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WO2012013012A1 - Composé d'hydroxyéthylamine benzo-azacyclique, son procédé de préparation et ses utilisations - Google Patents

Composé d'hydroxyéthylamine benzo-azacyclique, son procédé de préparation et ses utilisations Download PDF

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Publication number
WO2012013012A1
WO2012013012A1 PCT/CN2011/000966 CN2011000966W WO2012013012A1 WO 2012013012 A1 WO2012013012 A1 WO 2012013012A1 CN 2011000966 W CN2011000966 W CN 2011000966W WO 2012013012 A1 WO2012013012 A1 WO 2012013012A1
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alkyl
group
aryl
compound
benzyl
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PCT/CN2011/000966
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Chinese (zh)
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刘克良
何军林
赵侃
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中国人民解放军军事医学科学院毒物药物研究所
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Publication of WO2012013012A1 publication Critical patent/WO2012013012A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicinal chemical industry and relates to a benzoazepine heterocyclic hydroxyethylamine compound, a preparation method thereof and use thereof.
  • the invention also relates to a pharmaceutical composition comprising such a compound, a method of treating and/or preventing a disease characterized by elevated P-amyloid levels or P-amyloid deposits, in particular Alzheimer's disease And a method of modulating BACE1 activity or modulating P-amyloid levels in vivo or in vitro. Background technique
  • Alzheimer's disease is a common senile neurodegenerative disease that has become the fourth leading killer of cardiovascular disease, malignant tumors and post-stroke health threats in the elderly.
  • the key pathological feature of Alzheimer's disease is the formation of senile plaques (Seni le Plaque, SP) outside the nerve cells, and the main component of senile plaques is ⁇ -amyloid (A ⁇ ), which is neurotoxic and can cause inflammatory reactions. Nerve cell death.
  • ⁇ is a ⁇ -amyloid precursor protein ( ⁇ ) followed by ⁇ -secretase (BACE1), ⁇ -secretase Obtained by cleavage.
  • BACE1 (also known as Asp2, Memaps in2) belongs to the aspartic acid acid-drug family and has the characteristics of P-secretase. It is the rate-limiting enzyme catalyzed AP generated (Hardy J., Higgins GA Science, 1992, 256 (5054): 184-185) 0 BACE1 catalytic hydrolysis principle is: the catalytic center of a two aspartic acid residue activated water Molecule, nucleophilic attack on substrate peptide bonds causes hydrolysis to break (31111 ⁇ 211 11., 61 & 1., Mol. Cellar Biol., 2008, 28 (11): 3663-3671).
  • ACE ACE 1 is considered to be a valid ⁇ & standard for the treatment of Alzheimer's disease (Ghosh AK, et al., Neuro thera peu tics, 2008, 5: 399 - 408).
  • Strategies to alleviate or treat Alzheimer's disease by inhibiting BACE1 activity to reduce AP levels in the brain have been widely accepted.
  • BACE1 inhibitors are not only highly effective as a therapeutic agent for Alzheimer's disease, but their selectivity for BACE1 should be stronger than for other members of the aspartic protease family (eg BACE2, cathepsin D, etc.) Sex (Saunders AJ, et al., Science, 1999, 286 (5443): 1255-1255).
  • BACE1 inhibitor OM99-2 Since the first generation of the BACE1 inhibitor OM99-2, a large number of literatures have reported different types of BACE1 inhibitors. Most of these inhibitors are BACE1 catalyzed transition state mimics, that is, two days through the catalytic center. The amino acid residues interact to exert an inhibitory activity of 'I (Ghosh AK, Gemma S., Tang J. Neuro therapeutics, 2008, 5: 399-408). The core structures according to their action can be roughly divided into several categories, such as s tat ine, nors tat ine, hydroxye thy 1 amine inhibitors.
  • the inventors have obtained a class of benzodiazepine heterohydroxyethylamine compounds through creative labor and intensive research, and surprisingly found that these compounds can significantly inhibit BACE1, in which TruPointTMP-secretase is used.
  • the assay kit was evaluated at the molecular level, and some of the compounds even reached micromolar levels.
  • the compounds of the invention have the effect of preventing diseases characterized by elevated P-amyloid levels or P-amyloid deposits (eg, Alzheimer's disease, Parkinson's disease, or Down's syndrome, etc.) The prospect of drugs.
