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WO2019122421A1 - Réduction stéréosélective de cétone à l'aide d'une enzyme cétoréductase - Google Patents

Réduction stéréosélective de cétone à l'aide d'une enzyme cétoréductase Download PDF

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Publication number
WO2019122421A1
WO2019122421A1 PCT/EP2018/086777 EP2018086777W WO2019122421A1 WO 2019122421 A1 WO2019122421 A1 WO 2019122421A1 EP 2018086777 W EP2018086777 W EP 2018086777W WO 2019122421 A1 WO2019122421 A1 WO 2019122421A1
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Prior art keywords
compound
formula
salt
kred
aryl
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PCT/EP2018/086777
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English (en)
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Keith Raymond Mulholland
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture

Definitions

  • cyclohexanol ring systems that are useful in the preparation of compounds for treating at least one condition associated with inhibitition of the deposition of amyloid b peptide (Ab) and portions thereof by inhibiting or the beta site APP Cleaving Enzyme (BACE).
  • Abs amyloid b peptide
  • BACE beta site APP Cleaving Enzyme
  • AD Alzheimer's disease
  • the disease progresses with increasing dementia and elevated deposition of Ab.
  • a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function.
  • the prevailing working hypothesis regarding the temporal relationship between Ab and tau pathologies states that Ab deposition precedes tau aggregation in humans and animal models of the disease.
  • the Ab peptide is an integral fragment of the Type I protein APP (Ab amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Ab can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called a-, b-, and g-cleavages. The a-cleavage, which occurs roughly in the middle of the Ab domain in APP, is executed by the metalloproteases
  • ADAM110 or ADAM117 (the latter also known as TACE).
  • TACE transmembrane aspartyl protease Beta site
  • BACE1 Cleaving Enzymel
  • the g-cleavage, generating the Ab C termini and subsequent release of the peptide, is carried out by a multi-subunit aspartyl protease named g-secretase.
  • ADAM10/17 cleavage followed by g-secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated Ab fragment that fails to form amyloid deposits in humans.
  • This proteolytic route is commonly referred to as the nonamyloidogenic pathway.
  • Consecutive cleavages by BACE1 and g-secretase generate the intact Ab peptides; hence this processing scheme has been termed the amyloidogenic pathway.
  • Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHW A-D), and other neurodegenerative disorders.
  • b-amyloid deposits are predominately an aggregate of Ab peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • Ab peptide results from the cleavage of APP at the C-terminus by one or more g-secretases, and at the N- terminus by b-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the b-amyloidogenic pathway.
  • BACE b-secretase enzyme
  • BACE Beta site APP Cleaving Enzyme
  • BACE activity is correlated directly to the generation of Ab peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of Ab peptide (Roberds, S. L., et al, Human Molecular Structure
  • BACE amyloid ⁇ -peptide
  • Drugs that reduce or block BACE activity should therefore reduce Ab levels and levels of fragments of Ab in the brain, or elsewhere where Ab or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Ab or fragments thereof.
  • BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Ab-related pathologies such as Down's syndrome; b-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage; disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"); Alzheimer's Disease; memory loss; attention deficit symptoms associated with Alzheimer's disease; neurodegeneration associated with diseases, such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia, and dementia associated with Parkinson's disease; progressive supranuclear palsy or cortical basal degeneration. It would therefore be useful to inhibit the deposition of Ab and portions thereof by inhibiting BACE through inhibitors.
  • Described herein are stereo- and regioselective processes for preparing cyclohexanol ring systems that are useful in the preparation of such compounds.
  • the present application provides processes for preparing the compounds disclosed herein, wherein the compounds are BACE inhibitors, or salts thereof, and/or intermediates useful in the preparation of BACE inhibitors.
  • the BACE inhibitors are useful in the treatment or prevention of Ab-related pathologies, such as a b- amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's Disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • Ab-related pathologies such as a b- amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“mild
  • the present application provides a process comprising contacting a compound of o formula (I), , or a salt thereof, with a ketoreductase enzyme to form a O compound of formula (II), , or a salt thereof, wherein R 7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R 8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R 7 and R 8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; and o is 1 , 2, or 3.
  • the ketoreductase enzyme provides both stereoselective and regioselective reduction of the compound of formula (I), or a salt thereof.
