Patent Grant
8168630
This invention relates to a compound having an inhibitory activity against production of amyloid β protein and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
In the brain of Alzheimer's patient many insoluble spots (senile plaque) are found, which is formed by extraneuronal accumulation of a peptide called amyloid β protein comprised of about 40 amino acids. Neuronal death caused by the senile plaque is considered to develop Alzheimer's Disease and an enhancer of amyloid β protein decomposition or vaccine of amyloid β protein etc. are extensively studied as a remedy for Alzheimer's Disease.
Secretase is an enzyme producing amyloid β protein by intracellular cleavage of a protein called amyloid β protein precursor (APP). An enzyme playing a role for producing an N-terminal of the amyloid β protein is called BACE1 (beta-site APP-cleaving enzyme) and an inhibitor of the BACE1, which will reduce production of amyloid β protein, could be a remedy for treating Alzheimer's disease.
Patent literature 1 discloses a compound with a chemical structure similar to that of the compound of the present invention, having an inhibitory activity of NO synthetase and effective for treating dementia.
Patent literature 2-5 and non-patent literature 1-2 disclose compounds with a chemical structure similar to those of the compound of the present invention, and describe that each compound is useful as an anti-hypotensive agent, morphine-like analgesic or tranquilizer, intermediate of a therapeutic agent, NPYY5 antagonist, analgesic and the like.
Patent literatures 6-14 disclose BACE-1 inhibitors having a chemical structure different from that of the compound of the present invention. Also, patent literature 15 discloses a BACE-1 inhibitor.
Patent literature 1: WO 96/014842 Pamphlet
Patent literature 2: U.S. Pat. No. 3,235,551
Patent literature 3: U.S. Pat. No. 3,227,713
Patent literature 4: JP H09-067355
Patent literature 5: WO 2005/111031 Pamphlet
Patent literature 6: WO 02/96897 Pamphlet
Patent literature 7: WO 04/043916 Pamphlet
Patent literature 8: WO 2005/058311 Pamphlet
Patent literature 9: WO 2005/097767 Pamphlet
Patent literature 10: WO 2006/041404 Pamphlet
Patent literature 11: WO 2006/041405 Pamphlet
Patent literature 12: US 2007/0004786A
Patent literature 13: US 2007/0004730A
Patent literature 14: US 2007/27199A
Patent literature 15: WO 2007/049532 Pamphlet
Non-patent literature 1: Journal of Heterocyclic Chemistry, 14, 717-723 (1977)
Non-patent literature 2: Journal of Organic Chemistry, 33(8), 3126-3132 (1968).
This invention provides with a compound having an inhibitory activity against BACE-1 and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
The present invention provides with
wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted carbocyclyl lower alkyl, optionally substituted heterocyclyl lower alkyl, optionally substituted carbocyclyl lower alkoxy, optionally substituted heterocyclyl lower alkoxy, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkyloxy, optionally substituted heteroaralkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom or may form oxo,
provided the following compounds i) and ii) are excluded;
wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or
R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom, provided the following compounds i) and ii) are excluded:
wherein the ring A′ is a carbocyclic group or a heterocyclic group,
wherein R5 is hydrogen, lower alkyl or acyl,
wherein the ring A′ is a carbocyclic group or a heterocyclic group,
wherein R5 is hydrogen, lower alkyl or acyl,
The present invention also provides with
A compound of the present invention is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein (Alzheimer's disease etc.).
In this description, “halogen” includes fluorine, chlorine, bromine and iodine.
A moiety of halogen in “halogeno lower alkyl” and “halogeno lower alkoxycarbonyl” is the same as “halogen” above.
“Lower alkyl” includes C1-C15, preferably C1-C10, more preferably C1-C6 and further more preferably C1-C3 straight or branched alkyl, and for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl are exemplified.
A moiety of alkyl in “lower alkoxy”, “halogeno lower alkyl”, “hydroxyl lower alkyl”, “hydroxyl lower alkoxy”, “lower alkoxycarbonyl”, “halogeno lower alkoxycarbonyl”, “lower alkoxycarbonyl lower alkyl”, “lower alkylamino”, “lower alkoxy lower alkyl”, “hydroxyimino lower alkyl”, “lower alkoxyimino lower alkyl”. “amino lower alkyl” “lower alkoxy lower alkoxy”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “lower alkyl carbamoyl”, “hydroxyl lower alkyl carbamoyl”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkyl sulfamoyl”, “lower alkyl sulfinyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclyl lower alkylamino”, “carbocyclyl lower alkyl carbamoyl”, “cycloalkyl lower alkyl”, “cycloalkyl lower alkoxy”, “cycloalkyl lower alkylamino”, “cycloalkyl lower alkoxycarbonyl”, “cycloalkyl lower alkylcarbamoyl”, “aryl lower alkyl”, “aryl lower alkoxy”, “aryl lower alkylamino”, “aryl lower alkoxycarbonyl”, “aryl lower alkoxycarbamoyl”, “heterocyclyl lower alkyl”, “heterocyclyl lower alkoxy”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbamoyl” is the same as “alkyl” above.
“Optionally substituted lower alkyl” may be substituted with one or more of substituent(s) selected from a substituent group α.
Group α is a group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclic group.
One or more of substituent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkoxy”, “optionally substituted lower alkoxycarbonyl” and “optionally substituted lower alkylthio”
“Lower alkylidene” includes a divalent group derived from the “lower alkyl” above, and methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene etc. are exemplified.
“Lower alkenyl” includes C2-C15, preferably C2-C10, more preferably C2-C6 and further more preferably C2-C4 straight or branched alkenyl having one or more double bond(s) at any position thereof. Examples of lower alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
“Lower alkynyl” includes C2-C10, preferably C2-C8, more preferably C3-C6 straight or branched alkynyl having one or more triple bond(s) at any position thereof. Examples of lower alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Lower alkynyl may additionally have a double bond at any position thereof.
One or more of substituent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkenyl” and “optionally substituted lower alkynyl”.
A moiety of lower alkenyl in “hydroxyl lower alkenyl”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “carbocyclyl lower alkenyl”, “lower alkenyloxy”, “lower alkenylthio” and “lower alkenylamino” is the same as that of “lower alkenyl”.
A moiety of lower alkynyl in “hydroxyl lower alkynyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “carbocyclyl lower alkynyl”, “lower alkynyloxy”, “lower alkenylamino” and “lower alkynylamino” is the same as that of “lower alkynyl” above.
One or more substituents selected from lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group etc. is exemplified as a substituent of “optionally substituted amino” and “optionally substituted carbamoyl”.
“Acyl” includes C1-C10 aliphatic acyl, carbocyclyl carbonyl and heterocyclic carbonyl, and examples of acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzotriazolecarbonyl, pyrazinecarbonyl, piperidinecarbonyl, thiomorpholino and the like.
A moiety of acyl in “acylamino” and “acyloxy” is the same as described above.
One or more substituents selected from the substituent group α is exemplified as a substituent in “optionally substituted acyl” and a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is optionally substituted with one or more substituent(s) selected from lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α.
“A carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, and non-aromatic fused carbocyclic group etc.
“Cycloalkyl” includes C3-C10, preferably C3-C8 and more preferably C4-C8 carbocyclic group and examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
A moiety of cycloalkyl in “cycloalkyl lower alkyl”, “cycloalkyloxy”, “cycloalkyl lower alkoxy”, “cycloalkylthio”, “cycloalkylamino”, “cycloalkyl lower alkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”, “cycloalkylcarbamoyl”, “cycloalkyl lower alkylcarbamoyl”, “cycloalkyl lower alkoxycarbonyl” and “cycloalkylcarbonyl” is the same as “cycloalkyl” described above
“Cycloalkenyl” includes the above cycloalkyl having one or more double bond(s) at any position on the ring, and examples of the cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctynyl, and cyclohexadienyl etc.
Examples of “aryl” include phenyl, naphthyl, anthryl and phenanthryl etc. and especially phenyl is preferable.
“Non-aromatic fused carbocyclic group” includes a group in which two or more cyclic groups selected from “cycloalkyl”, “cycloalkenyl” and “aryl” described above fused, and examples of “Non-aromatic fused carbocyclic group” include indanyl, indenyl, tetrahydronaphthyl and fluorenyl etc.
“Forming a carbocyclic ring together with a linked carbon atom” means that two substituents jointly form “cycloalkyl” above.
A moiety of the carbocyclic ring in “carbocyclyloxy”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkenyl”, “carbocyclyl lower alkynyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclylthio”, “carbocyclyl amino”, “carbocyclyl lower alkylamino”, “carbocyclylcarbonyl”, “carbocyclylsulfonyl”, “carbocyclylsulfonyl”, “carbocyclylcarbamoyl”, “carbocyclyl lower alkyl carbamoyl”, “carbocyclyloxycarbonyl” is the same as the “carbocyclic group”.
