WO2000077030A1 - Statine-derived tetrapeptide inhibitors of beta-secretase - Google Patents
Statine-derived tetrapeptide inhibitors of beta-secretase Download PDFInfo
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- WO2000077030A1 WO2000077030A1 PCT/US2000/016643 US0016643W WO0077030A1 WO 2000077030 A1 WO2000077030 A1 WO 2000077030A1 US 0016643 W US0016643 W US 0016643W WO 0077030 A1 WO0077030 A1 WO 0077030A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention is directed to compounds useful in treatment of Alzheimer's disease and more specifically to compounds that are capable of ⁇ -secretase enzyme inhibition, thus interfering with cleavage of amyloid precursor protein to produce beta-amyloid, a major component of the amyloid plaques found in the brains of Alzheimer's sufferers.
- AD Alzheimer's disease
- Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and amyloid (or neuritic) plaques.
- Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders, while amyloid plaques are peculiar to AD. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD.
- Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D).
- a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
- Neurofibrillary tangles are characterized as networks of microtubules and microfilaments which were once structural supports running symmetrically through the nerve cells that transported nutrients but have degenerated into dysfunctional tangled masses. They can be described histologically as non-membrane bound bundles containing paired, helically wound filaments (PHF) that are approximately 10 nm in length and located in the pe ⁇ nuclear cytoplasm of certain neurons
- PEF-tau highly phosphorylated tau proteins of 60 kDa, 64 kDa and 68 kDa
- a ⁇ peptide is also a component of these tangles Tau belongs to the family of microtubule- associated proteins and plays a role in the microtubule assembly and stabilization
- PHF paired, helically wound filaments
- Amyloid plaques are peculiar to and a defining feature of AD
- Amyloid plaques are predominantly composed of amyloid beta peptide (A ⁇ , also sometimes designated as ⁇ A4)
- a ⁇ is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-43 ammo acids
- secretases l proteases l are involved in the processing of APP It appears that the abnormal processing and deposition of A ⁇ in areas of the brain responsible for cognitive activities is a major factor in the development of AD Cleavage of APP at the N-termmus of the A ⁇ peptide by ⁇ - secretase and the C -terminus by one or more ⁇ -secretases constitutes the amyloidogenic pathway, I e , the pathway by which A ⁇ peptide is formed Cleavage of APP by ⁇ - 0 secretase and the same or a different gamma secretase produces ⁇ -sAPP.
- a ⁇ amyloidogenic proteins
- CSF cerebrospinal fluid
- the A ⁇ peptide in amyloid plaques is always folded in a particular three-dimensional pattern called a beta-pleated sheet and appears to be chemically modified as well, which could explain the association of the A ⁇ peptides into the larger, denser plaques, rather than the diffuse deposits normally seen.
- Associated with this central core of A ⁇ peptide in the amyloid plaque are surrounding abnormal neurites and several types of altered glial cells. Glial cells normally associate with neurons and perform support and protective functions.
- On the outside of the plaque are reactive astrocytes, which are a type of glial cell typically found in injured brain areas. Additionally many other biochemical components, including enzymes, proteoglycans and apolipoproteins are present in the plaques.
- biochemical components including enzymes, proteoglycans and apolipoproteins are present in the plaques.
- a ⁇ peptide is neurotoxic in itself or if the secondary features of the amyloid plaques, e.g., the abnormal glial cells, cause the nerve cells to die.
- the A ⁇ peptide has neurotoxic effects in vitro.
- the 25-35 amino acid sequence of A ⁇ peptide is similar to that of substance P, an endogenous neuropeptide compound present in certain brain tissues and having neuroexcitatory effects.
- Co-administration of substance P in the study blocked the neurotoxic effect of A ⁇ peptide in rats. See: An in vivo model or the neurodegenerative effects of beta amyloid and protection by substance P.
- This invention is directed to the discovery of a class of compounds that inhibit ⁇ -amyloid peptide production by preferentially binding to and inhibiting the proteolytic function of the ⁇ -secretase enzyme. Inhibition of ⁇ -secretase enzyme stops or reduces the production of A ⁇ from APP and thus reduces or eliminates the formation of amyloid plaques and other types of A ⁇ deposition in the brain. Therefore, the compounds are useful in the prevention of Alzheimer's Disease in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further dete ⁇ oration in their condition. Now it has been discovered that the compounds of the present invention provide inhibitors of the ⁇ - secretase enzyme.
- the invention relates to compounds of formula 1
- A is a straight or branched chain alkanoxy or alkenoxy of 1 to 5 carbon atoms, aryl, arylalkyl, the aryl being optionally substituted with 1 to 2 carbon atoms or halogen, adamantyloxy, or 4-ammobutano ⁇ c acid,
- B is selected from the group consisting of hydroxy.
