MX2007014465A

MX2007014465A - Compounds useful for treating neurodegenerative disorders

Info

Publication number: MX2007014465A
Application number: MXMX/A/2007/014465A
Authority: MX
Inventors: Pal Kollol; A Findeis Mark; Schroeder Frank
Original assignee: A Findeis Mark; Pal Kollol; Satori Pharmaceuticals Inc; Schroeder Frank
Priority date: 2005-05-17
Filing date: 2007-11-16
Publication date: 2008-09-02

Abstract

As described herein, the present invention provides compounds useful for treating or lessening the severity of a neurodegenerative disorder. The present invention also provides methods of treating or lessening the severity of such disorders wherein said method comprises administering to a patient a compound of the present invention, or composition thereof. Said method is useful for treating or lessening the severity of, for example, Alzheimer's disease.

Description

USEFUL COMPOUNDS FOR TREATING NEURODEGENERATIVE DISORDERS FIELD OF THE INVENTION The present invention relates to pharmaceutically active compounds useful for treating, or decreasing the severity of, neurodegenerative disorders.

BACKGROUND OF THE INVENTION '• The central role of the long form of amyloid beta-peptide, in particular Aβ (1-42) in Alzheimer's disease has been established through a variety of histopathological, genetic and biochemical studies. See Selkoe, DJ, Physiol. Rev. 2001, 81: 741-766, Alzheimer's disease: genes, proteins, and therapy, and Younkin SG, J Physiol Paris. 1998, 92: 289 -92, The role of A beta 42 in Alzheimer's disease. Specifically, it has been found that the deposit in the brain of Aβ (1-42) is an early and constant feature of all forms of Alzheimer's disease. In fact, this occurs before a diagnosis of Alzheimer's disease is possible and before the deposit of the shortest primary form of A-beta, Aß (l-40). See Parvathy S, et al. Ar? H Neurol. 2001, 58: 2025-32, Correlation between Abetax- i 40-, Abetax-42, and Abetax-43- containing amyloid plaques and cognitive decline. The additional implication of Aß (1-42) in the etiology of the disease comes from the observation that REF .: 188065 mutations in the presenilin genes (gamma-secretase) associated with familial forms of early onset Alzheimer's disease result in a uniform manner I levels! increments of Aβ (1-42). See Ishii K, et al. Neurosci Lett. 1997, 228: 17-20, Increased A beta 42 (43) -plaque deposition in early-onset familial Alzheimer's disease brains with tb, deletion of exon 9 and the missense point mutation (H163R)! in the PS-1 gene Additional mutations in the APP amyloid precursor protein increase total Aβ and in some! cases increase only Aß (l-42). See Kosaka T, et al. Neuroldgy, 48: 741-5, The beta APP717 Alzheimer's mutation increases the percentage of plasma amyloid-beta protein ending at A beta42 (43). Although the various mutations of APP can influence the type, amount and location of deposited Aβ, it has been found that the predominant initial species deposited in the cerebral phalanchyme is Aβ long (Mann). See Mann DM, et al Am Pa thol. 1996, 148: 1257-66, Predominant deposition of amyloid'-beta 42 (43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the myloid precursor protein gene. In early deposits of Aβ, when the majority of the deposited protein is in the form of amorphous or diffuse plates, virtually all of the Aβ is of the long form. See Gravina SA, et al J Biol Chem, 270: 7013-6, Amyloid beta protein (A beta) in Alzheimer's disease brain. Biochemical and imrnunocytochemical analysis with antibodies specific for forms e; nding at A beta 40 or A beta 42 (43); Iwatsubo T, et al Am J Pk thol. 1996, 149: 1823-30, Full-length amyloid-beta (1-42 (43)) 'and amino-terminally modified and truncated amyloid-beta 42 (43) deposit in diffuse plaques; and Roher AE, et al Proc Na tl Aqad Sci US A. 1993, 90: 10836-40, beta-A yloid- (1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer's disease . These initial deposits of Aß (l-42) are then capable of I sow the additional deposit of both long and short forms of Aß. See Tamaoka A, et al Biochem Biophys Res Commun. 1994, 205: 834-42, Biochemical evidence for the long-tail from (A beta 1-42 / 43) of amyloid beta protein as a seed molecule in cerebral deposits of Alzheimer's disease. In transgenic animals expressing Aβ, deposits were associated with high levels of Aβ (1-42), and the deposit pattern is similar to that seen in human disease with Aβ (1-42) that is deposited early followed by the deposit of Aß (l-42). See Rockenstein E, et al J Neurosci Res. 2001, 66: 573-82, Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levéis of Abeta (l-42); and Terai K, et al Neuroscience 2001, 104: 299-310, beta-Amyloid deposits in transgehic mice expressing human beta-amyloid precursor protein have the same characteristics as those in Alzheimer's disease Similar patterns and similar timing of deposition are seen in patients with Down syndrome in whom Aβ expression is elevated and the deposit is accelerated. See 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. Therefore, the selective reduction of Aß (1-42) eme | rge in this way as a disease specific strategy to reduce the amyloid forming potential of all forms of Aß, decreasing or stopping the formation of new deposits of Aβ (1-42). Aβ, inhibits the formation of soluble toxic oligomers of Aβ, and thereby slowing or stopping the progress of neurodegeneration.

BRIEF DESCRIPTION OF THE INVENTION As described herein, the present invention provides compounds useful for treating or decreasing the severity of a neurodegenerative disorder. The present invention also provides methods for treating or decreasing the severity of these disorders wherein the method comprises administering to a patient a compound of the present invention, or composition thereof. This method is useful to treat or decrease the severity of, for example, Alzheimer's disease.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents the 1H NMR spectra of the satl4-9 and satl4-10 chromatographic fractions. Figure 2 represents the 1H NMR spectra of i the satl4-ll and satl4-12 chromatographic fractions. Figure 3 represents the 1H NMR spectra of the satl5-l and satl5-2 chromatographic fractions. Figure 4 represents the 1H NMR spectra of the satl5-4 and satl5-5 chromatographic fractions. Figure 5 represents an enlargement of the reverse phase HPLC chromatogram separation of satl5-5!, In which the numbers 1 to 5 correspond to the time windows for the fractions of satl-1 to satl-9. Figure 6 represents the 1H NMR spectrum of the satl6-3 fraction corresponding to compound 6 as 98% pure. Figure 7 represents a flow chart summary of isolation protocol 2. Figure 8 depicts a HPLC trace of black snake root extract after semi-preparative HPLC. Figure 9 depicts an HPLC trace of Compound 6 showing a minor peak of discil. Figure 10 represents a HPLC trace of Compound 6. Figure 11 represents a mass spectrum of the Disclose-Compound 6. Figure 12 depicts a 1 H NMR of desacyl-Compound 6. Figure 13 depicts a HPLC trace of Compound 6. Figure 14 represents an XH NMR (CD3OD) of Compound 6. Figure 15 represents a spectrum Mass of Compound 6. 'Figure 16 represents the HPLC trace of Compound 6 detected at 205 nm isolated according to protocol 2. Figure 17 represents the HPLC trace of Compound 6 detected at 230 nm isolated according to protocol 2 Figure 18 represents the HPLC of Compound 6 detected in ELSD. Figure 19 represents the XH NMR spectrum of Compound 6 isolated according to protocol 2. Figure 20 represents the mass spectrum of the Compound 6 isolated isolated according to protocol 2. Figure 21 represents the effect determined by IP-MS of Compound 6 in the relative amounts of amyloid-beta (1-40), (1-42), (1-37), (1-38), and (1-39). Figure 22 represents the effect determined by IP-MS djel Compound 6 in the amounts of amyloid-beta (1-40), (1-42), (1-37), (1-38), and (1-39) in the mutated 717 cells and type wild.