A moiety of aryl in “aryl lower alkyl”, “aryloxy”, “aryloxycarbonyl”, “aryloxycarbonyloxy”, “aryl lower alkoxycarbonyl”, “arylthio”, “arylamino”, “aryl lower alkoxy”, “aryl lower alkylamino”, “arylsulfonyl”, “arylsulfonyloxy”, “arylsulfinyl”, “arylsulfamoyl”, “arylcarbamoyl” and “aryl lower alkylcarbamoyl” is the same as the “aryl” above.
“Heterocyclic group” includes a heterocyclic group containing one or more heteroatom(s) each independently selected from O, S and N, and examples of “heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.; a non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, inmidazolidinyl, imidazolinyl, pyrazolidinyl, pirazolinyl, piperidyl, piperazinyl, morpholinyl, moipholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofinyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl and tetrahydropyridazinyl etc.;
a fused bicyclic heterocyclic group such as indolyl, isoindolyl, indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopynolyl, thienothienyl, imidazopyridyl pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthilidinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzinmidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl, dihydrobenzooxedinyl, dihydrobenzooxepinyl and dihydrothienodioxinyl etc.; and a fused tricyclic heterocyclic group such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxadinyl, dibenzofuryl, imidazoquinolyl and tetrahydrocarbazolyl etc.; and preferably includes 5- or 6-membered heteroaryl and a non-aromatic heterocyclic group.
A moiety of the heterocyclic group in “heterocyclyl lower alkyl”, “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonyl”, “heterocyclyl lower alkoxy”, “heterocyclyl amino”, “heterocyclyl carbonylamino”, “heterocyclyl sulfamoyl”, “heterocyclylsulfonyl”, “heterocyclylcarbamoyl”, “heterocyclyloxycarbonyl”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbamoyl” is the same as the “heterocyclic group” above.
“A nitrogen-containing aromatic heterocyclic group” means a group of the “heterocyclic group” above containing at least one nitrogen atom, and examples of the “nitrogen-containing aromatic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.;
“The heterocyclic group” or “nitrogen-containing aromatic heterocyclic group” above may be linked to other group at any position on the ring.
“Nitrogen-containing aromatic monocyclic heterocyclic group” means a monocyclic group in the “nitrogen-containing aromatic heterocyclic group” and examples of the “Nitrogen-containing aromatic monocyclic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.
“The nitrogen-containing aromatic monocyclic heterocyclic group” above may be linked to other group at any carbon atom on the ring.
Examples of a substituent in the “optionally substituted carbocyclic group” and “optionally substituted heterocyclic group” of the ring A and B include the substituent group α (preferably halogen, hydroxyl, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, cyano, lower alkylamino, lower alkylthio etc.); lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, hydroxyimino and lower alkoxyimino, wherein examples of preferable substituents include halogen, hydroxyl, lower alkoxy, lower alkoxycarbonyl etc.; amino lower alkyl substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include acyl, lower alkyl and/or lower alkoxy etc.;
Also the ring A may be substituted with one or more group(s) selected from
wherein Ak1, Ak2 and Ak3 are each independently a single bond, optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene;
Preferable examples of (i) to (xixi) above include
wherein Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene, and the other symbols are the same as described above.
In other cases of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”, one or more substituent(s) selected from a group of lower alkyl and the substituent group α may be exemplified as a substituent of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”
“Heteroaryl” includes an aromatic cyclic group among the “heterocyclic group” above.
“Lower alkylene” includes C1-C10, preferably C1-C6, more preferably C1-C3 straight or branched divalent carbon chain, and for example, methylene, dimethylene, trimethylene, tetramethylene and methyl trimethylene are exemplified.
A moiety of lower alkylene in “lower alkylenedioxy” is the same as the “lower alkylene” described above.
“Lower alkenylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a double bond at any arbitrary position thereof, and vinylene, propenylene, butenylene, butadienylene, methyl propenylene, pentenylene and hexenylene are exemplified.
“Lower alkynylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a triple bond and also a double bond at any arbitrary position thereof and for example, ethynylene, propynylene, butynylene, pentynylene and hexynylene are exemplified.
Examples of a substituent in “optionally substituted lower alkylene”, “optionally substituted lower alkenylene” and “optionally substituted lower alkynylene” include the substituent group α, and preferably halogen and hydroxyl etc. are exemplified.
Examples of a substituent in “optionally substituted carbocyclyl lower alkyl”, “optionally substituted heterocyclyl lower alkyl”, “optionally substituted carbocyclyl lower alkoxy”, and “optionally substituted heterocyclyl lower alkoxy” include one or more substituent(s) selected from lower alkyl and the substituent group α.
In this specification, “solvate” includes a solvate with an organic solvent and a hydrate etc. and hydrate may be coordinated with optional number of water molecule.
The compound (I) includes pharmaceutical acceptable salt thereof. Examples of the pharmaceutical acceptable salt include a salt with an alkali metal such as lithium, sodium and potassium etc., an alkali earth metal such as magnesium, calcium etc., ammonium, an organic base and an amino acid; a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid etc., and an organic acid such as acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. Especially hydrochloric acid, phosphoric acid, tartaric acid or methane sulfonic acid is preferable. These salts can be prepared by a method usually carried out.
The compound (I) is not construed to be limited to a specific isomer but to include all possible isomers such as a keto-enol isomer, an imine-enamine isomer, a diastereoisomer, an optical isomer and a rotational isomer etc. For example, a compound (I) in which R2a is hydrogen includes a tautomer as follows;
The compound (I) of the present invention can be prepared, for example, according to the non-patent literature 1 or a method described below;
Preparation of an Aminodihydrothiazine Ring (I-1) or (I-2):
(In the scheme above, at least one of R2b and R2c is hydrogen, R3b and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, and the other symbols are the same as described above.)
(In the scheme above. L is a leaving group such as halogen or lower alkylsulfonyl etc. and the other symbols are the same as described above.)
(In the scheme above, at least one of R2b and R2c is hydrogen and the other symbols are the same as described above.)
(In the Scheme, Each Symbol is the Same as Described Above)
(In the scheme, R17 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and other symbols are the same as described above)
An acylating agent corresponding to the objective compound such as benzoyl chloride, 2-furoyl chloride, acetic anhydride etc. is reacted with a compound (I-12) in which R2b is hydrogen under the presence of a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent and under the presence of a base such as pyridine or triethylamine etc. or without a solvent at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-12) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as amino acid or glycolic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-13) and/or (I-14)(when R2a is hydrogen).
Preparation of a Carbamoyl Derivative (I-17)
(In the scheme above, CONR18R19 is optionally substituted carbamoyl and the other symbols are the same as described above)
A compound (I-16) having a carboxyl group as a substituent on the ring A is reacted with a primary or secondary amine having a substituent corresponding to the objective compound (e.g., aniline, 2-aminopyridine, dimethylamine etc.) in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-17).
Preparation of an Acylamino Derivative (I-19)
(In the scheme, NHR20 is optionally substituted amino, NR20COR21 is optionally substituted acylamino, optionally substituted ureido or carboxyamino having a substituent on the oxygen atom and the other symbols are the same as described above.)
A compound (I-18) having an optionally substituted amino group on the ring A is reacted with a reagent having a substituent corresponding to the objective compound such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates etc. under the presence of a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-18) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-19).
Preparation of an Alkylamino Derivative (I-20)
(In the Scheme, NHR2 is optionally substituted amino and R22 is lower alkyl.)
A compound (I-18) having an amino group on the ring A is reacted with an aldehyde having a substituent corresponding to the objective compound such as benzaldehyde, pyridine-2-carboxaldehyde etc. and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride etc. in a solvent such as dichloromethane, tetrahydrofuran etc. under the presence of an acid such as acetic acid etc. or without an acid at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 24 hours to give a compound (I-20).
Preparation of a Substituted Alkoxy Derivative (I-22).
(In the scheme above, R23 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and the other symbols are the same as described above.)
A compound (I-21) having a hydroxy group on the ring A is reacted with an alkylating agent having a substituent corresponding to the objective compound such as benzyl chloride, methyl iodide etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 24 hours, or a compound (I-18) is reacted with an alcohol such as 2-aminoethanol etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a Mitsunobu reagent such as triphenylphosphine-azodicarboxylic acid diethyl ester etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound (I-22).
Introduction of a Substituent by Palladium Coupling
(In the scheme above, Hal is halogen, G is optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted alkoxycarbonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc. and the other symbols are the same as described above.)