  • the following invention is thus provided:
  • One aspect of the invention relates to a compound of formula U), a pharmaceutically acceptable salt thereof, or a solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, -S0 2 -R 5 , and -CO-R 5 ;
  • R 2 is selected from d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl group, ( ⁇ cycloalkyl, -d-6-alkyl -. C3-I O pit ring group, - Co- 6 pit-aryl, -Co-6-heteroaryl, and -Co-6 alkyl-heterocyclic;
  • R 3 is selected from the group consisting of hydrogen and Cw. Alkyl, CH. Alkenyl group, C 3 - 10 alkynyl, d. Cycloalkyl, -Cw. Cycloalkenyl, -C. — 6 alkyl-aryl, —C. - 6 alkyl-heteroaryl, -C 0 -6 alkyl-heterocyclyl, -Cl-6 alkyl-C3-0 cycloalkyl, -C 3 -10 cycloalkyl-aryl, -C 3 -] 0 ring-alkyl-heteroaryl, - Cw. Cycloalkyl-heterocyclyl, -C 3 - i.
  • R 8 R 9 -C. - 6 alkyl-heteroaryl, -C (R 8 R 9 ) -C. - 6 alkyl-heterocyclyl, -C 2 - 6 alkyl-0-C. - 6 alkyl-aryl, -C 2 - 6 alkyl-0-C. - 6 alkyl-heteroaryl, and -C 2 - 6 alkyl-0-C. a 6- alkyl-heterocyclic group, wherein R 8 and R 9 are each independently selected from hydrogen, d- 6 alkyl or R 8 and R 9 together with the carbon atom to which they are attached.
  • R ie and R 11 may independently represent hydrogen, d- 6 alkyl. a cycloalkyl group, and a nitrogen atom to which 1 and R 11 are attached Forming a nitrogen-containing heterocyclic group together;
  • R 4 is selected from the group consisting of hydrogen, d- 6 alkyl, halogen, halogenated d- 6 alkyl, -6 alkenyl, C 2 - 6 block, cyano, nitro, hydroxy, -C. - 6 alkyl-0R 6 , -C. - 6- alkyl-NR 6 R 7 , -Co-6 alkyl-SR 6 , -C. - 6 alkyl - 0C0R -C. - 6 alkyl - C00R 6 , -C. - 6- alkyl-NR 6 C0R', -C. - 6 alkyl-C0NR 6 R 7 , -C.
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, d- 6 alkyl, haloalkyl, C 3 -1Q cyclodecyl, and substituted. Cycloalkyl, -C. - 6 alkyl-aryl, -C. - 6 alkyl-heteroaryl, and -C. — 6 alkyl-heterocyclic groups;
  • n represents an integer from 0 - 3 (eg 0, 1, 2 or 3);
  • R 5 is selected from the group consisting of hydroxyl groups, -C. - 6 alkyl-0R 6 , - C. - 6 alkyl-NR 6 R 7 , C, - 6 fluorenyl, C 3 -6 alkenyl, C 3 - 6 block, C 3 -,.
  • d- 6 alkyl 3 ⁇ 4 element, 3 ⁇ 4 substituting d_ 6 alkyl, (: 2 - 6 alkenyl, C 2--6 alkynyl, cyano, nitro, oxo, - Co-6 alkyl-0R fi , -C 0 -6 alkyl-SR 6 , -Co-6 alkyl-0C0R 6 , -C._ 6 alkyl-C00R 6 , -C.- 6 alkyl-NR 6 C0R 7 , -C.- 6- alkyl-C0NR 6 R 7 , -C.— 6 -yl-S0 2
  • the aryl group is a C 6 - 12 monocyclic or bicyclic hydrocarbon ring, wherein at least one ring is an aromatic ring;
  • the heteroaryl group is 5 - 6 yuan containing 1 - 4 hetero atoms selected from oxygen, nitrogen and sulfur a monocyclic aromatic ring or a fused 8- to 12-membered bicyclic aromatic ring;
  • the heterocyclic group is 4 to 7 members containing 1 to 4 hetero atoms selected from oxygen, nitrogen and sulfur. Monocyclic or fused 8- 12-membered bicyclic rings which are saturated or partially unsaturated. Examples of the aryl group include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and the like.