DETAILED DESCRIPTION OF THE INVENTION 1. General description of the compounds of the invention: According to one embodiment, the present invention provides a compound of the formula I: I or a pharmaceutically acceptable salt thereof, wherein: each of Ring A, Ring B, Ring C, Ring D, and anilyl E is independently saturated, partially unsaturated or aromatic; G is S, CH2, NR, or O;; R1 and R2 are each independently halogen, R, OR, a suitably protected hydroxy group, SR, a suitably protected thiol group, N (R) 2 or an appropriately protected amino group, or R1 and R2 are taken together to form a saturated or partially unsaturated aryl ring of 3-7 'members having 0-2 independently heteroatoms selected from nitrogen, oxygen or sulfur; each R is independently hydrogen, an optionally substituted C 1 -6 aliphatic group, or an aryl ring I saturated or partially unsaturated, 3-8 membered, optionally substituted having 0-4 heteroatoms independently selected from nitrogen, oxygen, or I sulfur, wherein: two R in the same nitrogen atom are taken together or optionally with the nitrogen atom to form a saturated or partially unsaturated 3-8 membered aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; n is 0-2; R3, R4, R7 and R8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, OS02R, N (R) 2, an appropriately protected amino group, NR (C0) R, NR (C0) (C0) R, NR (C0) N (R) 2, NR (CO) OR, (CO) OR, '0 (C0) R, (CO) N (R) 2 , or 0 (CO) N (R) 2; m is 0-2; R5 is TC (R ') 3, TC (R') 2C (R ") 3, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, OS02R, N (R) 2, an appropriately protected amino group, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) 0, R, (CO) OR, 0 (CO) R, (CO) N (R) 2, or 0 (CO) N (R) 2. or; when R5 is TC (R ') 3 or TC (R') 2C (R ") 3, then R6 and a q R 'in R5 are taken together optionally to form a saturated or partially unsaturated aryl ring 3-8 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; each T is independently a valence bond or a straight or branched, saturated or unsaturated C, _6 alkylidene chain, optionally substituted wherein up to two methylene units of T are optionally and independently replaced by -O-, -N ( R) -, -S-, -C (O) -, -S (O) -, or -S (0) 2; each R 'and R "are independently selected from R, OR, SR, S02R, OS02R, N (R) 2, NR (CO) R, NR (CO) (CO) R, NR (CO) N¡ (R) 2, NR (CO) OR, (CO ) OR, 0 (CO) R, (C0) N (R) 2, or O (CO) N (R) 2; R6 is halogen, R, OR, SR, S02R, OS02R, N (R) 2, NR (CO) R ', NR (CO) (CO) R, NR (CO) N (R)) 2, NR (CO) OR, (CO) OR, 0 (CO) R, (CO) N (R) 2, or 0 (CO) N (R) 2; R9 and R9 'are each independently selected from halogen, R, OR, SR, or N (R) 2 or R1 and R2 are taken together to form a saturated or partially unsaturated 3-7 membered aryl ring having 0- 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Q is a valence link or a chain of Ci- Saturated or unsaturated, straight or branched alkyl, optionally substituted wherein up to two methylene units of Q are optionally and independently replaced by -O-, -N (R) -, -S-, -C (O) -, -S (O) -, or -S (0) 2-; and R10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a group 'Suitably protected amino, a saturated or partially unsaturated monocyclic ring, of 3-8 optionally substituted members having 0-4 heteroatoms i independently selected from nitrogen, oxygen or sulfur ^ a saturated or partially unsaturated bicyclic aryl ring 8-10 members optionally substituted that has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a detectable portion, a polymer residue, a peptide, or a sugar-containing sugar-type portion. According to another embodiment, the present invention provides a compound of the formula I: or a pharmaceutically acceptable salt thereof, wherein: each of Ring A, Ring B, Ring C, Ring D and Ring E is independently saturated, partially unsaturated or aromatic; G is S, CH2, NR or 0; R1 and R2 are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a thiol administration group, N (R) 2, or an appropriately protected amino group, or R1 and R2 are taken together to form a ring of saturated or partially unsaturated 3-7 membered aryl having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R is independently hydrogen, an optionally substituted C 1-6 aliphatic group, or an optionally substituted 3-8 membered unsaturated or partially unsaturated aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein: two R's on the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-8 membered saturated or partially unsaturated aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; n is 0-2; R3, R4, R7 and R8 are each selected independently of halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, OS02R, 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, 10 (CO) R, (CO) N (R) 2, or O (CO) N (R) 2; m is 0-2; R5 is TC (R ') 3, TC (R') 2C (R ") 3, R, OR, a suitably protected hydroxy group, SR, a suitably protected thiol group, S02R, 0S02R, N (R) 2 an appropriately protected amino group, NR (C0) R, NR (C0) (C0) R, NR (C0) N (R) 2, NR (C0) 0R, (CO) OR, 0 (CO) R, (CO) N (R) 2, or O (CO) N (R) 2, or: when R5 is TC (R ') 3 or TC (R ') 2C (R "), then R6 and a group R' on R5 are optionally taken together to form a saturated or partially unsaturated 3-8 membered aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; each T is independently a valence bond or a C, -6-alkylidene chain, saturated or unsaturated, straight or branched, optionally substituted wherein up to two methylene units of T are optionally and independently replaced by -0-, -N (R) -, -S -, - C (0) -, -S (O) -, or -S (0) 2-; each R 'and R "are independently selected from R, OR SR, S02R, 0S02R, N (R) 2, NR (CO) R, NR (CO) (C0) R, NR (C0) N! (R) 2, NR (CO) OR, (CO) OR, 0 (CO) R, (CO) N (R) 2, u OC (CO) N (R) 2; R6 is halogen, R, OR, SR, S02R, OS02R, N (R) 2, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) OR , (CO) OR, 0 (CO) R, (CO) N (R ^) 2 or 0 (CO) N (R) 2; 'R9 and R9' are each independently selected from halogen, R, OR, SR or N (R) 2, or R1 and R2 are taken together to form a saturated or partially unsaturated aryl ring of 3-7 members having 0 -2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Q is a valence bond or a chain of Cx_ ealkylidene, saturated or unsaturated, straight or branched, -optionally substituted where up to two methylene units of Q are optionally and independently replaced by -O-, -N (R ) -, -S-, -C (O) -, -S (O) -, or -S (0) 2-; and R10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, an appropriately protected amino group, an optionally substituted saturated or partially unsaturated monocyclic aryl ring of 3-8 members having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an optionally substituted 8-10 membered saturated or partially unsaturated bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a detectable portion, a polymer residue, a peptide, or a portion containing sugar or sugar type, with the proviso that the compound is different from: 2. Definitions: | The compounds of this invention include those generally described above, and are further illustrated, by the modalities, secondary moieties, and species described herein. As used herein, the following definitions should apply unless otherwise indicated. For the purposes of this Invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, the general principles of organic chemistry are described in i "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March 's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B and March, J., John Wiley & Sons, New York: i 2001, the complete contents of which are incorporated in the presentje as a reference. As generally defined above, each of Ring A, Ring B, Ring C, Ring D and Ring E is independently saturated, partially unsaturated or aromatic. It will be appreciated that the compounds of the present invention are contemplated as chemically feasible compounds. Accordingly, it will be understood by one skilled in the art that when any of Ring A, Ring B, Ring 'C, Ring D and Ring E is unsaturated, then certain substituents in that ring will be absent in order to satisfy the general rules of valence. For example, if Ring D is unsaturated at a link between Ring D and Ring E, then R6 will be absent. Alternatively, if Ring D is unsaturated at the bond between Anilyl D and Ring C, then R8 and R3 will be absent. All combinations of saturation and instauration of either Ring A, Ring B, Ring C, Ring D and Ring E are contemplated by the present invention. In this way, in order to satisfy the general rules of valence, and depending on the degree of saturation or establishment of any of the Ring A, Ring B, Ring C, Ring D and Ring E, the necessary presence or absence of each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R9 'and QR10. As described herein, the compounds of the invention may be optionally unsubstituted with one or more substituents, as generally illustrated above, or as exemplified by particular classes, subclasses and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogeny radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position in the group, and when more than one position may be substituted in a given structure with more than one substituent selected from a specified group, the substituent may be substituted. it can be either the same or different in each position. The combinations of substituents contemplated by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to enable their production, detection and preferably their recovery, purification, and use for one or more of the purposes described herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. The term "aliphatic" or "aliphatic group", as used herein, means a chain of substituted or unsubstituted hydrocarbon, straight (ie, unbranched) or branched, that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has a point 'individual binding to the rest of the molecule. Unless otherwise specified, the aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms.

In still other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or Ce-C2 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, which has a unique binding point to the rest of the molecule where any single ring in the bicyclic ring system has 3L7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. In other embodiments, an aliphatic group can have two geminal hydrogen atoms replaced with oxo (a bivalent carbonyl oxygen atom, = 0), or a ring-forming substituent, such as -0- (straight or branched alkylene or alkylidene) ) -0- to form an acetal or ketal. In certain embodiments, the aliphatic groups of example 1 include, but are not limited to, 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, pentyloyl, isopentyl, sec-pentyl, neo-pentyl, tert-pentyl, cyclopethyl, hexyl, isohexyl, sec-hexyl, cyclohexyl, 2- methylpentyl, tert -hexyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,3-dimethylbutyl and 2,3-dimethyl-but-2-yl. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more hydrogen atoms. The term "halogen" means F, Cl, Br or I. These "haloalkyl", "haloalkenyl" and "haloalkoxy" groups may have two or more halo substituents which may or may not be the same halogen and may or may not be the same carbon atom. Examples include chloromethyl, periodomethyl, 3,3-dichloropropyl, 1,3-difluorobutyl, trifluoromethyl, and 1-bromo-2-chloropropyl. The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems in which one or more ring member is a heteroatom independently selected. In some embodiments, the group "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" has three to fourteen ring members in which 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" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl). The term "unsaturated", as used herein, means that a portion has one or more units of instauration. The term "alkoxy", or "thioalkyl", as used in the pregent, refers to an alkyl group, as defined above, attached to the main carbon chain through an oxygen atom ("alkoxy") or sulfur ("thioalkyl"). The term "aryl" used alone or as part of a larger portion as in "aralkyl", "aralkoxy" or "aryloxaalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of fourteen fourteen ring members , wherein at least one ring in the system is aromatic and wherein each ring in the system 1 contains from 3 to 7 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 hereinafter. 'The term "heteroaryl", used alone or as part of a larger portion as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, less one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains from 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; N3, CN, R °; 0R °; MR; 1,2-methylene dioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R °; -O (Ph) optionally substituted with R °; (CH2)? _2 (Ph), optionally substituted with R °; CH = CH (Ph), optionally substituted with R °; N02; CN; N (R °) 2; NR ° C (0) R °; NR ° C (O) N (R °) 2; NR ° C02R °;; -NR ° NR ° C (O) R2; NR ° NR ° (O) N (R °) 2; NR ° NR ° C02R °; C (0) C (0) R °; C (0) CH2C (0) Rc; C02R °; C (0) R °; C (0) N (R °) 2; 0C (0) N (R °) 2; S (0) 2R °; S02N (R °) i2; S (0) R °; NR ° S02N (R °) 2; NR ° S02R °; C (= S) N (R °) 2; C (= NH) -N (R °) 2; or (CH2) 0-2NHC (O) R ° where each independent occurrence of R ° is selected from hydrogen, C? _6 aliphatic optionally substituted, a heteroaryl ring or I unsubstituted 5-6 membered heterocyclic, phenyl, O (Ph), or CH2 (Ph) or despite the above definition, two independent occurrences of R °, in the same substituent or different substituents, taken together with the atoms at the Wherein each R ° group is attached, they form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents in the aliphatic group of R ° are selected from N3, CN, NH2, NH (C? -4aliphatic), N (C? _4aliphatic) 2, halogen, C? -aliphatic, OH, 0 (C? -4aliphatic ), N02, CN, C02H, C02 (C? _4aliphatic), O (halo-C? -4aliphatic), or haloC? -4aliphatic, wherein each of the above C? -4aliphatic groups of R? Is unsubstituted. An aliphatic or heteroaliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and further include the following: -O, = S, = NNHR *, = NN (R *) 2, = NNHC (0) R *, = NNHC02 (alkyl), = NNHS02 ¡(alkyl), or = NR *, where each R * dr independently selects hydrogen or C? _6aliphatic optionally substituted. The optional substituents in the aliphatic group of R * are selected from NH2, NH (C? _4aliphatic), N (C? _4aliphatic) 2, halogen, C? -4aliphatic, OH, 0 (C? _4aliphatic), N02, CN, CO ^ H, C02 ( C α -aliphatic), 0 (halo-C 4 -aliphatic), or haloC 4 -aliphatic, wherein each of the above C 4 -aliphatic groups of R * is unsubstituted. Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from R +, N (R +) 2, C (0) R +, C02R +, C (0) C (0) R +, C (0) CH2C (0) R +, S02R +, S02N (R +) | 2, C (= S) N (R +) 2, C (= NH) -N (R +) 2, or NR + S02R +, where R + is hydrogen, an optionally C? _6 aliphatic substituted, optionally substituted phenyl, optionally substituted 0 (Ph), optionally substituted CH2 (Ph), (CH2)? 2 (Ph) optionally substituted; CH = CH (Ph) optionally substituted; or an unsubstituted 5-6 membered heteroaxyl or heterocyclic ring having from one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or despite the above definition, two independent occurrences of R +, in the miscellaneous substituent or different substituents , taken together with the atoms to which each R + group joins, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R + are selected from N 2, NH (C 4 aliphatic), N (C 4 aliphatic) 2, halogen, C α -aliphatic, OH, 0 (C? _4aliphatic), N02, CN, C02H, C02 (C? -4aliphatic), O (Halo-C? -4aliphatic), or haloC? 4aliphatic, wherein each of the C? -4aliphatic groups above R + is unsubstituted. As detailed above, in some embodiments, two independent occurrences of R ° (or R +, or any other variable similarly defined herein), are taken together with the atoms to which each variable joins to form a cycloalkyl ring, heterocyclic, aryl or 3-8 membered heteroaryl having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Example rings that are formed when two independent occurrences of R ° (or R + or any other variable similarly defined herein), are taken together with the atoms to which each variable binds include, but are not limited to the following : a) two independent occurrences of R ° (or R + or any other variable similarly defined herein) that bind to the same atom and are taken together with that atom to form a ring, for example, N (R °) 2, where both occurrences of R ° are taken in conjunction with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl group; and b) two independent occurrences of R ° (or R + or any other variable similarly defined herein) that bind to different atoms and are taken together with both of these atoms to form a ring, for example where a group phenyl is substituted with two occurrences of OR, or these two occurrences of R ° are taken together with the oxygen atoms to which they join to form a ring containing 6-member oxygen fused: . It will be appreciated that a variety of other rings can be formed when two independent occurrences of R ° (or R +, or any other variable similarly defined herein) are taken together with the atoms to which each variable is attached and that the detailed examples previously it is not proposed that they be limiting. As used herein, the term "detectable portion" is used interchangeably with the term "brand" I and refers to any portion capable of being detected, for example, primary marks and secondary marks. Primary labels, such as radioisotopes (eg, 32P, 33P, 35S, or 34C), mass labels, and fluorescent labels are signal generating signal groups that can be detected without further modifications. The term "secondary label" as used herein refers to portions such as biotin and various protein antigens that require the presence of a second intermediate compound for the production of a signal detect it. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen tags, the secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the non-radioactive fluorescent resonance energy transfer (FRET) process, and the second group produces the detected signal. The terms "fluorescent label", "fluorescent dye", and "fluorophore" as used herein refer to portions that absorb light energy at a defined excitation wavelength and emit light energy (aa at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA DYES, AMCA-S, 'BODIPY (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY' 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589 ', BODIPY 581 / 591, BODIPY 630/650, BODIPY 650/665), Carboxyrodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanuin stains (Cy3, Cy5, Cy3.5, Cy5. 5), Dansyl, Dapoxil, Dialkylaminoocoumarin, 4 ', 5'-Dichloro-2', 7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IR Dyes (IRD40, IRD 700, IRD 800), JOE, Lisamine-rhodamine B, Navy Blue, Methoxycoumarin, Naftofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Green rhodamine, Rhodamine Red, Rodol Green, 2 ', 4', 5 ', 7' - Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Red-X Texas. The term "mass label" as used herein refers to any portion that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass labels include electrophores release labels such as N- [3- ['- [(p-Methoxytetrafluorobenzyl) oxy] phenyl] -3-methylglyceronyl] isonipecotic, 4' - [2, 3, 5, 6-Tetrafluoro-4- (pentafluorophenoxy)] methylacetophenone, and its derivatives. The synthesis and utility of these mass marks is described in U.S. Patent 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 in mass labels include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of variable length and variable base composition, oligopeptides, oligosaccharides, and other synthetic polymers of variable monomer length and composition.