A compound (I-23) having halogen as a substituent on the ring A is reacted with a compound having a substituent corresponding to the objective compound (e.g., styrene, propargyl alcohol, aryl boronic acid, carbon monoxide etc.) in a solvent such as tetrahydrofuran, dimethylfomamide, 1,2-dimethoxyethane, methanol etc. under the presence of a base such as triethylamine, sodium carbonate etc., a palladium catalyst such as palladium acetate, palladium chloride etc. and a ligand such as triphenylphosphine etc. and under irradiation of microwave or without the irradiation, at −80° C. to 150° C., preferably 0° C. to 100° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound (I-24).
Preparation of an Oxime Derivative (I-26)
(In the scheme above. R24 is hydrogen, optionally substituted lower alkyl etc., R25 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc., and the other symbols are the same as described above.)
A compound (I-25) having an acyl group as a substituent of the ring A is reacted with a hydroxylamine having a substituent corresponding to the objective compound such as hydroxylamine, methoxylamine, O-benzylhydroxylamine etc. or a salt thereof in a solvent such as methanol, ethanol etc. under the presence of an additive such as potassium acetate etc. or without an additive at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 72 hours to give a compound (I-26).
Coupling Reaction
(In the scheme above, R26 is a substituent corresponding to each objective compound)
The 1st Step:
A compound v is reacted with a reagent having a substituent corresponding to the objective compound such as acyl halide, acid anhydride, chlorocarbonate ester, isocyanate etc. (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate, di-tert-butyl dicarbonate, phenyl isocyanate etc.) in a solvent such as tetrahydrofuran, dichloromethane, dimethylfomamide etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound A is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, methanol etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound w.
When the substituent R has a functional group which disturb the said reaction, it can be carried out by protecting the functional group with a suitable protecting group and then deprotecting it at a subsequent appropriate step.
The 2nd Step:
A compound w is reacted in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing trifluoroacetic acid etc. or in neat, or in neat trifluoroacetic acid at −30° C. to 100° C., preferably 0° C. to 90° C. for 0.5 to 12 hours to give a compound (I-27). Alternatively, the objective compound can be synthesized according to the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Preparation of an Optically Active Isomer
1) Preparation of an Optically Active Isomer ae
For example, an optically active isomer ae, one embodiment of the compounds of the present invention, can be prepared according to the following scheme:
(In the scheme above, R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl; R27 is a chiral sulfoxide having optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or a chiral auxiliary group such as α-methyl benzyl etc.; R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R28 is optionally substituted lower alkyl or optionally substituted lower alkenyl; R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; and the other symbols are the same as described above.)
The compounds y and z above can be prepared by a method described in
Alternatively, these compounds can be prepared by optical resolution of each intermediate or the final product, or according to methods described below. Examples of the optical resolution method include a separation of optical isomers using an optically active column, kinetic resolution by an enzyme reaction etc., crystallization of diastereomers by salt formulation using a chiral acid or chiral base, and a preferential crystallization etc.
When R2a and/or R2b is hydrogen in the resulting compound ae-i or ae-ii, a substituent of the objective compound, R2 and/or RTh, may be further introduced by a conventional method if it is necessary.
1′) Method for Preparing an Optically Active Isomer Method B
An optically active compound ah of the present invention can be also prepared by a method below:
(In the Scheme, the Symbols are the Same as Described Above.)
An optically active compound ae-iii or ae-iv of the present invention can be also prepared by introducing R3a and R3b as shown below:
(In the Scheme Above, Each Symbol is the Same as Described Above)
When preparing a compound ae-iii or ae-iv in which R3a and R are substituted on the carbon atom next to S atom, a compound z is processed through the 3rd and 4th steps in place of the 3rd and 4th steps of 1) described above, and R3a and R3b are introduced in advance.
The compound ab′ is processed in the same reactions as the 5th to 7th steps of 1) above to give the objective compound ae-iii or ae-iv.
When the substituent L of a compound ad′ is eliminated to give a compound ad″ shown below, the objective compound ae′-iii or ae′-iv is obtained by processing the compound ad′ it through the 7th step in place of the 7th step described in 1) above.
A preparation of a compound af-1 by conversion of the substituent is illustrated below:
(In the scheme, R8a and Rba are an amino-protecting group, and the other symbols are the same as described above.)
Trisdibenzylideneacetonedipalladiunm, palladium acetate, palladium(0) prepared in situ etc. and a phosphine ligand such as tri-tert-butylphosphine, dicyclohexylbiphenylphosphine etc. are added to a compound ae-1 in a solvent such as tetrahydrofuran, toluene, xylene etc. and further a reagent having a substituent corresponding to the objective compound such as lithium hexamethylenedisilazide, benzophenonimine etc. is added thereto at −10° C. to 30° C., then the reaction mixture is reacted at 30° C. to 120° C., preferably 50° C. to 100° C. for 0.5 to 48 hours, preferably 3 to 20 hours to give a compound af-1.
Any amino-protecting group which is deprotected by a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. can be used and examples of the protecting group include lower alkoxycarbonyl, lower alkenyloxycarbonyl, trialkylsilyl, acyl, methanesulfonyl, trifluoromethanesulfonyl and toluenesulfonyl etc.
4) Conversion of a Substituent (2)
A preparation of a compound af-2 by conversion of the substituent is illustrated below:
(In the scheme, each symbol is the same as described above.)
A catalyst of catalytic reduction such as 10% palladium-carbon etc. is added to a compound ae-2 in a solvent such as tetrahydrofuran, ethyl acetate, methanol etc. and it is reacted under the pressure of normal to 5 atom, preferably normal to 2 atom of hydrogen atmosphere at 30° C. to 120° C., preferably 50° C. to 80° C. for 0.5 to 48 hours, preferably 6 to 20 hours to give a compound af-2. Alternatively, the compound af-2 is obtained by a method described in Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill).
5) Conversion of a Substituent (3)
A preparation of a compound af-3 by conversion of the substituent is illustrated below:
(In the scheme, R9 is hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkyl amino, optionally substituted aromatic carbocyclyloxy, optionally substituted heterocyclyloxy, optionally substituted aromatic carbocyclylthio, optionally substituted heterocyclylthio, optionally substituted carbocyclylamino, optionally substituted heterocyclylamino, cyano, azide, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, optionally substituted carbamoyl etc. and the other symbols are the same as described above.)
A reagent having a substituent corresponding to the objective compound such as ethanol, methanthiol, dimethylamine etc. is added to a compound ae-3 in a solvent such as tetrahydrofuran, ethanol etc. under the presence of a base such as sodium methoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride etc. or without a base at −10° C. to 50° C. and it is reacted for 0.5 to 12 hours, preferably 1 to 8 hours to give a compound af-3. If necessary, a coupling reaction may be carried out in the same manner as the method for preparing a compound (I-19) described above.
In every step described above, if a starting compound has a functional group which disturb the reaction (e.g., hydroxyl, mercapto, amino, formyl, carbonyl, carboxyl etc.), it is recommended to protect the functional group and deprotect it at a subsequent appropriate step with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Further the order of steps may be changed and each reaction intermediate may be isolated and used in the subsequent step.
Examples of a preferable compound in the present invention include the followings:
In a formula (I′)
a compound in which the ring A′ is benzene, pyridine, indole, benzisoxazole, benzopyrazole, benzofuran, benzothiophene, benzodioxole, or dihydrobenzodioxolane (hereinafter called a compound in which the ring A′ is A′2),
a compound in which the ring A′ is benzene (hereinafter called a compound in which the ring A′ is A′3),
a compound in which the ring A′ is pyridine (hereinafter called a compound in which the ring A′ is A′4)
a compound in which R1 is methyl (hereinafter called a compound in which R1 is R1-2),
a compound in which both of R2a and R2b are hydrogens (hereinafter called a compound in which R2a and R2b are R2-2),
a compound in which R3a, and R3b, or R3c and R3d taken together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-2),
a compound in which R3a and R3b, or R3c and R3d are the same substituent selected from halogen and lower alkyl (hereinafter called a compound in which R3, R3b, R3c and R3d are R3-3),
a compound in which all of R3a, R3b, R3c and R3d are hydrogens (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-4),
a compound in which n is 0 to 2, R4 is each independently halogen (hereinafter called a compound in which R4 is R4-2),
a compound in which G is (ii′), (ii″), (iv′), (v′), (x′), (xiii′) or (xiv′) above (hereinafter called a compound in which G is G2),
a compound in which G is (ii′), (ii″), (iv′), (v′), (x′), (xiii′) or (xiv′) above, and the ring B is optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted benzothiazolyl, optionally substituted thiazolopyridyl, optionally substituted quinolyl, optionally substituted isoquinolyl or optionally substituted naphthylidinyl optionally substituted quinazolinyl, or optionally substituted pyridopyrimidinyl (hereinafter called a compound in which G is G3),
a compound in which G is (ii′) above (hereinafter called a compound in which G is G4),
a compound in which a combination of the ring A′, R1, R2a and R2b, R3a, R3b, R3c and R3d, n and R4, and G is as follows;
Compounds of the present invention are useful for treating diseases induced by production, secretion or deposition of amyloid β protein, and effective for the treatment and/or prophylaxis, or improvement of conditions for Alzheimer's dementia (Alzheimer's disease, senile dementia of Alzheimer type etc.), Down's disease, disturbance of memory, prion disease (Creutzfeldt-Jakob disease etc.), mild cognitive impairment (MCI), Dutch-type hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other degenerated dementia, vascular degenerated mixed dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy etc.