- a dithered line represents a point of attachment at B of formula 1 ,
- D is H or an oxo group
- L is a 5 or 6 membered saturated, unsaturated or aromatic heterocycle having from 1 to 3 heteroatoms chosen from nitrogen, oxygen or sulfur, or a saturated, unsaturated or aromatic carbocycle of 3 to 6 carbon atoms, any group represented by L having optional substitution with R', OR', or halogen, Q is a bond, or is a straight chain linking group of 1 to 3 non-hydrogen atoms chosen from the group consisting of-CH 2 -, -O-, and -NH- wherein O and N may not be adjacent, ⁇ ng M is a stable 5 to 7-membered saturated, unsaturated or aromatic heterocycle having ⁇ up to 2 additional N atoms and optionally having 1 to 2 atoms of O and S,
- T is independently selected from the group consisting of H, OH, NO?, C(O)N(R) 2 , F,
- Ci-Ci alkoxy, hydroxymethyl and CF 3 wherein at least one T is other than H, x is an integer of 1 to 3, y is an integer of 1 to 6,
- R' is independently H, -OH, C
- R is independently H, d- C alkyl, or phenyl, and E is H. or Ci-C ? alkyl,
- R is C-C- alkyl
- R 2 is 2-propyl, 2- methylpropyl- or phenyl optionally substituted with R', OR' or halogen,
- R 3 is phenyl, CpC-, alkyl, or l-(2-methylth ⁇ o-)ethyl-,
- R is 2-propyl, 2-butyl or 2-methylpropyl, and stereoisomers, hydrates or pharmaceutically acceptable salts or esters thereof to 0 reduce the formation of A ⁇ peptide
- Natural amino acids are available in abundance, and a great array of non-naturally 0 occu ⁇ ng ammo acids have been prepared by techniques well known to those skilled m the art of organic synthesis Roberts and Vellaccio provide a comprehensive listing of non- natural amino acids, and techniques for the synthesis of many - ariations thereof m The Peptides, Vol 5 Analysis, Synthesis, Biology, Academic Press.
- Statme is a non-standard ammo acid residue present m pepstatin that provides this peptide its inhibitory activity (Rich, D H , J Med Chem 28, p 262 (1985) Interestingly, pepstatin has no inhibitory activity in assays with ⁇ -secretase Statme has the chemical
- Some of the compounds descnbed herein contain one of more asymmetric centers and may thus e nse to enantiomers, diastereomers, and other stereoisometnc forms which 0 may be defined in terms of absolute stereochemistry as (R)- or (S)- .
- Stereoisomers refer to molecules wherein the same atoms attach to one other in the same order, but the positioning of the attachment vanes so that two molecules may not be spatially identical, they are classified according to the number and symmetry of the chiral centers m each molecule Chiral centers are atoms to which the same kinds of atoms are attached but have more than one possibility for arrangement around the chiral center l ⁇ atom
- Diastereomers are two molecules which are stereoisomers that have the same connectivity but are not mirror images of each other Chiral centers in diastereomers are ananged so that an internal plane of symmetry exists m the molecule
- the chemical and physical 1" properties of diastereomers tend to differ because different spatial shape changes the ways in which the molecules interact
- Enantiomers are two molecules which are exact minor images of one other, because each chiral center is a reflection of the chiral center of the other enantiomer Enantiomers 20 have identical chemical and physical properties, which make separations based on their physical properties extremely difficult Enantiomers are usually labeled R and S (for nght-handed and left-handed) to distinguish them
- Racemic mixtures are defined as mixtures of two minor image forms of the same - ⁇ molecule (enantiomers) in equal amounts
- stereoisomers may not vary greatly on a chemical level, on the biological level, different stereoisomers isomers "fit" differently into the vanous protein receptors that e biochemical processes and thus stereoisomers, and frequently even enantiomers, do "0 not bind equally Therefore, enantiomers of the same compound can have different effects w ithin the human body
- each ⁇ -ammo acid has a charactenstic "R-group".
- R-group being the residue -or side chain- attached to the ⁇ - carbon atom of the amino acid.
- the residue of glycine is H, for alanine it is methyl, for valine it is 2-propyl, for methionine it is methylthioethyl.
- the specific residues of the naturally occurring ⁇ -amino acids are well known to those of skill in the art. See, e.g, A. L.
- residues of naturally occurring ⁇ -amino acids are the residues of those about twenty ⁇ -amino acids found in nature which are inco ⁇ orated into a protein by the specific recognition of the tRNA molecule with its cognate m NA codon in humans.
- 2-aminobutyric acid Abu
- phenylglycine Phg
- amino acids of this type a change is made in the side chain of the amino acid, usually by varying the length or substitution thereon.
- 2- aminobutyric acid is an ⁇ -amino acid that varies from valine by the removal of one of the methyl groups from the side chain.
- Phenylglycine is a homolog of the naturally-occurring amino acid phenylalanine, which lacks the methylene linkage between the peptide backbone and the phenyl group found in phenylalanine.
- Norleucine is a slightly different example where the branching methyl group of leucine is shifted rather than deleted to make a non-branching (normal) chain having the same number of carbon atoms as leucine.
- These unusual amino acids can be inco ⁇ orated into peptide chains using the standard peptide linkage synthetic procedures described below for the naturally-occurring amino acids.
- alkyl includes the straight, branched-chain and hydrocarbons, the number of carbons atoms being generally specified. Where not specified the alkyl groups preferably contain from about 1 up to about 12, more preferably 1 to 6. and most preferably 1 to 5 carbons. Exemplary of such moieties are methyl, ethyl, n-propyl. isopropyl, n-butyl, t-butyl, sec-butyl, pentyl, n-hexyl, n-nonyl, n-decyl, and the like.
