ⁹ ′ are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ^{2 taken} together are from nitrogen, oxygen, or sulfur Forming a 3-7 membered saturated, partially unsaturated, or aryl ring having independently selected 0-2 heteroatoms;
Q is a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-6 alkylidene chain, wherein Q has up to two methylene units, —O—, Optionally and independently substituted by -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2-
R ¹⁰ is R, optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group; 0-4 independently selected from optionally substituted nitrogen, oxygen, or sulfur Independently selected from 3-8 membered saturated monocyclic ring, partially unsaturated monocyclic ring, or aryl monocyclic ring, optionally substituted, nitrogen, oxygen, or sulfur 8-10 membered saturated bicyclic ring having 0-4 heteroatoms, partially unsaturated bicyclic ring, or aryl bicyclic ring, detectable moiety, polymer residue, peptide, or sugar-containing or The sugar-like part.
Provided that the compound is

以外であることを条件とする］
を提供する。

On condition that it is not]
I will provide a.

2. Definition:
Compounds of the present invention include those described generally above, but are further exemplified by the embodiments, sub-embodiments, and species disclosed herein. In this specification, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry, Part 5”. B. and March, J.A. Edit, John Wiley & Sons, New York: 2001, the contents of which are incorporated herein by reference.

As defined generally above, Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic. It should be understood that the compounds of the present invention can be considered as chemically possible compounds. Thus, if any of ring A, ring B, ring C, ring D, and ring E is unsaturated, some substituents on the ring must satisfy the general rules for valence. Those skilled in the art will understand that it does not exist. For example, when ring D is unsaturated in the bond between ring D and ring E, R ⁶ is not present. Alternatively, when ring D is unsaturated in the bond between ring D and ring C, R ⁸ and R ³ are not present. All saturated and unsaturated combinations of ring A, ring B, ring C, ring D, and ring E are all contemplated by the present invention. Thus, the requirement that R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^{9 ′} , and QR ¹⁰ , respectively, is present or absent is an atom To meet the general rules of valence, and depending on the degree of saturation or unsaturation of any of ring A, ring B, ring C, ring D, and ring E.

  As described herein, compounds of the present invention may be optionally substituted with one or more substituents, such as those described generally above or specific for the present invention. By classes, subclasses, and species. It should be understood that the phrase “optionally substituted” is used synonymously with the phrase “substituted or unsubstituted”. In general, the term “substituted” means the replacement of a hydrogen group of a given structure with a group of a specified substituent, whether or not preceded by the term “optionally”. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and more than one position in any given structure can be If it can be substituted with more than one selected substituent, the substituents may be the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically possible compounds.

  As used herein, the term “stable” when exposed to conditions permitting production, detection, preferably recovery, purification, and use for one or more of the purposes disclosed herein. A compound that is not substantially altered is meant. In some embodiments, the stable or chemically possible compound is maintained at a temperature of 40 ° C. or lower for at least 1 week in the absence of moisture or other highly reactive conditions. A compound that is substantially unchanged.

As used herein, the term “aliphatic” or “aliphatic group” is a straight chain (ie, unbranched) or branched that is fully saturated or contains one or more unsaturated units. Substituted or unsubstituted hydrocarbon chains, or fully saturated or containing one or more unsaturated units but not aromatic (herein “carbocycle”, “alicyclic” Or alternatively referred to as “cycloalkyl”) means a monocyclic or bicyclic hydrocarbon having only one point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocycle” or “cycloalkyl”) is fully saturated or includes one or more unsaturated units but is not aromatic and is a molecule. is a bond to the remainder only one point, wherein said bicyclic any monocyclic C ₃ individual ring has 3-7 members -C ₈ hydrocarbon or bicyclic C ₈ -C ₁₂ ring system Means hydrocarbon. Suitable aliphatic groups include linear or branched substituted or unsubstituted alkyl groups, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl, alkenyl groups, alkynyl groups, and These hybrids can be mentioned but are not limited to these. In other embodiments, the aliphatic group contains 2 geminal hydrogen atoms, an oxo (divalent carbonyl oxygen atom = O) such as -O- (straight or branched alkylene or alkylidene) -O-, or Substitution with ring-forming substituents can form acetals or ketals.

  In some embodiments, examples of aliphatic groups include ethynyl, 2-propynyl, 1-propenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, vinyl (ethenyl), allyl, isopropenyl, methyl , Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neo-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, sec-hexyl, cyclohexyl, 2-methyl Examples include, but are not limited to, pentyl, tert-hexyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,3-dimethylbutyl, and 2,3-dimethylbut-2-yl.

  The terms “haloalkyl”, “haloalkenyl”, and “haloalkoxy” mean alkyl, alkenyl, or alkoxy, optionally substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I. Such “haloalkyl”, “haloalkenyl”, and “haloalkoxy” groups can have more than one halo substituent, which can be, or can be, the same halogen. It may or may not be on the same carbon atom. Examples include chloromethyl, periodomethyl, 3,3-dichloropropyl, 1,3-difluorobutyl, trifluoromethyl, and 1-bromo-2-chloropropyl.

  As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” are non-aromatic in which one or more ring members are independently selected heteroatoms. Means a monocyclic, bicyclic or tricyclic ring system of the family. In some embodiments, a “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has 3 to 14 ring members and one or more ring members Is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term “heteroatom” refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (the oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or Substitutable nitrogens of the formula ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in N-substituted pyrrolidinyl) 1 Means one or more.

  As used herein, the term “unsaturated” means that the moiety has one or more units of unsaturation.

  As used herein, the term “alkoxy” or “thioalkyl” means an alkyl group as defined above attached to the carbon backbone through an oxygen (“alkoxy”) atom or a sulfur (“thioalkyl”) atom. To do.

  The term “aryl” used alone or as part of a larger moiety such as “aralkyl”, “aralkoxy” or “aryloxyalkyl” means that at least one ring in the system is aromatic and each By monocyclic, bicyclic, and tricyclic ring systems, the ring contains 3-7 ring members and has a total of 5-14 ring members. The term “aryl” can be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as defined herein below.

  The term “heteroaryl” used alone or as part of a larger moiety such as “heteroaralkyl” or “heteroarylalkoxy” means that at least one ring in the system is aromatic and at least one in the system Monocyclic, bicyclic, and tricyclic rings containing one or more heteroatoms, each ring in the system containing 3-7 ring members, and a total of 5-14 ring members The ring system of The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like) or a heteroaryl group (including heteroaralkyl and heteroarylalkoxy and the like) can include one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group, _{halogen; N 3, CN, R °} ; OR °; SR °; 1,2- methylene - dioxy; 1,2-ethylenedioxy Phenyl (Ph) optionally substituted at R °; —O (Ph) optionally substituted at R °; (CH ₂ ) _1-2 (Ph) optionally substituted at R °; Optionally substituted CH═CH (Ph); NO ₂ ; CN; N (R °) ₂ ; NR ° (O) R °; NR ° (O) N (R °) ₂ ; NR ° O ₂ R ° -NR ° R ° (O) R °; NR ° NR ° C (O) N (R °) ₂ ; NR ° NR ° CO ₂ R °; C (O) C (O) R °; C (O _{) CH 2 C (O) R} °; CO 2 R °; C (O) R °; C (O) N (R °) 2; OC (O) N (R °) 2; S (O) 2 R °; _SO 2 N ( _{°) 2; S (O)} R °; NR ° SO 2 N (R °) 2; NR ° SO 2 R °; C (= S) N (R °) 2; C (= NH) -N (R °) ₂ ; or (CH ₂ ) _0-2 NHC (O) R °, where each time R ° appears independently, hydrogen, optionally substituted C _1-6 aliphatic, 5-6 Selected from membered unsubstituted heteroaryl or heterocyclic rings, phenyl, O (Ph), or CH ₂ (Ph), or, despite the above definitions, R ° is on the same or different substituents. When appearing independently, 3 to 8 members having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, together with the atoms to which each R ° group is attached. To form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring of It is. The optional substituents on the R ° aliphatic group are N ₃ , CN, NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic. group, OH, _{O (C 1 to 4 aliphatic), NO 2, CN, CO} 2 H, CO 2 (C 1~4 aliphatic), O (halo _{C 1 to 4} aliphatic), or halo _{C. 1 to 4} aliphatic (wherein each of the C _{1 to 4} aliphatic groups of R °, unsubstituted is) chosen from.

An aliphatic group, or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic group, or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of the aryl or heteroaryl group, and further below Roh ^{= O, = S, = NNHR} *, = NN (R *) 2, = NNHC (O) R *, = NNHCO 2 ( alkyl), = NNHSO ₂ (alkyl), or = NR ^* (wherein, R ^* Are each independently selected from hydrogen or optionally substituted C _1-6 aliphatic). Optional substituents on the aliphatic group of R ^* _are, NH 2, NH _{(C 1 to 4} aliphatic), _{N (C 1 to 4 aliphatic) 2, halogen, C 1 to 4} aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic), or halo (C _1-4 aliphatic) (Wherein the above _C1-4 aliphatic groups of R ^* are each unsubstituted).

Optional substituents on the nitrogen of the non-aromatic heterocyclic ring include R ⁺ , N (R ⁺ ) ₂ , C (O) R ⁺ , CO ₂ R ⁺ , C (O) C (O) R ⁺ , _{^{C (O) CH 2 C (}} O) R +, SO 2 R +, SO 2 N (R +) 2, C (= S) N (R +) 2, C (= NH) -N (R +) ₂ or NR ⁺ SO ₂ R ⁺ , where R ⁺ is hydrogen, optionally substituted C _1-6 aliphatic, optionally substituted phenyl, optionally substituted O (Ph), optionally Substituted CH ₂ (Ph), optionally substituted (CH ₂ ) _1-2 (Ph); optionally substituted CH═CH (Ph); or independently selected from oxygen, nitrogen, or sulfur A 5-6 membered unsubstituted heteroaryl or heterocyclic ring having 1 to 4 heteroatoms, Rui despite the above definitions, when R ⁺ is appearing two independently on the same substituent or different substituents, taken together with the atoms to which R ⁺ group is bound, respectively, nitrogen, oxygen, Or a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-4 heteroatoms independently selected from sulfur. The optional substituents on the R ⁺ aliphatic group or phenyl ring are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, _{O (C 1 to 4 aliphatic), NO 2, CN, CO} 2 H, CO 2 (C 1~4 aliphatic), O (halo _{C 1 to 4} aliphatic), or halo _{(C 1 to 4} Aliphatic) (wherein each of the above C _1-4 aliphatic groups of R ⁺ is unsubstituted).

As described in detail above, in some embodiments, two independently appearing R ° (or R ⁺ , or any other variable as defined herein) are each associated with a variable. Together with the atoms present, a 3-8 membered cycloalkyl ring, heterocyclyl ring, aryl ring, or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Form. As an example of a ring in which two independently appearing R ° (or R ⁺ , or any other variable as defined herein) are formed together with the atom to which each variable is attached. Is bonded to the same atom below, and together with that atom forms a ring, for example N (R °) ₂ (both appearing R ° together with the nitrogen atom, piperidine -1-yl, piperazin-1-yl, or morpholin-4-yl group), two independently appearing R ° (or R ⁺ , or any other variable as defined herein) ), And b) bonded to different atoms and together with both of them form a ring, for example OR ° where two phenyl groups appear.

で置換され、これらの２個出現するＲ°はそれらが結合している酸素原子と一緒になって、６員の酸素含有縮合環：

These two occurrences of R ° are taken together with the oxygen atom to which they are attached to form a 6-membered oxygen-containing fused ring:

を形成する独立に２個出現するＲ°（またはＲ^＋、または本明細書に同様に定義する他の任意の変数）が挙げられるが、これらに限定されない。独立に２個出現するＲ°（またはＲ^＋、または本明細書に同様に定義する他の任意の変数）が、変数がそれぞれ結合している原子と一緒になる場合、様々な他の環が形成され得ること、上記に詳述する例に限定されるものではないことを理解されたい。

^Including , but not limited to, two independently appearing R ° (or R ⁺ , or any other variable as defined herein). When two independently appearing R ° (or R ⁺ , or any other variable as defined herein) together with the atom to which each variable is attached, various other rings It should be understood that they can be formed and are not limited to the examples detailed above.

As used herein, the term “detectable moiety” is used interchangeably with the term “label” and relates to any detectable moiety, such as a primary label and a secondary label. Primary labels such as radioisotopes (eg, ³² P, ³³ P, ³⁵ S, or ¹⁴ C), mass tags, and fluorescent labels are signal generating reporter groups that can be detected without further modification.

  As used herein, the term “secondary label” refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. In the case of biotin, the second intermediate includes a streptavidin-enzyme conjugate. In the case of an antigen label, the second intermediate includes an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because the process of non-radiative fluorescence resonance energy transfer (FRET) transfers energy to another group and the second group generates a detected signal.