Since compounds of the present invention have several efficacies such as having a potent inhibitory activity against BACE-1 having a high selectivity against other enzymes etc., they can be a drug with less side effects. Moreover they can be a drug having a wide margin of safety by choosing an optically active isomer of appropriate stereochemistry. Further they have a lot of merits such as good metabolic stability, high solubility, high absorbability of oral administration, high bioavailability, good clearance and high transitivity to brain, long half-life, high ratio of non protein binding, lower inhibition of hERG channel and CYP, and/or negative result of Ames Test, and, therefore, they can be superior drugs.
A compound of the present invention may be administrated together with other agent (e.g., other agent for treating Alzheimer's disease such as acetylcholine esterase etc.). The compound can be given in combination with an antidementia drug such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, inemantine or vinpocetine, for example.
A compound of the present invention may be orally administrated as powder, granule, tablet, capsule, pill or liquid formulation, or parentally administrated as injection, suppository, formulation of transdermal absorption or inhalation. Also, an effective amount of the compound may be formulated together with medicinal additives suitable for the formulation such as an excipient, binder, moistening agent, disintegrant and/or lubricant etc.
Dose of a compounds of the present invention depends on condition of diseases, route of administration, age and body weight of a patient, but in the case of oral administration to an adult, the dose range is usually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day and in the case of parenteral administration the dose range is usually 1 g to 10 g/day, preferably 0.1 to 2 g/day.
The present invention is illustrated in details by examples and test examples but the present invention is not limited to these examples.
In EXAMPLES, each abbreviation has the following meaning:
1H-NMR (CDCl3): 2.71 (3H, d, J=5.1 Hz), 7.35 (1H, dd, J=9.3, 9.0 Hz), 8.41 (1H, ddd, J=9.0, 3.9, 3.0 Hz), 8.78 (1H, dd, J=6.3, 3.0 Hz).
1H-NMR (DMSO-d6): 2.50 (3H, d, J=4.8 Hz), 5.21 (2H, brs, 1H), 6.78 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 6.94 (1H, dd, J=6.3, 3.0 Hz), 6.99 (1H, dd, J=11.4, 8.7 Hz).
1H-NMR (CDCl3): 2.70 (3H, d, J=5.1 Hz), 7.24 (1H, dd, J=10.5, 9.3 Hz), 8.00 (1H, dd, J=6.2, 2.9 Hz), 8.21 (1H, m), 8.78 (1H, brs).
1H-NMR (CDCl3): 1.74 (3H, d, J=1.2 Hz), 5.16 (1H, dd, J=10.5, 0.9 Hz), 5.27 (1H, d, J=17.3, Hz), 6.26 (1H, ddd, J=17.3, 10.5, 1.7 Hz), 7.07 (1H, dd, J=11.1, 9.6 Hz), 7.64-7.69 (2H, m), 7.94 (1H, brs).
1H-NMR (DMSO-d6): 2.08 (3H, s), 4.10 (2H, d, J=7.8 Hz), 5.72 (1H, t, J=7.8 Hz), 7.23-7.32 (1H, m), 7.60-7.69 (2H, m), 9.25 (3H, brs), 11.39 (1H, brs).
1H-NMR (CDCl3): 1.72 (3H, s), 2.02-2.18 (1H, m), 2.54-2.76 (2H, m), 3.14-3.28 (1H, m), 7.37 (1H, dd, J=11.9, 8.8 Hz), 7.62 (1H, dd, J=7.5, 3.0 Hz), 7.80 (1H, ddd, J=8.8, 3.9, 3.0 Hz), 8.77 (1H, brs), 9.38 (1H, brs), 10.66 (1H, brs), 11.50 (1H, brs).
1H-NMR (CDCl3): 1.60 (3H, d, J=1.5 Hz), 1.76-1.87 (1H, m), 2.44-2.54 (1H, m), 2.66-2.76 (1H, m), 2.86-2.94 (1H, m), 6.50 (1H, ddd, J=8.7, 3.6, 3.0 Hz), 6.66 (1H, dd, J=7.1, 3.0 Hz), 6.81 (1H, dd, J=12.0, 8.7 Hz).
1H-NMR (CDCl3): 2.20 (3H, s), 2.66 (3H, d, J=5.1 Hz), 7.13 (1H, dd, J=10.5, 9.0 Hz), 7.70 (1H, dd, J=6.3, 3.0 Hz), 7.79 (1H, bis), 8.11 (1H, ddd, J=9.0, 4.1, 3.0 Hz).
1H-NMR (CDCl3): 1.69 (3H, s), 2.16 (3H, s), 5.12 (1H, d, J=10.5 Hz), 5.24 (11H, d, J=17.4 Hz), 6.26 (1H, ddd, J=17.4, 10.5, 1.5 Hz), 6.98 (1H, dd, J=11.1, 8.7 Hz), 7.33 (1H, brs), 7.50-7.59 (2H, m).
1H-NMR (DMSO-d6): 2.03 (3H, s), 2.06 (3H, s), 4.09 (2H, d, J=7.5 Hz), 5.67 (1H, t, J=7.5 Hz), 7.12 (1H, dd, J=10.7, 8.9 Hz), 7.46-7.59 (2H, m), 9.24 (4H, brs), 10.11 (1H, s).
1H-NMR (CDCl3): 1.62 (3H, d, J=0.9 Hz), 1.80-1.91 (1H, m), 2.16 (3H, s), 2.47-2.58 (1H, m), 2.62-2.73 (1H, m), 2.87-2.98 (1-1H, m), 4.36 (2H, brs), 6.99 (11H, dd, J=11.7, 8.7 Hz), 7.14 (1H, dd, J=7.1, 3.0 Hz), 7.80 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 7.97 (1H, brs),
1H NMR (CDCl3) δ1.52 (3H, t. J=6.8 Hz), 1.67 (3H, s), 1.93-2.00 (1H, m), 2.60-2.67 (2H, m), 2.94-3.00 (1H, m), 4.19 (2H, q, J=6.8 Hz), 6.93 (1H, d, J=9.3 Hz), 8.14 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.5 Hz).
1H NMR (DMSO-d6) δ 1:29 (3H, t, J=6.9 Hz), 1.45 (3H, s), 1.51-1.58 (1H, m), 2.46-2.48 (1H, m), 2.61-2.64 (1H, m), 2.80-2.83 (1H, m), 3.85-3.91 (2H, m), 6.38 (1H, dd, J=8.3, 2.5 Hz), 6.52 (1H, d, J=2.4 Hz), 6.67 (1H, d, J=8.6 Hz)
1H-NMR (CDCl3): 1.33 (9H, s), 2.75 (3H, s), 7.30 (1H, t. J=7.8) 7.59-7.63 (1H, m), 7.79 (1H, d, J=7.8) 8.0 (1H, s)
1H-NMR (CDCl3): 1.28 (9H, s), 1.71 (3H, s), 2.19-2.24 (2H, m), 3.27-3.32 (11H, n), 3.54-3.66 (1H, m), 3.87-3.97 (1H, m), 5.10-5.11 (1H, m), 7.22 (1H, t. J=8.1) 7.32-7.41 (2H, m), 7.56-7.58 (1H, m)
1H-NMR (CDCl3): 1.54 (9H, s), 1.57 (3H, s), 1.96 (2H, t, J=6.0), 2.80-2.92 (1H, m), 3.00-3.13 (1H, m), 7.21 (1H, t. J=8.1) 7.28-7.41 (2H, m), 7.52-7.55 (1H, m)
1H-NMR (CDCl3): 1.51 (9H, s), 1.69 (3H, s), 2.01-2.12 (1H, m), 2.40-2.51 (1H, m), 2.67-2.76 (2H, m), 6.55-6.67 (3H, m), 7.15 (1H, t. J=8.1).
1H-NMR (CDCl3) δ: 2.71 (3H, d, J=4.9 Hz), 7.34 (1H, t, J=9.3 Hz), 8.40 (1H, ddd, J=9.3, 6.2, 3.0 Hz), 8.78 (1H, dd, J=6.2, 3.0 Hz).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.81 (3H, d, J=3.5 Hz), 7.29 (1H, t, J=8.9 Hz), 8.31 (1H, dt, J=8.9, 2.9 Hz), 8.55 (1H, dd, J=6.3, 2.9 Hz).