  • the compound of formula (II), or salt thereof is produced in
  • the compound of formula (II), or salt thereof, and the compound of formula (III), or salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1,
  • the compound of formula (II), or salt thereof, and the compound of formula (IV), or salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1, or 100:1.
  • the compound of formula (II), or salt thereof is a compound
  • the compound of formula (lla), or salt thereof, and the compound of formula (lib), or salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1, or 100:1, such as at least 100:1.
  • the percent yield of compound of formula (Ila), or salt thereof is greater than 85%, 90%, 95%, or 99%.
  • the present application further provides a process comprising contacting a compound
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; o is 1, 2, or 3; and p is 0, 1, 2, 3, or 4.
  • the ketoreductase enzyme provides both stereoselective and regioselective reduction of the compound of formula (G), or a salt thereof.
  • the compound of formula (IG), or salt thereof is produced in
  • the compound of formula (IG), or salt thereof, and the compound of formula (IIG), or salt thereof are present in a ratio of at least 1: 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90:1, 95: 1, or 100: 1.
  • the compound of formula (IG), or salt thereof, and the compound of formula (IV’), or salt thereof are present in a ratio of at least 1 : 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 95: 1, or 100: 1.
  • the compound of formula (IG), or salt thereof is a compound (N’a)
  • the compound of formula (H’a), or salt thereof, and the compound of formula (H’b), or salt thereof are present in a ratio of at least 1: 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90:1, 95: 1, or 100: 1, such as at least 100: 1.
  • the percent yield of compound of formula (H’a), or salt thereof is greater than 85%, 90%, 95%, or 99%.
  • the compound of formula (G), or salt thereof is compound 1, (1 ) , or a salt thereof.
  • the compound of formula (IG), or salt thereof is compound salt thereof
  • the compound of formula (H’a), or salt thereof is compound
  • the ketoreductase enzyme is selected from the group consisting of KRED-P1-A04, KRED-P1-B02, KRED-P1-B05, KRED-P1-B10, KRED-P1-A04, KRED-P1-B02, KRED-P1-B05, KRED-P1-B10, KRED-P1-A04, KRED-P1-B02, KRED-P1-B05, KRED-P1-B10, KRED-P1-A04, KRED-P1-B02, KRED-P1-B05, KRED-P1-B10, KRED-P1-
  • KRED-P2-D12 such as KRED-P2-D12, KRED-P1-H10, KRED-P1-B05, KRED-P1-B04, and KRED-
  • P1-H08 e.g., KRED-P1-H08.
  • the ketoreductase enzyme is present in an amount selected from 1-100% w/w based on the weight of the compound of formula (I), or salt thereof, such as 5% w/w based on the weight of the compound of formula (I), or salt thereof.
  • the compound of formula (I), or salt thereof is present in an amount selected from 1-200 g/L, such as 100 g/L.
  • the process further comprises contacting the compound of formula (I), or salt thereof, with a cofactor.
  • the cofactor is selected from NAD or ADP, e.g., NADP.
  • the compound of formula (G), or salt thereof is contacted with the ketoreductase enzyme in the presence of isopropanol (IPA).
  • IPA isopropanol
  • the aqueous IPA is present in an amount selected from 5-95% v/v, such as 50% v/v.
  • the process is performed at a pH between about 5 and about 9, such as at a pH of about 5.5.
  • the process is performed at a temperature of between about 30 to 50 °C, such as at a temperature of about 40 °C.
  • the present application further provides a process for preparing a compound of
  • R 3 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R 7 and R 8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; and o is 1, 2, or 3.
  • the present application further provides a process for preparing a compound of
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • p is 0, 1, 2, 3, or 4
  • o is 1, 2, or 3.
  • the present application provides a process comprising contacting a compound of
  • R 7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 7 and R 8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring
  • o is 1 , 2, or 3.
  • R 7 and R 8 taken together with with the carbon(s) to which they are attached form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring.
  • R 7 and R 8 taken together with with the carbon(s) to which they are attached form an optionally substituted aryl ring, such as an optionally substituted benzene ring.
  • the optionally substituted aryl ring such as an optionally substituted benzene ring, is substituted with halogen, such as bromine.
  • o is 1.
  • the ketoreductase enzyme provides both stereoselective and regioselective reduction of the compound of formula (I), or a salt thereof.