  As used herein, the terms “fluorescent label”, “fluorescent dye”, and “phosphor” refer to moieties that absorb light energy at defined excitation wavelengths and emit light energy at different wavelengths. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 60 633, Alexa Fluor 633, AlexA Fluor 633, AlexA Fluor 633, AlexA Fluor 633, AlexA Fluor 633 , AMCA-S, BODIPY dye (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581 / 591B And BODIPY 650/665 , Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), cascade blue, cascade yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, and Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4 ′ , 5′-dichloro-2 ′, 7′-dimethoxy-fluorescein, DM-NERF, eosin, erythrocin, fluorescein, FAM, hydroxycoumarin, IRDye (IRD40, IRD 700, and IRD 800), JOE, lysaminerhodamine B, Marina Blue, Methoxycoumarin, Naphtofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6 Rhodamine Green, Rhodamine Red, Rhodol Green, 2 ′, 4 ′, 5 ′, 7′-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Examples include, but are not limited to, Red-X.

  As used herein, the term “mass tag” means any portion that can be uniquely detected based on its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include N- [3- [4 ′-[(p-methoxytetrafluorobenzyl) oxy] phenyl] -3-methylglyceronyl] isonipecotic acid, 4 ′-[2,3,5,6. Electrophoretic emission tags such as -tetrafluoro-4- (pentafluorophenoxyl)] methylacetophenone, and derivatives thereof. The synthesis and utility of these mass tags is described in US Pat. Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602. 273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. Not. A wide variety of neutral and charged organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100-2000 Daltons) can also be used as mass tags.

  As used herein, the term “substrate” means any material or polymer composite to which a functionalized end group of a compound of the invention can be attached. Examples of commonly used substrates include glass surfaces, silica surfaces, plastic surfaces, metal surfaces, surfaces that include metal or chemical coatings, membranes (eg, nylon, polysulfone, or silica), microbeads (eg, , Latex, polystyrene, or other polymers), porous polymer matrices (eg, polyacrylamide gels, polysaccharides, or polymethacrylates), and polymer complexes (eg, proteins, or polysaccharides). It is not limited.

  Unless otherwise stated, structures shown herein are inclusive of all isomers of the structure (eg, enantiomers, diastereomers, and geometric (or conformational) isomers), for example, stereoisomers for each asymmetric center. It is also meant to include configurations R and S, double bond isomers (Z) and (E), and conformers (Z) and (E). Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

  Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Further, unless otherwise stated, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically labeled atoms. For example, compounds having this structure except that hydrogen is replaced with deuterium or tritium, or carbon is replaced with ¹³ C- or ¹⁴ C-labeled carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes for bioassays.

3. Description of exemplary compounds:
As defined generally above, G moiety of formula I is _S, CH 2, NR or O,. In some embodiments, the G moiety of formula I is O.

As defined generally above, R ¹ and R ² of formula I are each independently halogen, R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol group, N (R ) ₂ , or an appropriately protected amino group, or R ¹ and R ^{2 taken} together have 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forms a 7-membered saturated, partially unsaturated, or aryl ring. In some embodiments, R ¹ and R ² of formula I are each independently R or OR. In other embodiments, R ¹ and R ² of formula I are each independently R, wherein R is hydrogen or an optionally substituted C _1-6 aliphatic group. According to another aspect of the present invention, R ¹ and R ² of formula I are taken together, 3-6 members having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A saturated ring, a partially unsaturated ring, or an aryl ring. Yet another aspect of the present invention provides a compound of formula I, wherein R ¹ and R ² together form a 3-6 membered saturated carbocyclic ring. In other embodiments, R ¹ and R ² of formula I are taken together to form a cyclopropyl ring.

  In some embodiments, the n moiety of formula I is 0-1. In other embodiments, the n moiety of formula I is 1.

As defined generally above, ^{R 5} group of formula I is ^{R 5, T-C (R} ') 3, T-C (R') 2 C (R ") 3, R, OR , Optionally protected hydroxyl group, SR, optionally protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , appropriately protected amino group, NR (CO) R, NR (CO) (CO ) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ Wherein T is each independently a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-6 alkylidene chain, wherein the methylene unit of T is 2 to pieces, -O -, - N (R ) -, - S -, - C (O) -, - S (O) -, or -S _{(O) 2} - optionally in the Li Kui independently are substituted. In some embodiments, T are each independently a valence bond, or a linear or branched C _{1 to 4} alkylidene chain wherein the T One methylene unit is optionally substituted with -O-, -N (R)-, or -S- In other embodiments, each T is independently a valence bond, or a straight chain. Or a branched C _1-4 alkylidene chain, In yet another embodiment, each T is a valence bond.

When the R ⁵ group of formula I is TC (R ′) ₃ or TC (R ′) ₂ C (R ″) ₃ , R ′ and R ″ are each independently R, OR, _{SR, SO 2 R, OSO 2} R, N (R) 2, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) OR, (CO) Selected from OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ . In some embodiments, R ′ and R ″ are each independently R, OR, OC (O) R, SR, or N (R) _{2. In} other embodiments, R ′ and R ′. Each independently represents R, OR, or OC (O) R. Examples of R ′ and R ″ groups include hydrogen, CH ₃ , OH, and OC (O) CH ₃ .

As defined generally above, when R ⁵ is TC (R ′) ₃ or T—CH (R ′) C (R ″) ₃ , R ⁶ and the R ′ group of R ⁵ are Together, if desired, form a 3-8 membered saturated, partially unsaturated ring, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In such embodiments, R ⁵ is TC (R ′) ₃ or TC (R ′) ₂ C (R ″) ₃ , and R ⁶ and the R ′ group of R ⁵ are taken together. To form a 5- to 7-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In other embodiments, R ⁵ is TC (R ′) ₃ or TC (R ′) ₂ C (R ″) ₃ , and R ⁶ and the R ′ group of R ⁵ are taken together. To form a 6-membered saturated ring having one oxygen atom, such compounds where, when T is a valence bond, Formula IIa (when R ⁵ is TC (R ′) ₃ ) and IIb (when R ⁵ is TC (R ′) ₂ C (R ″) ₃ ):

［式中、Ｒ’、Ｒ”、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^９’、Ｑ、およびＲ^１０はそれぞれ、上記で全体的に定義する通りであり、本明細書の上記で定義するクラスおよび下位クラスと同様である］
を有する。

Wherein R ′, R ″, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , R ^{9 ′} , Q, and R ¹⁰ are each defined above as a whole. And is similar to the classes and subclasses defined herein above]
Have

As defined generally above, the R ⁵ group of formula I is in particular a suitably protected hydroxyl group, a suitably protected thiol group, or a suitably protected amino group. Hydroxyl protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Further examples of suitably protected hydroxyl groups of the R ⁵ group of formula I include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. . Examples of such esters include formate, acetate, carbonate, and sulfonate. Specific examples include formic acid ester, benzoyl formic acid ester, chloroacetic acid ester, trifluoroacetic acid ester, methoxyacetic acid ester, triphenylmethoxyacetic acid ester, p-chlorophenoxyacetic acid ester, 3-phenylpropionic acid ester, 4-oxopentanoic acid Ester, 4,4- (ethylenedithio) pentanoic acid ester, pivaloate (trimethylacetyl), crotonic acid ester, 4-methoxy-crotonic acid ester, benzoic acid ester, p-benenylbenzoate, 2,4,4 6-trimethylbenzoate; and methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, vinyl, allyl, Carbonates, such as pre-p- nitrobenzyl and the like. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ether, or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy) methyl, benzyloxymethyl, β- (trimethylsilyl) ethoxymethyl, and tetrahydropyranyl ether. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl. , 2-picolyl, and 4-picolyl.

Thiol protecting groups are well known in the art and are disclosed in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Appropriately protected thiol groups of the R ⁵ moiety of formula I include, but are not limited to, disulfides, thioethers, silylthioethers, thioesters, thiocarbonates, thiocarbamates, and the like. Some examples of such groups include, but are not limited to, alkyl thioether, benzyl thioether, substituted benzyl thioether, triphenylmethyl thioether, trichloroethoxycarbonyl, and the like.

According to another aspect of the invention, the R ⁵ moiety of formula I is a thiol protecting group that can be removed under neutral conditions, such as with AgNO ₃ , HgCl ₂ , and the like. Other neutral conditions include reduction using an appropriate reducing agent. Suitable reducing agents include dithiothreitol (DTT), mercaptoethanol, dithionite, reduced glutathione, reduced glutaredoxin, reduced thioredoxin, substituted phosphines such as triscarboxyethylphosphine (TCEP), and any other peptide or organic base Reducing agents, or other reagents known to those skilled in the art. According to yet another aspect of the invention, the R ⁵ moiety of formula I is a “photocleavable” thiol protecting group. Such suitable thiol protecting groups are known in the art and include nitrobenzyl groups, tetrahydropyranyl (THP) groups, trityl groups, —CH ₂ SCH ₃ (MTM), dimethylmethoxymethyl, or —CH It includes ₂ -S-S- pyridin-2-yl, but not limited thereto. One skilled in the art will appreciate that many of the suitable hydroxyl protecting groups described herein are also suitable as thiol protecting groups.

In some embodiments, the R ⁵ group of formula I is an optionally protected amino group. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Examples of the appropriately protected amino group of the R ⁵ moiety include, but are not limited to, aralkylamine, carbamate, cyclic imide, allylamine, amide and the like. Examples of such groups are t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl and the like. In some embodiments, the amino protecting group of the R ⁵ moiety is phthalimide. In yet another embodiment, the amino protecting group of the R ⁵ moiety is a tert-butyloxycarbonyl (BOC) group.

As defined generally above, the Q group of formula I is a valence bond or an optionally substituted straight or branched saturated or unsaturated C _1-4 alkylidene chain, wherein , Q up to two methylene units, optionally by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. And independently substituted. In some embodiments, Q is an optionally substituted straight or branched saturated or unsaturated C _1-2 alkylidene chain, wherein Q has up to one methylene unit, —O Optionally substituted by-, -N (R)-, or -S-. In other embodiments, Q is —O—.

As defined generally above, the R ¹⁰ group of formula I is R, optionally protected hydroxyl group, optionally protected thiol group, optionally protected amino group, optionally substituted nitrogen, oxygen Or a 3-8 membered saturated monocyclic, partially unsaturated monocyclic or aryl monocyclic ring having 0-4 heteroatoms independently selected from sulfur, optionally substituted 8- to 10-membered saturated bicyclic ring, partially unsaturated bicyclic ring, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, detection Possible moieties, polymer residues, peptides, or sugar-containing or sugar-like groups.

In some embodiments, the R ¹⁰ group of formula I is a sugar-containing group. Such sugar-containing groups are well known to those skilled in the art and are described in “Essentials of Glycobiology”, Varki, A .; Et al., Cold Spring Harbor Laboratory Press. Cold Spring Harbor, N.A. Y. Those detailed in 2002 can be mentioned. In some embodiments, the R ¹⁰ group of formula I is a glycoside. Examples of R ¹⁰ groups include arabinopyranoside and xylopyranoside. In some embodiments, the R ¹⁰ group of formula I is a xylopyranoside. In some embodiments, the R ¹⁰ group of formula I is arabinopyranoside. In yet another embodiment, R ¹⁰ group of formula I

である。別の実施形態によれば、式ＩのＲ^１０基は

It is. According to another embodiment, the R ¹⁰ group of formula I is

である。さらに別の実施形態は、式Ｉの化合物（式中、Ｒ^１０は

It is. Yet another embodiment is a compound of formula I wherein R ¹⁰ is

である）を提供する。

Is).

According to another aspect of the invention, the R ¹⁰ group of formula I is a pseudosaccharide. Such pseudo sugars are well known to those skilled in the art and include those detailed in “Essentials of Glycobiology”. For example, pseudo sugar groups contemplated by the present invention include cyclitol and the like. In some embodiments, R ¹⁰ is a cyclitol moiety, wherein the cyclitol is a cycloalkane containing one hydroxyl group on each of three or more ring atoms as defined by the IUPAC convention. In other embodiments, such cyclitol moieties include inositols such as sylinositol.

Further, suitable sugar-like moieties of the R ¹⁰ group of formula I include acyclic sugar groups. Some examples of such groups include linear alkitols and erythritol. It should be understood that sugar groups can exist in cyclic or acyclic forms. Thus, an acyclic form of a sugar group is contemplated by the present invention as a suitable sugar-like moiety of the R ¹⁰ group of formula I.

In some embodiments, the R ¹⁰ group of formula I is a detectable moiety. In other embodiments, the R ¹⁰ group of formula I is a fluorescent label, fluorescent dye, or fluorophore as defined herein above.

According to another aspect of the invention, the R ¹⁰ group of formula I is a polymer residue. Polymer residues are well known in the art and are described in “Chemistry of Protein Conjugation and Cross-Linking”, Shan S .; Wong, CRC Press. Boca Raton, Florida. Those described in detail in 1991. Suitable polymer residues of the R ¹⁰ group of formula I include poly (alkylene oxides) such as PEG, poly (amino acids), and other polymer residues that can be conjugated with the compounds of the present invention.