1H-NMR (CDCl3): 1.30 (9H, s), 1.35 (9H, s), 1.86 (3H, s), 3.11 (1H, dd, J=16.2, 2.1 Hz), 3.26 (1H, dd, J=16.2, 2.1 Hz), 5.55 (1H, s), 7.18 (1H, dd, J=11.1, 8.9 Hz), 8.18 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 8.53 (1H, dd, J=7.0, 2.9 Hz).
Ratio of diastereomers (3S:3R=97:3) HPLC Column: CHIRALPAK AS-RH, Detection:254 nm: Column temp.: 25° C., Mobile phase: 40% MeCNaq., Flow rate: 0.5 ml/min.
Note: As to the stereochemistry of compound (27) obtained above, it is known that 3S-isomer is preferentially prepared as written in the literature A etc. and it is also possible to prepare each diastereomer selectively by choosing appropriate metal species and/or a reaction condition.
Literature A: (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996), (2) D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999), (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4) Yong Qin et al., J. Org. Chem., 71, 1588-1591 (2006).
1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 3.25 (2H, s), 7.62 (1H, dd, J=11.4, 9.4 Hz), 8.33-8.48 (2H, m).
1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 2.13-2.24 (1H, m), 2.68-2.74 (2H, m), 3.19-3.25 (1H, m), 7.63 (1H, dd, J=11.4, 8.9 Hz), 8.07 (1H, dd, J=7.0, 3.5 Hz), 8.36 (1H, dt, J=8.9, 3.5 Hz), 11.22 (1H, s).
1H-NMR (CDCl3): 1.59 (3H, s), 1.81 (1H, ddd, J=14.1, 10.9, 3.5 Hz), 2.47 (1H, ddd, J=14.1, 5.9, 3.5 Hz), 2.71 (1H, td, J=10.9, 3.5 Hz), 2.89 (1H, ddd, J=10.9, 5.9, 3.5 Hz), 3.57 (2H, br s), 6.49 (1H, dt, J=8.5, 3.3 Hz), 6.67 (1H, dd, J=6.9, 3.3 Hz), 6.80 (1H, dd, J=11.8, 8.5 Hz).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.79 (3H, s), 8.26 (1H, t, J=2.3 Hz), 8.76 (1H, d, J=2.3 Hz), 8.96 (1H, d, J=2.3 Hz).
1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.01 (3H, s), 0.85 (9H, s), 1.51 (3H, s), 1.98 (2H, t, J=6.0 Hz), 3.49-3.54 (1H, m), 3.65 (1H, dt, J=11.1, 6.0 Hz), 8.02 (1H, t, J=2.2 Hz), 8.53 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=2.2 Hz).
1H-NMR (CDCl3): 1.53 (18H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.9, 1.9 Hz), 2.91 (1H, ddd, J=12.9, 3.9, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.4, 3.9 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
1H-NMR (CDCl3) δ: 1.51 (9H, s), 1.68 (3H, s), 2.12 (1H, ddd, J=14.8, 11.0, 3.0 Hz), 2.38-2.47 (1H, m), 2.64-2.70 (1H, m), 2.78-2.82 (1H, m), 3.80 (2H, br s), 6.90 (1H, t, J=2.4 Hz), 7.98 (1H, dd, J=10.4, 2.4 Hz).
1H-NMR (CDCl3) δ: 1.32 (9H, s), 2.83 (3H, s), 7.55-7.65 (2H, m), 8.06 (1H, d, J=8.5 Hz).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.65 (3H, s), 3.01 (1H, d, J=16.5 Hz), 3.38 (1H, d, J=16.5 Hz), 5.60 (1H, s), 7.31 (1H, dd, J=5.9, 2.7 Hz), 7.48-7.50 (2H, m).
1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.02 (3H, s), 0.84 (9H, s), 1.47 (3H, s), 1.95-2.15 (2H, m), 3.54-3.63 (2H, m), 7.29 (1H, dd, J=6.1, 2.6 Hz), 7.45-7.48 (2H, m).
1H-NMR (CDCl3) δ: −0.03 (6H, s), 0.82 (9H, s), 1.80 (3H, s), 2.21-2.24 (1H, m), 2.44-2.48 (1H, m), 3.57 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 3.71 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 7.37 (1H, dd, J=7.5, 1.2 Hz), 7.48-7.58 (2H, m).
1H-NMR (CDCl3) δ: 1.85 (3H, s), 2.27-2.31 (2H, br m), 3.73-3.83 (2H, m), 5.86 (2H, br s), 7.43 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.61 (1H, t, J=7.8 Hz), 7.81 (1H, br s).
1H-NMR (CDCl3) δ: 1.53 (3H, s), 1.88 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.40 (1H, ddd, J=13.9, 6.6, 3.8 Hz), 2.71 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.95 (1H, tt, J=6.6, 3.8 Hz), 4.33 (2H, br s), 7.29 (11H, dd, J=7.5, 1.2 Hz), 7.41-7.50 (1H, m).
1H-NMR (CDCl3) δ: 1.53 (23H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.7, 1.8 Hz), 2.91 (1H, ddd, J=12.7, 3.7, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.2, 3.7 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
1H-NMR (CDCl3) δ: 1.61 (3H, s), 1.74-1.80 (1H, m), 1.96-2.11 (1H, m), 2.64-2.82 (2H, m), 4.41 (2H, br s), 6.39 (1H, dd, J=8.1, 0.6 Hz), 6.71 (1H, dd, J=8.1, 0.6 Hz), 7.42 (1H, t, J=8.1 Hz).
1H-NMR (CDCl3): −0.10 (3H, s), −0.07 (3H, s), 0.77 (9H, s), 1.93 (3H, s), 2.08-2.27 (1H, m), 3.06-3.28 (1H, m), 3.38 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.55 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.78 (6H, s), 3.79 (6H, s), 4.81-5.05 (1H, br), 6.43-6.50 (4H, m), 7.07 (1H, d, J=1.9 Hz), 7.17 (2H, d, J=7.3 Hz), 8.05-8.16 (2H, m).
1H-NMR (CDCl3): 1.99 (3H, s), 1.91-2.02 (1H, m), 3.10 (1H, ddd, J=14.6, 6.6, 5.2), 3.36-3.51 (2H, m), 3.78 (6H, s), 3.80 (6H, s), 4.58 (2H, d, J=15.8 Hz), 4.72 (2H, d, J=15.8 Hz), 6.43-6.51 (4H, m), 7.12 (1H, dd, J=5.3, 2.0 Hz), 7.18-7.29 (3H, m), 8.20 (1H, dd, J=5.3, 0.6 Hz), 8.28-8.31 (1H, br).
1H-NMR (CDCl3): 1.49 (3H, s), 1.99 (1H, ddd, J=13.3, 7.6, 3.2 Hz), 2.31 (1H, ddd, J=13.3, 8.6, 3.7), 2.78 (1H, ddd, J=12.2, 8.6, 3.2 Hz), 3.04 (1H, ddd, J=12.2, 7.6, 3.7 Hz), 3.77 (6H, s), 3.79 (6H, s), 4.60 (2H, d, J=15.8 Hz), 4.76 (2H, d, J=15.8 Hz), 6.45-6.52 (4H, m), 7.08 (1H, dd, J=5.3, 2.1 Hz), 7.17-7.27 (3H, m), 8.40 (1H, dd, J=5.3, 0.5 Hz).
1H-NMR (DMSO-d6): 0.75 (3H, s), 1.09 (3H, s), 1.21 (9H, s), 1.79 (3H, s), 2.06 (1H, m), 2.29 (11H, m), 4.97 (1H, s), 6.57 (1H, s), 7.17 (1H, dd, J=8.7, 12.0 Hz), 7.48-7.53 (1H, m), 7.99-8.03 (1H, m), 11.26 (1H, bs).
1H-NMR (DMSO-d6): 0.65 (3H, s), 1.10 (3H, s), 1.43 (3H, s), 1.85 (1H, d. J=14.4 Hz), 2.17 (1H, dd, J=1.5, 14.4 Hz), 7.12 (1H, dd, J=2.7, 12.0 Hz), 7.60-7.64 (1H, m), 7.90 (1H, dd, J=2.7, 7.5 Hz), 11.35 (1H, bs).
1H-NMR (DMSO-d6): 1.54 (3H, s), 1.86 (3H, s), 2.81 (1H, d, J=13.8 Hz), 2.92 (1H, d. J=13.8 Hz), 4.73 (1H, s), 4.85 (1H, m), 7.28-7.35 (1H, m), 7.77-7.82 (2H, m), 11.39 (1H, bs).