  • the compound of formula (II), or salt thereof is produced in
  • the compound of formula (II), or salt thereof is produced in excess of a OH compound of formula (IV), or a salt thereof.
  • the compound of formula (II), or salt thereof is produced in excess of a
  • the compound of formula (IV), , or a salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1,
  • the compound of formula (II), or salt thereof, and the compound of formula (IV), or salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1, or 100:1.
  • the compound of formula (II), or salt thereof is a compound
  • the compound of formula (Ila), or salt thereof, and the compound of formula (lib), or salt thereof are present in a ratio of at least 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1, or 100:1, such as at least 100:1.
  • the percent yield of compound of formula (Ila), or salt thereof is greater than 85%, 90%, 95%, or 99%.
  • the present application further provides a process comprising contacting a compound
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; o is 1, 2, or 3; and p is 0, 1, 2, 3, or 4.
  • R 2 is halogen, such as bromine.
  • o is 1.
  • p is 1.
  • the ketoreductase enzyme provides both stereoselective and regioselective reduction of the compound of formula (G), or a salt thereof.
  • the compound of formula (IG), or salt thereof is produced in
  • the compound of formula (IG), or salt thereof is produced in excess of a
  • the compound of formula (IG), or salt thereof, and the compound of formula (IIG), or salt thereof are present in a ratio of at least 1 : 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 95: 1, or 100: 1.
  • the compound of formula (IG), or salt thereof, and the compound of formula (IV’), or salt thereof are present in a ratio of at least 1 : 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 95: 1, or 100: 1.
  • the compound of formula (IG), or salt thereof is a compound a)
  • the compound of formula (H’a), or salt thereof, and the compound of formula (H’b), or salt thereof are present in a ratio of at least 1: 1, 5: 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90:1, 95: 1, or 100: 1, such as at least 100: 1.
  • the percent yield of compound of formula (H’a), or salt thereof is greater than 85%, 90%, 95%, or 99%.
  • the compound of formula (G), or salt thereof is compound 1, il) or a salt thereof.
  • the compound of formula (IG), or salt thereof is compound salt thereof
  • the compound of formula (H’a), or salt thereof is compound
  • O or salt thereof is compound (2b), , or a salt thereof.
  • the ketoreductase enzyme may be a natural or genetically engineered enzyme. In certain embodiments, the ketoreductase enzyme may be used with any suitable cofactor, such as NADH or NADPH. In certain embodiments, the ketoreductase enzyme is a NADPH-dependent ketoreductase enzyme that is used in conjunction with NADPH as a co-factor. In other embodiments, the ketoreductase enzyme is a NADPH- dependent ketoreductase enzyme that is used in conjunction with with cofactors other than NADPH, such as NADH. In other embodiments, the ketoreductase enzyme is a NADH- dependent ketoreductase enzyme that is used in conjunction with NADPH as a co-factor.
  • the ketoreductase enzyme is a NADH-dependent ketoreductase enzyme that is used in conjunction in conjunction with cofactors other than NADH, such as NADPH.
  • the ketoreductase enzyme is selected from the group consisting of KRED-P 1 -A04, KRED-P1-B02, KRED-P1-B05, KRED-P1-B10, KRED-P1- B12, KRED-P1-C01, KRED-P 1-H08, KRED-P l-H 10, KRED-P2-B02, KRED-P2-C02, KRED-P2-C11, KRED-P2-D03, KRED-P2-D11, KRED-P2-D12, KRED-P2-G03, KRED- P2-H07, KRED-P3-B03, KRED-P3-G09, KRED-P3-H12, ADH-101, ADH-105, and ADH- 112, all available from Codex
  • the ketoreductase enzyme is selected from the group consisting of KRED-P2- D12, KRED-P l-H 10, KRED-P 1-B05, KRED-P 1-B04, and KRED-P 1-H08, such as KRED- P1-H08.
  • the ketoreductase enzyme is present in an amount selected from 1-100% w/w based on the weight of the compound of formula (I), or salt thereof. In certain embodiments, the ketoreductase enzyme is present in an amount selected from 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w based on the weight of the compound of formula (I), or salt thereof, such as 5% w/w based on the weight of the compound of formula (I), or salt thereof.