As defined generally above, the R ¹⁰ group of formula I is, inter alia, a suitably protected hydroxyl group, a suitably protected thiol group, or a suitably protected amino group. Hydroxyl protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Examples of suitable hydroxyl protecting groups for the R ¹⁰ group of formula I further include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formate, acetate, carbonate, and sulfonate. Specific examples include formic acid ester, benzoyl formic acid ester, chloroacetic acid ester, trifluoroacetic acid ester, methoxyacetic acid ester, triphenylmethoxyacetic acid ester, p-chlorophenoxyacetic acid ester, 3-phenylpropionic acid ester, 4-oxopentane. Acid ester, 4,4- (ethylenedithio) pentanoic acid ester, pivaloate (trimethylacetyl), crotonic acid ester, 4-methoxy-crotonic acid ester, benzoic acid ester, p-benenylbenzoate, 2,4 , 6-trimethylbenzoate; methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, vinyl, allyl, and - it includes carbonates such as nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ether, or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy) methyl, benzyloxymethyl, β- (trimethylsilyl) ethoxymethyl, and tetrahydropyranyl ether. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl. , 2-picolyl, and 4-picolyl.

Thiol protecting groups are well known in the art and are disclosed in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Suitable thiol protecting groups for the R ¹⁰ moiety of formula I include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, thiocarbamates, and the like. Some examples of such groups include, but are not limited to, alkyl thioether, benzyl thioether, substituted benzyl thioether, triphenylmethyl thioether, trichloroethoxycarbonyl, and the like.

According to another aspect of the invention, the R ¹⁰ moiety of formula I is a thiol protecting group that can be removed under neutral conditions, eg, AgNO ₃ , HgCl ₂ , and the like. Other neutral conditions include reduction using an appropriate reducing agent. Suitable reducing agents include dithiothreitol (DTT), mercaptoethanol, dithionite, reduced glutathione, reduced glutaredoxin, reduced thioredoxin, substituted phosphines such as triscarboxyethylphosphine (TCEP), and any other peptide or organic based Reducing agents, or other reagents known to those skilled in the art. According to yet another aspect of the invention, the R ¹⁰ moiety of formula I is a “photocleavable” thiol protecting group. Such suitable thiol protecting groups are known in the art and include nitrobenzyl groups, tetrahydropyranyl (THP) groups, trityl groups, —CH ₂ SCH ₃ (MTM), dimethylmethoxymethyl, or —CH It includes ₂ -S-S- pyridin-2-yl, but not limited thereto. One skilled in the art will appreciate that many of the suitable hydroxyl protecting groups described herein are also suitable as thiol protecting groups.

In some embodiments, the R ¹⁰ group of formula I is an optionally protected amino group. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T., which is incorporated herein by reference in its entirety. W. Greene and P.M. G. M.M. Those detailed in Wuts, 3rd edition, John Wiley & Sons, 1999. Suitable amino protecting groups for the R ¹⁰ moiety further include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups are t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl and the like. In some embodiments, the amino protecting group of the R ¹⁰ moiety is phthalimide. In yet another embodiment, the amino protecting group of the R ¹⁰ moiety is a tert-butyloxycarbonyl (BOC) group.

  In some embodiments, the present invention is a compound of formula I, comprising:

の任意の１つ、２つ、または３つ全部、およびそれらの各立体異性体以外の化合物を提供する。

Compounds other than any one, two, or all three, and their respective stereoisomers are provided.

  As described generally above, the present invention provides compounds of formula I:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、本明細書の上記で定義するクラスおよび下位クラスで定義される）を提供する。いくつかの実施形態では、本発明は、式Ｉ−ａで示される立体化学を有する式Ｉの化合物：

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and defined in the classes and subclasses defined herein above. In some embodiments, the present invention provides a compound of formula I having the stereochemistry of formula Ia:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書で定義するクラスおよび下位クラスで定義される）を提供する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and defined in the classes and subclasses defined herein for the compound of formula I.

In some embodiments, the R ¹ and R ² groups of formula I are taken together to form a 3-7 membered having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A saturated ring, a partially unsaturated ring, or an aryl ring is formed. In other embodiments, the R ¹ and R ² groups of formula I are taken together, 3-6 membered saturated having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Form a ring. In yet another embodiment, the R ¹ and R ² groups of formula I are taken together to form a 3-6 membered saturated carbocyclic ring. According to yet another aspect of the invention, the compound of formula Ib:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）が提供される。他の実施形態では、本発明は、式Ｉ−ｃの化合物：

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I. In another embodiment, the present invention provides a compound of formula Ic:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を提供する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

As defined generally above, Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic. In some embodiments, Ring B is unsaturated and R ¹ and R ² are absent, and thus compounds of formula II:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を形成する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

  In some embodiments, the n group of formula II is 0-1 and the G group of formula II is oxygen.

  According to another aspect, the present invention provides a compound of formula II-a:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を提供する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

  In some embodiments, the n group of formula II-a is 0-1 and the G group of formula II-a is oxygen.

In other embodiments, ring B and ring D are both unsaturated, and R ¹ , R ² , and R ⁶ are absent, and thus compound I of formula III:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を形成する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

  In some embodiments, the n group of formula III is 0-1 and the G group of formula III is oxygen.

  According to another embodiment, the present invention provides a compound of formula IV:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を提供する。本明細書では、

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I. In this specification:

は単結合または二重結合を示す。

Represents a single bond or a double bond.

が二重結合を示す場合、Ｒ^６は存在しないことを当業者は理解されよう。一方、

One skilled in the art will appreciate that R ⁶ is not present when represents a double bond. on the other hand,

が単結合を示す場合、Ｒ^６は存在する。したがって、いくつかの実施形態では、

Is a single bond, R ⁶ is present. Thus, in some embodiments,

は二重結合を示し、Ｒ^６は存在しない。他の実施形態では、

Represents a double bond and R ⁶ is absent. In other embodiments,

は単結合を示し、Ｒ^６は上記に定義する通りである。

Represents a single bond and R ⁶ is as defined above.

  According to another aspect, the present invention provides a compound of formula IV-a:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）を提供する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

In some embodiments, the G group of formula IV-a is oxygen. In another embodiment, R ⁴ group of formula IV-a may, R, OR, or a suitably protected hydroxyl group. In yet another embodiment, the R ⁴ group of formula IV-a is R.

  Yet another embodiment of the present invention is a compound of formula IV-b:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）に関する。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and defined in the classes and subclasses defined herein above for compounds of formula I.

In some embodiments, the R ¹ and R ² groups of formula IV-b are taken together, 3-7 members having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A saturated ring, a partially unsaturated ring, or an aryl ring. In other embodiments, the R ¹ and R ² groups of formula IV-b are taken together to form a 3-6 membered having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A saturated ring is formed. In yet another embodiment, the R ¹ and R ² groups of formula IV-b are taken together to form a 3-6 membered saturated carbocyclic ring. According to yet another aspect of the invention, compounds of formula IV-c:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）が提供される。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

In some embodiments, the R ⁷ group of formula IV-c is —OH.

  According to yet another aspect of the invention, a compound of formula IV-d:

またはその医薬上許容される塩（式中、各変数は、上記で定義され、式Ｉの化合物に関して本明細書の上記で定義するクラスおよび下位クラスで定義される）が提供される。

Or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and is defined in the classes and subclasses defined hereinabove for compounds of formula I.

In some embodiments, the R ⁷ group of formula IV-d is —OH.

［式中：
環Ａ、環Ｂ、環Ｃ、環Ｄおよび環Ｅは、各々独立して、飽和、部分的に不飽和または芳香族であり；
Ｇは、Ｓ、ＣＨ_２、ＮＲまたはＯであり；
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、Ｎ（Ｒ）_２、または適当に保護されているアミノ基であるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒは、各々独立して、水素、置換されていてもよいＣ_１−６脂肪族基、または窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和環、部分的に不飽和の環またはアリール環であり：
同じ窒素原子上の２つのＲは、該窒素原子と一緒になって、窒素、酸素、または硫黄から独立して選択される１〜４個のヘテロ原子を有する３〜８員の飽和環、部分的に不飽和の環またはアリール環を形成してもよく；
ｎは０〜２であり；
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
ｍは０〜２であり；
Ｒ^５は、Ｔ−Ｃ（Ｒ’）_３、Ｔ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｔは、各々独立して、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｔの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよく；
Ｒ’およびＲ”は、各々独立して、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択されるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｑは、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｑの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよい］
で示される化合物またはその医薬上許容される塩を提供する。 In other embodiments, the present invention provides compounds of formula V:

[Where:
Ring A, Ring B, Ring C, Ring D and Ring E are each independently saturated, partially unsaturated or aromatic;
G is S, CH ₂ , NR or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
Q is a valence bond or an optionally substituted linear or branched, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of Q are optionally independent. And may be substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2- .
Or a pharmaceutically acceptable salt thereof.

  Specific examples described herein with respect to the compounds of formula I apply individually and in combination to the individual variables of the compounds of formula V.

  In certain embodiments, Q is —O—. In other embodiments, Q is —NH—.

［式中：
環Ａ、環Ｂ、環Ｃ、環Ｄ、および環Ｅは、各々独立して、飽和、部分的に不飽和または芳香族であり；
Ｇは、Ｓ、ＣＨ_２、ＮＲ、またはＯであり；
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、Ｎ（Ｒ）_２、または適当に保護されているアミノ基であるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒは、各々独立して、水素、置換されていてもよいＣ_１−６脂肪族基、または窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和環、部分的に不飽和の環またはアリール環であり：
同じ窒素原子上の２つのＲは、該窒素原子と一緒になって、窒素、酸素、または硫黄から独立して選択される１〜４個のヘテロ原子を有する３〜８員の飽和環、部分的に不飽和の環またはアリール環を形成してもよく；
ｎは０〜２であり；
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
ｍは０〜２であり；
Ｒ^５は、Ｔ−Ｃ（Ｒ’）_３、Ｔ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｔは、各々独立して、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｔの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよく；
Ｒ’およびＲ”は、各々独立して、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択されるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成する］
で示される化合物またはその医薬上許容される塩の製造方法であって：
（ａ）式Ｖ−ｂ：

［式中：
環Ａ、環Ｂ、環Ｃ、環Ｄ、および環Ｅは、各々独立して、飽和、部分的に不飽和または芳香族であり；
Ｇは、Ｓ、ＣＨ_２、ＮＲ、またはＯであり；
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、Ｎ（Ｒ）_２、または適当に保護されているアミノ基であるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒは、各々独立して、水素、置換されていてもよいＣ_１−６脂肪族基、または窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和環、部分的に不飽和の環またはアリール環であり：
同じ窒素原子上の２つのＲは、該窒素原子と一緒になって、窒素、酸素、または硫黄から独立して選択される１〜４個のヘテロ原子を有する３〜８員の飽和環、部分的に不飽和の環またはアリール環を形成してもよく；
ｎは０〜２であり；
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
ｍは０〜２であり；
Ｒ^５は、Ｔ−Ｃ（Ｒ’）_３、Ｔ−Ｃ（Ｒ’）_２Ｃ（Ｒ”）_３、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｔは、各々独立して、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｔの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよく；
Ｒ’およびＲ”は、各々独立して、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択されるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒ^１０は、糖含有または糖様基である］
で示される化合物またはその医薬上許容される塩を提供し：
（ｂ）式Ｖ−ｂで示される化合物を、適当な酵素で処理して、式Ｖ−ａで示される化合物を得ること；
を含む方法を提供する。 In another embodiment, the present invention provides compounds of formula Va:

[Where:
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ^{2 taken} together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from sulfur]
Or a pharmaceutically acceptable salt thereof, wherein:
(A) Formula Vb:

[Where:
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
R ¹⁰ is a sugar-containing or sugar-like group]
Or a pharmaceutically acceptable salt thereof:
(B) treating a compound of formula Vb with a suitable enzyme to obtain a compound of formula Va;
A method comprising:

  The specific examples described herein apply singly and in combination to the individual variables of the compounds of formula Va and Vb.

As used herein, the term “appropriate enzyme” can remove the R ¹⁰ sugar moiety of a compound of formula Vb to form a compound of formula Va, , Means any enzyme capable of hydrolyzing glycosidic bonds. Such enzymes are known to those skilled in the art. In certain embodiments, suitable enzymes are cellulases, xylanases, xylosidases, glycyrrhizic acid hydrolases, or glucuronidases. In certain embodiments, a suitable enzyme is cellulase. In other embodiments, the sugar moiety of the R ¹⁰ group of formula Vb is arabinopyranoside or xylopyranoside. Details of this conversion are described in the examples.

［式中、各々の可変基は、式Ｉの化合物に関する記載と同意義である］
で示される化合物またはその医薬上許容される塩を提供する。 In certain embodiments, the present invention provides compounds of formula Vc, Vd, Ve, Vf, Vg, or Vh:

[Wherein each variable is as defined for the compound of formula I]
Or a pharmaceutically acceptable salt thereof.