1H-NMR (DMSO-d6): 1.47 (3H, bs), 1.66 (3H, bs), 2.58 (1H, d, J=12.3 Hz), 4.71 (1H, s), 4.87 (3H, bs), 6.42 (1H, bs), 6.51 (1H, dd, J=2.7, 7.2 Hz), 6.75 (2H, bs), 7.54 (1H, bs).
1H-NMR (DMSO-d6): 0.83 (3H, s), 1.27 (3H, s), 1.44 (3H, s), 1.54 (1H, d, J=14.1 Hz), 2.45 (1H, d, J=14.1 Hz), 4.79 (2H, s), 5.89 (2H, bs), 6.32-6.37 (1H, m), 6.58 (1H, dd, J=2.7, 7.2 Hz), 6.72 (1H, dd, J=8.7, 12.3 Hz).
1H-NMR (DMSO-d6) δ: 1.17 (3H, t, J=7.2 Hz), 1.18 (9H, s), 2.00 (3H, brs), 4.24 (2H, q, J=7.2 Hz), 5.56 (1H, brs), 7.56 (dd, J=9.0, 11.7 Hz), 8.36 (1H, m), 8.49 (1H, dd, J=3.0, 6.6 Hz).
1H-NMR (DMSO-d6) δ: 1.20 (9H, s), 2.00 (3H, d, J=3.6 Hz), 3.80 (1H, m), 4.00 (1H, m), 5.99 (1H, s), 6.34 (1H, t, J=5.7 Hz), 7.53 (1H, dd, J=9.0, 12.0 Hz), 8.31 (1H, m), 8.50 (1H, dd, J=2.7, 6.6 Hz).
1H-NMR (DMSO-d6) δ: 1.62 (3H, d, J=2.7 Hz), 2.62 (2H, brs), 3.65-3.83 (2H, m), 5.31 (1H, brt), 7.44 (1H, dd, J=9.0, 11.4 Hz), 8.23 (1H, m), 8.59 (1H, dd, J=3.0, 6.9 Hz).
1H-NMR (DMSO-d6) δ: 2.30 (3H, brs), 3.65-3.96 (2H, m), 5.90 (1H, brt), 7.42-7.68 (4H, m), 7.93-7.96 (2H, m), 8.17-8.33 (2H, m), 11.42 (1H, brs), 12.31 (1H, brs).
1H-NMR (CDCl3) δ: 1.89 (3H, d, J=3.0 Hz), 3.17 (1H, ddd, J=8.4, 10.2, 13.2 Hz), 3.51 (1H, ddd, J=6.0, 13.2, 19.2 Hz), 7.23 (1H, dd, J=9.0, 10.8 Hz), 7.49-7.64 (3H, m), 7.91 (2H, d, J=7.2 Hz), 8.24 (1H, m), 8.43 (1H, dd, J=3.0, 6.6 Hz), 8.57 (1H, br).
1H-NMR (CDCl3) δ: 1.85 (3H, d, J=3.6 Hz), 3.15 (1H, ddd, J=8.7, 10.5, 12.9 Hz), 3.50 (1H, ddd, J=5.4, 12.9, 18.3 Hz), 4.51 (2H, brs), 7.19 (1H, dd, J=9.0, 11.1 Hz), 8.20 (1H, ddd, J=3.0, 6.9, 9.0 Hz), 8.54 (1H, dd, J=3.0, 6.9 Hz).
1H-NMR (CDCl3) δ: 1.56 (18H, S), 1.90 (3H, d, J=3.6 Hz), 3.27 (1H, ddd, J=6.6, 9.3, 12.9 Hz), 3.69 (1H, ddd, J=4.2, 12.9, 17.4 Hz), 7.23 (1H, dd. J=9.0, 12.0 Hz), 8.24 (1H, ddd, J=3.0, 9.0, 12.0 Hz), 8.41 (1H, ddd, J=2.4, 3.0, 6.0 Hz).
1H-NMR (CDCl3) δ: 1.54 (18H, S), 1.85 (3H, d, J=2.4 Hz), 3.24 (1H, m), 3.44 (1H, m), 3.53 (2H, brs), 6.61 (1H, m), 6.82-6.89 (2H, m).
1H-NMR (CDCl3) δ: 1.12 (3H, s), 1.22 (3H, s), 1.35 (9H, s), 1.99 (3H, d, J=5.8 Hz), 3.75 (3H, s), 5.65 (1H, s), 7.20 (0H, dd, J=11.5, 8.9 Hz), 8.18-8.21 (1H, m), 8.45 (1H, dd, J=6.9, 2.9 Hz).
1H-NMR (DMSO-d6) δ: 0.65 (3H, d, J=1.8 Hz), 0.93 (3H, s), 1.22 (9H, s), 1.93 (3H, d, J=6.6 Hz), 3.24 (1H, d, J=8.4 Hz), 3.74 (1H, d, J=8.4 Hz), 5.96 (1H, bs), 6.75 (1H, s), 7.47 (1H, dd, J=9.0, 12.0 Hz), 8.23 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.39 (1H, dd, J=3.0, 6.9 Hz).
1H-NMR (D{dot over (M)}SO-d6) δ: 0.80 (6H, s), 1.59 (3H, d, J=4.5 Hz), 3.16 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.0, 12.0 Hz), 8.17 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.64 (1H, dd, J=3.0, 6.9 Hz)
LCMS: 420 m/z[M+H]+
1H-NMR (DMSO-d) δ: 0.83 (3H, s), 1.12 (3H, s), 1.72 (3H, s), 2.69 (1H, d, J=13.2 Hz), 2.90-3.10 (1H, m), 7.44-7.58 (4H, m), 8.00 (2H, d J=7.5 Hz), 8.23-8.35 (2H, m), 10.75 (1H, bs).
1H-NMR (DMSO-d6): 0.72 (3H, s), 1.00 (3H, d, J=3.6 Hz), 1.54 (3H, d, J=4.8 Hz), 2.61 (1H, d, J=12.3 Hz), 3.09 (1H, d, J=12.3 Hz), 5.98 (2H, s), 7.41 (1H, dd, J=9.0, 11.7 Hz), 8.16-8.21 (1H, m), 8.42 (1H, dd, J=3.0, 6.9 Hz).
1H-NMR (DMSO-d) δ: 0.70 (3H, s), 1.02 (3H, s), 1.43 (9H, s), 1.56 (3H, bs), 2.61 (1H, d, J=12.9 Hz), 3.16 (1H, m), 7.45 (11H, dd, J=9.0, 11.4 Hz), 8.20-8.24 (1H, m), 8.35 (1H, m), 9.87 (1H, bs).
1H-NMR (DMSO-d6) δ: 0.87 (3H, bs), 1.06 (3H, bs), 1.39 (9H, s), 1.57 (3H, bs), 2.66-2.72 (2H, m), 4.97 (2H, bs), 6.45-6.47 (2H, m), 6.78 (1H, m), 9.65 (1H, bs).
1H-NMR (CDCl3) δ: 4.08 (3H, s), 6.81 (1K d, J=2.5 Hz), 8.65 (1H, s), 9.14 (1H, s), 9.45 (1H, s).
1H-NMR (DMSO-d6) δ: 7.20 (1H, d, J=2.5 Hz), 8.93 (1H, s), 9.12 (1H, s), 9.33 (1H, s).
1H-NMR (CDCl3) δ: 1.63 (9H, s), 5.04 (2H, br s), 8.03 (1H, s), 8.69 (1H, s).
1H-NMR (CDCl3) δ: 1.46 (3H, t, J=7.1 Hz), 1.66 (9H, s), 4.50 (2H, q, J=7.1 Hz), 8.35 (1H, s), 8.89 (1H, s), 9.24 (1H, s).
1H-NMR of the crude product (CDCl3) δ: 1.67 (9H, s), 5.79 (1H, br s), 8.35 (1H, s), 8.90 (1H, s), 9.15 (1H, s).
1H-NMR (CDCl3) δ: 1.14 (3.6H, s), 1.22 (3.6H, s), 1.27 (5.4H, s), 1.39 (5.4H, s), 1.96 (1.2H, s), 1.99 (1.8H, s), 4.31 (0.4H, s), 4.34 (0.6H, d, J=11.6 Hz), 4.41 (0.4H, d, J=11.6 Hz), 4.45 (0.6H, s), 4.56 (0.4H, s), 4.68 (0.6H, d, J=11.6 Hz), 4.81 (0.4H, d, J=11.6 Hz), 5.01 (0.6H, s), 7.06-7.38 (6H, m), 8.18 (0.6H, d, J=8.8 Hz), 8.24 (0.4H, d, J=9.1 Hz), 8.42-8.47 (1H, m).