Also, a wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-200 Daltons) can be used as mass labels. The term "substrate", as used herein, refers to any material or macromolecular complex to which a functionalized terminal group of a compound of the present invention can be attached. Examples of commonly used substrates include, but are not limited to, glass surfaces, silica surfaces, plastic surfaces, surfaces and foils, surfaces containing a metallic or chemical coating, membranes (e.g., nylon, polysulfones, silica). ), micro-beads (eg, latex, polystyrene, or other polymer), porous polymer matrices (eg, polyacrylamide gel, polysaccharide, polymethacrylate), macromolecular complexes (eg, protein, polysaccharide). Unless stated otherwise, structures represented herein are also proposed to include all isomeric (e.g., enantiomeric, diasteomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E), and conformational isomers (Z) and (E). For the; both, the individual stereochemical isomers as well as the enantiomeric, diatereomeric and geometric (or conflormational) mixtures of the present compounds are within the scope of the invention. Unless stated otherwise, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless stated otherwise, the structures depicted herein are also proposed to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a carbon enriched with 13C or 1C are within the scope of this invention. These compounds are useful, for example, as analytical probes or tools in biochemical assays. 3. Description of Example Compounds: As generally defined above, portion G of formula I is S, CH2, NR, or O. In certain embodiments, portion G of formula I is O. As generally defined above , R1 and R2 of the formula I are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) 2, or an amino group suitably protected, or R1 and R2 are taken together to form a saturated or partially unsaturated aryl ring of 3-7 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, R1 and R2 of formula I are each independently R or OR. In other embodiments, R1 and R2 of formula I are each independently R, wherein R is hydrogen or an optionally substituted Ci-ealiphatic group. According to another aspect of the present invention, R1 and R2 of formula I are taken together to form a saturated or partially unsaturated aryl ring of 3-6 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. Yet another aspect of the present invention provides a compound of formula I, wherein R1 and R2 are taken together to form a 3-6 membered saturated carbocyclic ring. In other embodiments, R1 and R2 of formula I are taken together to form a cyclopropyl ring. In certain embodiments, portion n of formula I is 0-1. In other embodiments, the n portion of the formula I is 1. As generally defined above, the group R5 of the formula I is R5 is TC (R ') 3, TC (R') 2C (R ") 3, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, OS02R, N (R) 2, an amino group adequately protected, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) OR, (CO) OR, 0 (CO) R, (CO) N ( R) 2, or 0 (CO) N (R) 2, wherein each T1 is independently a valence bond or an unsaturated or saturated, straight or branched C, _6 alkylidene chain, optionally substituted wherein up to two methylene units of T are optionally and independently replaced by -0-, -N (R) -, -S-, -C (0) -, -S (0) -, or -S (0) 2-. In certain embodiments, each T is independently a valence bond or a straight or branched C? -4-alkylidene chain in which a methylene unit of T is optionally replaced by -O-, -N (R) -, or - S-. In other embodiments, each T is independently a valence bond or a straight or branched C? _4 alkylidene chain. In still other modalities, each T is a valence bond. When the group R5 of the formula I is TC (R ') 3 or T-C (R') 2 (C (R ") 3, each R 'and R" is independently selected from R, OR, SR, S02R, OS02R, N (R) 2, NR (C0) R, NR (C0) (C0) R, NR (CO) N (R) 2, NR (C0) 0R, (CO) OR, 0 (C0) R, (C0) N (R) 2, or 0 (C0) N (R) 2. In certain embodiments, each R 'and R "is independently R, OR, 0C (0) R, SR, ON (R 2. In other embodiments, each R 'and R "is independently R, OR, or OC (0) R. The example groups R' and R" include hydrogen, CH3, OH, and 0C (0) CH3 As generally defined above, when R5 is TC (R ') 3 or T-CH (R') C (R ") 3, then R6 and a group R 'on R5 are optionally taken together to form a saturated or partially unsaturated aryl ring of 3-8 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, R5 is TC (R ') 3 or TC (R') 2 (C (R ") 3, and R6 and a group R 'in R' are taken together to form a saturated ring of 5-7. members having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur In certain embodiments, R6 is TC (R ') 3 or TC (R') 2 (C (R ") 3, and R6 and a group R R5 are taken together to form a saturated 6-membered ring having an oxygen atom.These compounds, when T is a valent bond, are of the formula lya, when R5 is TC (R ') 3, and Ilb , when R5 is TC (R ') 2 (C (R ") 3: n where each of R ', R ", R1, R2, R3, R4, R7, R8, R9, R9', Q and R10 are 'as defined in general above and in classes and sub-classes defined above and at the moment. As generally defined above, the group R5 of the formula I is, inter alia, a suitably protected hydroxyl group, a thiol group suitably protected, or an appropriately protected amino group. Hydroxyl protecting groups are well known in the art1 and include those described in Protecting Groups in Organi c * Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiiey & Sons, 1999, the entirety of which is incorporated herein by reference. Examples of suitably protected hydroxyl groups of the group R5 of the formula I also include! but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of these esters include formates, acetates, carbonates and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trichloroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4'- (ethylendithio) pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy -crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2, 2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, vinyl, allyl and p-nitrobenzyl. Examples of these silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldi-phenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. The alkyl ethers include methyl-, benzyl-, p-methoxybenzyl-, 3,4-dimethoxybenzyl-, trityl-, t- butyl-, allyl-, and allyloxycarbonyl-ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl-, methylthiomethyl-, (2-methoxyethoxy) methyl-, benzyloxymethyl-, beta- (trimethylsilyl) ethoxymethyl-, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobehcyl, 2- and 4-picolyl . Thiol protecting groups are well known in the art, and include those described in detail in Protecting Groups in Organi c Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley &; Sons, 1999, the entirety of which is incorporated herein by reference. Appropriately protected thiol groups of the R 5 portion of the formula I include, but are not limited to, disulfides, thioethers, silyl-thioethers, thioesters, thiocarbonates, thiocarbamates, and the like. Examples of these groups include, but are not limited to, substituted alkyl thioethers, benzyl and benzyl thioethers, triphenylmethyl thioethers, trichloroethoxycarbonyl, to name a few. According to another aspect of the present invention, the R5 portion of the formula I is a thiol protecting group that is removable under neutral conditions, for example, with AgN03, HgCl2, and the like. Other neutralizing conditions include reduction using a reducing agent suitable. Suitable reducing agents include dithiothreitol (DTT), mercaptoethanol, dithionite, reduced glutathione, reduced glutaredoxin, thioredoxin reductase, substituted phosphions such as tris-carboxyethyl-phosphine (TCEP), and any other peptide or peptide-based reducing agent or organic, or other reagents known to those skilled in the art. According to yet another aspect of the present invention, the R 5 portion of the formula I is a thiol protecting group that is "photocleavable". These suitable thiol protecting groups are known in the art and include, but are not limited to, a nitrobenzyl group, a tetrahydropyranyl group (THP), a trityl group, -CH2SCH3 (MTM), dimethylmethoxymethyl, or -CH2-SS-pyridin. -2-ilo. One skilled in the art will recognize that many of the suitable hydroxyl protecting groups, as disclosed herein, are also suitable as thiol protecting groups. In certain embodiments, the R 5 group of the formula I is an appropriately protected amino group. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Syn thesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wi | law & Sons, 1999, the whole of which are incorporated in the piresente as a reference. The suitably protected amino groups of the R 5 portion further include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of these groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl and the like. In certain embodiments, the amino protecting group of the R 5 moiety is phthalic. In still other embodiments, the amino protecting moiety of the R 5 moiety is a tert-butyloxycarbonyl group (BOC). As generally defined above, the group Q of the formula I is a valence bond or a chain of saturated or unsaturated, straight or branched, optionally substituted C? _ 4 alkylidene wherein up to two methylene units of Q are replaced in a manner optional and independent by -O-, -N (R) -, -S-, -C (O) -, -S (O) -, or -S (0) 2-. In certain embodiments, Q is an optionally substituted saturated or unsaturated, straight or branched C? -2alkylidene chain in which up to one methylene unit of Q is optionally replaced by -O-, -N (R) -, or -S -. In other modalities, Q is -0-. As generally defined above, the group R10 of the formula I is R, a suitably protected hydroxyl group, a suitably protected thiol group, a group suitably protected amino, a saturated or partially unsaturated, 3-8 membered monocyclic aryl ring, optionally substituted having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a saturated or partially unsaturated bicyclic aryl ring, of 8- 10 members optionally substituted having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a detectable portion, a residue; of polymer, a peptide, or a group containing sugar, or a sugar type group. In certain embodiments, the R10 group of the formula I is a sugar-containing group. These sugar-containing groups are well known to one skilled in the art and include those described in detail in "Essentials of Glycobiology" Edited by Varki, A., et al. , Cold Spring Harbor Laboratbry Press. Cold springs Harbor, N.Y. 2002. In certain embodiments, the group R10 of the formula I is a glycoside. The Exemplary R10 groups include arabinopyranosides and xylopyranosides. In certain embodiments, the R10 group of the formula I is a xylopyranoside. In certain embodiments, the R 10 group of the formula I is an arabinopyranoside. In still other 'modalities, the R10 group of formula I is . According to another modality, the R group of the Formula I is . Still another modality provides a composed of the formula I wherein R10 is According to another aspect of the present invention, the group R10 of the formula I is a sugar mimic. These sugar mimics are well known to those skilled in the art and include those described in detail in "Essentials of Glycobiology". For example, the sugar mimic groups contemplated by the present invention include cyclitol and the like. In certain embodiments, R10 is a portion of cyclitol, wherein the cyclitol is a cycloalkane containing a hydroxyl group in each of the three or more ring atoms, as defined by the IUPAC convention. In other embodiments, these portions of cyclotol include inositol such as scyllo-inositol. In addition, suitable sugar-type portions of the R10 group of the formula I include acyclic sugar groups. These groups include linear alkyls and erythritols, to name a few. It will be appreciated that there may be sugar groups in either the cyclic or acyclic form. Accordingly, acyclical forms of a group of sugar by the present invention as a suitable sugar-type portion of the group R10 of the formula I. In certain embodiments, the group R10 of the formula I is a detectable portion. In other embodiments, the R10 group of formula I is a fluorescent moiety, fluorescent dye, or fluorophore as defined herein, supra. According to another aspect of the present invention, the group R10 of the formula I is a polymer residue. Polymer residues are well known in the art and include those described in detail in "Chemistry of Protein Conjugation and Cross-Linking" Shan S. Wong, CRC Press. Boca Raton, Florida, 1991. Suitable polymer residues of the R10 group of the formula I include poly (alkylene oxides), such as PEG, poly (amino acids), and other polymer residues capable of conjugation to a compound of the present invention. invention. As generally defined above, the group R10 of formula I is, inter alia, a suitably protected hydroxyl group, a suitably protected thiol group, or an appropriately protected amino group. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Without Thesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, all of which is incorporated herein by reference. Examples of suitable protecting groups of hydroxyl groups of the group R10 of the formula I also include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers and alkoxyalkyl ethers. Examples of these esters include formates, acetates, carbonates and sulfonates. Specific examples include formate, formate of benzoyl, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4, 4- (ethylendithio) pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate , 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, vinyl, allyl, and p-nitrobenzyl . Examples of these silyl ethers include trimethylsilyl-, triethylsilyl-, t-butyldimethylsilyl-, t-butyldiphenylsilyl-, triisopropylsilyl-, and other trialkylsilyl ethers. The alkyl ethers include methyl-, benzyl-, p-methoxybenzyl-, 3, -dimethoxybenzyl-, trityl-, t-butyl-, allyl-, and allyloxycarbonyl-ethers or derivatives. The alkoxyalkyl ethers include acetals such as methoxymethyl-, methylthiomethyl-, (2-methoxyethoxy) methyl-, benzyloxymethyl-, beta- (trimethylsilyl) ethoxymethyl-, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanob nyl, 2- and 4-picolyl. Thiol protecting groups are well known in the art and include those described in detail in ProtecÚing Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, rd edition, John Wiley & Sons, 1999, all of which is incorporated herein by reference. Suitable thiol protecting groups of the R 10 portion of the formula I include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, thiocarboxylates, and the like. Examples of these groups include, but are not limited to, alkyl thioethers, benzyl- or benzyl-substituted thioethers, triphenylmethyl thioethers, trichloroethoxycarbonyl, to name a few. According to another aspect of the present invention, the R10 portion of the formula I is a thiol protecting group that can be removed under neutral conditions, for example with Ag03, HgCl2, and the like. Other neutral conditions include reduction using an appropriate reducing agent. Suitable reducing agents include dithiothreitol (DTT), mercaptol ethanol, dithionite, reduced glutathione, reduced glutaredoxin, reduced thioredoxin, substituted phosphines such as tris-ca.boxyethyl-phosphine (TCEP), and any other peptide-based reducing agent. organic, or other reagents known to those skilled in the art. Agree yet In another aspect of the operation, the R10 portion of the formula I is a thiol protecting group that is "photocleavable". These suitable thiol protecting groups are known in the art and include, but are not limited to, a nitrobenzyl group, a tetrahydropyranyl group (THP), a trityl group, -CH2SCH3 (MTM), dimethylmethoxymethyl, or -CH2-SS-pyridin. -2-ilo. One skilled in the art will recognize that many of the suitable hydroxyl protecting groups, as described herein, are also suitable as thiol protecting groups. In certain embodiments, the R10 group of the formula I is an appropriately protected amino group. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, all of which is incorporated herein by reference. Suitable amino protecting groups of the R 10 moiety further include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of these groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc) i, benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl and the like. In certain embodiments, the amino protecting group of the R10 portion is phthalimido. In still other embodiments, the amino protecting group of the R10 portion is a tert-butyloxycarbonyl group (BOC). In certain embodiments, the present invention provides a compound of formula I, wherein this compound is different from any of, two, or all three of the following: including each stereoisomer thereof. As generally described above, the present invention provides a compound of the formula I: I or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein. In certain embodiments, the present invention provides a compound of formula I having the stereochemistry as represented in formula I-a: Ia or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for compounds of formula I. In certain embodiments, groups R1 and R2 of formula I are taken together to form a ring saturated or partially unsaturated, 3-7 membered aryl having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, the groups R1 and R2 of the formula I are taken together to form a saturated ring of 3-6 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In still other embodiments, the R1 and R2 groups of the formula I are taken together to form a 3-6 membered saturated carbocyclic ring. In accordance with yet another aspect of the present invention, a compound of the formula I-b is provided: I-faith or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for compounds of formula I. In other embodiments, the present invention provides a compound of formula Ic : l-c or a pharmaceutically acceptable sjal thereof, wherein each variant is defined above and in classes and subclasses i described above and herein for compounds of the formula I. As generally defined above, each I of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic. In certain embodiments, Ring B is unsuitable and R 1 and R 2 are absent, thereby forming a compound of formula II: II or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and in the present for compounds of the formula I In certain embodiments, group n of formula II is 0-1 and group G of formula II is oxygen. 1 According to another aspect, the present invention provides a compound of the formula Il-a: H-a or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for the compounds of formula I. In certain embodiments, group n of formula II-a is 0-1 and group G of formula Il-a is oxygen. In other embodiments, Ring B and Ring D are both unsaturated and R 1, R 2 and R 6 are absent, thereby forming a compound of formula III: III or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for compounds of formula I. i In certain embodiments, group n of formula III is 0- 1 and group G of formula III is oxygen. According to other embodiments, the present invention provides a compound of formula IV: IV or a pharmaceutically acceptable sjal thereof, wherein each variable is defined above and in classes and subclasses described above and herein for compounds of the formula, I. As used herein, == denotes a bond individual or double bond. It will be understood by one skilled in the art that when == designates a double bond, then R6 is present. In contrast, when == designates an individual link, then R6 is present. Therefore, in certain modalities, == designates a double bond and R6 is absent. In other modalities, === designates an individual link and R6 is as defined above. According to another aspect, the present invention provides a compound of formula IV-a: IV-a or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for compounds of formula I. In certain embodiments, the group G of formula IV-a is oxygen. In other embodiments, the group R 4 of the formula IV-a eg R, OR, or a suitably protected hydroxyl group. In still other embodiments, the group R4 of the formula IV-a is R. Yet another aspect of the present invention is to a compound of formula IV-b: ? V-b or a pharmaceutically acceptable salt thereof, wherein each I variable is defined above and in classes and subclasses described above and herein for compounds of formula I. In certain embodiments, groups R1 and R2 of formula IV-b are taken together to form a saturated aryl ring or partially unsaturated, 3-7 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other modalities, groups R1 and R2 of formula IV-b are taken together to form a 3-6 membered saturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.1 In still other embodiments, the R1 and R2 groups of the formula; IV-b are taken together to form a 3-6 membered saturated carbocyclic ring. In accordance with yet another aspect of the present invention, a compound of the formula IV-c is provided: or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and in the present for compounds of the formula I In certain embodiments, the group R7 of the formula IV-c is -OH . In accordance with yet another aspect of the present invention, a compound of the formula IV-d is provided: IV-d or a pharmaceutically acceptable salt thereof, wherein each variable is defined above and in classes and subclasses described above and herein for the compounds of the formula I In certain embodiments, the group R7 of the formula IV-d is -OH. The exemplary compounds of the present invention are set forth in Table 1, below: Table 1. Example compounds of the formula I 1-3 1-4 1-9 1-13 The exemplary compounds of the formula IVa are set forth in Table 2, below: 4. General Methods for Providing the Present and Compounds: The compounds of this invention can be prepared or isolated in general by synthesis and / or semi-synthesis methods known to those skilled in the art for analogous compounds and by methods described herein in US Pat. examples, later.