［式中：
環Ａ、環Ｂ、環Ｃ、環Ｄおよび環Ｅは、各々独立して、飽和、部分的に不飽和または芳香族であり；
Ｇは、Ｓ、ＣＨ_２、ＮＲまたはＯであり；
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、Ｎ（Ｒ）_２、または適当に保護されているアミノ基であるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒは、各々独立して、水素、置換されていてもよいＣ_１−６脂肪族基、または窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和環、部分的に不飽和の環またはアリール環であり：
同じ窒素原子上の２つのＲは、該窒素原子と一緒になって、窒素、酸素、または硫黄から独立して選択される１〜４個のヘテロ原子を有する３〜８員の飽和環、部分的に不飽和の環またはアリール環を形成してもよく；
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択されるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｑは、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｑの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよく；
Ｒ^１０は、Ｒ、適当に保護されているヒドロキシル基、適当に保護されているチオール基、適当に保護されているアミノ基、窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和単環、部分的に不飽和の単環、アリール単環、窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい８〜１０員の飽和二環、部分的に不飽和の二環またはアリール二環、検出可能な基、ポリマー残渣、ペプチド、または糖含有または糖様基である］
で示される化合物またはその医薬上許容される塩を提供する。 In other embodiments, the present invention provides compounds of formula VI:

[Where:
Ring A, Ring B, Ring C, Ring D and Ring E are each independently saturated, partially unsaturated or aromatic;
G is S, CH ₂ , NR or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
Q is a valence bond or an optionally substituted linear or branched, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of Q are optionally independent. And optionally substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2- .
R ¹⁰ is 0-4 independently selected from R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, nitrogen, oxygen, or sulfur. 0 to 4 independently selected from optionally substituted 3-8 membered saturated monocyclic, partially unsaturated monocyclic, aryl monocyclic, nitrogen, oxygen, or sulfur Optionally substituted 8- to 10-membered saturated bicyclic, partially unsaturated bicyclic or aryl bicyclic, detectable group, polymer residue, peptide, or sugar-containing or sugar-like group Is]
Or a pharmaceutically acceptable salt thereof.

  Specific examples described herein with respect to compounds of formula I apply singly and in combination to the individual variables of the compounds of formula VI.

［式中：
環Ａ、環Ｂ、環Ｃ、環Ｄおよび環Ｅは、各々独立して、飽和、部分的に不飽和または芳香族であり；
Ｇは、Ｓ、ＣＨ_２、ＮＲまたはＯであり；
Ｒ^１およびＲ^２は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、Ｎ（Ｒ）_２、または適当に保護されているアミノ基であるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｒは、各々独立して、水素、置換されていてもよいＣ_１−６脂肪族基、または窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和環、部分的に不飽和の環またはアリール環であり：
同じ窒素原子上の２つのＲは、該窒素原子と一緒になって、窒素、酸素、または硫黄から独立して選択される１〜４個のヘテロ原子を有する３〜８員の飽和環、部分的に不飽和の環またはアリール環を形成してもよく；
Ｒ^３、Ｒ^４、Ｒ^７、およびＲ^８は、各々独立して、ハロゲン、Ｒ、ＯＲ、適当に保護されているヒドロキシル基、ＳＲ、適当に保護されているチオール基、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、適当に保護されているアミノ基、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２から選択され；
Ｒ^６は、ハロゲン、Ｒ、ＯＲ、ＳＲ、ＳＯ_２Ｒ、ＯＳＯ_２Ｒ、Ｎ（Ｒ）_２、ＮＲ（ＣＯ）Ｒ、ＮＲ（ＣＯ）（ＣＯ）Ｒ、ＮＲ（ＣＯ）Ｎ（Ｒ）_２、ＮＲ（ＣＯ）ＯＲ、（ＣＯ）ＯＲ、Ｏ（ＣＯ）Ｒ、（ＣＯ）Ｎ（Ｒ）_２、またはＯ（ＣＯ）Ｎ（Ｒ）_２であり；
Ｒ^９およびＲ^９’は、各々独立して、ハロゲン、Ｒ、ＯＲ、ＳＲ、またはＮ（Ｒ）_２から選択されるか、あるいは、Ｒ^１およびＲ^２は、一緒になって、窒素、酸素、または硫黄から独立して選択される０〜２個のヘテロ原子を有する３〜７員の飽和環、部分的に不飽和の環またはアリール環を形成し；
Ｑは、原子価結合または置換されていてもよい直鎖または分枝鎖、飽和または不飽和Ｃ_１−６アルキリデン鎖であり、ここに、Ｑの２個までのメチレンユニットは、所望により独立して、−Ｏ−、−Ｎ（Ｒ）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−、または−Ｓ（Ｏ）_２−により置換されていてもよく；
Ｒ^１０は、Ｒ、適当に保護されているヒドロキシル基、適当に保護されているチオール基、適当に保護されているアミノ基、窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい３〜８員の飽和単環、部分的に不飽和の単環、アリール単環、窒素、酸素、または硫黄から独立して選択される０〜４個のヘテロ原子を有する置換されていてもよい８〜１０員の飽和二環、部分的に不飽和の二環またはアリール二環、検出可能な基、ポリマー残渣、ペプチド、または糖含有または糖様基である］
で示される化合物またはその医薬上許容される塩の製造方法であって：
（ａ）式ＩＶ−ａ：

［式中、各々の可変基は、式ＶＩの化合物に関する記載と同意義である］
で示される化合物またはその塩を提供すること；および
（ｂ）式ＶＩ−ａのアセチル基を除去して式ＶＩで示される化合物を得ること；
を含む方法を提供する。 In other embodiments, the present invention provides compounds of formula VI:

[Where:
Ring A, Ring B, Ring C, Ring D and Ring E are each independently saturated, partially unsaturated or aromatic;
G is S, CH ₂ , NR or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
Q is a valence bond or an optionally substituted linear or branched, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of Q are optionally independent. And optionally substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2- .
R ¹⁰ is 0-4 independently selected from R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, nitrogen, oxygen, or sulfur. 0 to 4 independently selected from optionally substituted 3-8 membered saturated monocyclic, partially unsaturated monocyclic, aryl monocyclic, nitrogen, oxygen, or sulfur Optionally substituted 8- to 10-membered saturated bicyclic, partially unsaturated bicyclic or aryl bicyclic, detectable group, polymer residue, peptide, or sugar-containing or sugar-like group Is]
Or a pharmaceutically acceptable salt thereof, wherein:
(A) Formula IV-a:

[Wherein each variable is as defined for the compound of formula VI]
And (b) removing the acetyl group of formula VI-a to obtain a compound of formula VI;
A method comprising:

  Specific examples described herein with respect to compounds of formula I apply individually and in combination to the individual variables of the compounds of formula VI-a.

  In certain embodiments, the removal of the acetyl group in step (b) is performed by treatment with a suitable base. In another embodiment, the removal of the acetyl group in step (b) is performed by heating in a suitable solvent. In yet another embodiment, the removal of the acetyl group in step (b) is performed by heating at about 40-114 ° C. In another embodiment, step (b) is performed at about 60 to about 90 ° C.

  A suitable solvent is a single solvent or solvent mixture that can facilitate the progress of the reaction. A suitable solvent can solubilize one or more reaction components, or alternatively, a suitable solvent can facilitate stirring of a suspension of one or more reaction components. . Examples of suitable solvents useful in the present invention include protic solvents, halogenated hydrocarbons, ethers, esters, aromatic hydrocarbons, polar or nonpolar aprotic solvents or mixtures thereof. Such mixtures include, for example, a mixture of protic and aprotic solvents such as benzene / methanol / water; benzene / water; DME / water and the like. In certain embodiments, a suitable solvent is a polar aprotic solvent, such as an alcohol.

  A suitable base is a reagent that is sufficiently basic to effect removal of the acetyl group of the compound of formula VI-a to form the compound of formula VI. In certain embodiments, the suitable base is the appropriate solvent itself. As an example, a methanolic solution of a compound of formula VI-a was found to be sufficiently basic to achieve removal of the acetyl group to form a compound of formula VI. It was. Details of this transformation are given in the examples below. In other embodiments, a suitable solvent is an organic base. In still other embodiments, a suitable base is an alkali or alkaline earth alkoxide or hydroxide. Such bases include sodium methoxide or sodium hydroxide. In other embodiments, the suitable base is ammonia.

［式中、各々の可変基は、式Ｉの化合物に関する記載と同意義である］
で示される化合物またはその医薬上許容される塩を提供する。 In certain embodiments, the present invention provides compounds of formula VII or VIII:

[Wherein each variable is as defined for the compound of formula I]
Or a pharmaceutically acceptable salt thereof.

［式中、各々の可変基は、式Ｉの化合物に関する記載と同意義である］
で示される化合物またはその医薬上許容される塩を提供する。 In other embodiments, the invention provides compounds of formula IX or X:

[Wherein each variable is as defined for the compound of formula I]
Or a pharmaceutically acceptable salt thereof.

Representative compounds of the present invention are shown in Table 1 below.

Representative compounds of formula IV-a and Vg are shown in Table 2 below.

4). General methods for providing the compounds:
The compounds of the invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds, and by the methods detailed in the examples below.
Isolation of active ingredients

  Several compounds of the present invention were isolated from black cohosh roots (also known as cimicifuga racemosa or actea racemosa) and the structures of these compounds were elucidated. Black cohosh root extracts, powders, and capsules are commercially available for the treatment of various menopausal and gynecological disorders. Surprisingly, however, it has been found that some compounds present in black cohosh root are useful in modulating and / or inhibiting amyloid β peptide production. Specifically, several compounds were isolated and identified from black cohosh roots. These compounds are useful in modulating and / or inhibiting amyloid β peptide production, particularly amyloid β peptide (1-42). Such compounds are encompassed by Formula I. These compounds can be isolated and utilized in a form substantially free of other compounds commonly found in roots. Alternatively, the extract can be prepared from roots, said extract being concentrated in a compound of the invention.

  As described hereinabove, some of the compounds of the invention are isolated from standard extracts of cultured or wild black cohosh roots and rhizomes. It is also contemplated that the present compounds can be isolated from plant root tissue grown during culture or from cultured plant tissue medium. Such methods of growing plant root tissue in culture are well known to those of skill in the art and are described herein by Hairy Roots, Culture and Applications, Pauline M., incorporated herein by reference in its entirety. Doran, published by Harwood Academic Publishers, Amsterdam, The Netherlands. Copyright 1997 OPA (Overseas Publishers Association) Amsterdam B.C. V. What is described in ISBN 90-5702-117-X is mentioned.

  Alternatively, the compounds of the present invention are based on other compounds found in extracts of these plants, whether from the roots and rhizomes of black cohosh and related Simifuga species, or from the aerial part. It can be prepared by a semi-synthetic method. Those skilled in the art, the synthetic precursors, but are not limited to, Cimicifuga racemosa, Cimicifuga dahurica, Cimicifuga foetida, Cimicifuga heracleifolia, Cimicifuga japonica, Cimicifuga acerina, Cimicifuga acerima, Cimicifuga simplex, and Cimicifugaelata, Cimicifuga calthaefolia, Cimicifuga frigida , Cimicifuga lacinia, Cimicifuga mairei, Cimicifuga rubifolia, Cimicifuga americana, Cimicif It will be appreciated that it can be obtained from one or more Cimicifuga species, including uga bitternata and Cimicifuga bifida or subspecies thereof. This can be achieved by chemical or biological transformation of the isolated compound, or extract fraction, or mixture of compounds. Chemical transformation can be achieved by, but is not limited to, manipulation of temperature, pH, and / or treatment with various solvents. Biological transformation treats an isolated compound, or extract fraction, or mixture of compounds with plant tissue, plant tissue extracts, other microbial organisms, or enzymes isolated from any organism However, the present invention is not limited to these.

  In some embodiments, the present invention provides black cohosh root extract comprising at least 10% by weight of a compound of the present invention. In another embodiment, the present invention provides a black cohosh root extract comprising from about 10% to about 50% by weight of a compound of the present invention. In yet another embodiment, the present invention provides an extract of black cohosh root comprising about 10% to about 50% by weight of a compound of the present invention and substantially free of actein.

  According to another embodiment, the present invention provides a compound of formula I that is substantially free of other compounds found in black cohosh roots. As used herein, the term “substantially free” means that the compound is composed of a significantly higher proportion of the compound of Formula I as compared to the compound found in black cohosh root or its extract. . In some embodiments, the present invention provides a compound of formula I in an amount of about 1 weight percent to about 99 weight percent. In some embodiments, the compound of formula I is provided in chemical purity greater than about 80%. In other embodiments, the compound of Formula I is provided with a chemical purity greater than about 90%. In other embodiments, the compound of Formula I contains no more than about 10.0 area percent HPLC of other components of black cohosh root relative to the total area of the HPLC chromatogram. In other embodiments, the compound of Formula I is about 8.0 area percent HPLC or less, and in another embodiment about 3 area percent or less other components of black cohosh root relative to the total area of the HPLC chromatogram. Containing.

を有する。 As described below, methods of determining whether a compound of the present invention is in a form substantially free of other compounds normally found in black cohosh root are known to those skilled in the art. Compounds previously isolated and identified from black cohosh root include several cycloartanols including acteol, acetylacteol, 26-deoxyacteol, shimigenol, actein, 26-deoxyactein, and shimisifgoside System triterpenes. Formononetin, (E) -isoferulic acid and isoflavone, was also isolated and identified. Representative examples of these compounds are the following structures:

Have

  Accordingly, another embodiment of the present invention is a compound of formula I substantially free of one or more of acteol, acetylacteol, 26-deoxyacteol, shimigenol, actein, 26-deoxyactein, and shimisifgoside. A compound is provided. In some embodiments, the invention provides compounds of formula I that are substantially free of actol, acetylacteol, 26-deoxyacteol, shimigenol, actein, 26-deoxyactein, and shimisifgoside.