1H-NMR (CDCl3) δ: 2.14 (1.35H, s), 2.21 (1.65H, s), 3.73-4.07 (3H, m), 4.43 (0.55H, d, J=11.5 Hz), 4.63 (0.55H, d, J=11.5 Hz), 4.74 (0.45H, d, J=11.5 Hz), 4.78 (0.45H, d, J=11.5 Hz), 7.20-7.38 (4H, m), 7.43-7.51 (2H, m), 7.56-7.63 (1H, m), 7.75-7.86 (2H, m), 8.08-8.17 (1H, m), 8.24-8.34 (11H, m), 8.91-9.01 (1H, m), 11.81 (0.55H, s), 11.90 (0.45H, s).
1H-NMR (CDCl3) δ: 1.58 (3bH, s), 1.81 (3aH, s), 2.76 (bH, dd, J=13.4, 1.8 Hz), 3.09 (bH, dd, J=13.4, 6.1 Hz), 3.16 (aH, dd, J=13.8, 3.9 Hz), 3.35 (aH, dd, J=13.8, 1.8 Hz), 4.21-4.25 (aH, m), 4.28 (aH, d, J=12.4 Hz), 4.33-4.38 (bH, m), 4.49-4.56 (a+bH, m), 4.73 (bH, d, J=11.9 Hz), 6.83-7.60 (10H, m), 7.91-8.23 (3H, m), 8.25-8.30 (bH, m), 8.74 (aH, m).
1H-NMR (CDCl3) δ: 1.47 (8.1H, s), 1.51 (9.9H, s), 1.53 (1.35H, s), 1.75 (1.65H, s), 3.01-3.49 (2H, m), 3.81-3.86 (0.55H, m), 4.07-4.09 (0.45H, m), 4.17 (0.45H, d, J=12.1 Hz), 4.25 (0.55H, d, J=11.6 Hz), 4.41 (0.45H, d, J=12.1 Hz), 4.49 (0.55H, d, J=11.6 Hz), 6.73-6.78 (1H, m), 6.94-7.23 (5H, m), 8.11-8.18 (1H, m), 8.22-8.27 (0.55H, m), 8.51-8.55 (0.45H, m).
1H-NMR (CDCl3) δ: 1.46 (8.1H, s), 1.51 (9.9H, s), 1.54 (1.35H, s), 1.74 (1.65H, s), 2.91 (0.55H, d, J=12.9 Hz), 3.02 (0.55H, dd, J=12.9, 6.3 Hz), 3.15 (0.45H, dd, J=13.3, 3.0 Hz), 3.37-3.73 (2H, br), 3.43 (0.45H, d, J=13.3 Hz), 4.13-4.18 (1H, m), 4.22 (0.45H, d, J=11.9 Hz), 4.34 (0.45H, d, J=11.9 Hz), 4.49 (0.55H, d. J=1.6 Hz), 4.59 (0.55H, d, J=11.6 Hz), 6.45-6.61 (1H, m), 6.71-7.39 (7H, m).
Compound (34)(125 mg) and DMT-MM (162 mg) were suspended in methanol (1.2 ml), stirred at room temperature for 30 minutes and compound (33)(117 mg) was added therein. After stirring for 5 hours, the product was isolated by a silicagel thin-layer chromatography to give the objective compound (46)(13.5 mg).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.81 (1H, d, J=11.6 Hz), 2.12 (1H, bs), 2.54-2.59 (1H, m), 2.97 (1H, bs), 3.28 (2H, d, 6.4 Hz), 3.52 (2H, d, 6.5 Hz), 3.88 (3H, s), 5.69 (2H, s), 7.09 (1H, dd, J=11.8, 6.8 Hz), 7.50 (1H, s), 7.60 (1H, d, J=7.8 Hz), 7.67 (1H, s), 10.06 (1H, s).
1H-NMR (DMSO-d6) δ: 1.65 (3H, s), 2.03-2.09 (1H, m), 2.34-2.38 (1H, m), 2.51-2.61 (2H, m), 3.10-3.13 (1H, m), 3.57 (2H, t, J=4.4 Hz), 4.45 (2H, t, J=6.4 Hz), 5.13 (2H, dd, J=29.1, 13.9 Hz), 5.83-5.92 (1H, m), 7.08 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=8.0 Hz), 7.84 (1H, s), 7.91 (1H, d, J=8.1 Hz), 8.36 (1H, s), 8.87 (1H, s), 10.56 (1H, s).
A carboxylic acid, R—COOH corresponding to the objective compound (0.115 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.106 mmol) were dissolved in methanol (0.4 ml) and stirred by shaking at room temperature for 1.5 hours. A solution of compound A (0.0884 mmol) in methanol (0.4 ml) was added and the mixture was stirred for 8 hours. The reaction solvent was concentrated, dissolved in ethyl acetate (1 ml) and dimethylsulfoxide (0.5 ml), a 2N aqueous solution of sodium hydroxide (1 ml) was added and stirred by shaking for 2 hours. The organic layer was separated and concentrated to give a crude product of compound B. Trifluoroacetic acid (0.3 ml) was added and stirred by shaking at room temperature for 14 horns, dimethylsulfoxide (0.4 ml) was added and the product was purified with preparative LC/MS to give the objective compound C.
1H-NMR (DMSO-d) δ: 1.44 (9H, s), 1.51 (3H, s), 1.60 (1H, s), 2.17 (1H, s), 2.68 (1H, s), 3.05 (1H, s), 7.30 (1H, t, J=10.1 Hz), 7.42 (1H, s), 7.58 (1H, s).
1H-NMR (DMSO-d6) δ: 1.46 (9H, s), 1.65 (3H, s), 2.05 (2H, s), 2.57 (1H, s), 2.97 (1H, s), 4.86 (2H, s), 7.29 (3H, m), 7.40 (1H, d, J=7.3 Hz), 7.66 (1H, s), 7.84 (1H, s), 8.27 (1H, s), 8.58 (1H, s), 9.96 (1H, s).
1H-NMR (DMSO-d6) δ: 1.40 (9H, s), 1.61 (3H, s), 1.94 (2H, s), 2.57 (1H, s), 2.88 (1H, s), 6.55 (1H, d, J=6.3 Hz), 6.59 (1H, d, J=8.6 Hz), 7.07 (1H, d, 8.6 Hz), 7.13 (2H, s), 7.29 (1H, s), 7.41 (1H, s, J=9.3H), 7.96 (1H, d, J=6.8 Hz), 8.85 (1H, s).
1H-NMR (DMSO-d6) δ: 1.58 (3H, s), 1.90 (1H, s), 2.44 (1H, s), 2.62 (1H, t, J=9.7 Hz), 3.06 (1H, s), 6.57 (2H, td, J=15.0, 6.3 Hz), 7.05 (1H, dd, J=12.1, 10.6 Hz), 7.15 (1H, s), 7.24 (1H, d, J=5.3 Hz), 7.31 (1H, dd, J=7.7, 3.7 Hz), 7.42 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=6.8 Hz), 8.85 (1H, s).
1H-NMR (CDCl3) δ: 1.16-1.19 (2H, m), 1.24 (9H, s), 1.28-1.32 (2H, m), 1.36 (9H, s), 1.46 (3H, s), 1.50-1.55 (2H, m), 1.64-1.72 (2H, m), 5.45 (1H, s), 7.11-7.16 (1H, m), 8.11-8.16 (1H, m), 8.67 (1H, dd, J=6.9, 2.9 Hz).
1H-NMR (CDCl3) δ: 0.67-0.73 (3H, m), 0.84-0.88 (1H, m), 1.73 (1H, t, J=5.6 Hz), 2.29 (3H, d. J=2.0 Hz), 3.44 (1H, dd, J=12.2, 5.1 Hz), 3.82 (1H, dd, J=12.2, 5.1 Hz), 7.14 (1H, dd, J=11.0, 9.0 Hz), 7.52 (2H, t, J=7.6 Hz), 7.63 (1H, t, J=7.6 Hz), 7.87 (2H, d, J=7.6 Hz), 8.17 (1H, ddd, J=9.0, 3.9, 2.9 Hz), 8.27 (1H, dd, J=6.8, 2.9 Hz), 8.82 (1H, s), 11.75 (1H, s).
1H-NMR (CDCl3) δ: 0.77-0.82 (1H, m), 0.95-1.07 (2H, m), 1.38-1.40 (1H, m), 1.52 (3H, d, J=1.1 Hz), 2.25 (1H, d, J=13.0 Hz), 3.05 (1H, d, J=13.0 Hz), 7.27 (1H, dd, J=10.8, 8.9 Hz), 7.40-7.54 (3H, m), 8.18-8.27 (3H, m), 8.36 (1H, dd, J=6.7, 2.7 Hz).