Isolation of Active Components Certain compounds of the present invention were isolated from black snake root, also known as cimicifuga racemosa or a ctaea racemosa, and the structure of these compounds became clear. Extracts, powders and black commercial snake root capsules are available to treat a variety of menopausal and gynecological disorders. However, it has surprisingly been found that certain compounds present in the black snake root are useful for modulating and / or inhibiting the production of the amyloid-beta peptide. In particular, certain compounds of the black snake root have been isolated and identified, where these compounds are useful for modulating and / or inhibiting the production of amyloid-beta peptide especially beta-amyloid peptide (1-42). These compounds are encompassed by formula I. These compounds can be isolated and used in a form substantially free of other compounds normally found in the root. Alternatively, a root extract may be prepared wherein the extrudate is enriched in a compound of the present invention. As described above and in the present, certain compounds of the present invention are isolated from normal extract of root and rhizomes of black snake, cultured or wild. It is also contemplated that the present compounds may also be isolated from plant root tissue grown in culture or from the tissue culture medium in culture. These methods of growing tissue and plant root in culture are well known to those skilled in the art and include those described in Hairy Roots, Culture and Applications, edited by Pauline M. Doran, published by Harwood Academic Publishers, Amsterdam, The Netherljands. Copyright 1997 OPA (Overseas Publishers Association) Amsterdam B. V. ISBN 90-5702-117-X, the totality of which is incorporated herein by reference. Alternatively, the compounds of the present invention can be prepared by semi-synthetic processes starting from other compounds found in extracts of the black snake root and related cemicifuga species, either from the roots and rhizomes or aerial parts of these plants. This can be achieved either by chemical transformation or of an isolated compound or extract fraction or mixture of compounds. Chemical manipulation can be achieved by, but not limited to, temperature manipulation, pH and / or treatment with various solvents. The biological transformation can be achieved by, but not limited to, treatment of an isolated compound or an extract fraction or a mixture of compounds with plant tissue, extracts of plant tissue, other microbiological organisms or an enzyme isolated from any organism. In certain embodiments, the present invention provides a black snake root extract wherein the extractb comprises at least 10% by weight of a compound of the present invention. In other embodiments, the present invention provides a black snake root extract wherein the extract comprises from about 10 wt% to about 50 wt% of a compound of the present invention. In still other embodiments, the present invention provides a black snake root extract wherein the extract comprises from about 10 wt% to about 50 wt% of a compound of the present invention, wherein the extract is substantially free. of acteína. According to another embodiment, the present invention provides a compound of formula I substantially free of other compounds found in the black snake root.