- lower alkyl includes Ci -Cs alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, and the like.
- heteroatom(s) is/are selected from O, N or S, unless otherwise specified.
- alkenyl moieties are 2-methyl-2-propenyl, 2-methyl-l-propenyl, propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 2,2-difluoroethenyl, as well as those straight and branched chained moieties having more than one double bond.
- lower alkyl includes Ci -C 5 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, and the like.
- halo and halogen refer to chloro, bromo, fluoro, and iodo.
- “Lower alkenyl” refers to those C 2 -C 6 unsaturated groups such as vinyl, l-propene-2-yl, 1 -butene-4-yl, l-pentene-5-yl, 2-methyl-2-butene-4-yl and the like.
- alkanoxy refers to those groups having an alkyl moiety from 1 to 6 carbon atoms linked to an oxygen atom. This oxygen is linked to the carbon atom of another group. Examples of alkanoxy groups are: methoxy, ethoxy, propoxy, butoxy, iso-butoxy, and the like.
- alkenoxy includes C 2 -C 6 groups having a C-C double bond and an oxygen atom, such as ethenyloxy, propenyloxy, iso-butoxyethenyl and the like.
- amine includes pirmary, secondary and tertiary amine which may be in straight or branched chains or, in the case of secondary and tertiary amines within rings, and are optionally substituted with, C ⁇ -C acyloxy, Ci -C 6 alkyl, C] -C 6 alkoxy, nitro, carboxy, carbamoyl, carbanoyloxy, cyano halogen, amino and the like.
- carboxyl is all terms referring to functional groups containing the a carbon atom double bonded to an oxygen as well as single bonded to another oygen. in the case of carbamoyl the carbon is addionally bonded to a nitrogen atom. These terms all include the corcesponding pharmaceutically acceptable C, -C alkyl and aryl esters.
- aryl includes 3 to 8 membered stable saturated or unsaturated organic monocyclic rings having 0 to 4 hetero atoms selected from S, O, and N; and 7 to 10 membered organic stable, saturated or unsaturated, bicyclic rings having 0 to 5 hetero atoms selected from S, O, N; both of which may be substituted by halo, Ci -C 6 alkyl, Ci - C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted Ci -C alkyl, d -C 6 substituted alkoxy, substituted C2 -C 6 alkenyl, or substituted C2 -C alkynyl, hydroxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, Ci -C 4 alkylthio, Ci -C 4 alkanoyloxy, carbamoyl, or halo-substituted Ci -C 6 alkyl.
- aryl also includes fused ring carbocyclic and heterocyclic moieties having at least one aromatic nucleus.
- arylalkyl refers to any of the above aryl groups also having an alkyl radical though which the group connects to the larger structure.
- Prefened aryl and aralkyl moieties are phenyl, benzyl, phenethyl, 1- and 2-naphthyl, naphthylmethyl, 5-, 6-, 7-, and 8- quinolinyl, benzofuryl, indenyl, or indanyl, benzimidazolyl, indolyl, benzothiophenyl, indole-3 -ethyl and 5-, 6-, 7-, and 8-tetrahydroisoquinoline.
- Other examples of such ring systems may be found in J. Fletcher, O. Dermer, R. Fox, Nomenclature of Organic Compounds, pp. 20-63 (1974), and in the Examples herein.
- substituted alkyl, substituted alkenyl, substituted alkynyl and substituted alkoxy are these radicals substituted with halogen, hydroxy, amino, Ci -C 7 acyloxy, nitro, carboxy, carbamoyl, carbamoyloxy, cyano, or Ci -C 6 alkoxy, and may be substituted one or more times with the same or a different group, preferably substituted 1 to 3 times.
- a linking group is defined as a divalent linear chain facilitating the reach of a binding group, for example a carboxyl group to binding sites within the target enzyme.
- the facilitation occurs as a result of either or both the extension of the group at a particularly advantageous distance from another binding site on the molecule or in providing an advantageous flexibility to the group in being able to adopt a conformation that allows for optimal binding.
- a pharmaceutically acceptable salt is any salt which substantially retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered Such salts are those formed with pharmaceutically acceptable cations, e g , alkali metals, alkali earth metals, etc
- a pharmaceutically acceptable ester is any ester formed on a parent carboxyhc acid which substantially retains the activity of the parent compound and does ⁇ not impart any deletenous or undesirable effect on the subject to whom it is administered and in the context in which it is administered
- a pharmaceutically acceptable excipient or diluent is any excipient which retains the activity of the therapeutic compound with which it is admixed and does not impart any deletenous or undesirable effect on the subject to whom it is administered and in the context in which it is administered 0
- EDC ethyl- l-(3-d ⁇ methylam ⁇ nopropyl)carbodnm ⁇ de 0
- TFA tnfluoroacetic acid
- THF tetrahydrofuran >
- N-termmal or N-terminus refer to that terminal or end group of a peptide beanng the free or denvatized ammo group of an amino acid residue
- C- terminal or C-terminus refers to that terminal or end group of a peptide beanng the free or derivatized carboxy group of an amino acid residue.