  According to another embodiment, the present invention provides a compound having reduced amounts of one or more of acteol, acetylacteol, 26-deoxyacteol, simigenol, actein, 26-deoxyactein, and shimisifgoside. An extract of black cohosh root concentrated in a compound of I is provided. According to yet another embodiment, the present invention provides compounds of formula I wherein the amount of each of acteol, acetylacteol, 26-deoxyacteol, shimigenol, actein, 26-deoxyactein, and shimisifgoside is reduced. An extract of black cohosh root concentrated in is provided.

  Various techniques for extracting, isolating and / or purifying individual active ingredients of black cohosh root are well known in the art. The invention encompasses identifying active ingredients as described herein and incorporating such ingredients into the compositions of the invention described herein.

  Individual active ingredients of black cohosh extract can be identified as described herein and can be isolated and / or purified using any technique known in the art. . The active ingredient can be purified from any form of root itself, or in particular from a mixture of extracts of the invention or exudates of commercial extracts. Various techniques that can be used in purification include filtration, selective precipitation, extraction with organic solvents, extraction with aqueous solvents, column chromatography (silica gel), high performance liquid chromatography (HPLC), and are known to those skilled in the art. Other methods are mentioned.

  According to some embodiments, the extract uses an isolated fraction of black cohosh root. By isolated fraction is meant a minor amount of root material removed from the root itself, eg, by chromatographic means, distillation, precipitation, extraction, filtration, or otherwise. In other embodiments, root extracts and fractions are removed therefrom by chromatography, distillation, precipitation, or extraction. Such extraction and isolation techniques are well known to those skilled in the art. Some details of these techniques are described in the Examples section below.

  According to other embodiments of the present invention, the presence and purity of the active compound is determined by nuclear magnetic spectroscopy (NMR), mass spectroscopy, infrared spectroscopy (IR), UV-visible spectroscopy, to name a few cases. Evaluation by chemical methods, including elemental analysis, optical rotation analysis, and refractometry. Such analytical methods are known to those skilled in the art. In other embodiments, the chemical structure of an active compound isolated from black cohosh roots is described by NMR, mass spectroscopy, infrared spectroscopy (IR), UV-visible spectroscopy, elemental analysis, to name a few cases. , Optical rotation analysis method, refractometer method, X-ray crystal structure analysis method, etc.

  Several exemplary embodiments are described hereinabove, but are generally described according to the methods generally described above, using appropriate starting materials according to methods generally available to those skilled in the art. It should be understood that the root extract of the invention can be prepared.

5). Uses, Formulations, and Administration Pharmaceutically Acceptable Compositions According to another aspect of the present invention, optionally comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle comprising any of the compounds described herein. Pharmaceutically acceptable compositions comprising are provided. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

  It will also be appreciated that some of the compounds of the present invention may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt thereof.

  As used herein, the term “pharmaceutically acceptable salt” is used within the scope of good medical judgment and in contact with human and lower animal tissues without excessive toxicity, irritation, allergic response, etc. Means those salts corresponding to the appropriate benefit / risk ratio. A “pharmaceutically acceptable salt” is a non-toxicity of a compound of the present invention that can directly or indirectly become a pharmaceutically active metabolite or residue thereof when administered to a recipient. Or any ester salt. As used herein, the term “pharmaceutically active metabolite or residue” means that the metabolite or residue is also a pharmaceutically active compound according to the invention.

Pharmaceutically acceptable salts are well known in the art. For example, S.M. M.M. Berge et al., J. B., incorporated herein by reference. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic acids, organic acids, and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, A salt of an amino group formed using an organic acid such as succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate , Heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate , Methanesulfonate, 2-naphthalenesulfonate, nicotinic acid, nitrate, oleate, oxalate, palmitate, pamoic acid , Pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, Examples thereof include p-toluenesulfonate, undecanoate, and valerate. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternizing any basic nitrogen-containing groups of the compounds disclosed herein. By such quaternization, a water-soluble, oil-soluble or dispersible product can be obtained. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts were formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates where appropriate. Non-toxic ammonium, quaternary ammonium, and amine cations are included.

  The compositions of the present invention can further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, where any solvent, diluent, or other liquid suitable for the particular dosage form desired. Vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like can be mentioned. Remington's Pharmaceutical Sciences, 16th edition, E.I. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions, and well-known preparation techniques thereof. Any conventional carrier medium may produce any undesirable biological effect, or otherwise adversely interact with any other component of the pharmaceutically acceptable composition, etc. Except as otherwise incompatible with the compound, its use is considered to be within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include ion exchangers, serum proteins such as alumina, aluminum stearate, lecithin, human serum albumin, buffer substances such as phosphate, glycine, sorbine Acid or potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, salt or electrolyte such as water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinyl Sugars such as pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, wool fat, lactose, glucose, and sucrose; starches such as corn starch and potato starch; carboxymethyl Cellulose and its derivatives such as sodium cellulose, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; Oils, and oils such as soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free Water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, but not limited to other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring Agent, release , Coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and also antioxidants, according to the judgment of the formulator, can be present in the composition.

  The compositions provided by the present invention can be used in combination therapy. That is, the composition can be administered concurrently with, prior to, or after one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutic agents or procedures) used in the combination regimen takes into account the suitability of the desired therapeutic agent and / or procedure, and the desired therapeutic effect to be realized. The therapy used can achieve the desired effect on the same disorder (eg, a compound described herein can be administered concurrently with another therapeutic agent used to treat the same disorder) It will also be appreciated that different effects (eg, control of any side effects) can be achieved.

  For example, a known useful neurodegenerative disorder therapeutic agent can be combined with the composition of the present invention to treat a neurodegenerative disorder such as Alzheimer's disease. Examples of such well known useful neurodegenerative disorder therapeutic agents include donepezil, memantine (and related compounds such as NMDA inhibitors), Exelon®, and the like, such as acetylcholinesterase inhibitors Alzheimer's disease treatments; Parkinson's treatments such as L-DOPA / carbidopa, entacapone, lopinlol, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; β-interferons (eg, Avonex® and Rebif®) )), Copaxone®, and multiple sclerosis (MS) therapeutic agents such as mitoxantrone; riluzole, and anti-parkinsonian agents. For a more comprehensive discussion of the latest therapies useful for treating neurodegenerative disorders, see http: // www. fda. See gov's FDA Approved Drug List and Merck Manual, 17th Edition, 1999.

  In other embodiments, the compounds of the invention are combined with other therapeutic agents useful for neurodegenerative disorders such as Alzheimer's disease. Such therapeutic agents include β-secretase inhibitors, γ-secretase inhibitors, aggregation inhibitors, metal chelators, antioxidants, and neuroprotective agents.

  As used herein, the terms “combination”, “combined”, and related terms mean simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention and another therapeutic agent can be co-administered or separately in separate unit dosage forms or together in a single dosage form. Accordingly, the present invention provides a single dosage form comprising a compound of formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

  Other examples of therapeutic agents that can also be combined with the inhibitors of the present invention include asthma therapeutic agents such as albuterol and Singulair®; schizophrenia therapeutic agents such as diplexa, rispadar, seroquel, and haloperidol; cortico Anti-inflammatory agents such as steroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, And immunosuppressive agents such as sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers; beta blockers, AC Cardiovascular disease therapeutic agents such as E inhibitors, diuretics, nitrates, calcium channel inhibitors, and statins; liver disease therapeutic agents such as corticosteroids, cholestyramine, interferon, and antiviral agents; corticosteroids, anti-leukemia Examples include, but are not limited to, drugs, and blood disorder therapeutic agents such as growth factors; and immunodeficiency disorder therapeutic agents such as γ-globulin.

  The amount of additional therapeutic agent present in the composition of the present invention is below the amount that would normally be administered as a composition comprising that therapeutic agent as the only active agent. In some embodiments, the amount of additional therapeutic agent in the present composition containing that therapeutic agent as the only therapeutically active agent ranges from about 50% to 100% of the amount normally present in the composition. is there.

  In an alternative embodiment, a method of the invention that utilizes a composition that does not contain an additional therapeutic agent includes the additional step of separately administering the additional therapeutic agent to the patient. If these additional therapeutic agents are administered separately, they can be administered to the patient prior to, sequentially with, or after administration of the composition of the present invention.

  The pharmaceutically acceptable composition of the present invention is administered to humans and other animals according to the severity of the disorder to be treated, oral administration, rectal administration, parenteral administration, intracisternal administration, intravaginal administration, It can be administered as intraperitoneal administration, topical administration (by powder, ointment, drops, etc.), buccal administration, oral spray or nasal spray. In some embodiments, the subject's body weight / day, one or more daily dose levels, is about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg. These compounds of the present invention can be administered orally or parenterally to obtain the desired therapeutic effect.

  Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms are generally inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers (ethyl alcohol, isopropyl alcohol, carbonate Ethyl, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (specifically, cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil, and sesame oil) ), Fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof). In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

  Injectable preparations, for example, sterile aqueous or oily suspension injections can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, water, Ringer's solution, U.S.A. S. P. , And isotonic saline are useful. In addition, sterile, fixed oils are usually used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  The injectable preparation may be filtered using, for example, a bacteria-retaining filter, or a sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. It can be sterilized by incorporation.

  In order to prolong the effect of the compounds of the invention, it is often desirable to delay the absorption of the compound by subcutaneous or intramuscular injection. This can be done by using a liquid suspension consisting of a crystalline or amorphous material with low water solubility. At this time, the absorption rate of the compound depends on its dissolution rate, and this dissolution rate can depend on the crystal size and crystal form. Alternatively, delayed absorption of a compound in a parenteral dosage form is accomplished by dissolving or suspending the compound in an oil vehicle. Depot injectable dosage forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter or polyethylene glycol. Or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is selected from at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) starch, lactose, sucrose, Fillers or extenders such as glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) agar, Calcium carbonate, potato or tapioca starch, alginic acid, some silicic acids, disintegrants such as sodium carbonate, e) dissolution retardants such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) Cetyl alcohol and mono Humectants such as glycerol tealine, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof Mix. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents.

  Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. These solid dosage forms can optionally contain opacifiers, and can be active ingredients alone or preferentially as a composition that optionally delays release at a site in the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycols.

  The active compound can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain additional materials other than inert diluents, such as tableting lubricants such as magnesium stearate and microcrystalline cellulose, and other tableting aids in accordance with normal practice. it can. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. These can optionally contain opacifiers, and can also be compositions that release only the active ingredient or preferentially in a part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. . If required, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches that add the advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  In some embodiments, the present invention provides a compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Compositions are provided containing in an amount of 1 weight percent to about 99 weight percent. In other embodiments, the composition containing any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X is Contains no more than about 10.0 area percent other components of black cohosh root by HPLC, based on the total area of the HPLC chromatogram. In other embodiments, the composition containing any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X is Contains no more than about 8.0 area percent by HPLC, and in another embodiment no more than about 3 area percent of other components of black cohosh root, based on the total area of the HPLC chromatogram.

Use of Compounds and Pharmaceutically Acceptable Compositions The compounds of the present invention are useful for modulating and / or inhibiting amyloid β (1-42) peptide production in a patient. Accordingly, the compounds of the present invention are useful for treating or reducing the severity of disorders associated with amyloid β (1-42) peptide production in a patient.

  The compounds, extracts, and compositions according to the methods of the invention can be administered using any amount and any route of administration effective to treat or reduce the severity of a neurodegenerative disorder. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, severity of infection, the particular agent, its mode of administration, and the like.

  In some embodiments, the present invention provides a method of modulating and / or inhibiting amyloid β (1-42) peptide production in a patient comprising the steps of formula I, II, III, IV-a, IV -B, IV-c, V, VI, VII, VIII, IX, or a compound represented by X, or a pharmaceutically acceptable composition comprising said compound. In another embodiment, the present invention provides a method for selectively modulating and / or inhibiting amyloid β (1-42) peptide production in a patient comprising the steps of formula I, II, III, IV-a , IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. In yet another embodiment, the invention relates to a method of reducing amyloid β (1-42) peptide levels in a patient, wherein said patient is treated with Formula I, II, III, IV-a, IV-b, IV -Providing a method comprising administering any compound represented by c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. In another embodiment, the invention relates to a method of reducing amyloid β (1-42) peptide levels in a cell, wherein said cell is of formula I, II, III, IV-a, IV-b, IV-c. , V, VI, VII, VIII, IX, or X is provided. Another embodiment is a method of reducing amyloid β (1-42) in a cell without substantially reducing amyloid β (1-40) peptide levels in the cell, wherein the cell is of formula I, II , III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X is provided. Yet another embodiment is a method of reducing amyloid β (1-42) in a cell and increasing at least one of amyloid β (1-37) and amyloid β (1-39) in the cell, wherein the cell Is contacted with any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X.

  As used herein, the term “reducing” or “reducing” refers to the formulas I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Compared to the amount of amyloid β without administration of any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or It means the relative decrease in amyloid β realized by administering any compound represented by X. As an example, a reduction in amyloid β (1-42) is any of the formulas I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X The amount of amyloid β (1-42) in the presence of the compound is represented by formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Means less than the amount of amyloid β (1-42) in the absence of any compound.

  In yet another embodiment, the present invention provides a method for selectively reducing amyloid β (1-42) peptide levels in a patient comprising the steps of formula I, II, III, IV-a, IV− There is provided a method comprising administering any compound represented by b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method of reducing amyloid β (1-42) peptide levels without substantially reducing amyloid β (1-40) peptide levels in a patient, comprising: Any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. A method comprising administering is provided.