As used herein, the term "substantially free" is meant to mean that the compound is composed of a significantly greater proportion of a compound of the formula I as compared to the compound as found in the black-snake rai-f or extract thereof. In some embodiments, the present invention provides a compound of the formula I in an amount of about 1 percent by weight to about 99 percent by weight. In certain embodiments, the compound of formula I is provided in more than! approximately 80% chemical purity. In other embodiments, the compound of formula I is provided in greater than about 90% chemical purity. In other embodiments, the compound of formula I contains no more than about 10.0 percent HPLC area of other components of the black snake root relative to the total area of the HPLC chromatogram. In other embodiments, the compound of formula I contains no more than about 8.0 per cent HPLC area of other components of the black snake root relative to the total area of the HPLC chromatogram, and in still other embodiments, no more than about 3 per area area. The methods for determining whether the compounds of the present invention are in a form substantially free of other compounds normally found in the black snake root are known to one skilled in the art as described. later. Compounds that were previously isolated, and identified, from the black snake root include certain triterpenes based on cycloartanol, which include acteol, acetylacteol, 26-deoxyacteol, cimigenol, actein, 26-deoxyactein, and cimicifugoside. The e-isoferulic acid and the isoflavone formononetin have also been isolated and identified. The representatives of these compounds have the following structures: acteol cimigenol cimicifugoside acteine Accordingly, another embodiment of the present invention provides a compound of formula I substantially free of one or more of acteol, acetylacteol, 26-desoxylacteol, cimigenol, acteine, 26-deoxyactein, and cimicii'ugosido. In certain embodiments, the present invention provides a compound of the formula I substantially free of actol, acetylacteol, 26-deoxyacteol, cimigenol, acteine, 26-desoxyacteine, and cimicifugoside. According to another embodiment, the present invention provides a black snake root extract enriched in a compound of formula I with a diminished amount of one or more of acteol, acetylacteol, 26-deoxyacteol, cimigenol, acteina, 26-deoxyacteína, and cimicifugosido. According to still another embodiment, the present invention provides a black snake root extract enriched in a compound of formula I with a diminished amount of each of acteol, acetylacteol, 26-deoxyacteol, cimigenol, acteine, 26-deoxyactein, and cimicifugoside. A variety of techniques for extracting, isolating and / or purifying individual active components of black snake root are well known. The present invention encompasses both the identification of these active components as described herein and the incorporation of these components in the compositions of the present invention as described herein. Individual active components of black snake extracts can be identified as described herein and can be isolated and / or purified using any known technique. The active component can be purified from the root itself in any form or the cooking of a mixture of an extract of the present invention or a commercially available extract, among others. The various techniques that can be used in the purification include filtration, selective precipitation, extraction with organic solvents, extraction with aqueous solvents, column chromatography (silica gel), high performance liquid chromatography (HPLC) and other methods known to one skilled in the art. According to certain modalities, the present extractives are those that use a fraction isolated from the root of black snake. An isolated fraction means a subsidiary amount of root substances that have been removed, for example, by chromatographic means, distillation, precipitation, distraction, filtration or other ways of the root itself. In other embodiments, root extracts and fractions are removed from them by chromatography, distillation, precipitation or extraction. These extraction or isolation techniques are well known to one skilled in the art. The details of some of these techniques are discussed in the later Examples section. According to other embodiments of the present invention, the presence and purity of the active compound is assessed by chemical methods that include nuclear magnetic spectroscopy (NMR), mass spectroscopy, infrared (IR) spectroscopy, visible spectroscopy ultraviolet, elemental analysis, and polarimetry, refractometry, to name a few. These methods of analysis are known to one skilled in the art. In other embodiments, the chemical structure of the active compounds isolated from the black snake root is determined by methods known to one skilled in the art, including NMR, mass spectroscopy, infrared (IR) spectroscopy, ultraviolet visible spectroscopy, elemental analysis, i polaripietry, refractometry, and X-ray crystallography, by name a few. Although certain exemplary embodiments are described above and herein, it will be appreciated that the root extracts of the present invention can be prepared according to the methods generally described above using appropriate starting materials by generally available methods. for a person skilled in the art.

. USES, FORMULATION AND ADMINISTRATION Pharmaceutically Acceptable Compositions i According to another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a carrier, adjuvant or pharmaceutically acceptable carrier i. In certain modalities, these The compositions further comprise optionally one or more additional therapeutic agents. It will also be appreciated that certain 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" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like, and are provided with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention which, in the administration of a receptor, is capable of providing, either directly or indirectly, a compound of this invention or a metabolite or pharmaceutically active residue thereof. As used herein, the term "pharmaceutically active metabolite or residue thereof" means that a metabolite or residue thereof is also a pharmaceutically active compound according to the present invention. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ! al., describe pharmaceutically acceptable salts in detail in J. pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of this invention include those times derived from suitable organic and inorganic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuripic acid and perchloric acid or with organic acids such as alloic acid , oxalic acid, maleic acid, tartaric acid, citric acid, 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, camphorrate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate. , heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobipnate, lactate, laurate, lauryl-sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin, persulfate, 3-phenylpropionate, phosphate, picrate, pivalatp, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, salts of valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 4 alkyl) salts. This invention also contemplates the quaternization of any basic nitrogen containing group of the compounds described herein. Dispersible or water or oil soluble products can be obtained for this quaternization. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The compositions of the present invention may further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents or other liquid vehicle, dispersion or suspension aids, agents surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, as is appropriate to the particular form of dosage desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Pubiishing Co., Easton, Pa., 1980) describes several carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except for the fact that some conventional carrier medium is incompatible with the compounds of the invention, such as by producing some undesirable biological effect or otherwise interacting in a harmful manner with some other component of the pharmaceutically acceptable composition, its use is contemplated. that is within the scope of this invention. Any? Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, phosphatized disodium acid, potassium hydrogen phosphate, sodium chloride, r zinc salts, colloidal silica, magnesium tricilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool grease, zuccans such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and waxes suppository; oils such as peanut oil, cotton oil); safflower oil; Sesame oil; olive oil; ceite of corn and soybean oil; glycols; such as a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavorings and flavors, preservatives and antioxidants They may also be present in the composition, according to the formulator's judgment. The compositions provided by the present invention can be used in combination therapies, that is, the present compositions can be administered concurrently with, before, or subsequent to, one or more desired therapeutic agents or medical procedures. The particular combination of therapies (agents or therapeutic procedures) to be used in a combination regimen will take into account the compatibility of the agents and / or I desired therapeutic procedures and the desired therapeutic effect that will be achieved. It will also be appreciated that the Therapeutic products employed can achieve a desired effect for the same disorder (for example, a compound described herein can be administered concurrently with another therapeutic agent used to treat the same disorder) or can achieve different effects (e.g., control). of some adverse effects). For example, known agents useful for treating neurodegenerative disorders can be combined with the compositions of this invention to treat neurodegenerative disorders, such as Alzheimer's disease. Examples of these known agents useful for treating neurodegenerative disorders include, but are not limited to, treatments for Alzheimer's disease such as acetylcholinesterase inhibitors, including donepezil, memantine (and related compounds such as NMDA inhibitors), Exelon ™; treatments for Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinrol, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadite, agents; for treating multiple sclerosis (MS) such as beta-interferon (e.g., AvonexMR and Rebif ™), Copaxone ™, and mitoxantrone; riluzole, and anti-Parquinsonian agents. For a more comprehensive analysis of updated therapies useful for treating neurodegenerative disorders, see, a list of FDA approved drugs at http://www.fda.gov, and The Merck Manual, Seventeenth Ed. 1999, the complete contents of which they are incorporated in this way as a reference. In other embodiments, the compounds of the present invention are combined with other agents useful for treating neurodegenerative disorders, such as Alzheimers disease, wherein these agents include beta-se [cretase inhibitors, gamma-secretase inhibitors, aggregation inhibitors, metal chelators, antioxidants and neuroprotectors. As used herein, the term "combination", "combined", and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in the form of separate unit doses or together in a single unit dose form. By Accordingly, the present invention provides a single unit dosage form comprising a compound of formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle. Other examples of agents that can also be combined with the inhibitors of the invention include, without I limitation: treatments for asthma such as albuterol and SinguláirMR; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-aging agents inflammatory drugs such as corticosteroids, TNF blockers, RA of 'IL-1, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate-mofetil, corticosteroids, cyclophosphamide, azathioprine, and neurotropic factors such as inhibitors of acetylcholinesterase, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating 'liver disease such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders such as corticosteroids, anti-leukemia agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma-globulin. The amount of the additional therapeutic agent present in the compositions of this invention will be no more than the amount that would ordinarily be administered in a composition comprising that therapeutic agent as the sole active agent. In certain embodiments, the amount of the additional therapeutic agent in the present compositions will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In an alternative embodiment, the methods of this invention that utilize compositions that do not contain an additional therapeutic agent comprise the additional step of separately administering to the patient an additional therapeutic agent. When these additional therapeutic agents are administered separately, they can be administered to the patient before, sequentially with or after the administration of the compositions of this invention.

I invention. The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), orally, as an oral or nasal spray, or the like, depending on the severity of the disorder being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dose levels of from about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, body weight of the subject per day, one or more times a day, to obtain the desired therapeutic effect. 'Liquid dosage forms for administration oral include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as I for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular , cotton oil, I peanut, corn, germ, olive, resinous and sesame seeds), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures} thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavors, and flavorings. | Injectable preparations, for example, sterile injectable oleaginous or aqueous suspensions according to the known art can be formulated using suitable dispersing agents or humectants and suitable suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are used conventionally as a solvent or suspending medium. For this purpose, any insipid, fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable products. The injectable formulations can be sterilized, eg, by filtration through a bacterial retention filter, or by incorporating stabilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a compound of the present invention, it is often desirable to decelerate the absorption of the subcutaneous or intramuscular injection compound. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystalline form. In a way | Alternatively, delayed absorption of a parenterally administered form of compound is achieved by dissolving or suspend the compound in an oily vehicle. They are made Injectable depot forms by forming microcapsule matrices of the compound into biodegradable polymers such as p-plylactide-polyglycolide. Depending on the ratio of the compound to polymer and the nature of the polymer In particular, the speed of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides).

Depot injectable formulations are also prepared to entrap the compound in liposomes or microemulsions that are compatible with body tissues. The compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at room temperature. body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dose forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or entenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humitants such as glycerol, d) disintegrating agents such a co-agar agar , calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate, 'e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such such as, for example, cetyl alcohol and glycerol monostearate, h) absorbers such caolin coitus and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. . In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in hard and soft fill gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 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 formulating art. They may contain optionally opacifying agents and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inlay compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in hard and soft fill gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds may also be in micro-encapsulated 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, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredients only or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric waxes and substances. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as may be required. Ophthalmic formulation, ear drops and eye drops are also contemplated as being within the scope of the invention. Additionally, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled distribution of a compound to the body! These dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. It is also possible to use absorption enhancers to increase the flow of the compound through the skin. The speed can be control either by providing a speed control membrane or by dispersing the compound in a polymer or gel matrix. In some embodiments, the present invention provides a composition containing a compound of the formula I in an amount of about 1 weight percent to about 99 weight percent. In other embodiments, the composition contains a compound of formula I which contains no more than about 10.0 per cent! of HPLC area of other components of the black culebrum root in relation to the total area of the chromatogram of HPLC. In other embodiments, the composition containing a compound of formula I contains no more than about 8. 0 percent HPLC area of other components of black snake root in relation to the total area of the chromatogram of HPLC, and in still other modalities, no more than about 3 percent area.