  • the compound of formula (I), or salt thereof is present in an amount selected from 1-200 g/L. In certain embodiments, the compound of formula (I), or salt thereof, is present in an amount selected from 1-150 g/L, 25-150 g/L, 50-150 g/L, 75-150 g/L, 75-125 g/L, or 75-100 g/L, such as 100 g/L.
  • the compound of formula (G), or salt thereof is contacted with the ketoreductase enzyme in the presence of an alcohol, such as methanol, ethanol, or isopropanol (IP A).
  • an alcohol such as methanol, ethanol, or isopropanol (IP A).
  • the compound of formula (G), or salt thereof is contacted with the ketoreductase enzyme in the presence of isopropanol (IP A).
  • the alcohol such as aqueous IPA, is present in an amount selected from 5-95% v/v.
  • the alcohol such as aqueous IPA
  • the alcohol is present in an amount selected from 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% v/v, such as 50% v/v.
  • the process is performed at a pH between about 5 and about 9. In certain such embodiments, the process is performed at a pH between about 4.5 and about 6.5, such as at a pH of between about 5 and about 6. In certain embodiments, the process is performed at a pH of about 5.5.
  • the process is performed at a temperature of between about 30 to 50 °C, such as at a temperature of between about 35-45 °C. In certain such embodiments, the process is performed at a temperature of about 40 °C.
  • the present application further provides a process for preparing a compound of
  • R 3 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R 7 and R 8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; and o is 1, 2, or 3.
  • R 7 and R 8 taken together with with the carbon(s) to which they are attached form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring.
  • R 7 and R 8 taken together with with the carbon(s) to which they are attached form an optionally substituted fused aryl ring, such as an optionaly substituted fused benzene ring.
  • the fused aryl ring, such as a fused benzene ring is substituted with halogen, such as bromine.
  • o is 1.
  • the present application further provides a process for preparing a compound of
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • p is 0, 1, 2, 3, or 4
  • o is 1, 2, or 3.
  • R 2 is halogen, such as bromine. In certain embodiments, p is 1.
  • o is 1.
  • alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product; the type of transformation is limited only by the inherent incompatibility of other functional groups contained in the molecule to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood by one skilled in the art of organic synthesis.
  • the present application provides processes for the preparation of BACE inhibitors that are useful in the treatment or prevention of Ab-related pathologies.
  • the Ab-related pathology is Down's syndrome, a b-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's Disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • MCI mimild cognitive impairment
  • any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, or a mixture thereof.
  • any formula given herein is intended to refer also to a solvate, such as a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • Any formula given herein is intended to refer to amorphous and/or crystalline physical forms of the compound.
  • the compounds described herein may be analytically pure, or a mixture in which the compound comprises at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% by weight of the mixture.
  • “subject” refers to both mammals and non-mammals.
  • Mammals include, e.g., humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. mice, rats, rabbits, dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, e.g., worms, fish and birds.
  • the subject is a human.
  • substantially refers to being completely or almost completely; e.g., a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is
  • substantially pure is there are only negligible traces of impurities present.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino refers to an amino group substituted with an acyl group and may be represented, e.g., by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. E.g., substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing one or more hydrogens on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. E.g., substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated.
  • a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, such as from 1 to 12 carbon atoms, preferably from 1 to about 10, more preferably from 1 to 4, unless otherwise defined.
  • straight chained and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec -butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, pentyl and octyl.
  • a Ci-Ce straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen or more hydrogens on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, e.g., a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like.
  • (ATOM)i-j” with j > i when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from i to j (including i and j) atoms.
  • a chemical moiety such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
  • Co alkyl refers to a hydrogen atom where the group is in a terminal position, a bond if internal.
  • C 3-6 cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6 carbon ring atoms.
  • the terms“C2- y alkenyl” and “C2- y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • amine and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein each R 30 independently represents a hydrogen or a hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • R 30 independently represents a hydrogen or a hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • amide refers to a group: R 30 , wherein each R 30 independently represent a hydrogen or hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • R 29 and R 30 independently represent hydrogen or a hydrocarbyl group, such as an alkyl
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group with one or more halo substituents, or one, two, or three halo substituents.
  • haloalkyl groups include - CFs, -CH 2 F, -CHF2, -CH 2 Br, -CfFCFs, and -CH 2 CH 2 F.