  In some embodiments, the invention is a method of reducing amyloid β (1-42) peptide levels and increasing at least one of amyloid β (1-37) and amyloid β (1-39) in a patient. And said patient is any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof. A method comprising administering a composition.

  As used herein, the term “increased” or “increased” with respect to the amount of amyloid β is the formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII. , IX, or X is not administered (or the cells are of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X As compared to the amount of amyloid β when not in contact with any of the compounds shown), formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or Any compound of X is administered (or the cells are of any of the formulas I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X In contact with the compound) Means the relative increase of amyloid β realized. As an example, an increase in amyloid β (1-37) is any of the formulas I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X The amount of amyloid β (1-37) in the presence of the compound is represented by the formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Means greater than the amount of amyloid β (1-37) in the absence of any compound. For example, a relative amount of either amyloid β (1-37) and amyloid β (1-39) increases production of either amyloid β (1-37) or amyloid β (1-39); Or it can be increased by reducing the production of longer amyloid β peptides, such as amyloid β (1-40) and / or amyloid β (1-42). Further, as used herein, the term “increased” or “increased” with respect to the amount of amyloid β is the formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII. It should be understood that it means the absolute increase in amyloid β achieved by administering any of the compounds designated, VIII, IX, or X. Thus, in certain embodiments, the present invention provides a method for increasing the level of absorption of at least one amyloid-beta (1-37) and amyloid-beta (1-39), comprising formulas I, II, III, IV -A, IV-b, IV-c, V, VI, VII, VIII, IX, or a method comprising administering to the patient any compound or pharmaceutically acceptable composition thereof provide. In another embodiment, the invention provides a method of increasing the level of at least one amyloid-beta (1-37) and amyloid-beta (1-39), wherein the increase is a longer amyloid-beta peptide. In relation to the amount of amyloid-beta (1-40) and / or amyloid-beta (1-42), or total amyloid-beta, for example, formulas I, II, III, IV-a, IV-b, IV -Providing a method comprising administering to the patient any compound of c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof.

  One skilled in the art will appreciate that the total proportion of amyloid β peptide is important where selective reduction of amyloid β (1-42) is particularly advantageous. In some embodiments, the compound reduces the total ratio of amyloid β (1-42) peptide to amyloid β (1-40) peptide. Accordingly, another aspect of the present invention is a method of reducing the ratio of amyloid β (1-42) peptide to amyloid β (1-40) peptide in a patient comprising the formula I, II, III, Provided is a method comprising administering any compound represented by IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. . In some embodiments, the ratio of amyloid β (1-42) peptide to amyloid β (1-40) peptide ranges from about 0.1 to about 0.4 to about 0.05 to about 0.08. Reduced to range.

  In another embodiment, the present invention provides a method of reducing the ratio of amyloid β (1-42) peptide to amyloid β (1-40) peptide in a cell, wherein the cell is of formula I, II, III, IV− There is provided a method comprising contacting with any compound of a, IV-b, IV-c, V, VI, VII, VIII, IX, or X. In some embodiments, the ratio of amyloid β (1-42) peptide to amyloid β (1-40) peptide ranges from about 0.1 to about 0.4 to about 0.05 to about 0.08. Reduced to range.

  According to one aspect, the present invention provides a method for treating or reducing the severity of a disorder associated with amyloid β (1-42) peptide, wherein said patient is treated with Formula I, II, III, IV. -A, IV-b, IV-c, V, VI, VII, VIII, IX, or a compound comprising any compound represented by X, or a pharmaceutically acceptable composition thereof is provided. Such disorders include neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Down's syndrome.

  Such disorders also include inclusion body myositis (A-beta deposition in peripheral muscles, resulting in peripheral neuropathy), cerebral amyloid angiopathy (amyloid in brain vessels), and mild cognitive impairment.

  “High A-beta42” is a symptom preceding symptomatic disease, particularly in familial patients, that can be measured based on plasma and CSF measurements and / or genetic testing. This concept is similar to the link between high cholesterol and heart disease. Thus, another aspect of the present invention is a method for the prevention of disorders associated with high amyloid-beta (1-42) peptides comprising the formulas I, II, III, IV-a, IV-b, IV-c, There is provided a method comprising administering to the patient any compound represented by V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof.

  In other embodiments, the invention provides a method for treating a disease in which A-beta amyloidosis is a fundamental aspect or symbiotic and exacerbation factor, comprising Formulas I, II, III, IV-a, IV-b, There is provided a method comprising administering to the patient any compound represented by IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof.

  In yet another embodiment, the present invention provides a method of treating a patient, comprising formulas I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Or a pharmaceutically acceptable composition thereof, wherein the disorder is associated with dementia of Lewy bodies (deposition of alpha-synuclein in cognitive neurons on Lewy bodies) L; a-synuclein is commonly associated with deposition in motor neurons and the pathogenesis of Parkinson's disease, Parkinson's disease, cataract (a-beta aggregates in eyepieces), tauopathy (eg, frontotemporal cognition Disease), Huntington's disease, ALS / Lou Gehrig's disease, type 2 diabetes (IAPP aggregates in pancreatic islets of Langerhans) ), Transthyretin amyloid disease (TTR, an example of this disease is in the myocardium involved in cardiomyopathy), prion disease (Including Creutzfeldt-Jakob disease, Gerstmann-Streisler-Scheinker syndrome, fatal familial insomnia, and Kool), and methods that are CJD.

  In another embodiment, the present invention provides a method of treating or reducing the severity of Alzheimer's disease in a patient, said patient comprising a compound of formula I, II, III, IV-a, IV-b, IV -Providing a method comprising administering any compound represented by c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof.

  Without being bound by a particular theory, it is believed that the present compounds are modulators of γ-secretase that selectively reduce amyloid β (1-42) levels. Accordingly, another embodiment of the present invention is a method of modulating γ-secretase in a patient comprising the steps of formula I, II, III, IV-a, IV-b, IV-c, V, VI , VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof. In some embodiments, the compound is an inhibitor of γ-secretase. The method is useful for treating or reducing the severity of any disorder associated with γ-secretase. Such disorders include but are not limited to neurodegenerative disorders such as Alzheimer's disease.

  The Notch / Delta signaling pathway is highly conserved across species and is widely used during vertebrate and invertebrate growth to control cell fate in the developing embryo. Giano and Fishell, “The Role of Notch in Promoting Gial and Neural Stem Cell Fates” Annu. Rev. Neurosci. 2002, 25: 471-90. Notch interacts with the gamma-secretase complex and has interactions with various other proteins and signaling pathways. Notch1 competes with amyloid precursor protein for gamma-secretase and activation of the Notch signaling pathway down regulates PS-1 gene expression. See Lleo et al., “Notch1 Competes with the Amyloid Precursor Protein for γ-Secretase and Down-regulates Presenilin-1 Gene Expression 48, Journal of Biolog. Notch receptors are processed by the action of gamma-secretase in synergy with T cell receptor signaling, thereby maintaining peripheral T cell activation. Notch 1 can directly control Tbx21 via the complex formed above with the Tbx21 promoter. Minter et al., “Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preserving notch up of ol. In vitro, gamma-secretase inhibitors abolish expression of Notch, interferon-gamma and Tbx21 in TH1-polarized CD4 + cells. In vivo administration of a gamma-secretase inhibitor substantially in a murine experimental autoimmune encephalomyelitis model of multiple sclerosis suggesting the potential use of such compounds for the treatment of TH1-mediated autoimmunity. Slows the progression of TH1-mediated diseases. Inhibition of gamma-secretase can alter intestinal cell differentiation, including lymphocyte production and germ cell metaplasia production (Wong et al., “Chronic Treatment with the γ-Secretase Inhibitor LY-411, 575 Inhibits β-Americoid Peptide Peptide and Alters Lymphopoiesis and Intestinal Cell Differentiation ", Journal of Biological Chemistry 2004, 26: 12876-12882). Milano et al., "Modulation of Notch Processing by g-Secretase Inhibitors Causes Intestinal Goblet Cell Metaplasia and Induction of Genes Known to Specify Gut Secretory Lineage Differentiation" Toxicological Sciences 2004, 82: 341-358.

  A strategy that can modify amyloid precursor protein (“APP”) processing and reduce the production of pathological forms of amyloid-beta without affecting Notch processing is highly desirable. Furthermore, as noted above, inhibition of gamma-secretase has been shown to inhibit Th cell polarization in vitro and in vivo and thus be useful in the treatment of disorders associated with Th1 cells. Th1 cells are involved in the pathology of various organ-specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and recurrent miscarriage of unknown cause, to name a few.

  According to one embodiment, the present invention relates to a method for inhibiting the formation of Th1 cells in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention includes one or more of the following: Further methods of treating autoimmune disorders, wherein the patient has the formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X Or a pharmaceutically acceptable composition comprising the compound.

  In certain embodiments, the invention provides a method of modulating and / or inhibiting amyloid-beta peptide production without affecting Notch processing, wherein the patient is treated with Formula I, II, III, IV-a. , IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition comprising the compound. .

  In certain embodiments, the present invention provides a method of inhibiting amyloid-beta (1-42) peptide production without affecting Notch processing, wherein the patient is treated with Formula I, II, III, IV-a. , IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition comprising the compound. .

  In certain embodiments, the present invention reduces amyloid-beta (1-42) peptide levels in a patient without affecting notch processing, such that at least one amyloid-beta (1-37) and amyloid-beta ( Wherein the patient has the formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X There is provided a method comprising administering any compound, or pharmaceutically acceptable composition thereof.

  Accordingly, a further aspect of the invention is a method of reducing the ratio of amyloid-beta (1-42) peptide to amyloid-beta (1-40) peptide without affecting Notch processing, comprising: Administering any compound of formula I, II, III, IV-a, IV-b, IV-c, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition thereof Providing a method comprising: In certain embodiments, the ratio of amyloid-beta (1-42) peptide to amyloid-beta (1-40) peptide ranges from about 0.1 to about 0.4, and from about 0.05 to about 0.08. Decrease to the range.

  The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression “dosage unit form” means a physically separate agent unit suitable for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of good medical judgment. The particular effective dose level for a particular patient or organism is the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the age, weight, systemicity of the patient Health status, gender, and diet; number of administrations, route of administration, and excretion rate of specific compounds used; duration of treatment; drugs used in combination with or simultaneously with specific compounds used, and similar well known in the medical field Depends on various factors such as factors. As used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

  The black cohosh extract used in the separation protocol described below was obtained as a special order from Boehringer Ingelheim Nutritionals. This extract is substantially equivalent to a USP-prepared black cohosh extract that uses about 50% aqueous ethanol to extract root powder and rhizomes, and then concentrates to near dryness.

  In the present specification, the compound numbers described below correspond to the following compounds.

Compound 1: β-D-xylopyranoside, (3,12,16,23R, 24R, 25S, 26S) -12- (acetyloxy) -16,23: 23,26: 24,25-triepoxy26-hydroxy -9,19-Cyclolanostan-3-yl.
Also known as “actein”. C37H56O11; molecular weight: 676.83; registry number 18642-44-9.

Compound 2: Simigenol 3- [beta] -D-xylopyranoside; C35H56O9, molecular weight: 620.81; registry number 27994-11-2.

Compound 3: Simigenol 3-α-L-arabinoside. C35H56O9, molecular weight: 620.81; registration number 256925-92-5.

Compound 4: 24-O-acetylhydroshengmanol 3-β-D-xylopyranoside. C37H60O11, molecular weight: 680.87; registration number 78213-32-8.

Compound 5: 24-O-acetylhydroshengmanol 3-α-L-arabinopyranoside. C37H60O11, molecular weight: 680.87.

Compound 6: 24-O-acetylhydroshengmanol 3-β-D-xylopyranoside (δ-16,17) -enol ether. C37H58O10, molecular weight: 662.85.

Compound 7: 24-O-acetylhydroshengmanol 3-α-L-arabinopyranoside (δ-16,17) -enol ether. C37H58O10, molecular weight: 662.85.

Compound 8: 24-epi-24-O-acetylhydroshengmanol 3-β-D-xylopyranoside. C37H60O11, molecular weight: 680.87.

Compound 9: 24-epi-24-O-acetylhydroshengmanol 3-β-D-xylopyranoside (δ-16,17) -enol ether. C37H58O10, molecular weight: 662.85.

Isolation protocol 1
Flash column chromatography Black cohosh extract (15.6 g) was suspended in 150 ml of methanol-water (4: 1 (v / v)) mixture at 25 ° C. The resulting slurry was stirred vigorously at this temperature for 30 minutes using a mechanical stirrer to give a brown emulsion. While continuing to stir, 51 g of silica gel (ICN silica 32-63 60Å) was added to the emulsion. Using a rotary evaporator, the mixture was concentrated in vacuo at 25 ° C. until a very homogeneous beige-brown powder was obtained. This material was subjected to silica gel column chromatography (ICN silica 32-63 60Å) using a glass column with a length of 60 cm and an internal diameter of 50 mm.