Applications; of Pharmaceutically Acceptable Compounds and Compositions The compounds of the present invention are useful for modulating and / or inhibiting the production of amyloid-beta peptide (1-42) in a patient. Accordingly, the compounds of the present invention are useful for treating, or for decreasing the severity of, disorders associated with production of amyloid-beta peptide (1-42) in a patient. The compounds, extracts and compositions, according to the method of the present invention, can be administered using any amount and any route of effective administration to treat or decrease the severity of a neurodegenerative disorder. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. In certain embodiments, the present invention provides a method for modulating and / or inhibiting the production of amyloid-beta peptide (1-42) in a patient, wherein the method comprises administering to the patient a compound of formula I, or a pharmaceutically acceptable composition comprising the compound. In other embodiments, the present invention provides a method for selectively modulating and / or inhibiting the production of amyloid-beta peptide (1-42) in a patient, wherein the method comprises administering to the patient a compound of formula I , or a pharmaceutically acceptable composition thereof. In still other embodiments, the present invention provides a method for reducing amyloid-beta (1-42) peptide levels in a patient, wherein the method comprises administering to the patient a compound of formula I, or a composition pharmaceutically acceptable thereof. In other modalities, The present invention provides a method for reducing the levels [of the amyloid-beta peptide (1-42) in a cell, which comprises contacting a cell with a compound of the formula! • Another embodiment provides a method for reducing amyloid-beta (1-42) in a cell without substantially reducing the levels of amyloid-beta peptide (1-40) in the cell, which comprises contacting the cell with a cell. composed of the formula I. Yet another embodiment provides a method for reducing amyloid-beta (1-42) in a cell and increasing at least one of amyloid-beta (1-37) and amyloid-beta (1-39) in the cell, which comprises in contact the cell with a compound of the formula I. As used herein, the term "reduction" or "reduce" refers to the relative decrease in the amount of an amyloid-beta achieved by administering a compound of the formula I compared to the amount of that amyloid-beta in the absence of the administration of a compound of formula I. In example rfianera, a reduction of amyloid-beta (1-42) means that the amount of amyloid-beta ( 1-42) in the presence of a compound of the formula I is less than the amount of amyloid-beta (1-42) in the absence of a compound of the formula I. In still other embodiments, the present invention provides a method to selectively reduce the levels of the amyloid-beta peptide (1-42) in a patient, wherein the method comprises administering to the patient a compound of the formula I, or a pharmaceutically acceptable composition thereof. In certain embodiments, the present invention provides a method for reducing amyloid-beta (1-42) peptide levels in a patient without substantially reducing the levels of amyloid-beta peptide (1-40), wherein the method comprises administering the patient a compound of the formula I, or a pharmaceutically acceptable composition thereof. In certain embodiments, the present invention provides a method for reducing amyloid-beta (1-42) peptide levels in a patient and for increasing at least one of amyloid-beta (1-37) and amyloid-beta (1-39). ), wherein the method comprises administering to the patient a compound of formula I, or a pharmaceutically acceptable composition thereof. The term "increase" or "increase", as used herein with reference to an amount of amyloid-beta, refers to the relative increase in the amount of an amyloid-beta achieved by administering a compound of formula I (or contacting a cell with a compound of formula I) compared to the amount of that amyloid-beta in the absence of the administration of a compound of formula I (or contacting a cell with a compound of the formula I). By way of example, an increase in amyloid-beta (1-37) means that the amount of amyloid-beta (1; -37) in the presence of a compound of formula I is greater than the amount of amyloid-beta ( 1-37) in the absence of an omponent of formula I. For example, the relative amounts of either amyloid-beta (1-37) and amyloid-beta (1-39) can be increased either by increased production of either amyloid-beta (1-37) and amyloid-beta (1-39) or by a decreased production of longer amyloid-beta peptides, for example, amyloid-beta (1-40) and / or amyloid-beta (1-42). In addition, it will be appreciated that the term "increase" or "increase", as used herein in reference to an amount of an amyloid-beta, refers to the absolute increase in the amount of an amyloid-beta achieved by administering a compound of the formula I. One skilled in the art will appreciate that the total ratio of amyloid-beta peptide is significant where the selective reduction of amyloid-beta (1-42) is especially advantageous. In certain embodiments, the present compounds reduce the total ratio of amyloid-beta peptide (1-42) or amyloid-beta peptide (1-40). Accordingly, another aspect of the present invention provides a method for reducing the ratio of amyloid-beta peptide (1-42) to amyloid-beta peptide (1-40) in a patient, which comprises administering to the patient a compound of the formula I, or a composition pharmaceutically acceptable thereof. In certain embodiments, the ratio of amyloid-beta peptide (1-42) to amyloid-beta peptide (1-40) is reduced from a range of about 0.1 to about 0.4 to a range of about 0.05 to about 0.08. In other embodiments, the present invention provides a method for reducing the ratio of amyloid-beta peptide (1-42) to amyloid-beta peptide (1-40) in a cell, which comprises contacting the cell with a compound of Formula I. In certain embodiments, the ratio of amyloid-beta peptide (1-42) to amyloid-beta peptide (1-40) is reduced from a range of about 0.1 to about 0.4 to a range of about 0.05 to about 0.08. . According to one aspect, the present invention provides a method for treating or decreasing the severity of a disorder associated with amyloid-beta peptide (1-42), wherein the method comprises administering to the patient a compound of formula I, or a pharmaceutically acceptable composition thereof. These disorders include neurodegenerative disorders such as Alzheimer's disease, 'Parkinson's disease and Down syndrome. In other embodiments, the present invention provides a method for treating or decreasing the severity of! Alzheimer's disease in a patient, where the method it comprises administering to the patient a compound of formula I, or pharmaceutically acceptable composition urjia thereof. Without wishing to be bound by any particular theory, it is believed that the present compounds are modulafores of gamma-secretase that selectively reduce the levels of amyloid-beta (1-42). Accordingly, another embodiment of the present invention provides a method for modulating gamma-secretase in a patient, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable composition thereof. In certain embodiments, the present compounds are inhibitors of gamma-ecrecrease. This method is useful to treat or decrease the severity of any disorder associated with gamma-secrese. These disorders include, without limitation, neurodegenerative disorders, for example Alzheimer's disease. The compounds of the invention are preferably formulated in the unit dosage form for ease of administration and uniformity of dosage. The term "two unit form" as used herein refers to a physically discrete unit i of agent appropriate for the patient being treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the physician who deals within the scope of the correct medical judgment. The specific level of Effective dose for any particular patient or organism and particulate will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; age, body weight, general health, sex and diet of the patient; the administration time, route of administration and the rate of excretion of the specific compound used; the duration of the treatment; drugs used in combination or coincident with the compound 'specific employee, and similar factors well known in medical techniques. The term "patient", as used in the present, means an animal, preferably a mammal, and more preferably a human.

Examples i The black snake root extract, used in the separation protocol described below, was obtained as '' a customer order from Boehringer Ingelheim Nutritionals. This extract is substantially equivalent to the USP preparation of black snake root extract (cohosh), in which approximately 50% ethanol is used 'watery' to extract root powder and then concentrate to almost dryness. As used herein, the numbers of compounds cited 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-triepoxy-26-hydroxy-9 , 19-cyclolanostan-3-yl. Also known as "acteína". C37H56011; Molecular weight: 676.83; Record 18642-44-9. 1 Compound 2: Cimigenol-3-β-D-xylopyranoside, C23H5609, molecular weight: 620.81; Record 27994-11-2. 2 Compound 3: Cimigenol-3-a-L-arabinoside, C35H5609, molecular weight: 620.81; Record 256925-92-5. 3 Compound 4: 24-0-acetylhydrosengmanol-3-ß-D-xylopyiyanoside. C37H60O11, molecular weight: 680.87; Registry 78213- ^ 2-8.

Compound 5: 24-0-acetylhydrosengmanol-3-a-L-arabinopyranoside. C37H60O11, molecular weight: 680.87. 1 Compound 6: 24-0-acetylhydrosengmanol-3-β-D-xylopyranoside (delta-16, 17) -enol-ether. C37H58O10, molecular weight: 662.85, 1 Compound 7: 24-0-acetylhydrosengmanol-3-a-L-arabinopyranoside (delta-16, 17) -enol-ether. C37H58O10, molecular weight: 662.85.

Compound 8: 24-epi-24-0-acetylhydrosengmanol-3-β-D-xylopyranoside. C37H60O11, molecular weight: 680.87.

Compound 9: 24-epi-24-0-acetylhydrosengmanol-3-ß-D-xylo pylifenoside (delta-16, 17) -enol-ether. C37H58O10, weight ! Molecular: 662.85.

Isolation Protocol 1 Instant column chromatography The extract of black snake root (15.6 g) was suspended in 150 ml of a 4: 1 (v / v) methanol-water mixture at 25 ° C. Using a mechanical stirrer, the resulting slurry was stirred vigorously for 30 minutes at this temperature, which resulted in a brown emulsion. To this emulsion, 51 g of silica gel (silica 32-63 ICN, 60 A) were added with continuous stirring. The mixture was concentrated at 25 ° C in vacuo using a rotary evaporator, until a largely homogenous beige brown powder was obtained. This material was subjected to column chromatography on silica gel (silica 32-63 ICN 60A) using a 60 cm long glass column with an inside diameter of 50 mm. In the preparation for the column chromatography, the silica gel was poured into 500 ml of a dichloromethane-methanol mixture of 20 to 1, and the resulting slurry was poured into the glass column. The gel silica was allowed to settle for 30 minutes, and covered with a thick layer of 1 cm of sand. Subsequently, the extract absorbed in the silica was poured into a 20 to 1 dichloromethane-methanol 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 mixtures under a pressure of 0.4 bar (argon): 1.0 ml of dichloromethane-methanol, 20 to 1, followed by 770 ml of dichloromethane-methanol, 10 to 1, followed by 800 ml of dichloromethane-methanol, 7 to 1, followed by 550 ml of dichloromethane-methanol 5 to 1. Eight fractions of 200 were collected. ml (marked as satl4-0 to satl4-7), followed by eleven 100 ml fractions (marked as satl4-8 to satl4-18). All fractions were analyzed by thin layer chromatography (TLC), using Bakerflex silica plates, eluted with a solvent mixture of dichloromethane-methanol 5 to 1. After development, the silica gel plates were stained with anisaldehyde Based on the results of the TLC analyzes, the satl4-9 to satl4-12 fractions were evaporated to dryness in vacuo at 25 ° C, and 10 mg samples of the fractions were analyzed by 1 H NMR spectroscopy, using CD3OD as solvent. See figures 1 and 2, respectively. The spectra were analyzed with respect to the presence of a multiplot broad at 2.53 ppm, and a doublet from 2.2 Hz to 4.86 ppm, because these signals are characteristic for compounds 7 and 6. Additionally, the dqf-COZY spectra of these four samples confirmed that the signals at 2.53 and 4.86 ppm they actually correspond to compounds 7 and 6. From the 1H NMR spectra of the satl4-10 fraction it was concluded that this sample contained the highest concentration of compounds 7 and 6, while slightly smaller amounts of these can be detected. compounds in the satl4- fraction 9. The satl4-ll fraction appeared to contain traces of 7 and 6, whereas these compounds can not be detected in the satl4-12 fraction. Based on these results, the satl4-10 fraction was chosen for further purification by HPLC. Alternatively, the satl4-9 fraction can be used to obtain additional amounts of compounds 4 through 7 as needed. The main component of the satl4-10 fraction was acteine (1) (JNP 2002, 65, 601-605), which crystallized from a metabolic solution of this fraction. Pure acheine was obtained through recrystallization. The main components of the satl4-ll fraction were cimigenol-beta-D-xylopyranoside (2) and cimigenol-alpha-L-arabinoside (3), which crystallized from this fraction as a mixture of approximately 2: 1 (JNP 2000, 65, 905-910, and 1391-1397).

Fractionation by Reverse Phase HPLC in Column C-18 i The satl4-10 fraction was dissolved in 3.5 ml of methane !. This solution was fractionated by HPLC using a SUPELCO Discovery RP-18 column (25 cm long, 10 mm inner diameter), and an AGILENT 1100 series HPLC system, including auto-injector and a used diode array detector. for the detection of wavelength from 190-400 nm.