- capping group refers to a non-amino acid moiety bonded to the C- or N-terminal of the peptide chain. Examples of N-terminal capping groups used in peptide synthesis are BOC (t-butoxycarbonyl,) and CBZ (benzyloxycarbonyl) and glutamic acid. Other capping groups are acetyl and adamantyloxycarbonyl. Non-limiting examples of are shown in Table 1.
- Reaction scheme 1 illustrates the construction of some of the peptides provided herein and the variety of reactions that may be used to prepare intermediates from which compounds for formula 1 may be prepared, and provides a generic method for the synthesis of the tetrapeptides.
- statine and valine are employed as the N-terminal amino acids. It is to be understood that other peptides may be also be substituted in place of valine and that derivatives of statine may be employed as alternatives in the steps below to provide further tetrapeptides as provided herein.
- Step A Coupling of the C-terminal amino acid with statine.
- Boc-Sta(s) ( 1.0 equiv.) was dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-Val-OBzl .HCl (1.0 equiv.) and TEA (5 equiv.) were added and the mixture was sthred for 20 minutes. EDC (1.2 equiv.) was then added and allowed to stir overnight under an atmosphere of nitrogen. The reaction was diluted with water and extracted with EtOAc (3x). The organic layers were washed with aqueous citnc acid (2x), sat. NaHCO3 (2x), brine, then dried with MgSO 4 .
- Step B Removal of the Boc-protecting group from the resulting dipeptide.
- the Boc-protecting group of the dipeptide was dissolved in a trifluoroacetic acid/methylene chloride (1/1) solution. The reaction was monitored by TLC to confirm the consumption of starting material at which time the solvents were removed under vacuum to yield the free amine which was used without further purification.
- Step C Coupling deprotected amine with a selected amino acid residue (AAi).
- Boc-AAi-OH (1.0 equiv.) is dissolved in 30 mL of dry dichloromethane, then HOBT
- Step D Coupling of the tripeptide with a selected amino acid residue (AA 2 ).
- Step E Removal of the Carboxybenzyl (Cbz) protecting group from the C- terminus R-AA.-AArStat-Val-OBz ( 1.2 g) is dissolved in 100 ml of MeOH and Pd/C (l g, 10%) is added. The reaction is subjected to a hydrogen gas atmosphere of 50psi for 2 hours. The resulting slurry is filtered through a pad of celite, and rotoevaporated to yield the desired material.
- Cbz Carboxybenzyl
- Step F Coupling of the C-terminal end of the tetrapeptide with a functionalized amine
- R-AA 2 -AA ⁇ -Stat-Val-OH (1.0 equiv.) is dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-R (1.0 equiv.) and TEA (5 equiv.) were added and the reaction mixture is stirred for 20 minutes. EDC (1.2 equiv.) is added and allowed to stir overnight under an atmosphere of nitrogen. The reaction is diluted with water and extracted with EtOAc (3x). The organic layers are washed with aqueous citric acid (2x), sat. NaHCO3 (2x), brine, then dried over MgSO 4 .
- amine groups (R-NH2) of the examples shown below are commercially available unless otherwise indicated by reference to a citation in a journal. Some of the compounds are supplied as the methyl ester, if a carboxylic acid function is present. If only the free carboxylic acid group is available commercially, the methyl ester can be prepared as indicated in step H below.
- Step G Cleavage of the C-terminal capping group methyl ester to provide free carboxylic acid or carboxylate salt
- methyl ester (1 equiv.) is dissolved in a suitable solvent (MeOH/water, dioxane/water. or THF/water). Hydroxide (2-20 equiv., KOH. NaOH, or LiOH) is added and the reaction mixture is allowed to stir until the all of the ester is converted to acid as evidenced by TLC. Volatile solvents are removed and the reaction is acidified with citric acid The resulting precipitate is collected and charactenzed to insure the desired matenal is obtained
- a suitable solvent MeOH/water, dioxane/water. or THF/water.
- Hydroxide (2-20 equiv., KOH. NaOH, or LiOH) is added and the reaction mixture is allowed to stir until the all of the ester is converted to acid as evidenced by TLC. Volatile solvents are removed and the reaction is acidified with citric acid The resulting precipitate is collected and charactenzed to insure the desired matenal is obtained
- Step H Preparation of the methyl ester for the C-terminal capping reaction
- the selected acid is dissolved in dry methanol HCL (gas) is bubbled through the mixture for 5 minutes
- the reaction is then stnred overnight and rotoevaporated to yield the desired methyl ester
- Step J Aminoaryl diesters to Aminocyclohexyl diesters
- the amine (4 1 mmole) was dissolved in THF and methyl iodide was added, followed by sodium hydnde. The reaction was stmed overnight under nitrogen Workup: the reaction was concentrated on a rotary evaporator and the residue was taken up with ethyl acetate and then washed with water, citnc acid, sodium bicarbonate, and bnne The organic solvent was dned over MgSO 4 .
- Steps K, L and O are employed in the order set forth below:
- the compounds of Group II have an IC 50 concentration of from between 10 ⁇ M and 99 ⁇ M and are the more prefened compounds of the invention.
- the compounds of Group I have an ICsoConcentration of ⁇ 10 ⁇ M and are the most prefened compounds of the invention.