  • heteroaryl groups wherein examples of monocyclic aromatic rings include, but are not limited to, hayl, thiol, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, Oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl, tris
  • fused aromatic ring groups include, but are not limited to, quinolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, acridinyl, porphyrinyl, 2, 3- Naphthyridinyl, naphthyridinyl, fluorenyl, isodecyl, azaindole, mesoindolyl,
  • heterocyclic group wherein, examples of the monocyclic ring include, but are not limited to, pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl , thiomorphol inyl, thiazolyl group, hydantoinyl, valerolactamyl, oxiranyl, azetidinyl, dioxolane, Dioxolyl, oxathiolanyl, oxathianyl, di thianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyridyl Meryl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diaze
  • bicyclic rings include, but are not limited to, dihydroindenyl, isoindoline, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1 3-benzonitrile Weed (benzazepine), tetrahydrogen Isoquinolyl and the like.
  • the compound of the formula (I) contains at least one amino group which can form various salts with an acid as a form of pharmaceutical application. It should be understood that when used in medicine, the salt of the compound of formula (I) should be pharmaceutically acceptable, including
  • Salts as described in J. Pharm. Sci., 1977, 66, 1-19 such as acid addition salts with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates , acetate, benzoate, citrate, nitrate, succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palm An acid salt, a methanesulfonate, a p-toluenesulfonate, a naphthalenesulfonate, a decanoate, or a trifluoroacetate.
  • inorganic or organic acids such as hydrochlorides, hydrobromides, sulfates, phosphates , acetate, benzoate, citrate, nitrate, succinate, lactate, tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palm An acid salt, a methanesulf
  • the compound of formula (I) can be prepared in crystalline or amorphous form, the crystalline form of which may contain solvent molecules, and if crystalline, may optionally be solvated, such as a hydrate.
  • the present invention includes stoichiometric solvates (e.g., hydrates) and compounds containing variable solvents (e.g., water) within its scope.
  • the compound of formula (I) contains a plurality of chiral centers, and some of the compounds of formula (I) can exist in stereoisomeric forms (such as diastereomers and enantiomers), and the invention extends to these stereo Each of the isomeric forms and mixtures thereof, including racemates.
  • the different stereoisomeric forms can be separated from other forms by conventional methods, or any of the formulated isomers can be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric form and mixtures thereof.
  • the compound of formula (I) is a single enantiomer or diastereomeric form of the compound of formula (I a):
  • R 1 is -S0 2 -R 5 or -C0-R 5 ;
  • R 2 is d- 6 alkyl or -C. — 6 alkyl-aryl ⁇
  • R 3 is -C 3 -iocycloalkyl or -C. - 6 alkyl-aryl;
  • R 4 is selected from the group consisting of hydrogen, d- 6 alkyl, halogen, NR 6 R ⁇ and -OR 6 ;
  • R 5 is selected from -C. - 6 alkyl-0R 6 , - C. - 6- alkyl-NR 6 R 7 , d- 6 alkyl, - C. - 6 alkyl-aryl, and -C. a 6 alkyl-heteroaryl group; wherein the aryl, heteroaryl or heterocyclic group in R 5 may be substituted at a different substitution position by one of the following groups: halogen, -C. - 6 alkyl-0R 6 , -C. - 6 alkyl-NR 6 R 7 , or -C. - 6 alkyl-C0NR 6 R 7 ;
  • R 6 and R 7 are each independently selected from hydrogen, d- 6 alkyl. Cycloalkyl, -C. - 6 alkyl-aryl, -C. - 6- mercapto-heteroaryl, and -C. - 6 alkyl-heterocyclic group ⁇
  • the heteroaryl group is selected from the group consisting of: thienyl, furyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, pyranyl, pyrazolyl, pyrimidinyl , pyridazinyl, pyrazinyl, pyridyl, fused aromatic ring group, etc., wherein the fused aromatic ring group includes quinolyl, isoquinolyl, fluorenyl, isodecyl, nitrogen a heterocyclic group, a carbazolyl group, a fluorenyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, and a benzisothiazolyl group;
  • the group is selected from the following structures: pyrrolidinyl,
  • R 1 is - SO wide R 5 ;
  • R 2 is a benzyl group
  • R 3 is selected from the group consisting of benzyl, methoxybenzyl, and cyclopropyl;
  • R 4 is hydrogen
  • R 5 is selected from the group consisting of phenyl, decyloxyphenyl, propyl, thienyl, benzylamino-phenyl, ethyl-phenyl, and phenyl substituted by one fluorine or chlorine.