I A gradient of solvents was extended, starting with 30% (v / v) i of methanol in methanol for the first two minutes, followed by a linear increase in water content reaching 100%. % m-ethanol at 20 minutes. After 2 minutes at 100% methanol, the water content was increased to 30% and maintained at that concentration for another 8 minutes. For the separation of the complete satl4-10 sample, 100 injections of 35 μl each were required. Nine fractions were collected, which were labeled satl-l until satl-5-9. See i figuraf 3 and 4, respectively. Compounds 4 to 7 were eluted in the satl5-1, 15-2, 15-4 and 15-5 fractions; the H-NMR spectra of the satl5-l, 15-2, 15-4 and 15-5 fractions are shown in Figures 4a and 4b.

Fractionation by reverse phase HPLC on column C-8 for The isolation of 6, 4 and 9 The satl5-5 fraction was dissolved in 3.5 ml of methanol. This solution was fractionated by HPLC using a column SUPELCO supelcosil LC-18 (25 cm long, 10 mm inner diameter), and the AGILENT 1100 series HPLC system, described above. A gradient of solvents was expanded, starting with 40% (v / v) of water in methanol during the first two minutes, followed by a linear decrease in water content reaching 100% methanol at 20 minutes. After 2 minutes to 100% methanol, the water content was increased to 40% and maintained at that concentration for 1 hour. another 8 minutes. For the separation of the complete satl5-5 sample, 50 injections of 30 μl each were required. Sie collected five fractions, which were marked satl6-1 to satl6-5 (Figure 5). Compound 6 was eluted in the satl-6 fraction, while compound 4 eluted in the satl-6 fraction. A small amount of 9 pure was obtained in the satl5-5 fra- tion. Figure 6 shows the XH NMR spectrum of lfs 9.8 mg of the pure 98% obtained.

Fractionation by Reverse Phase HPLC in Column C-8 for the Isolation of 8 The satl5-8 fraction was dissolved in 0.65 ml of methanol. This solution was fractionated by HPLC using a SUPELCO supelcosil LC-8 column (25 cm length, 10 mm internal diameter), and the AGILENT 1100 series HPLC system, described above. A gradient of solvents was expanded, starting with 40% (v / v) of water in methanol during the first two minutes, followed by a linear decrease in water content that reaches 100% methanol at 20 minutes. After 2 minutes at 100% methanol, the water content was increased to 40% and maintained at that concentration for another 8 minutes. Seven fractions were collected, which were labeled satl-l until satl-7-7. Compound 8 was eluted in the satl8-6 fraction. NMR spectroscopic analyzes including the NOESY spectra showed that in the methanolic solution compound 8 is interconnected with the corresponding ketone. Diluted methanolic solutions contain approximately 4% ketone and 96% hemiacetal form.

Fractionation by Reverse Phase HPLC in Column C-8 for Isolation of 7 and 5 'The satl5-2 fraction was dissolved in 0.5 ml of methanol. This solution was fractionated by HPLC using a SUPELCO supelcosil LC-8 column (25 cm length, 10 mm internal diameter), and the AGILENT 1100 series HPLC system, described above. A solvent gradient was amplified, starting with 40% (v / v) of water in methanol during the first two minutes, followed by a linear decrease in the water content reaching 100% methanol in 20 minutes.

After 2 minutes at 100% methanol, the water content was increased to 40% and maintained at that concentration for another 8 minutes. Five fractions were collected, which were marked satl9-3 to satl9-7. Pure compound 7 was obtained in the satl9-7 fraction, while pure compound 5 was obtained in the satl9-5 fraction.

Isolation Protocol 2 An alternative isolation / purification protocol is set forth below to isolate compound 6. One skilled in the art will recognize that as long as compound 6 is isolated, other compounds of the present invention become enriched and / or isolated. isolate by this process. The summary of this isolation process is depicted in Figure 7. The purification protocol used the following equipment: (a) Hitachi HPLC system with diode array detector (DAD) (b) Nova PrepMR 8000 semi-preparative column with remote PC controller using the LC application software ReSpondeMR (c) Hitachi L-7400 UV detector (d) Sedex 55 evaporative light scattering detector (EL ^ D) (e) Biotage 75L silica column (KP-Sil; P / N FKO-1107-19073; Lot 027075L ); (f) column C18 75L Biotage (Bakerbond, 40 μ) (g) column C18 75S Biotage (Vydac, 40 μ) (h) analytical HPLC column: Phenomenex Luna C18, 3μ, 4.6¡ x 100 mm (i) semi-preparative HPLC column: Phenomenex Luna C81 HPLC column, 20 x 250 mm (j) semi-preparative HPLC column: YMC AQ C18 HPLC column, 21.2 x 250 mm; and i (k) preparative HPLC column: preparative HPLC column C18 ES Industries; 5 x 25 cm. The analytical method used to determine the purity of compound 6 is as follows: Column: Phenomenex Lunz C18, 3μ, 4.6 x 100 mm Mobile phase Isocratic elution with 35% A. acetonitrile; B. 30% nanopure water containing 0.05% acetic acid; and C. MeOH at 35 Flow rate: 1 mL / min Detection: 205, 230 nm, DAD; and ELSD Running time: 8 min Column temperature 32 ° C This method was used for the analysis of the extract, fractions and the final product. Compound 6 is eluted to I about 5.5 minutes under these conditions. 50 g of the crude black snake root extract ("BCE") were fractionated in a Biotage silica cartridge (7.5 x 5 30 cm). After loading, the cartridge was eluted with 5% MeOH / DClJ4 (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 presented in fractions 23 (2.6 g) and 24 (2.3 g). The 10 fraction 23 (F23) was selected for further purification in I a C8 semi-prep column. Ten runs were made to obtain approximately 10 mg of compound 6. 50 mg of F23 erji 0.3 ml of MeOH was loaded onto a semi-preparative column Phenomenex Luna C-8 (21.2 x 250 mm, 10 μA, 100 A). The column was eluted at a flow rate of 9.9 mL / min with 70% MeOH in H0 with UV monitoring at 205 nm. The peaks eluting at 35 min and 38 min as shown in the semi-prep HPLC trace (Figure 8) were collected separately. 20 The fractions collected for the peak at 35 min of the 10 runs were mixed and the solvents were evaporated at room temperature. The resulting solids were dried in a lyoifilizer to yield 10.3 mg of compound 6 (2609-165-7). The HPLC (Figure 9) of product 2609-165-7 revealed a , r? D peak polar impurity (11.3%) with a retention time (RT) a, 4.5 min, although the HPLC of individual fractions showed only one major peak (Figure 10). Apparently, compound 6 was slowly converted during the process to a more polar compound. The more polar compound was found to be derived from deacetyl of compound 6 as is evident from SSI-MS which showed an intense peak of [M + Na] + at m / z 643 (Figure 11) and proton NMR (Figure 12) of the impurity isolated at 4.5 min in which the singlet was absent for acetyl-methyl. A few stability experiments with compound 6 indicated that the deacetylation that occurred in the MeOH solution is slightly basic. However, it was stable in slightly acidic solution. Therefore, 2609-165-7 was re-processed in the Luna C8 column using 70% MeOH / 30% water containing 0.05% AcOH as eluent to give 3.4 mg of compound 6 (2609-172-11) . An HPLC chromatogram of 2609-172-11 is shown in Figure 13. Proton NMR (in CD3OD) and SSI-MS are shown in Figures 14 and 15. In another process, 250 g of root extract was stirred. of black snake (BCE) with 1250 mL of MeOH for 1 hour at room temperature in a laboratory beaker. Not all solids were dissolved, but HPLC analysis of a filtrate indicated that all compound 6 in the start extract was dissolved (approximately 250 mg). However, the Unfiltered mixture was added to 750 g of silica gel (ICN, 60-200 μm) in a 5 L round bottom flask. The MeOH was removed in the rotoevaporator with the aid of vacuum to a dry powder weighing 1100 g with residual MeOH at 9%. The dried ECB in the silica preparation was divided into four parts of approximately 270 g each. The mixture was charged to the SIM and was first washed with 500-600 mL of methylene chloride to remove non-polar and residual MeOH. The SIM was connected to the 75 L silica column (KP-Sil; P / N FKO-1107-19073; Lot 027075L; 7.5 x 25 cm or 1750 mL). The main column was radially compressed at 60 lbs / in2. The system was eluted with acetone at a flow rate of approximately 100 mL / min, and fractions of 500-1000 mL were collected. After elution of compound 6, the column was washed with 1.0 L of MeOH and re-equilibrated with 2 L of acetone. Compound 6 was observed to elute mainly fraction 3 (1000 mL) after approximately 900-1000 mL of acetone eluted from the column of fractions 1 and 2. The first four runs yielded approximately 224 mg of compound 6. A second batch of starting material was prepared for the Biotage silica of 100 g of BCE and 500 mL of MeOH and 300 g of silica. Two additional Biotage runs (5 and 6) were made similar to the first four with that starting material that produced another 93 mg of compound 6. The mixtures of the product of the six Runs were combined and evaporated to a dry solid under reduced pressure. The dry solids (90 g) of the Biotage silica were dissolved in 720 mL of MeOH and 480 mL of H20 were added slowly with stirring. Some dark tar-like solids were precipitated and removed on a filter. The cloudy filtrate was loaded onto a C18 75L column (7.5 x 25 cm) Bakerb? Nd 60 Á, 40 μ Biotage. After loading, which tested negative for compound 6, the column was washed with 5 L MeOH I at 60% (v / v) / H20 followed by 4 L of 70% MeOH / H20, and eluted with compound 6 using 4 L of 80% MeOH / H20.

After elution, the column was washed with 2 L of MeOH. The flow rate was approximately 60 mL / min throughout and the mobile phases of MeOH / H20 contained 0.05% acetic acid in order to prevent the degradation of compound 6. The mixture of the compound (4 L) concentrated under reduced pressure until essentially all the MeOH was removed and the resulting precipitated solids were collected in a Buchner funnel and dried with high vacuum at room temperature. The tar-like solids removed by filtration of the first large-scale C18 feed preparation and containing about 32 mg of compound 6 were dissolved in 2 L of MeOH wash of the experiment on a large scale and contained approximately 22 mg of compound 6. The mixture was evaporated to 1 L and mixed with 0.67 L of water. Some precipitated tar solids that were collected on a filter were dissolved in 200 | mL of MeOH, and mixed with 134 mL of water. This mixture was also filtered to remove a small amount of tar and the filtrate was combined with the first filtrate and loaded onto a C18 75S (7.5 x 9.0 cm; 400 mL) Vydac 300 Á, 40 μ Biotage column. The column was washed with 1 L of MeOH at 60 % / H20 and 2 L of 70% MeOH / H20, and eluted with 1 L of 80% MeOH / H20 (mobile phases also contained acetic acid ! 0.05%). The product mixture was evaporated and the solids were collected by filtration similar to the large-scale Biotage experiment. The first product mixture (16.69 g) of the C18 Biotage column was mixed with 70 mL of MeOH. The mixture was treated with ultrasound, and the precipitate was removed by filtration. The filtrate was chromatographed (five runs, 14 mL each) on an ES Industries Chromegabond R C18 column at a flow rate of 177 mL / min using 70% MeOH / 30% gua containing 0.05% AcOH as eluent. The fractions of minutes 6-14 of each run were combined, and evaporated to remove MeOH. The precipitate after MeOH removal was collected by centrifugation, and dried in a lyophilizer to give 6.6 g dry solids, 2609-173-16 (compound 6, 3.2%).