- R 2 is 2-methylpropyl
- R 3 is methylthioethyl
- A is tert- butyloxycarbonyl.
- Table 1 continued for variations of amino acid substituents and/or N-terminal capping groups.
- R is 2-methylpropyl. R is
- Steps A through F were employed, substituting H2N-Val-OMe (the methyl ester) for the benzyloxycarbonyl protected starting material, and selecting L-Met as AAi and L-Val as AA-.
- Example 1 The product of Example 1 was further subjected to Step G to remove the methyl ester. leaving the free C-terminal acid.
- Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA and usim benzylamine as NH 2 in step F.
- Steps A tlirough F were employed, selecting L-Met as AAi and L-Val as AA? and using 1-pentanamme as RNH 2 in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using ethylam e as RNH in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using methyl 4-aminobutanoate as RNH 2 in step F.
- Steps A through F were employed, selecting L-Met as AA. and L-Val as AA 2 and using methyl 3-aminopropanoate as RNH in step F.
- Example 8 The product of Example 6 was further subjected to Step G to remove the methyl ester, leaving the free C-terminal acid.
- Example 7 was further subjected to Step G to remove the methyl ester leaving the free C-termmal acid.
- Steps A through F were employed, selecting L-Met as AA . and L-Val as AA; and using methyl 2-am ⁇ nomethylfhiazole-5-carboxylate as RNH 2 in step F and then removal of the methyl ester according to step G.
- the methyl 2-aminomethy thizaole-5-carboxylate was prepared according to Synthesis 1986, page 992.
- Steps A through F w ere employed, selecting L-Met as AA. and L-Val as AA; and using methyl 4-aminomethylbenzoate as RNH; in step F and then removal of the methyl ester according to step G.
- Steps A tlirough F were employed, selecting L-Met as AAi and L-Val as AA; and using methyl 4-aminomethylpyridine as RNH 2 in step F.
- Steps A through F were employed, selecting L-Met as AA. and L-Val as AA? and using methyl 4-am ⁇ nomethylbenzoxyacetate as RNH; in step F and then removal of the l ester according to step G.
- Methyl 4-aminomethylbenzoxyacetate was prepared according to the procedure provided in J. Med. Chem. 1998. Vol. 31. No. 10
- Steps A through F were employed, selecting L-Met as AA. and L-Val as AA; and using methyl 3-aminomethylbenzoate as RNH; in step F and then removal of the methyl ester according to step G.
- Steps A through F were employed, selecting L-.Met as AA , and L-Val as AA; and using methyl 4-ammocyclohexylcarboxylate as RNH 2 in step F and then removal of the methyl ester according to step G.
- Steps A through F were employed, selecting L-Met as AA. and L-Val as AA; and usins. 2-aminoglutaramide as RNH; in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Val as AA; and using methyl 1-am ⁇ nocyclopropane-l-carboxylate as RNH; in step F and then removal of the methyl ester according to step G.
- Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA; and usi 3-am ⁇ no-dihydro-2(3H)-furanone as RNH; in step F.
- Steps A through F were employed, selecting L-Met as AA; and L-Val as AA; and usim methyl 4-am ⁇ nobutan-l-ol as RNH; in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA; and using methyl 3-ammobenzoate as RNH; in step F and then removal of the methyl ester according to step G.
- Steps A through F were employed, selecting L-Met as AA] and L-Yal as AA; and usi methyl 4-p ⁇ pe ⁇ dine-acetate as RNH; in step F and then removal of the methyl ester according to step G.
- Steps A through F were employed, selecting L-Met as AA. and L-Yal as AA; and using ethyl piperazine-X '-carboxylate as RNH; in step F and then removal of the ethyl ester according to step G.
- Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using l-acetam ⁇ do-2-ammoefhane as R-NH 2 in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Val as AA; and using 1 -ammo 4-fluorobenzene as RNH; in step F.
- Steps A through F were employed, selecting L-Met as AAi and L-Y ' al as AA; and using 4-ammomethylbenzocarboxam ⁇ de as RNFL in step F Molecular Formula C ,H,, ⁇ OsS
- Steps A through F were employed, selecting L-Met as A ⁇ and L- ⁇ al as A. ; and using 3.5-d ⁇ carbo ⁇ c ⁇ clohe ⁇ tamine as RNH; in step F
- the amine was prepared as follows To 25 g oi d ⁇ meth ⁇ l 5-am ⁇ no ⁇ sophthalate in 40 ml ol methanol 48ml acetic acid ( added 125 g of 5° u rhodium on alum ⁇ na(50°o w w ).
- the mixed slum was saturated with hydrogen at 55 PSI and shaken for a total of 72 hrs Lpon completion of they h ⁇ drogenat ⁇ on the reaction w as filtered through Celite and dned o ⁇ er anhydrous sodium sulfate Filtration ana subsequent rotoevaporation yielded 385g of crude product, which as then subjected to suica gel chromatographic purification to afford 076g of Di-Methyl l-Am ⁇ nocyclohe ⁇ >l-3, 5-D ⁇ - Carboxy ate as a pale white solid See also Fieser & Fieser. Reagents for Org S ⁇ n 4.418 and Freifelder. M . Ng. V H . Helgren. P F . J Oi? Chem 30.2485-6
- the amine utilized was dimethyl 1 -amino- 1.3-propane-dicarboxylate and then the dicarboxylate was saponified to provide the dicarboxylic acid.
