Clearance of amyloid beta

A method for reducing the fall in Aβ42 CSF of patients which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group or 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient who has been assessed by one or more standard tests (MMSE, ADAS-cog, Logical Memory Delayed Paragraph Recall, WAIS-R Digit Symbol Substitution, CDR-global, CDR-SB, NIB, logical memory IIA (delayed) and 1A (immediate), category fluency, delayed and immediate wordlist recall, progressive matrices, ELSMEM, CogState, trailmaking, executive function, neuromotor speed, ADCS-ADL, DAD, and others) or a composite test composed of elements of these or other tests, to have impaired cognition or function, but not to be displaying dementia, and not having a condition not associated with Alzheimer pathology to which the impaired cognition or function can be solely attributed, so as to delay deterioration of cognition and/or function.

A method for reducing the fall in Aβ42 in CSF of patients comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient having medial temporal lobe, paralimbic, and/or temporoparietal lobe atrophy on structural MRI, or decreased fluorodeoxyglucose uptake in the temporoparietal cortices on PET scan.

A method for reducing the fall in Aβ42 in CSF of patients comprises administering a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient whose CSF Aβ42 is decreasing, as determined by for example, a drop of >1%/year when the lumbar puncture is done at the same time of day, or 10% from baseline, or decreases on two successive post-baseline samplings, in order to reduce the rate of decrease.

A method for treating patients which comprises administering a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient in need thereof in combination with a nicotinic agonist in order to inhibit plaque deposition or aid in removal of plaques of Aβ, prevent the decrease or cause an increase in Aβ42 in CSF, delay progression to Alzheimer's disease dementia, or reduce the loss of cognition and/or activities of daily living.

A method for treating an individual who has been determined to have the ApoE4 isoform of Apolipoprotein E which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient who has been determined to have the ApoE4 isoform of Apolipoprotein E but who is not exhibiting signs of dementia in an amount sufficient to inhibit plaque deposition or aid in removal of plaques of Aβ, or to reduce the fall in CSF Aβ42, or prevent progression of cognitive and/or functional decline, or prevent progression to Alzheimer's dementia.

A method for treating an individual with Down's syndrome which comprises administering a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to an individual with Down's syndrome to inhibit β-amyloid plaque deposition in brain, or decrease the fall in CSF Aβ42, or decrease the loss of cognitive and functional abilities, or prevent progression to Alzheimer's dementia.

A method for reducing the fall in Aβ42 in CSF of patients exhibiting a decreased Aβ42 level in CSF or one which is falling at >1%/year, or more than 10% from baseline, or falling on two successive postbaseline samples at least three months apart, but not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient who has been determined to carry a fully-penetrant mutation which causes Alzheimer's dementia.

A method for reducing the fall in Aβ42 in CSF of patients exhibiting a decreased Aβ42 level in CSF, or a level by >1%/year, or 10% from baseline, or falling on two successive post-baseline samples at least 3 months apart, but not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof
• to a patient who has not developed Alzheimer's dementia but who has been determined to have a potential for Alzheimer's disease based on lowered or falling CSF Aβ42 (>1%/year, or a 10% fall from baseline, or decreases from baseline on two successive postbaseline samples at least 3 months apart), reduced cognitive or functional ability beyond that expected for age, MRI or fluorodeoxyglucose PET Alzheimer-type changes decrease of Aβ42 CSF, increased or increasing Aβ amyloid in brain or presence of the ApoE4 isoform of Apolipoprotein E or who have a penetrant mutation known to correlate with Alzheimer's dementia in co-administration with an agent which promotes clearance by administering Aβ antibodies or stimulating antibody production, or binding or resulting in binding to Aβ species, including but not limited to solanezumab, aducanumab, ganterenumab, in order to enhance clearance of Aβ, enhance or slow the decline of cognitive and/or functional abilities, or retard conversion to Alzheimer's dementia.

A method to improve performance, or to slow decline greater than expected for age on tests such as the MMSE, ADAS-cog, Logical Memory Delayed Paragraph Recall, WAIS-R Digit Symbol Substitution, CDR-global, CDR-SB, NTB, logical memory IIA (delayed) and 1A (immediate, category, fluency, delayed and immediate word-list recall, progressive matrices, ELSMEM, CogState, trailmaking, executive function, neuromotor speed, ADCS-ADL, DAD, or a combination of elements of these or other cognitive and/or functional tests, in a patient not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or diaikyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof.

A method to delay the onset of dementia in patients having a CSF Abeta to tau ratio below the discrimination line determined by Aβ42=240+1.18×tau, using the procedures of Andreasen et al, op cit, or a ratio of CSF Aβ1-42 to ptau less than 6.16, using the methods of Bucchave et al, op cit, but not exhibiting signs of dementia which comprises administering thereto a therapeutically acceptable dose of a compound of an analog of (4aS,6R,8aS)-5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol of the formula:

• wherein
• R1 is a carbamate, carbonate or carboxylate group;
• R2 is an alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group of 2 to 10 carbon atoms, a benzoyloxy or substituted benzoyloxy group, a carbonate group of 1 to 10 carbon atoms or a carbamate group selected from a mono alkyl or dialkyl or an aryl carbamate wherein the alkyl groups or aryl groups contain from 1 to 10 carbons;
• and
• R3 is hydrogen, alkyl of 1 to 10 carbon atoms, benzyl, cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group
• or a pharmaceutically acceptable salt thereof.