In the preparation of column chromatography, silica gel was poured into 500 ml of dichloromethane-methanol (20: 1) mixture and the resulting slurry was poured into a glass column. The silica gel is allowed to stand for 30 minutes, and a 1 cm thick sand layer is placed thereon. Subsequently, the extract absorbed on silica was poured into a dichloromethane-methanol (20: 1) mixture, and the resulting slurry was poured into the sand layer at the top of the column. The silica column was then eluted with the following solvent mixture under a pressure of 0.4 bar (argon).
1.0 ml dichloromethane-methanol (20: 1) followed by 770 ml dichloromethane-methanol (10: 1) followed by 800 ml dichloromethane-methanol (7: 1) followed by 550 ml dichloromethane-methanol (5: 1 ).

Eight 200 ml fractions (named sat14-0 to sat14-7) were collected, followed by eleven 100-ml fractions (named sat14-8 to sat14-18). All fractions were analyzed by thin layer chromatography (TLC) using Bakerflex silica plates, eluting with a dichloromethane-methanol (5: 1) solvent mixture. After development, the silica gel plate was stained with anisaldehyde staining solution. Based on the results of TLC analysis, fractions sat14-9 to sat14-12 were evaporated to dryness under vacuum at 25 ° C., and 10 mg of these fraction samples were used as a solvent in ¹ H-NMR spectroscopy using CD ₃ OD. And analyzed. See Figures 1 and 2, respectively. The spectrum was analyzed for the presence of a broad multiplet at 2.53 ppm and a 2.2 Hz doublet at 4.86 ppm. This is because these signals are characteristic of compounds 7 and 6. Furthermore, from the dqf-COSY spectra of these four samples, it was confirmed that the signals at 2.53 and 4.86 ppm actually belong to compounds 7 and 6. From the ¹ H-NMR spectrum of fraction sat14-10, it can be concluded that this sample contains the highest concentrations of compounds 7 and 6, and a slightly lower amount of these compounds is detected in fraction 14-9. I was able to. Fraction sat14-11 appeared to contain trace amounts of 7 and 6, but fraction sat14-12 failed to detect these compounds. Based on these results, fraction sat14-10 was selected and further purified by HPLC. Alternatively, fraction sat14-9 could be used to obtain additional amounts of compounds 4-7 as needed.

  The main component of the fraction sat14-10 is actein (1) (JNP 2002, 65, 601-605), which was crystallized from a methanol solution of this fraction. Reacting gave highly pure actein. The main components of fraction sat14-11 are shimigenol β-D-xylopyranoside (2) and shimigenol α-L-arabinoside (3), which crystallized as an approximately 2: 1 mixture from this fraction (JNP 2000, 65,905). -910 and 1391-1397).

C-18 Column Reversed Phase HPLC Fraction Fraction sat14-10 was dissolved in 3.5 ml methanol. This solution was analyzed on an AGILENT 1100 series HPLC system, including a SUPELCO Discovery RP-18 column (length 25 cm, internal diameter 10 mm) and an autoinjector and a diode array detector used for detection of wavelengths from 190 to 400 nm on HPLC. Fractionation using A solvent gradient was used, starting with 30% (v / v) water in methanol for the first 2 minutes, followed by a linear reduction in water content to 100% methanol in 20 minutes. After 2 minutes with 100% methanol, the water content was increased to 30% and maintained at that concentration for an additional 8 minutes. In order to separate the entire sample of sat14-10, it was necessary to inject 35 μl 100 times. Nine fractions were collected and named sat15-1 to sat15-9. See Figures 3 and 4, respectively. Compounds 4-7 were eluted in fractions sat15-1, 15-2, 15-4, and 15-5. ¹ H NMR spectra of fractions sat15-1, 15-2, 15-4, and 15-5 are shown in FIGS. 4a and 4b.

C-8 column reverse phase HPLC fractionation for isolating 6, 4, and 9 Fraction sat15-5 was dissolved in 1.5 ml methanol. This solution was fractionated on HPLC using a SUPELCO supelcosil LC-8 column (length 25 cm, internal diameter 10 mm) and the AGILENT 1100 series HPLC system described above. A solvent gradient was used, starting with 40% (v / v) water in methanol for the first 2 minutes, followed by a linear reduction in water content to 100% methanol over 20 minutes. After 2 minutes with 100% methanol, the water content was increased to 40% and maintained at that concentration for an additional 8 minutes. In order to separate the entire sample of sat15-5, it was necessary to inject 30 μl 50 times. Five fractions were collected and named sat16-1 to sat16-5 (FIG. 5). In fraction sat16-3, compound 6 was eluted, and in fraction sat16-1, compound 4 was eluted. In fraction sat15-5, a small amount of 9 with high purity was obtained. FIG. 6 shows the ¹ H NMR spectrum of 6 obtained (9.8 mg, purity 98%).

C-8 column reverse phase HPLC fractionation for isolating 8 Fraction sat15-8 was dissolved in 0.65 ml methanol. This solution was fractionated on HPLC using a SUPELCO supelcosil LC-8 column (length 25 cm, internal diameter 10 mm) and the AGILENT 1100 series HPLC system described above. A solvent gradient was used, starting with 40% (v / v) water in methanol for the first 2 minutes, followed by a linear reduction in water content to 100% methanol over 20 minutes. After 2 minutes with 100% methanol, the water content was increased to 40% and maintained at that concentration for an additional 8 minutes. Seven fractions were collected and named sat18-1 to sat18-7. Compound 8 was eluted in fraction sat18-6. NMR spectroscopy analysis including NOESY spectra showed that the methanol solution of compound 8 interconverted with the corresponding ketone. The dilute methanol solution contains about 4% ketone type and 96% hemiacetal type.

C-8 column reverse phase HPLC fractionation for isolating 7 and 5 Fraction sat15-2 was dissolved in 0.5 ml methanol. This solution was fractionated on HPLC using a SUPELCO supelcosil LC-8 column (length 25 cm, internal diameter 10 mm) and the AGILENT 1100 series HPLC system described above. A solvent gradient was used, starting with 40% (v / v) water in methanol for the first 2 minutes, followed by a linear reduction in water content to 100% methanol over 20 minutes. After 2 minutes with 100% methanol, the water content was increased to 40% and maintained at that concentration for an additional 8 minutes. Five fractions were collected and named sat19-3 to sat19-7. In fraction sat19-7, compound 7 having high purity was obtained, and in fraction sat19-5, compound 5 having high purity was obtained.

Isolation protocol 2
An alternative isolation / purification protocol for isolating compound 6 is described below. One skilled in the art will appreciate that while isolating compound 6, this method concentrates and / or isolates other compounds of the present invention. A summary of this isolation method is shown in FIG.

In this purification protocol, the following equipment was used.
(A) Hitachi HPLC system with diode array detector (DAD) (b) Nova Prep (TM) 8000 semi-preparative HPLC with PC remote controller using LC ReSponder (TM) application software
(C) Hitachi UV detector L-7400
(D) Sedex 55 evaporative light scattering (ELSD) detector (e) 75L Biotage silica column (KP-Sil; P / N FKO-1107-19073; Lot 027075L)
(F) 75L Biotage C18 column (Bakerbond, 40μ)
(G) 75S Biotage C18 column (Vydac, 40μ)
(H) Analytical HPLC column: Phenomenex Luna C18, 3μ, 4.6 × 100 mm
(I) Semi-preparative HPLC column: Phenomenex Luna C8 HPLC column, 20 x 250 mm
(J) Semi-preparative HPLC column: YMC AQ C18 HPLC column, 21.2 × 250 mm; and (k) Preparative HPLC column: ES Industries C18 preparative HPLC column; 5 × 25 cm.

The analytical method utilized to determine the purity of compound 6 is as follows.
Column: Phenomenex Luna C18, 3μ, 4.6 × 100mm
Mobile phase: 35% acetonitrile; 30% containing 0.05% acetic acid
NANOPURE water; and C.I. Isotopic elution of 35% MeOH Flow rate: 1 mL / min Detection: 205, 230 nm, DAD; and ELSD
Run time: 8 minutes Column temperature: 32 ° C
This method was used to analyze the extract, fractions, and final product. Compound 6 elutes at about 5.5 minutes under these conditions.

  50 g of crude black cohosh extract (“BCE”) was fractionated on a Biotage silica cartridge (7.5 × 30 cm). After loading, the cartridge was eluted with 5% MeOH / DCM (10 L) and 10% MeOH / DCM (5 L) and 500 ml fractions were collected. The flow rate was 150-200 ml / min. HPLC (UV at 230 nm) revealed that compound 6 was present in fractions 23 (2.6 g) and 24 (2.3 g). Fraction 23 (F23) was selected and further purified on a semi-preparative C8 column.

After 10 runs, about 10 mg of compound 6 was obtained. 50 mg of F23 dissolved in 0.3 ml of MeOH was loaded onto a Phenomenex Luna C-8 (21.2 × 250 mm, 10 μ, 100 A) semi-preparative column. The column was eluted with 70% MeOH / H ₂ O (flow rate 9.9 mL / min) with UV monitoring at 205 nm. The elution peaks at 35 and 38 minutes shown in the semi-preparative HPLC trace (Figure 8) were collected separately.

The fraction collected for the 35 minute peak in 10 runs was stored and the solvent was evaporated at ambient temperature. The obtained solid was dried with a freeze dryer to obtain 10.3 mg of Compound 6 (2609-165-7). The HPLC of the individual fractions (FIG. 10) shows only one main peak, but the HPLC of product 2609-165-7 (FIG. 9) shows a retention time (RT) of 4.5 minutes. A polar impurity peak (11.3%) was revealed. It is clear that compound 6 gradually converted to a more polar compound during the process. SSI-MS showing a strong [M + Na] ⁺ peak at m / z 643 (FIG. 11), and proton NMR of the impurity isolated at 4.5 minutes without acetylmethyl singlet (FIG. 11) As is apparent from 12), the more polar compound was found to be a deacetyl derivative of compound 6.

Several stability experiments on compound 6 suggested that deacetylation occurred in a slightly basic MeOH solution. However, it was stable with a slightly acidic solution. Therefore, 2609-165-7 was reprocessed on a Luna C8 column using 70% MeOH / 30% water containing 0.05% AcOH as eluent and 3.4 mg of compound 6 (2609- 172-11). The HPLC chromatogram of 2609-172-11 is shown in FIG. Proton NMR (in CD ₃ OD) and SSI-MS are shown in FIGS.

  In another method, 250 g of black cohosh extract (BCE) and 1250 mL of MeOH were stirred for 1 hour at room temperature in a beaker. Not all solids were dissolved, but HPLC analysis of the filtrate indicated that all compound 6 in the starting extract was dissolved (about 250 mg). Nevertheless, in a 5 L round bottom flask, the unfiltered mixture was added to 750 g of silica gel (ICN, 60-200 μ). The MeOH was removed under vacuum with a rotary evaporator to give a dry powder (weight 1100 g, residual MeOH 9%).

  BCE dried with the silica preparation was divided into 4 portions of about 270 g each. The mixture was loaded onto the SIM and washed first with 500-600 mL of methylene chloride to remove non-polar and residual MeOH. The SIM was connected to a 75 L silica column (KP-Sil; P / N FK0-1107-19073; Lot 027075 L; 7.5 × 25 cm, or 1750 mL). The main column was radially compressed at 60 psi. The system was eluted with acetone at a flow rate of 100 mL / min, and 500-1000 mL fractions were collected. After eluting compound 6, the column was washed with 1.0 L MeOH and re-equilibrated with 2 L acetone. It was observed that compound 6 eluted from the column in fractions 1 and 2 with about 900-1000 mL of acetone and then eluted primarily in fraction 3 (1000 mL). The first four runs yielded approximately 224 mg of compound 6. A second batch of starting material for silica Biotage was prepared from 100 g BCE and 500 mL MeOH and 300 g silica. Similar to the first four times of this starting material, two additional Biotage runs (5 and 6) were performed to give an additional 93 mg of compound 6. The product stock from the six runs was combined and evaporated to dryness under reduced pressure.

Dry solid (90 g) from silica Biotage was dissolved in 720 mL MeOH and 480 mL H ₂ O was added slowly with stirring. Some dark tar-like solid precipitated and was removed with a filter. The cloudy filtrate was loaded onto a 75 L (7.5 × 25 cm) Bakerbond 60Å, 40 μBiotage C18 column. After loading, the compound 6 test was negative, but the column was washed with 5 L of 60% (v / v) MeOH / H ₂ O, followed by 4 L of 70% MeOH / H ₂ O, then 4 L Of 80% MeOH / H ₂ O was used to elute compound 6. After elution, the column was washed with 2 L MeOH. The flow rate was approximately 60 mL / min throughout. In order to prevent decomposition of compound 6, the MeOH / H ₂ O mobile phase contained 0.05% acetic acid. The product stock (4 L) was concentrated under reduced pressure until essentially all MeOH was removed, and the resulting precipitated solid was collected on a Buchner funnel and dried at room temperature using a high vacuum.

A tar-like solid containing about 32 mg of compound 6, removed by filtration from the initial large C18 feed preparation, was dissolved in a 2 L MeOH wash of a large scale experiment containing about 22 mg of compound 6. The mixture was evaporated to 1 L and mixed with 0.67 L water. Some tar-like solid precipitated and was collected on a filter, dissolved in 200 mL MeOH and mixed with 134 mL water. The mixture was also filtered to remove a small amount of tar material, and the filtrate was combined with the first filtrate and loaded onto a 75S (7.5 × 9.0 cm; 400 mL) Vydac 300Å, 40 μ Biotage C18 column. The column was washed with 70% MeOH / _{H 2} O of 60% MeOH / _{H 2} O and 2L of 1L, and eluted with 80% MeOH / _{H 2} O in 1L (also containing 0.05% acetic acid mobile phase) . The product stock was evaporated and the solid was collected by filtration as in a large scale Biotage experiment.