  • heteroatom refers to an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms include but are not limited to nitrogen, oxygen, and sulfur.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • aryl includes substituted or unsubstituted monocyclic aromatic rings in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • the term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • An“aroyl” group refers to an aryl group bonded via an exocyclic carbonyl group, such as a benzoyl group.
  • heteroaryl includes substituted or unsubstituted monocyclic aromatic ring system, preferably 5- to 7-membered aromatic rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one to two heteroatoms.
  • a 5- membered heteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a 6- membered heteroaryl is pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • heteroaryl also include substituted or unsubstituted“polycyclic” ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • heteroaryl groups include but are not limited to the following entities, in the form of properly bonded moieties:
  • heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
  • A“heteroaroyl” group refers to a heteroaryl group bonded via an exocyclic carbonyl group, analogous to a benzoyl group but wherein the phenyl ring of the benzoyl group is replaced by a heteroaryl group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to lO-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and“heterocyclic” also include substituted or unsubstituted polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or
  • heterocyclyls include, e.g., piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group which is optionally substituted.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. l]heptane, l,5-cyclooctadiene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4. l.0]hept-3-ene.“Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • A“cycloalkyl” group refers to a substituted or unsubstituted cyclic hydrocarbon which is completely saturated.“Cycloalkyl” includes substituted or
  • a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. Such a monocyclic cycloalkyl group may be substituted or unsubstituted.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings that are substituted or unsubstituted.
  • Cycloalkyl includes substituted or unsubstituted bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused cycloalkyl refers to a substituted or unsubstituted bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • A“cycloalkenyl” group refers to a cyclic hydrocarbon containing one or more double bonds.
  • A“cycloalkynyl” group is a cyclic hydrocarbon containing one or more triple bonds.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”.
  • rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • carbonate is art-recognized and refers to a group -OCO2-R 30 , wherein R 30 represents a hydrocarbyl group.
  • ester refers to a group -C(0)0R 3 ° wherein R 30 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle.
  • Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • sulfate is art-recognized and refers to the group -OSO3H, or a
  • R 29 and R 30 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(0)-R 3 °, wherein R 30 represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SO3H, or a
  • sulfone is art-recognized and refers to the group -S(0)2-R 3 °, wherein R 30 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR 3 ° or -SC(0)R 3 ° wherein R 30 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with asulfur.
  • R 29 and R 30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 29 taken together with R 30 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • substitution refers to moieties having substituents replacing one or more hydrogens on one or more carbons of the backbone. It will be understood that“substitution” or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • “substituted” means that the specified group or moiety bears one, two, or three substituents.
  • “substituted” means that the specified group or moiety bears one or two substituents.
  • “substituted” refers to the specified group or moiety bears one substituent.
  • Substituents can include any substituents described herein, e.g., a lower alkyl (such as Ci-6 alkyl, e.g., -methyl, -ethyl, and -propyl), a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the term“unsubstituted” refers to that the specified group bears no substituents.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the iunctional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al, Compendium of Synthetic Organic Methods , Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxy lprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • A“pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, e.g., treatment of the free base with an inorganic acid, such as hydrochloric acid,
  • hydrobromic acid sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a s
  • base addition salts can be prepared by any suitable method available in the art, e.g., treatment of such compound with a sufficient amount of the desired the desired base, either neat or in a suitable inert solvent.
  • suitable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, ammonium, zinc, or magnesium salt, or other metal salts; organic amino salts, such as, alkyl, dialkyl, trialkyl, or tetra-alkyl ammonium salts.
  • salts include, but are not limited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsul
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.
  • A“hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • A“solvate” is a similar composition except that a solvent other that water, such as with methanol, ethanol, dimethylformamide, diethyl ether and the like replaces the water.
  • methanol or ethanol can form an“alcoholate,”” which can again be stoichiometic or non-stoichiometric.
  • Mixtures of such solvates or hydrates can also be prepared.
  • the source of such solvate or hydrate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • the compounds of the application can exist as various polymorphs, pseudo-polymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound.
  • pseudo-polymorphs such as hydrates, solvates, or salts of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents.
  • crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
  • the present application further embraces isolated compounds according to formula II, such as formula Ila, formula IT, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’.