  • the compound of formula (I) is selected from the group consisting of:
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I) above, which comprises the steps of: using dimethylformamide and/or dichloromethane as solvent, carbodiimide and/or HOBt as condensing agent,
  • the reaction temperature of the compound of the formula ( ⁇ ) with the compound of the formula (m) in the presence of triethylamine is between ox: and room temperature,
  • Step (i) is typically included at a suitable temperature, such as 0-60 ⁇ €, in the presence of a suitable base such as NaH, potassium carbonate, with a compound of the formula R 5 S0 2 C1
  • a solvent such as disulfoxide (DMS0) and tetrahydrofuran (THF) are reacted.
  • Step (ii) typically involves the formation of hydrazine in a suitable solvent such as dioxane or methanol (MeOH) at a suitable temperature, such as room temperature, under conditions of 1.5 N LiOH/H 2 0. The reaction of the base protection removal.
  • a suitable solvent such as dioxane or methanol (MeOH)
  • MeOH methanol
  • R 3 and R 4 are as defined above, and P 1 represents a suitable amino protecting group such as t-butoxycarbonyl.
  • Step (iii) typically comprises reacting a compound of formula (VI) with an amine (NH 2 -R 3) a suitable temperature in a suitable solvent such as ethanol in the presence of, as at the reflux temperature of the reaction.
  • Step (iv) typically includes, as when P 1 represents a tert-butoxycarbonyl group, the deprotection reaction typically uses trifluoroacetic acid in a suitable solvent such as dichloromethane at a suitable temperature, such as between 0 and room temperature. Carry out the reaction.
  • a suitable solvent such as dichloromethane
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier or adjuvant.
  • the pharmaceutical composition further comprises at least one of the following: an acetylcholinesterase inhibitor, an inhibitor against amyloid aggregation, a Y-secretase inhibitor, an a-secretase agonist Agents, anti-inflammatory agents, and antioxidants.
  • a further aspect of the invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof thereof as a BACE1 inhibitor.
  • the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as a secretase inhibitor is contemplated.
  • a further aspect of the invention relates to the preparation of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof thereof, for reducing P-amyloid in a mammal, particularly a human, particularly in the brain Use in medicine.
  • Still another aspect of the present invention relates to the use of the above compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof for the preparation of a medicament for treating Alzheimer's disease, Parkinson's disease, or Down's syndrome .
  • a further aspect of the invention relates to a method of treating and/or preventing a disease characterized by elevated amyloid levels or P-amyloid deposits in a human or animal, the method comprising administering to a human or An animal effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the diseases characterized by elevated P-amyloid levels or P-amyloid deposits include, but are not limited to, Alzheimer's disease, Parkinson's disease, Down's syndrome, and the like.
  • the compound of formula (I) can be formulated in any conventional manner
  • the compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is formulated with one or more physiologically acceptable diluents or carriers.
  • a therapeutically and/or prophylactically effective amount of a compound of the invention may be applied in pure form or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of such forms) .
  • the compound can be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients.
  • prophylactically and/or therapeutically effective amount refers to a sufficient amount of a compound to treat the disorder in a reasonable effect/risk ratio suitable for any medical prophylaxis and/or treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • a further aspect of the invention relates to a method of modulating BACE1 activity or modulating P-amyloid levels in vivo or in vitro, comprising using an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof A step of.
  • the alkyl, alkenyl, alkynyl and cycloalkyl groups not specifically mentioned above may be optionally substituted by one or more (for example, 1 to 6) of the following groups: halogen, D- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, halo d- 6 alkyl, d- 6 alkoxy, amino, cyano, hydroxy, -C00R 12 , -Sd- 6 alkyl or -d- 6 alkyl-NR 12 R 13 .
  • R 12 and R 1 3 independently represent hydrogen, d- 6 alkyl or. Cycloalkyl.
  • aryl, heteroaryl or heterocyclic group not specifically indicated as described above may be optionally substituted by one or more (e.g., 1-6) of the following groups at different substitution positions: d- 6 alkyl, Prime, ⁇ 6 alkyl, halogenated d- 6 alkoxy, hydroxy, d-6 alkoxy,
  • C alkyl group means a term as a group or part of a group used herein containing X to y carbon atoms, straight-chain or branched saturated hydrocarbon chain.
  • Examples of such groups include mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl Wait.
  • C X - Y chain dilute refers to one or more carbons
  • a linear or branched hydrocarbon group having a carbon double bond and having x-y carbon atoms examples include a vinyl group, a propenyl group, a butenyl group, a pentenyl group or a hexenyl group.