  The initial product stock (16.69 g) from the C18 Biotage column was mixed with 70 mL MeOH. The mixture was sonicated and the precipitate was removed by filtration. The filtrate was chromatographed on an ES Industries Chromemegabond WR C18 column (5 runs, 14 mL each) using 70% MeOH / 30% water containing 0.05% AcOH as the eluent at a flow rate of 177 mL / min. Fractions of 6-14 minutes in each run are combined and evaporated to remove MeOH. The precipitate after removal of MeOH was collected by centrifugation and dried in a lyophilizer to give 6.6 g of dried solid 2609-173-16 (Compound 6, 3.2%).

  A second product stock (4.3 g) from the C18 Biotage column was processed in a similar manner to give 2.0 g of dry solid 2609-173-27 (compound 6, 3.06%). It was. 2609-173-16 and 2609-176-27 were combined to give 8.6 g of 2609-174-6.

  2609-174-6 (400 mg) was dissolved in MeOH (1.3 mL) containing 0.1% AcOH. The solution was loaded onto a Phenomenex Luna C8 column and eluted with 68% MeOH / 32% water containing 0.05% AcOH at a flow rate of 24 mL / min.

  Based on analytical HPLC, fractions from 15.8 to 19.8 minutes in each run (22 runs total) were combined, evaporated to remove MeOH, lyophilized to 2609-174-28 (1. 4 g, containing 12.6% of compound 6). Compound 6 was finally isolated on a YMC-AQ C18 column using 2609-174-28. A total of 28 runs were performed.

  2609-174-28 (50 mg) was dissolved in 0.25 mL of MeOH containing 0.1% AcOH. The solution was injected onto a YMC AQ C18 column. The column was eluted at 9.9 mL / min with 70% MeOH / 30% water containing 0.05% AcOH. Based on the analytical HPLC profile, fractions of typically 48.4-50.4 minutes were selected from 28 runs, stored, evaporated and lyophilized to give compound 6 (2609-176-30, 85 mg )

Fractions collected just before 48.4 minutes and containing mainly compound 6 were also combined and dried to give 2609-176-35 (50 mg). Using the same column and mobile phase, 2609-176-35 was reprocessed (run 3 times) to give another lot of Compound 6. This was combined with 2609-176-30 to give 102 mg of product (2609-177-10) (chromatographic purity: about 95%). The HPLC chromatogram (205, UV at 230 nm, and ELSD) and the proton NMR spectrum of compound 6 (2609-176-10) are shown in FIGS. 16, 17, 18, and 19, respectively. The proton NMR of 2609-176-10 was consistent with the proton NMR of the standard sample of compound 6. From the SSI-MS of compound 6 (FIG. 20), it was found that the strong [M + Na] ⁺ peak at m / z 685 corresponds to the molecular formula C ₃₇ H ₅₈ O ₁₀ of compound 6.

Enzymatic carbohydrate removal Compound 6 (10 mg) was dissolved in 5 mL of MeOH. Potassium phosphate buffer (50 mM, pH 6.0, 10 mL) was added to the MeOH solution. Cellulase (Sigma product # C0615, 20 mg) was dissolved in 10 mL of potassium phosphate buffer solution. The solution of compound 6 was added to the cellulase solution and the mixture was incubated at 37 ° C. for 3 days.

  The progress of the reaction was monitored by the following HPLC: An aliquot (20 μL) of the reaction mixture was added to MeOH (80 μL) containing 0.1% acetic acid (v / v). The sample was then analyzed on a 25 cm × 4.6 mm ID SUPERCOSIL LC-8 reverse phase HPLC column (5 um particle size) using a 20 min MeOH-water gradient.

After 3 days of incubation, 20 mL of CH ₂ Cl ₂ was added to the reaction mixture, which was shaken vigorously and then centrifuged at 2000 rpm for 3 minutes. The aqueous layer was removed and extracted twice more with 20 mL CH ₂ Cl ₂ . The organic layers were combined and the solvent was removed to give 9.6 mg of crude product. The crude product, a minimal volume of _20: 1 _CH 2 Cl 2 was dissolved in -MeOH, was chromatographed on a silica column eluting with the same solvent mixture. The column expansion, molybdate cesium stain _{(1% CeSO 4, 5%} (NH 4) Mo 7 O 24 · 4H 2 O (w / v) and 10% concentrated _{H 2 SO 4 (v / v} )) and 15: Monitored by TLC using 1 CH ₂ Cl ₂ -MeOH solvent mixture. Fractions containing the material with Rf of 0.26 were pooled to give compound I-16 (above, compound number in Table 1).

Deacetylation of Compound 6 Compound 6 (88% chromatographic purity) was treated with 1% ammonia to give compound I-13 (above, compound number in Table 1).
Compound 6 (88% chromatographic purity) was heated at 85 ° C. for 1 hour to give compound I-13 (compound number in Table 1 above).

Biological Assay A. Assay for Determining Ability of Compounds of Formula I to Inhibit Aβ-42 Compounds of the present invention and extracts containing said compounds can be obtained by in vitro or in vivo inhibitors of amyloid β (1-42) peptide. Can be assayed. Such assay methods are described in detail in US Pat. No. 6,649,196, which is hereby incorporated by reference in its entirety.

  The compounds of the present invention selectively reduce amyloid β (1-42) peptide according to a cell-based assay performed in substantially the same manner as described in US Pat. No. 6,649,196. It was found.

B. Assays for Determining the Ability of Compounds of Formula I to Affect the Total Aβ Ratio Compounds of the invention are prepared according to the procedure of Wang et al., J. Chem. Biol. Chem. 1996, 50: 31894-31902, The Profile of Soluble Amyloid β Protein in Cultured Cell Media was assayed using an assay protocol substantially similar to that described by Cell Media to produce amyloid β in vitro (1 -42) The effect on the total proportion of peptides was determined. This assay quantifies amyloid β protein using immunoprecipitation and mass spectrometry (IP-MS). Using compound 6 as an example, this compound was found to reduce amyloid β (1-42) peptide while increasing amyloid β (1-37) peptide and amyloid β (1-39) peptide. . These results are shown in FIG.

Compound 6 was also assayed according to the method described in Wang et al., 7W cells (APP _wt ) and 7PA2 cells (APP _V717F ). The APP ₇₁₇ mutation increases the relative amount of amyloid β (1-42) peptide. In this assay, compound 6 was found to reduce amyloid β (1-42) peptide while increasing amyloid β (1-39) peptide. These results are shown in FIG.

  While several embodiments of the present invention have been described, it is clear that basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it is to be understood that the scope of the invention is defined by the appended claims and not by the specific embodiments shown as examples.

Claims (27)

Formula I:

[Where:
Ring A, Ring B, Ring C, Ring D and Ring E are each independently saturated, partially unsaturated or aromatic;
G is S, CH ₂ , NR or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
Q is a valence bond or an optionally substituted linear or branched, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of Q are optionally independent. And may be substituted by -O-, -N (R)-, -S-, -C (O)-, -S (O)-, or -S (O) _2- .
Or a pharmaceutically acceptable salt thereof. G is O;
R ¹ and R ² are each independently R or OR.
The compound of claim 1. The compound according to claim 2, wherein R ¹ and R ² are each independently R which is hydrogen or an optionally substituted C _1-6 aliphatic group. R ¹ and R ² together are a 3-6 membered saturated, partially unsaturated ring or aryl having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur The compound according to claim 2, which forms a ring. R ⁵ is TC (R ′) ₃ or TC (R ′) ₂ C (R ″) ₃ ;
Each T is independently a valence bond or a linear or branched C _1-4 alkylidene chain, wherein one methylene unit of T is —O—, —N (R) —, Or optionally substituted by -S-;
R ′ and R ″ are each independently R, OR, OC (O) R, SR, or N (R) ₂ .
5. A compound according to claim 4. Q is an optionally substituted straight or branched chain, saturated or unsaturated C _1-2 alkylidene chain, and up to one methylene unit of Q is —O—, —N (R) —, Or optionally substituted by -S-,
6. A compound according to claim 5.   The compound according to claim 6, wherein Q is -O-. Formula Vc:

The compound of Claim 1 which is a compound shown by these, or its pharmaceutically acceptable salt. Formula Vd or Ve:

The compound of Claim 1 which is a compound shown by these, or its pharmaceutically acceptable salt. Formula Vf:

The compound of Claim 1 which is a compound shown by these, or its pharmaceutically acceptable salt. Formula Vg or Vh:

The compound of Claim 10 which is a compound shown by these, or its pharmaceutically acceptable salt. R ¹ and ^{R 2,} taken together, form a saturated carbocyclic ring of 3-6 members, ^{R 7} is -OH, compound of claim 11. Formula VII, VIII, IX or X:

The compound of Claim 1 which is a compound selected from the compound shown by these, or its pharmaceutically acceptable salt.

A compound selected from:

15. A compound according to claim 14 selected from. Formula Va:

[Where:
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ^{2 taken} together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from sulfur]
Or a pharmaceutically acceptable salt thereof, wherein:
(A) Formula Vb:

[Where:
Ring A, Ring B, Ring C, Ring D, and Ring E are each independently saturated, partially unsaturated, or aromatic;
G is S, CH ₂ , NR, or O;
R ¹ and R ² are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) ₂ , or a suitably protected group. A 3-7 membered saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R ¹ and R ² are Form a partially unsaturated ring or aryl ring;
Each R is independently substituted with 0-4 heteroatoms independently selected from hydrogen, an optionally substituted C _1-6 aliphatic group, or nitrogen, oxygen, or sulfur; May be a 3-8 membered saturated, partially unsaturated or aryl ring:
Two R on the same nitrogen atom, together with the nitrogen atom, a 3-8 membered saturated ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; May form a partially unsaturated ring or an aryl ring;
n is 0-2;
R ³ , R ⁴ , R ⁷ , and R ⁸ are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, ( Selected from CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
m is 0-2;
R ⁵ is TC (R ′) ₃ , TC (R ′) ₂ C (R ″) ₃ , R, OR, an appropriately protected hydroxyl group, SR, an appropriately protected thiol Group, SO ₂ R, OSO ₂ R, N (R) ₂ , an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
Each T is independently a valence bond or an optionally substituted straight or branched chain, saturated or unsaturated C _1-6 alkylidene chain, wherein up to two methylene units of T are Optionally substituted independently by —O—, —N (R) —, —S—, —C (O) —, —S (O) —, or —S (O) ₂ —. Often;
R ′ and R ″ are each independently R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO ) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁶ is halogen, R, OR, SR, SO ₂ R, OSO ₂ R, N (R) ₂ , NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) ₂ , NR (CO) OR, (CO) OR, O (CO) R, (CO) N (R) ₂ , or O (CO) N (R) ₂ ;
R ⁹ and R ^{9 ′} are each independently selected from halogen, R, OR, SR, or N (R) ₂ , or R ¹ and R ² together are nitrogen, oxygen Or a 3-7 membered saturated, partially unsaturated or aryl ring having 0-2 heteroatoms independently selected from sulfur;
R ¹⁰ is a sugar-containing or sugar-like group]
Or a pharmaceutically acceptable salt thereof:
(B) treating a compound of formula Vb with a suitable enzyme to obtain a compound of formula Va;
Including methods.   17. The method of claim 16, wherein the suitable enzyme is cellulase, xylanase, xylosidase, glycyrrhizate hydrolase, or glucuronidase.   A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, adjuvant or vehicle.   19. A method of inhibiting amyloid-beta peptide production in a patient, comprising administering to the patient the composition of claim 18.   19. A method of inhibiting amyloid-beta (1-42) peptide production in a patient comprising administering to the patient the composition of claim 18.   20. The method of claim 19, wherein the method does not affect notch processing.   23. The method of claim 21, wherein amyloid-beta (1-42) peptide levels are reduced and amyloid-beta (1-40) peptide levels are not substantially reduced.   24. The method of claim 22, wherein the level of at least one of amyloid-beta (1-37) and amyloid-beta (1-39) is increased.   19. A method of treating or reducing the severity of a disorder associated with amyloid-beta (1-42) peptide, comprising administering to a patient the composition of claim 18.   The disorder is Alzheimer's disease, Parkinson's disease, Down's syndrome, inclusion body myositis, cerebral amyloid angiopathy, mild cognitive impairment, Lewy body dementia, Parkinson's disease, cataract, taupathy, Huntington's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), type 2 diabetes, transthyretin amyloid disease, prion disease (including Creutzfeld-Jakob disease, Gerstmann-Streisler-Scheinker syndrome, lethal familial insomnia, and Kuru) Item 25. The method according to Item 24.   26. The method of claim 25, wherein the disorder is Alzheimer's disease, Parkinson's disease, or Down's syndrome.   A method of reducing cellular amyloid-beta (1-42) peptide levels, comprising contacting a compound of claim 1 with the cell.

Images