1H-NMR (CDCl3) δ: 0.37-0.41 (1H, m), 0.50-0.54 (1H, m), 0.68 (2H, t, J=7.7 Hz), 1.56 (18H, s), 1.78 (3H, d, J=4.0 Hz), 2.35 (1H, d, J=12.7 Hz), 3.57 (1H, dd, J=12.7, 1.8 Hz), 7.12-7.21 (1H, m), 8.15 (1H, ddd, J=8.9, 3.9, 3.0 Hz), 8.39 (1H, dd, J=6.7, 3.0 Hz).
1H-NMR (CDCl3) δ: 0.51-0.58 (2H, m), 0.81-0.86 (2H, m), 1.54 (18H, s), 1.64 (3H, d, J=3.0 Hz), 2.60 (1H, d, J=12.4 Hz), 3.08 (1H, d, J=12.4 Hz), 3.50 (2H, s), 6.51 (1H, ddd, J=8.6, 3.7, 3.0 Hz), 6.78-6.84 (2H, m), 7.18-7.21 (1H, m).
1H-NMR (CDCl3) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H, m), 1.14-1.17 (1H, m), 1.47 (3H, d, J=2.0 Hz), 2.46 (1H, d, J=12.1 Hz), 2.69 (3H, s), 2.89 (1H, dd, J=12.1, 1.3 Hz), 7.06 (1H, dd, J=11.5, 8.8 Hz), 7.45 (1H, dd, J=6.8, 2.8 Hz), 7.94 (1H, ddd, J=8.8, 4.0, 2.8 Hz), 8.44 (1H, d, J=1.3 Hz), 9.36 (1H, d, J=1.3 Hz), 9.60 (1H, s).
1H-NMR (CDCl3) δ: 1.78 (3H, s), 3.52 (1H, d, J=15.1 Hz), 3.73 (1H, d, 15.1 Hz), 7.06 (1H, dd, J=10.4, 8.6 Hz), 7.73 (1H, dd, J=6.6, 1.3 Hz), 7.82-7.86 (1H, m), 7.90 (1H, d, J=1.3 Hz), 8.48 (1H, d, J=1.3 Hz), 9.79 (1H, s).
1H-NMR (CDCl3) δ: 1.32 (17H, s), 1.93 (3H, s), 3.15 (1H, d, J=16.4 Hz), 3.66 (1H, d, J=16.2 Hz), 5.50 (1H, s), 8.12 (1H, s), 8.36 (1H, s).
MS: 385 m/z[M+H]+
1H-NMR (CDCl3) δ: 1.56 (3H, s), 2.54-2.64 (1H, m), 3.07-3.17 (1H, m), 3.29-3.38 (1H, m), 3.50-3.57 (1H, m), 8.13 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz).
1H-NMR (CDCl3) δ: 1.70 (3H, s), 2.15-2.21 (1H, m), 2.52-2.58 (1H, m), 2.70-2.77 (1H, m), 3.05-3.11 (1H, m), 4.44 (2H, br s), 8.12 (11H, s), 8.34 (1H, s).
1H-NMR (CDCl3) δ: 1.53 (18H, s), 1.73 (3H, s), 1.90-1.97 (1H, m), 2.63-2.69 (1H, m), 2.93-2.99 (1H, m), 3.21-3.28 (1H, m), 8.24 (1H, d, J=2.3 Hz), 8.36 (1H, d, J=2.3 Hz).
1H-NMR (CDCl1-3) δ: 1.52 (9H, s), 1.70 (3H, s), 1.96-2.03 (1H, m), 2.54-2.61 (1H, m), 2.80-2.85 (1H, m), 2.97-3.00 (1H, m), 3.97 (3H, s), 7.62 (1H, d, J=1.5 Hz), 8.15 (1H, d, J=1.5 Hz).
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.72 (3H, s), 1.86-1.93 (1H, m), 2.02 (2H, s), 2.52-2.59 (1H, m), 2.74-2.79 (1H, m), 3.13-3.18 (1H, m), 3.90 (3H, s), 6.96 (1H, d. J=2.3 Hz), 7.59 (1H, d, J=1.8 Hz).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63 (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H, s), 9.14 (1H, s), 10.69 (11H, s).
1H-NMR (DMSO-d6) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz), 7.96 (1H, d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).
1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J=2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).
The other compounds are prepared in the same manner. Chemical structures and physical constants are shown below.
1H-HNMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63 (3H, s) 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H, s), 9.14 (1H, s), 10.69 (1H, s).
1H-NMR (DMSO-d6) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz), 7.96 (1H, d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).
1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J= 2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).
Forty eight point five μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X=ε-amino-n-caponic acid, Eu=Europium cryptate) was added to each well of 96-hole half-area plate (a black plate: Corning Incorporated), and after addition of 0.5 d of the test sample (dissolved in N,N′-dimethylformaldehyde) and 1 μl of Recombinant human BACE-1(R&D Systems), the reaction mixture was incubated at 30° C. for 3 hours. The substrate peptide was synthesized by reacting Cryptate TBPCOOH mono SMP (CIS bio international) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.). The final concentrations of the substrate peptide and Recombinant human BACE-1 were adjusted to 18 nM and 7.4 nM respectively, and the reaction was performed in sodium acetate buffer (50 mM sodium acetate, pH 5.0, 0.008% Triton X-10).
After the incubation for reaction, 50 μl of 8.0 μg/ml Streptavidin-XL665(CIS bio international) dissolved in phosphate buffer (150 mM K2 HPO4—KH2PO4, pH 7.0, 0.008% Triton X-100, 0.8 M KF) was added to each well and left stand at 30° C. for an hour. After then, fluorescence intensity was measured (excitation wavelength: 320 nm, measuring wavelength: 620 nm and 665 min) using Wallac 1420 multilabel counter (Perkin Elmer life sciences). Enzymatic activity was determined from counting ratio of each wavelength (10,000×Count 665/Count 620) and 50% inhibitory concentration against the enzymatic activity was calculated. IC50 values of the test compounds are indicated in Table 139.
The following compounds have shown IC50 values equal to or under 1 μM in the same assay;
compounds 4, 5, 6, 8, 10, 18, 19, 20, 21, 22, 29, 32, 33, 35, 43, 45, 46, 58, 59, 63, 64, 68, 69, 75, 77, 78, 79, 81, 82, 83, 84, 85, 88, 89, 90, 91, 95, 96, 97, 98, 100, 102, 103, 104, 107, 108, 110, 112, 113, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 127, 131, 132, 133, 134, 135, 142, 143, 144, 145, 148, 152, 157, 158, 162 and 165.
Also, compounds 462, 463, 465, 467, 469, 470, 471, 472, 479, 482, 483, 486, 489, 490, 492, 501, 503, 507, 508, 509, 510, 511, 512, 516, 518, 519, 523, 527, 528, 529, 531, 532, 533, 536, 538, 539, 540, 542, 545, 546, 547, 548, 549, 552, 553, 554, 555, 556, 557, 558, 560, 561, 562, 564, 565, 567, 568, 569, 570, 571, 572, 573, 574, 575, 555, 556, 557, 558, 560, 561, 562, 564, 565, 567, 568, 569, 570, 571, 572, 573, 574, 575, 578, 581, 582, 583, 584, 586, 587, 590, 595, 596, 600, 601, 602, 603, 604, 605, 606, 609, 612, 613, 637, 644, 646, 461, 468, 478, 491, 502, 505, 508, 517, 530, 537, 542, 544, 559, 563, 566, 576, 577, 597, 598, 599 and 645 showed IC50 values equal to or under 1 μM in the same assay.
The following compounds also showed IC50 values equal to or under 1 μM in the same assay;
compounds 647, 648, 649, 650, 651, 654, 656, 657, 658, 659, 661, 666, 670, 671, 672, 673, 675, 676, 677, 678, 679, 683, 684, 685, 686, 687, 688, 690, 691, 692, 693, 694, 695, 696 and 697, 652, 655, 660, 662, 664, 665, 667, 669, 674 and 689.
Granular formulation is prepared with the following ingredients;
Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed with V-shaped mixer.
An aqueous solution of HPC-L (Hydroxypropyl cellulose of Low viscosity) is added to the mixed powder, kneaded, granulated (extrusion granulation; pore diameter 0.5-1 mm) and put into a drying process. The resulted dried granule is sieved with vibrating screen (12/60 mesh) to give a granular formulation.
Granular formulation for capsule filling is prepared with the following ingredients;
Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated and dried. Particle size of the resulted dried granule is regulated and each of 150 mg is filled in No. 5 hard-gelatin capsule.
Tablet is prepared with the following ingredients;
Compound of the formula (I), lactose, microcrystalline cellulose and CMC—Na (sodium salt of carboxymethylcellulose) are put through a sieve of No. 60 mesh and mixed. Magnesium stearate is mixed with the mixed granule above to give a mixed powder for tablet, which is compressed by a tabletting machine to give a tablet of 150 mg.
The following ingredients were warmed, mixed and sterilized to give an injection.
A compound of the present invention can be a useful drug for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
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