- the tetrapeptide was coupled to the N-terminal capping group.
- the capping groups was prepared by reacting l -bromo-l -(4-benzoic acid) ethane with sodium azide, reducing the resulting azide to the amine and coupling the product with the tetrapeptide.
- the tetrapeptide was coupled with l -ammo-indan-2-ol usmg step F.
- the methyl ester of 2-carboxy-cyclohexylamine was prepared according to setp H. then coupled with the tetrapeptide and the free carboxlyic acid was generated according to step G.
- the tetrapeptide was coupled with the methyl ester of phenylglycine and the ester group was subsequently removed.
- the compound was prepared in a manner similar to Example 1 1 with the following vanations: Phenyl-statme (Phe-Sta) was employed in place of statine and phenylglycine (Phg) w as selected as AAi and N-Ac-L-Val was used as AA;
- the compound was prepared in a manner similar to Example 1 1 with the following variation: Phenvlglvcme (Phg) was selected as AAi .
- the MBP-C125 assay determines relative inhibition of ⁇ -secretase cleavage of an MPB- C125 substrate by the compounds assayed.
- Human brain ⁇ -Secretase from the concentrated HiQ pool prepared 7/16/97 in 0.20% Triton is used in the assay .
- Inhibition data was obtained from an ELISA which uses an anti-MBP capture antibody (on precoated and blocked 96-well high binding plates) followed by incubation with diluted enzyme reaction supernatant, incubation with an anti-SW192 specific biotinylated reporter antibody and incubation with streptavidin alkahne phosphatase. Detection was effected by a fluorescent substrate signal on cleavage by the phosphatase. The ELISA only detected cleavage following Leu 596 at the substrate's Swedish APP 751 mutation site.
- test compounds were weighed out into a vial and DMSO was added to make up a lOmM solution.
- 100 ⁇ L of the 10 mM solution was added to well CI of a 96-well V-bottom plate.
- Fifty ⁇ L of DMSO was added to odd wells of ro C across the plate and 1 : 1 serial dilutions were made.
- 10 ⁇ L of each dilution was added to each of two wells on row C of a conesponding V-bottom plate to which 190 ⁇ L of 52 mM NaOAc/7.9% DMSO, pH 4.5 were pre-added.
- the NaOAc diluted compound plate was spun down to pellet precipitant and 20 ⁇ L/well was transfened to a conesponding flat- bottom plate to which 30 ⁇ L of ice-cold enzyme-substrate mixture (2.5 ⁇ L MBP-C125 substrate, 0.03 ⁇ L enzyme and 24.5 ice cold 0.09% TXl 00 per 30 ⁇ l) was added.
- the compound concentration in the final enzyme reaction was thus 50 times less than the starting concentration.
- the final reaction mixture of 200 ⁇ M compound for the highest curve point was in 5% DMSO, 20 mM NaAc, 0.06% TXl 00, at pH 4.5.
- the enzyme reaction was started by warming the plates to 37° C.
- This invention also relates to a method of treatment for patients suffenng from disorders or diseases which can be attnaded to A ⁇ plaque formation as previously descnbed and, more specifically, a method of treatment involving the administration of the ⁇ -secretase inhibitors of formula 1 as the active constituents
- the compounds of formula lean be used among other things in the treatment Alzheimer's disease, and in diseases and indications resulting from the over-expression of A ⁇ -peptide such as found in certain genetic defect diseases such as plaque formation associated with Tnsomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage 0 with Amyloidosis of the Dutch-Type (HCHW A-D)
- a method of management by which is meant treatment or prophylaxis of disease or conditions mediated by ⁇ -secretase m mammals, in particular in humans, which method compnses admmistenng to the mammal an effectiv e, amount of a compound of formula 1 above, or a pharmaceutically acceptable salt or ester thereof, and
- the disease or conditions refened to above include Alzheimer's disease, plaque formation associated with Tnsomy 21 (Down's Syndrome) and Hereditary Cerebral 0 Hemonhage with Amyloidosis of the Dutch-Type (HCHW A-D)
- the compunds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, mtrasternal injection or infusion techniques
- the compounds may be administered in an amount from about 0 1 mg/kg/day to about 500 mg/kg/day
- Preferced amounts for daily administration are from about 1 mg/ kg to about 50 mg/kg It will be understood however, that the amount of the compound actually administered will be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the seventy of the patient's symptoms, and the like
- compositions that contain therapeutically effective amounts of the compounds of formula 1
- the compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or m stenle solutions or suspensions for parenteral administration
- suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or m stenle solutions or suspensions for parenteral administration
- the compounds descnbed above are formulated into pharmaceutical compositions using techniques and procedures well known m the art
- compositions are preferably formulated in a unit dosage form, each dosage containing from about 2 to about 100 mg, more preferably about 10 to about 30 mg of the active ingredient
- unit dosage from refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active matenal calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient
- the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carner(s)
- the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carner(s)
- the resulting mixture may be a solution, suspension, emulsion or the like.
- Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art.
- the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
- compositions suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
- active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action or have other action.