  • isolated compound refers to a preparation of a compound of formula II, such as formula Ila, formula IT, such as formula IT a (e.g., compound 2a), or formula V, such as formula V’, or a mixture of compounds according to formula II, such as formula Ila, formula IT, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an“isolated compound” refers to a preparation of a compound of formula II, such as formula Ila, formula IT, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’, or a mixture of compounds according to formula II, such as formula Ila, formula IT, such as formula IT a (e.g., compound 2a), or formula V, such as formula V’, which contains the named compound or mixture of compounds according to formula II, such as formula Ila, formula IG, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’, in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50% by weight of the total weight; more preferably at least 80% by weight of the total weight; and most preferably at least 90%, at least 95% or at least 98% by weight of the total weight of the preparation.
  • the compounds of the application and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
  • a compound described herein or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the application encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3 -methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. E.g., the equilibrium: o OH
  • tautomerism is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called“enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • the molecule is designated ( R ) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S).
  • the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques, such as but not limited to, normal and reverse phase chromatography, and crystallization. According to one such method, a racemic mixture of a compound of the application, or a chiral intermediate thereof, is separated using a chiral salt or carried out on a Chiralcell OD column. The column is operated according to the manufacturer’s instructions.
  • Isolated optical isomers can also be prepared by the use of chiral intermediates or catalysts in synthesis.
  • the optical center chiral center
  • Chiral catalyst can be used to impart at least some degree of enantiomeric purity to products of reactions catalyzed by the chiral catalyst.
  • compounds having at least some degree of enantiomeric enrichment can be obtained by physical processes such as selective
  • compounds of the application may be racemic. In certain embodiments, compounds of the application may be enriched in one enantiomer. For example, a compound of the application may have greater than 30% ee, 40% ee, 50% ee,
  • the compound prepared according to any one of the foregoing processes may be enriched to include predominantly one enantiomer (e.g., of formula II, such as formula Ila; formula IF, such as formula IFa (e.g., compound 2a); or formula V, such as formula V’).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • the compound prepared according to any one of the foregoing processes may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula II, such as formula Ila; formula IF, such as formula IFa (e.g., compound 2a); or formula V, such as formula V’).
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • a variety of compounds in the present application may exist in particular geometric or stereoisomeric forms.
  • the present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated.
  • the preferred compounds of the present application have a particular spatial arrangement of substituents on the aromatic rings, which are related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature“para” for 1, 4-substitution,“meta” for
  • the present application further includes all pharmaceutically acceptable isotopically labeled compound [e.g., of formula II, such as formula Ila, formula IT, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’].
  • An “isotopically” or “radio-labeled” compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Certain isotopically labeled compounds e.g., compounds of formula II, such as formula Ila, formula IG, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’, are useful in drug and/or substrate tissue distribution studies.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • positron emitting isotopes such as n C, 18 F, 15 0, and 13 N
  • PET Positron Emission Topography
  • Isotopically labeled compounds e.g., of formula II, such as formula Ila, formula IT, such as formula H’a (e.g., compound 2a), or formula V, such as formula V’] or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl , 82 B r, 75 Br, 76 B r, 77 Br, 123 I, 124 I, 125 1, 131 1, 31 P, and 32 P.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as 2 H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl , 82 B r, 75 Br, 76
  • Isotopically labeled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Provisos may apply to any of the disclosed categories or embodiments such that specific embodiments or species may be excluded from such categories or embodiments.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • the solvents used in preparing the example compounds were commercial anhydrous grades and were used without further drying or purification.
  • MgS0 4 anhydrous magnesium sulfate (drying agent); MPLC: medium pressure liquid chromatography; MTBE: methyl /er/-butyl ether; NaHCC : sodium bicarbonate; NH 4 Q: ammonium chloride; q: quartet; quin: quintet; rt: room temperature; sat: saturated; t: triplet; TEA: triethylamine; tBuOH: /er/-butanol; td: triplet of doublet; TFA: trifluoroacetic acid; and THF : tetrahydrofuran.
  • MPLC medium pressure liquid chromatography
  • MTBE methyl /er/-butyl ether
  • NaHCC sodium bicarbonate
  • NH 4 Q ammonium chloride
  • q quartet
  • quin quintet
  • rt room temperature
  • sat saturated
  • t triplet
  • TEA triethylamine
  • tBuOH
  • the 1H NMR spectra were recorded on a Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software.
  • NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 1 l.0.2.Bruker UltraShield Advance 400MHz / 54mm spectrometer and processed with XWIN-NMR version 2.6 software. The chemical shifts (d) are reported in parts-per-million from the deuterated solvent used.
  • the 13C NMR spectra were recorded on Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software.
  • NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 11.0.2.
  • the chemical shifts (d) are reported in parts-per-million from the deuterated solvent used.
  • a solution of dibasic Potassium Phosphate (2.18g, 0.125 mol) in water (100 mL) was prepared-Solution A.
  • a solution of monobasic Potassium Phosphate (l.70g, 0.125 mol) in water (100 mL) was prepared-Solution B.
  • 8 mL of Solution A was mixed with 92 mL of Solution B to give 0.125M Potassium Phosphate Buffer.
  • the pH of this solution was adjusted to pH 5.5 with the addition of 5M NaOH dropwise to give Solution C.
  • the resulting suspension was stirred at 40 °C under a slow stream of nitrogen. After 24h, HPLC analysis showed that less than 0.5% by area of compound 1 was present.
  • the reaction mixture was heated to 70 °C for l.5h, before being cooled to 25 °C.
  • the cloudy solution produced was fdtered.
  • the jacketed vessel was washed out with a mixture of Isopropanol (60 mL) and Water (60 mL). The vessel washings were then used to wash the fdter pad.
  • the combined filtrate was then concentrated under vacuum on the Rotary Evaporator (to remove isopropanol) to give an oily suspension.
  • the b-secretase enzyme used in the TR-LRET is prepared as follows:
  • Human BACE1 the cDNA for the soluble part of the human b-Secretasel (AA1-AA460) is cloned using the BACE 1(1 -460)-(AVT)-E c-pGEN-IRES-neo mammalian expression vector. The gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells. Purified sBACE-Fc is stored in -80°C in Tris buffer, pH 9.2 and has a purity of -40%.
  • Human BACE2 the cDNA for the soluble part of the human b-8eoGe ⁇ h8e2 (AA1-AA473) is cloned using BACE2(l-473)-(AVT)-Fc-pDESTl2.2 mammalian expression vector. The gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells. Purified sBACE-Fc is stored in -80°C in 50 mM Glycine, 10 mM Tris-HCl, pH 7-8, and has a purity of -70%.
  • the enzyme (truncated form) is diluted to 6 pg/mL (stock hBacel: l.3mg/mL, hBace2: l.6mg/ml) and the TruPoint BACE1 Substrate to 200 nM (stock 120 uM) in reaction buffer (NaAcetate, chaps, triton c-100, EDTA pH4.5).
  • reaction buffer NaAcetate, chaps, triton c-100, EDTA pH4.5
  • a multidrop Combi is used for the liquid handling.
  • Enzyme (7 pF) is added to the compound plate (containing 0.8 pL of compound in dimethy lsulphoxide) . The plate is incubated for 10 minutes.
  • Substrate (8 pL) is then added, and the reaction proceeds for 17 minutes at r.t.
  • the reaction is stopped with the addition of Stop solution (5.5 pL, NaOAc, pH 9). Fluorescence is measured on a Pherastar plate reader using HTRF module.
  • the assay is performed in a 384 well polystyrene, black, round bottom, small volume plate (Greiner 784076).
  • the final concentration of the enzyme is 2.7 pg/mL; the final concentration of substrate is 100 nM (Km hBACEl: 250 nM, hBACE2: 350 nM).
  • the dimethylsulphoxide control instead of test compound, defines the 100% activity level and 0% activity is defined by a control inhibitor compound (2-amino-6-(3'-methoxybiphenyl- 3 -yl)-3 ,6-dimethyl-5 ,6-dihydropyrimidin-4(3 H)-one, at a final concentration of 50 pM). 5 reference inhibitors with different affinities are used at all screen occasions in dose response. Diluted TR-FRET Assay
  • SH-SY5Y cells are cultured in DMEM/F-12 with Glutamax, 10% FCS and 1% non- essential amino acids and cryopreserved and stored at -140 °C at a concentration of 7.5- 9.5xl0 6 cells per vial.