  • C X -Y alkynyl refers to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds and having xy carbon atoms. Examples of such a group include an ethynyl group, a propynyl group, a butyl group, a pentynyl group or a hexynyl group and the like.
  • d- y-alkoxy refers to -0-C x - y alkyl, wherein C X - Y group as defined herein. Examples of such groups include decyloxy, ethoxy, Propyloxy, butoxy, pentyloxy, hexyloxy and the like.
  • Cx - ycycloalkyl refers to a saturated monocyclic hydrocarbon group containing from X to y carbon atoms. Examples of such a group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.
  • ( ⁇ cycloalkenyl) refers to an unsaturated non-aromatic monocyclic hydrocarbon group of from X to y carbon atoms of one or more carbon-carbon double bonds. Examples of such groups include Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
  • C x - y X and Y respectively indicate that the number of carbon atoms of the group is from X to Y, and when the number of carbon atoms is zero, it means that there is no such group, for example, C.
  • Alkyl-aryl represents the absence of an alkyl group, i.e., only an aryl group.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • substituted C alkyl refers to a Cx - y alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halogen. Examples of such a group include a fluoroethyl group, a trifluoromethyl group.
  • 3 ⁇ 4 Cx - y alkoxy refers to a C alkoxy group, as defined herein, wherein at least one hydrogen atom is replaced by a halogen.
  • HOBt 1-Hydroxybenzotriazole The following Examples 1 - 8 relate to the preparation of the acid A1 - A8.
  • Example 1 Preparation of 1-(methylsulfonyl)-indole-4-carboxylic acid (No. A1) NaH (0.55 g, 16 mmol) was placed in a one-neck round bottom flask, and DMSO (6 ml) was added. , I ⁇ -4-carboxylic acid oxime ester (2 g, 11. 4 mmol) was dissolved in THF, the solution in which the ruthenium substrate was dissolved was slowly added dropwise to the DMS0 solution, and the reaction was carried out for 3 hours or more. . Further, mercaptosulfonyl chloride (1.32 ml, 24 mmol) was added to the reaction mixture, and the reaction was carried out for 2 h or more.
  • the reaction solution was poured into H 2 0, extracted with DCM, and the organic layer was combined, washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 for 6 h or more. 8 ⁇ The drying agent was filtered, and the solvent was evaporated under reduced pressure.
  • the solid was placed in a single-necked round bottom flask, Diox was added, 1.5 N LiOH/H 2 0 solution (15 ml) was added dropwise, and the reaction was carried out for 1 h or more, and H 2 0 (30 ml) was added thereto, and pH 2 was adjusted by IN HC1 to precipitate.
  • the title compound (Al) was obtained as a white solid.
  • Example 2 Preparation of 1-(phenylsulfonyl)-indole-4-carboxylic acid (No. A2) according to the similar procedure described for the synthesis of (A1), but using phenylsulfonyl chloride instead of mercaptosulfonate The acid chloride is prepared to give 1-(phenylsulfonyl)-indole-4-carboxylic acid (A2).
  • Example 3 Preparation of 1-(4-methoxyphenylsulfonyl)-indole-4-carboxylic acid (No. A3) NaH (0. 235 g, 6.
  • Example 7 Preparation of 1-(propylsulfonyl)-indole-4-carboxylic acid (No. A7) according to the similar procedure described for the synthesis of (A1), but using propylsulfonyl chloride instead of methylsulfonate The acid chloride was prepared to give 1-(propylsulfonyl)-indole-4-carboxylic acid (A7).
  • Example 8 Preparation of 1-(3-(benzylcarbamoyl)-benzenesulfonyl)-indole-4-carboxylic acid (No. A8)
  • (2R, 3S) -3-amino-1-(benzylamino)-4-phenyl-but-2 was prepared according to the similar method used for the synthesis of (B1), but using benzylamine instead of cyclopropylamine. - alcohol di-trifluoroacetate (B2).
  • Example 11 (2R, 3S)-3-amino-1-(3-methoxy-benzylamino)-4-phenyl-butan-2-ol-trifluoroacetate (No. B3) Preparation
  • A1 (0.224 g, 0.94 mmol), 1-hydroxybenzotriazole (HOBt) (0.127 g, 0.94 mmol), N-ethyl-N,-3-dimethylaminocarbodiimide hydrochloride ( EDO HC1) (0.18 g, 0.94 mmol) was placed in a one-neck round bottom flask, dissolved in dichloromethane, and stirred for 2 or more.