- the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
- solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
- cosolvents such as dimethylsulfoxide (DMSO)
- surfactants such as Tween®
- dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
- the concentrations of the compounds are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the disorder for which the compounds are administered.
- the compositions are formulated for single dosage administration.
- the compounds of formula 1 may be prepared with carriers that protect them against rapid elimination from the body, such as time release formulations or coatings.
- Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems,
- the active compound is included in the pharmaceutically acceptable earner in an amount sufficient to exert a therapeutically useful effect m the absence of undesirable side effects on the patient treated
- the therapeutically effective concentration may be determined empirically by testing the compounds in known vitro and in vivo model systems for the treated disorder
- compositions can be enclosed in ampoules, disposable synnges or multiple or single dose vials made of glass, plastic or other suitable matenal Such enclosed compositions can be provided m kits
- the concentration of active compound in the drug composition will depend on absorption, mactivation and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art
- the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empincally using known testing protocols or by extrapolation from in vivo or in vitro test data It is to be noted that concentrations and dosage values may also vary 0 with the seventy of the condition to be alleviated It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person admmistenng or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the 5 claimed compositions
- the compound should be provided in a composition that protects it from the acidic environment of the stomach
- the composition can be formulated in an enteric coating that maintains its mtegnty in the stomach and releases 0 the activ e compound in the intestine
- the composition may also be formulated in combination with an antacid or other such ingredient
- Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules.
- the active compound or compounds can be inco ⁇ orated with excipients and used in the form of tablets, capsules or troches.
- Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as, but not limited to, gum tragacanth. acacia, corn starch or gelatin; an excipient such as microcrystallme cellulose, starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, and fruit flavoring.
- a binder such as, but not limited to, gum tragacanth. acacia, corn starch or gelatin
- an excipient such as microcrystallme cellulose, starch and lactose, a disintegrating agent such as, but not limited to,
- the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
- dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
- the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
- a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
- the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc.
- a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc.
- a synthetic fatty vehicle like ethyl oleate or the like, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates, and agents for the adjustment of tomcity such as sodium chlonde or dextrose Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass, plastic or other suitable material Buffers, preservatives, antioxidants and the like can be inco ⁇ orated as required
- suitable earners include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropyleneglycol and mixtures thereof
- PBS physiological saline or phosphate buffered saline
- thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropyleneglycol and mixtures thereof
- Liposomal suspensions, including tissue-targeted hposomes may also be suitable as pharmaceutically acceptable earners
- hposome formulations may be prepared as described m U S Pat No 4.522.811
- the active compounds may be prepared with earners that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
- earners include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydndes, polyglycohc acid, polyorthoesters, polylactic acid and others Methods for preparation of such formulations are known to those skilled in the art
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002376420A CA2376420A1 (en) | 1999-06-15 | 2000-06-15 | Statine-derived tetrapeptide inhibitors of beta-secretase |
EP00941491A EP1192177A1 (en) | 1999-06-15 | 2000-06-15 | Statine-derived tetrapeptide inhibitors of beta-secretase |
JP2001503887A JP2003502342A (en) | 1999-06-15 | 2000-06-15 | Statin-induced tetrapeptide inhibitors of beta-secretase |
AU56194/00A AU5619400A (en) | 1999-06-15 | 2000-06-15 | Statine-derived tetrapeptide inhibitors of beta-secretase |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13917399P | 1999-06-15 | 1999-06-15 | |
US60/139,173 | 1999-06-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000077030A1 true WO2000077030A1 (en) | 2000-12-21 |
Family
ID=22485425
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/016643 WO2000077030A1 (en) | 1999-06-15 | 2000-06-15 | Statine-derived tetrapeptide inhibitors of beta-secretase |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1192177A1 (en) |
JP (1) | JP2003502342A (en) |
AU (1) | AU5619400A (en) |
CA (1) | CA2376420A1 (en) |
WO (1) | WO2000077030A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002100856A1 (en) * | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