  • DMEM/F- 12 with Glutamax, 10% FCS and 1 % non-essential amino acids to a 384-well tissue culture treated plate, 30 pL cell susp/well. The cell plates are then incubated for 7-24 h at 37 °C, 5% C0 2 .
  • the cell medium is removed, followed by addition of 50 pL compound diluted in DMEM/F- 12 with Glutamax, 10% FCS, 1 % non-essential amino acids to a final cone of 0.5% DMSO.
  • the compounds are incubated with the cells for 16-17 h (overnight) at 37 °C, 5%
  • MSD Meso Scale Discovery
  • the plates are used to analyse cytotoxicity using the
  • ViaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex Bioscience that measures total cellular ATP.
  • the assay is performed according to the manufacture's protocol. Briefly, 10 uL cell lysis reagent is added per well. The plates are incubated at r.t. for 10 min. Two min after addition of 25 pL reconstituted ViaLightTM Plus ATP reagent, the luminescence is measured in an Envision reader. Tox threshold is a signal below 70% of the control.

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Abstract

La présente invention concerne des procédés de réduction stéréo et régiosélective de cyclohexanones à l'aide d'une enzyme cétoréductase. Les composés préparés selon les procédés décrits sont utiles dans la préparation de composés pour traiter au moins un état associé à une inhibition du dépôt du peptide β-amyloïde (Aβ) et des parties de celui-ci par inhibition de l'enzyme de clivage APP du site bêta (BACE).
PCT/EP2018/086777 2017-12-22 2018-12-21 Réduction stéréosélective de cétone à l'aide d'une enzyme cétoréductase WO2019122421A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151324A1 (fr) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédés de réduction pour la préparation d'ézétimibe
WO2012087237A1 (fr) 2010-12-22 2012-06-28 Astrazeneca Ab Composés et leur utilisation en tant qu'inhibiteurs de bace
WO2013173784A1 (fr) * 2012-05-17 2013-11-21 Genentech, Inc. Procédé de fabrication de composés de cyclopentapyrimidine hydroxylée et sels de ceux-ci
WO2013190298A1 (fr) * 2012-06-20 2013-12-27 Astrazeneca Ab Composés 2h-imidazol-4-amine et leur utilisation en tant qu'inhibiteurs de bace
WO2016055858A1 (fr) 2014-10-07 2016-04-14 Astrazeneca Ab Composés et leur utilisation en tant qu'inhibiteurs de bace

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151324A1 (fr) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédés de réduction pour la préparation d'ézétimibe
WO2012087237A1 (fr) 2010-12-22 2012-06-28 Astrazeneca Ab Composés et leur utilisation en tant qu'inhibiteurs de bace
WO2013173784A1 (fr) * 2012-05-17 2013-11-21 Genentech, Inc. Procédé de fabrication de composés de cyclopentapyrimidine hydroxylée et sels de ceux-ci
WO2013190298A1 (fr) * 2012-06-20 2013-12-27 Astrazeneca Ab Composés 2h-imidazol-4-amine et leur utilisation en tant qu'inhibiteurs de bace
WO2016055858A1 (fr) 2014-10-07 2016-04-14 Astrazeneca Ab Composés et leur utilisation en tant qu'inhibiteurs de bace

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Advanced Organic Chemistry", March 2007, WILEY INTERSCIENCE
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
GREENE; WUTS: "Protective Groups in Organic Chemistry", 1999, JOHN WILEY & SONS
HARRISON ET AL.: "Compendium of Synthetic Organic Methods,", vol. 1-8, 1971, JOHN WILEY & SONS
LOUDON: "Organic Chemistry", 2002, OXFORD UNIVERSITY PRESS, pages: 1084 - 1085
R. C. LAROCK: "Comprehensive Organic Transformations—A Guide to Functional Group Preparations", 1999, WILEY VCH
ROBERDS, S. L. ET AL., HUMAN MOLECULAR GENETICS, vol. 10, 2001, pages 1317 - 1324
S.M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
SINHA ET AL., NATURE, vol. 402, 1999, pages 537 - 540
SMITH: "Organic Synthesis", 2001, MCGRAW HILL
SMITH; MARCH: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2001, WILEY-INTERSCIENCE
T. W. GREEN; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
VARGHESE, J. ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, 2003, pages 4625 - 4630

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