The second product mixture (4.3 g) of the column C18 Bicjtage was processed in a similar manner to give 2.05 g dry solids 2609-173-27 (compound 6, 3.06%). 2609-173-16 and 2609-176-27 were combined to produce 8.6 g of 2609-174-6. 2609-174-6 (400 mg) was dissolved in 1.3 mL of MeOH containing 0.1% AcOH. The solution was loaded onto a Phenomenex Luna C8 column which was eluted at a flow rate of 24 mL / min with 68% MeOH / 32% water containing 0.05% AcOH. Based on the analytical HPLC, the fractions from 15.8 to 19.8 minutes of each run were combined (22 runs in total), evaporated to remove the MeOH, and lyophilized to dryness to give 2609-174-28 (1.4 g containing 12.6% of compound 6). 2609-174-28 was used for the final isolation of compound 6 on a YMC-AQ C18 column. A total of 28 runs were made. 2609-174-28 (50 mg) was dissolved in 0.25 mL of MeOH containing 0.1% AcOH. The solution was injected into the 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 profiles, the selected fractions, typically between 48.4-50.4 minutes, of the 28 runs were mixed, evaporated and lyophilized to yield compound 6 (2609-176-30, 85 mg).

The fractions that were collected immediately before 48.4 minutes and contained mainly compound 6 were also combined, and dried to give 2609-176-35 (50 mg). 2609-176-35 (3 runs) was re-processed using the same column and mobile phase to produce another batch of compound 6 which was combined with 2609-176-30 to give 102 mg of the product (2609-177-10) with approximately 95% chromatographic purity. The HPLC chromatograms (UV at 205, 230 nm and ELSD) and the NMR spectrum of the proton of compound 6 (2609-176-10) are shown in Figures 16, 17, 18 and 19, respectively. The proton NMR of 2609-176-10 was consistent with that of a normal sample of compound 6. The SSI-MS of compound 6 (Figure 20) showed an intense peak [M + Na] + at m / z 685 consistent with the molecular formula C37H58O? o of compound 6.

Biological Assays A. Assay to Determine the Capacity of a Compound of the Formula I for Inhibiting Aß-42 The compounds of the present invention, and extracts comprising these compounds, can be evaluated as inhibitors of amyloid-beta peptide (1-42) in vi tro or in vivo. These test methods are described in detail in U.S. Patent No. 6,649,196, all of which are hereby incorporated herein by reference. reference. The compounds of the present invention were found to selectively decrease the amyloid-beta (1-42) peptide according to the cell-based assay performed in substantially the same manner as described in US 6,639,196.

B. Ens to Determine the Capacity of a Compound of Formula I to Affect the Ratio of Total Aβ The compounds of the present invention were evaluated to determine their effect on the total ratio of amyloid-β peptide (1-42) in vi using a test protocol substantially similar to that described by Wang et al, J. Biol. Chem. 1996, 50: 31894-31902, The Profile of Soluble A yloid ß Protein in Cultured Cell Media, the entirety of which is hereby incorporated herein by reference. This assay quantifies the amyloid-β protein using immunoprecipitation and mass spectrometry (IP-MS). Using compound 6 to exemplify, this compound was found to reduce amyloid-β peptide (1-42), while increasing amyloid-β peptide (1-37) and amyloid-beta peptide (1-39). These results are shown in Figure 21. Compound 6 was also evaluated according to the method; described in Wang et al, in 7W cells (APPwt) and cells TPA2 (ÁPPV I-7F) • APP717 mutations increase the relative amount of amyloid-β peptide (1-42). In this test, compound 6 was shown to reduce amyloid-β (1-42) peptide while increasing amyloid-β (1-39) peptide. These results are depicted in Figure 22. While various embodiments of this invention have been described, it is evident that the present basic examples can be altered to provide other embodiments utilizing the compounds and methods of this invention. Therefore, it will be appreciated that the scope of the invention will be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. It is noted that in relation to this date, the best method known by the applicant to bring the invention into practice, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of the formula I: I or a pharmaceutically acceptable salt thereof, characterized in that: each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic; G is S, CH2, NR, or O; R1 and R2 are each independently halogen, R, OR, a (suitably protected hydroxyl group, SR, a suitably protected thiol group, N (R) 2, or an appropriately protected amino group, or R1 and R2 are taken together to forming a saturated or partially unsaturated aryl ring of 3-7: members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, each R is independently hydrogen, a C-group optionally substituted ealiphatic, or a saturated, partially unsaturated, 3-8 membered aryl ring, optionally substituted having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein: two R on the same nitrogen atom are taken optionally together with the nitrogen atom to form a saturated or partially unsaturated aryl ring of 3-8 membered having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; n is 0-2; R3, R4, R7, and R8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, 0S02R, N (R) 2, an appropriately protected amino group, NR (C0) R, NR (C0) (C0) R, NR (C0) N (R) 2, NR (C0) 0R, (COOR 0 (C0) R, (CO) N (R) 2, or O (CO) N (R) 2; m is 0-2; R5 is TC (R ') 3, TC (R') 2C ( R ") 3, R, OR, or a suitably protected hydroxyl group, SR, a suitably protected thiol group, S02R, 0S02R, N (R) 2, an appropriately protected amino group, NR (CO) R, NR (CO) (C0) R, NR (C0) N (R) 2 NR (CO) (j) R, (CO) OR, 0 (C0) R, (CO) N (R) 2 or 0 (CO) N (R) 2, or: when R5 is TC (R ') 3 , or TC (R ') 2C (R ") 3, then R6 and a group R' in R5 are optionally taken together to form an aryl ring saturated or partially I insatured from 3-8 members that has 0-2 heteroatoms i independently selected from nitrogen, oxygen or sulfur; each T is independently a valence bond or a saturated or unsaturated, straight or branched C, _6 alkylidene chain, optionally substituted wherein up to two i methylene units of T are optionally and independently replaced by -O-, -N (R) -, -S-, -C (O) -, -S (O) -, or -S (0) 2-; ¡each R 'and R "is independently selected from R, OR, SR, S02R, OS02R, N (R) 2, NR (CO) R, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) OR, (CO) OR, 0 (CO) R, (CO) N (R) 2, or O (CO) N (R) 2; ! R6 is halogen, R, OR, SR, S02R, OS02R, N (R) 2, NR (CO) I ^, NR (CO) (CO) R, NR (CO) N (R) 2, NR (CO) OR, (CO) OR, 0 (CO) R, (CO) N () 2, u 0 (CO) N (R) 2; R9 and R9 'are each independently selected from halogen, R, OR, SR, or N (R) 2, or R1 and R2 are taken together to form a saturated or partially unsaturated 3-7 membered aryl ring having 0 -2 heteroatoms independently selected from nitrogen, oxygenate or sulfur; Q is a valence bond or a chain of C? _ 6 saturated or unsaturated alkyl, straight or branched, optionally substituted where up to two units of Methylery of Q are optionally and independently replaced by -O-, -N (R) -, -S-, -C (O) -, -S (O) -, or -S (0) 2-; and R10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, an appropriately protected amino group, an optionally substituted saturated or partially unsaturated monocyclic aryl ring of 3-8 members having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, an optionally substituted saturated or unsaturated 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a detectable moiety, a polymer residue, a peptide, a moiety contains sugar or sugar type, with the proviso that the compound is different from: 2. Compound according to claim 1, characterized in that: G is O; and R1 and R2 are each independently R or OR. Compound according to claim 2, characterized in that R1 and R2 are each independently R, wherein R is hydrogen or an optionally substituted Ci-β-alpha group. 4. Compound according to claim 2, characterized in that R1 and R2 are taken together to form a saturated or partially unsaturated aryl ring of 3-6 members having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 5. Compound according to claim 1, characterized in that: is T-C (R ') 3, or T-C (R') 2C (R '•; 3; each T is independent of a valence bond or a straight or branched C? -alkylidene chain, where a 'Methylene unit of T is optionally replaced by -O-, -N (R) -, or -S-; Y each R 'and R "is independently R, OR, OC (0) R, SR, or N (R) 2. 6. Compound according to claim 5, characterized in that R5 is TC (R ') 3, or TC (R') 2C (R ") 3, and R6 and a group R 'in R5 are taken together to form a 5-7 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; 7. Compound according to claim 6, characterized in that the compound is of the formula Ilia or Ilb: Ha? Lb. 8. Compound according to claim 1, characterized in that: Q is a saturated or unsaturated, straight or branched C? _2 alkylidene chain, optionally substituted wherein; up to a methylene unit of Q is optionally replaced by -O-, -N (R) -, or -S-; and R10 is glycoside. 9. Compound according to claim 8, characterized in that Q is -O- and R > It is an arabinopiranoside or a xylopyranoside. 10. Compound according to claim 1, characterized in that the compound is of the formula I-a: or a pharmaceutically acceptable sjal thereof. 11. Compound according to claim 1, characterized in that the compound is of the formula I-b or I-c: l-b l-c or a pharmaceutically acceptable salt thereof. 12. Compound according to claim 1, characterized in that the compound is of the formula II or II-a: II H-a or a pharmaceutically acceptable salt thereof. 13. Compound according to claim 1, face characterized in that the compound is of formula IV: or a pharmaceutically acceptable thereof. 14. Compound according to claim 13, characterized in that the compound is of the formula IV-a or IV-b: IV-a IV-b or a pharmaceutically acceptable salt thereof. 15. Compound according to claim 14, characterized in that R1 and R2 are taken together to form a saturated 3-6 membered carbocyclic ring and R7 is -OH. 16. Compound according to claim 1, characterized in that the compound is selected from: MY I-lí or 1-13. 17. Compound according to claim 13, characterized in that the compound is selected from: 18. Compound according to claim 1, characterized in that the compound is substantially free of other compounds present in the black snake root. ! 19. Compound in accordance with the claim 18, characterized in that the compound is substantially Free one or more of acteol, acetylacteol, 26-deoxyacteol, cimigerjiol, acteína, 26-deoxiacteina, and cimicifugosido. 20. Composition, characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 21. Communication, characterized in that it comprises a compound according to claim 18, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 22. Extract of black snake root, characterized in that the extract comprises at least 10% by weight of a compound according to claim 1. 23. Extract according to claim 21, characterized in that the extract comprises from about 10% by weight to about 50% by weight of a compound according to claim 1. 24. Method for inhibiting production of amyloid-beta peptide in a patient, characterized in that the method comprises administering the A composition according to claim 20. 25. Method for inhibiting the production of amyloid-beta peptide (1-42) in a patient, characterized in that it comprises administering to the patient a composition according to claim 21. i. according to claim 25, characterized in that the levels of amyloid-beta peptide (1-42) are reduced and the amyloid-beta (1-40) peptide levels are not substantially reduced. 27. Method according to claim 25, characterized in that the level of at least one of amyloid-beta (1-37) and amyloid-beta (1-39) is increased. 28. Method for treating or reducing the severity of a disorder associated with amyloid-beta peptide (1-42), characterized in that the method comprises administering to a patient a composition according to claim 20. 29. Method according to claim 28, characterized in that the disorder is Alzheimer's disease, Parkinson's disease or Down syndrome. , 30. Method for reducing the levels of amyloid-beta peptide (1-42) in a patient, characterized in that the method comprises administering to the patient a composition according to claim 20. 31. Method for reducing amyloid peptide levels; e-beta (1-42) in a cell, characterized in that it comprises contacting a cell with a compound according to claim 1.