  • a solution containing B1 (0.4 g, 0.89 leg 01) and 81 ⁇ (0,64 ml, 4.46 mmol) in dichloromethane was placed in a single-necked round bottom flask, and the reaction solution of the above A1 was added dropwise thereto in portions. 4 or more.
  • Example 27 BACE1 Inhibitory Activity Test of Compounds 1 - 15 of the Invention in Vitro
  • the activity was evaluated using the TruPointTM Secretase Assay Kit (PerkinElmer), and the final concentrations of the test compounds were 10 - 4 , 10 - 5 , and 10 - 6 mol / L , respectively.
  • the specific operations are as follows:
  • the screening system selected catechol EGCG as a positive control (EGCG is a natural BACE1 inhibitor), and its final concentration is reported according to its literature IC 5 . (1.6 ⁇ ⁇ ), to 10- 7, 5 x 10- 7, 10 6, 5 10 "6 10 5, 10- 4 mol / L, the dose-dependent inhibition of BACE1, percent inhibition at six concentrations 2.2, 14.4, 28.1, 62.0, 81.5, 92.6, measured BACE1-IC 5 is 0.76 ⁇ M, which is consistent with 1.6 ⁇ reported in the literature, and the activity test method is stable and reliable.
  • the BACE1 inhibition rate of compound 1 - 15 was between 80% and 100% (Table 2).
  • the IC 5 of compound 11, 12, 13, 14, 15 was 173 nM, respectively. , 158 nM, 130 nM, 813 nM, and 116 nM.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un composé d'hydroxyéthylamine benzo-azacyclique, sur un procédé de préparation de celui-ci et sur ses utilisations, le composé étant représenté par la formule (I). L'invention porte également sur une composition contenant un tel composé. Le composé est capable d'inhiber nettement la β-sécrétase 1 (BACE 1) et sera utilisé comme médicament pour la prévention ou le traitement de maladies caractérisées par un taux de β-amyloïde accru ou des dépôts de β-amyloïde telles que la maladie d'Alzheimer, la maladie de Parkinson ou la trisomie 21 et ainsi de suite.
PCT/CN2011/000966 2010-07-30 2011-06-09 Composé d'hydroxyéthylamine benzo-azacyclique, son procédé de préparation et ses utilisations WO2012013012A1 (fr)

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CN201010246893.X 2010-07-30
CN201010246893.XA CN102344402B (zh) 2010-07-30 2010-07-30 苯并氮杂环羟乙基胺类化合物、其制备方法和用途

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WO2012013012A1 true WO2012013012A1 (fr) 2012-02-02

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PCT/CN2011/000966 WO2012013012A1 (fr) 2010-07-30 2011-06-09 Composé d'hydroxyéthylamine benzo-azacyclique, son procédé de préparation et ses utilisations

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CN (1) CN102344402B (fr)
WO (1) WO2012013012A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006032999A1 (fr) * 2004-09-21 2006-03-30 Pfizer Products Inc. N-methyl hydroxyethylamine utile dans le traitement d'affections du systeme nerveux central
CN1759095A (zh) * 2001-11-08 2006-04-12 艾伦药物公司 N,n'－取代的－1,3－二氨基－2－羟基丙烷衍生物
WO2007061930A1 (fr) * 2005-11-21 2007-05-31 Amgen Inc. Modulateurs de beta-secretase et procedes d'utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2323927C2 (ru) * 2002-06-05 2008-05-10 Ф.Хоффманн-Ля Рош Аг Производные 1-сульфонил-4-аминоалкоксииндола и фармацевтическая композиция, обладающая активностью модулятора 5-нт6 рецептора

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1759095A (zh) * 2001-11-08 2006-04-12 艾伦药物公司 N,n'－取代的－1,3－二氨基－2－羟基丙烷衍生物
WO2006032999A1 (fr) * 2004-09-21 2006-03-30 Pfizer Products Inc. N-methyl hydroxyethylamine utile dans le traitement d'affections du systeme nerveux central
WO2007061930A1 (fr) * 2005-11-21 2007-05-31 Amgen Inc. Modulateurs de beta-secretase et procedes d'utilisation

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CN102344402B (zh) 2015-01-07

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