US6545127B1 (en) | 1999-06-28 | 2003-04-08 | Oklahoma Medical Research Foundation | Catalytically active recombinant memapsin and methods of use thereof |
WO2003057721A2 (en) * | 2002-01-04 | 2003-07-17 | Elan Pharmaceuticals, Inc. | Substituted amino carboxamides for the treatment of alzheimer's disease |
WO2004101603A1 (en) * | 2003-05-13 | 2004-11-25 | Boehringer Ingelheim International Gmbh | Statine derivatives for the treatment of alzheimer's disease |
US6864290B2 (en) | 2001-07-10 | 2005-03-08 | Pharmacia & Upjohn, Llp | Statine derivatives for the treatment of Alzheimer's disease |
EP1551801A1 (en) * | 2002-08-05 | 2005-07-13 | Bristol-Myers Squibb Company | Novel gamma-lactams as beta-secretase inhibitors |
US6974829B2 (en) | 2002-05-07 | 2005-12-13 | Elan Pharmaceuticals, Inc. | Succinoyl aminopyrazoles and related compounds |
WO2006050862A1 (en) * | 2004-11-10 | 2006-05-18 | Boehringer Ingelheim International Gmbh | Statine derivatives for the treatment of alzheimer's disease |
WO2006050861A2 (en) * | 2004-11-10 | 2006-05-18 | Boehringer Ingelheim International Gmbh | Statine derivatives for the treatment of alzheimer's disease |
EP1666452A2 (en) | 2000-06-30 | 2006-06-07 | Elan Pharmaceuticals, Inc. | Compounds to treat Alzheimer's disease |
US7312360B2 (en) | 2001-12-06 | 2007-12-25 | Elan Pharmaceuticals, Inc. | Substituted hydroxyethylamines |
US7312188B2 (en) | 2003-02-28 | 2007-12-25 | Yoshiaki Kiso | Peptide derivatives having β-secretase inhibitory activity |
WO2007149033A1 (en) | 2006-06-22 | 2007-12-27 | Astrazeneca Ab | Substituted isoindoles as bace inhibitors and their use |
US7335632B2 (en) | 2001-10-23 | 2008-02-26 | Comentis, Inc. | Beta-secretase inhibitors and methods of use thereof |
US7351738B2 (en) | 2002-11-27 | 2008-04-01 | Elan Pharmaceuticals, Inc. | Substituted ureas and carbamates |
US7759382B2 (en) | 2003-06-05 | 2010-07-20 | Elan Pharmaceuticals, Inc. | Acylated amino acid amidyl pyrazoles and related compounds |
EP2281824A1 (en) | 2009-08-07 | 2011-02-09 | Noscira, S.A. | Furan-imidazolone derivatives, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
CN101348456B (en) * | 2007-07-17 | 2011-05-11 | 中国科学院上海药物研究所 | Benzyl piperidine compound, and preparation and use thereof |
US8030500B2 (en) | 2008-11-14 | 2011-10-04 | Astrazeneca Ab | Substituted isoindoles for the treatment and/or prevention of Aβ- related pathologies |
WO2012069428A1 (en) | 2010-11-22 | 2012-05-31 | Noscira, S.A. | Bipyridine sulfonamide derivatives for the treatment of neurodegenerative diseases or conditions |
US8859628B2 (en) | 2003-02-27 | 2014-10-14 | JoAnne McLaurin | Method for preventing, treating and diagnosing disorders of protein aggregation |
-
2000
- 2000-06-15 WO PCT/US2000/016643 patent/WO2000077030A1/en not_active Application Discontinuation
- 2000-06-15 JP JP2001503887A patent/JP2003502342A/en active Pending
- 2000-06-15 EP EP00941491A patent/EP1192177A1/en not_active Withdrawn
- 2000-06-15 AU AU56194/00A patent/AU5619400A/en not_active Abandoned
- 2000-06-15 CA CA002376420A patent/CA2376420A1/en not_active Abandoned
Non-Patent Citations (4)
Title |
---|
CHEMICAL ABSTRACTS, vol. 108, no. 17, 25 April 1988, Columbus, Ohio, US; abstract no. 146147, PRECIGOUX, G. ET AL: "X-ray crystallography of linear peptides through the renin-angiotensin system" XP002151368 * |
K SHIOSAKI ET AL.: "Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung", JOURNAL OF MEDICINAL CHEMISTRY., vol. 36, no. 4, 1993, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 468 - 478, XP002151366, ISSN: 0022-2623 * |
N S AGARWAL & D H RICH: "Inhibition of cathepsin D by substrate analogues containing statine and by analogues of pepstatin", JOURNAL OF MEDICINAL CHEMISTRY., vol. 29, no. 12, 1986, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 2519 - 2524, XP002151367, ISSN: 0022-2623 * |
PROTIDES BIOL. FLUIDS, 35, 473-6, 1987 * |
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US7351738B2 (en) | 2002-11-27 | 2008-04-01 | Elan Pharmaceuticals, Inc. | Substituted ureas and carbamates |
US9833420B2 (en) | 2003-02-27 | 2017-12-05 | JoAnne McLaurin | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
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WO2006050861A3 (en) * | 2004-11-10 | 2006-08-10 | Boehringer Ingelheim Int | Statine derivatives for the treatment of alzheimer's disease |
WO2006050861A2 (en) * | 2004-11-10 | 2006-05-18 | Boehringer Ingelheim International Gmbh | Statine derivatives for the treatment of alzheimer's disease |
US7238774B2 (en) | 2004-11-10 | 2007-07-03 | Boehringer Ingelheim International Gmbh | Statine derivatives for the treatment of Alzheimer's disease III |
WO2007149033A1 (en) | 2006-06-22 | 2007-12-27 | Astrazeneca Ab | Substituted isoindoles as bace inhibitors and their use |
US7855213B2 (en) | 2006-06-22 | 2010-12-21 | Astrazeneca Ab | Compounds |
CN101348456B (en) * | 2007-07-17 | 2011-05-11 | 中国科学院上海药物研究所 | Benzyl piperidine compound, and preparation and use thereof |
US8030500B2 (en) | 2008-11-14 | 2011-10-04 | Astrazeneca Ab | Substituted isoindoles for the treatment and/or prevention of Aβ- related pathologies |
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Also Published As
Publication number | Publication date |
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JP2003502342A (en) | 2003-01-21 |
EP1192177A1 (en) | 2002-04-03 |
CA2376420A1 (en) | 2000-12-21 |
AU5619400A (en) | 2001-01-02 |
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