CN1255161A - Protease inhibitors - Google Patents

Protease inhibitors Download PDF

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Publication number
CN1255161A
CN1255161A CN98804791A CN98804791A CN1255161A CN 1255161 A CN1255161 A CN 1255161A CN 98804791 A CN98804791 A CN 98804791A CN 98804791 A CN98804791 A CN 98804791A CN 1255161 A CN1255161 A CN 1255161A
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alkyl
amino
leucine
tetrahydrofuran
het
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A·D·格里布尔
A·E·芬威克
R·W·马奎斯
D·F·韦贝尔
J·威辛顿
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SmithKline Beecham Ltd
SmithKline Beecham Corp
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SmithKline Beecham Ltd
SmithKline Beecham Corp
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Abstract

The invention relates to 3-hydroxy-and 3-keto-cyclohetero-substituted leucine compounds that are inhibitors of cysteine proteases, particularly cathepsin K, and are useful in the treatment of diseases in which inhibition of bone loss is a factor. The 3-hydroxy-or 3-keto-moiety is bonded to a tetrahydrothiophene, tetrahydrothiopyran, tetrahydrofuran or tetrahydropyran ring.

Description

Proteinase inhibitor
The field of the invention
The present invention relates to new proteinase inhibitor, relate to halfcystine and serpin specifically, more particularly relate to the compound that suppresses L-Cysteine HCL Anhydrous.Compound of the present invention even relate more specifically to suppress the L-Cysteine HCL Anhydrous, the particularly compound of the L-Cysteine HCL Anhydrous of tissue protein enzyme family of papoid superfamily.In the most preferred embodiment, the present invention relates to the compound of inhibition of histone enzyme K.This compounds pair is useful especially with disease such as osteoporosis, periodontitis and arthritic treatment that L-Cysteine HCL Anhydrous diseases associated, especially excessive bone or cartilage are lost.
Background of the present invention
Cathepsin K is a member of the papoid superfamily enzyme family partly of L-Cysteine HCL Anhydrous.Cathepsin B, H, L, N and S be existing the description in relevant document.Recently, the cDNA of cathepsin K polypeptide and this polypeptide of coding is at U.S. Patent number 5,501, and is open in 969 (wherein being called as kethepsin O).Recently, to cathepsin K carried out expression, purifying and evaluation (Bossard, M.J., etc., J.Biol.Chem. (1996,271,12517-12524); Drake, and J.Biol.Chem. such as F.H. (1996,271,12511-12516); Bromme, J.Biol.Chem. such as D. (1996,271,2126-2132)).
In relevant document, cathepsin K is represented as kethepsin O, kethepsin X or cathepsin O 2 respectively.Think that the called after cathepsin K is more suitably a kind of (it is by the specified title of biological chemistry and molecular biology internation combination NK).
Kethepsin in the papoid superfamily of L-Cysteine HCL Anhydrous works in animal body comprises the normal physiological processes of human body normal protein matter degraded (as the degraded of reticular tissue).Yet the rising of the level of these enzymes can cause causing the pathological conditions of disease in the body.Therefore, kethepsin is relevant with various disease states, and it includes but not limited to the infection that caused by following various pathogenic micro-organisms: Pneumocystis carinii (pneumocystis carinii), Ke Shi dimension worm (trypsanoma cruzi), Bu Shi dimension worm (trypsanoma brucei brucei) and Crithidia (Crithidia fusiculata); In addition also relevant with schistosomicide, malaria, metastases, metachromatism brain protein malnutrition, muscular dystrophy, myatrophy diseases such as (amytrophy).Referring to international publication number WO94/04172 (being disclosed on March 3rd, 1994), and reference wherein.Also referring to European patent application EP 0603873 A1, and reference wherein.L-Cysteine HCL Anhydrous (being called gingipains) from two kinds of bacteriums of P.gingivallis relevant with the pathogenesis of oulitis (Potempa, Perspectives in DrugDiscovery and Design such as J., 1994,2,445-458).
Cathepsin K is considered to work causing that excessive bone or cartilage are lost in the reason of disease.Bone is by forming with fusiformis or flaky hydroxyapatite crystal bonded albumen substrate.Type i collagen albumen is represented most of structural protein of bone, and bone is made up of about 90% structural protein.Remain 10% matrix and form, comprise osteocalcin, proteoglycan, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein by some noncollagen protein matter.In the independent focus of whole vital process, bone has experienced process of reconstruction.Described focus or reconstruction unit experience heavily absorb the phase by bone, the cycle for bone replacement period composition of continuing.
Carry out bone by osteoclast and heavily absorb, this cell is the syncyte of green blood pedigree.Described osteoclast adheres to bone surface, forms the citadel, big area film crumple on its top end face afterwards (just heavily absorbing).Thus on the film of crumple, by proton pump acidifying bone surface produce airtight extracellular chamber every, and osteoclast excretory protease enters wherein.The hydroxyapatite crystal body of chamber on the dissolving bone surface that the pH value is low, described protease digestible protein matrix simultaneously.Formed so heavy absorbing cavity every or cavity.When the end in described cycle, scleroblast produces albumen substrate new, that mineralized subsequently.At several morbid states for example in osteoporosis and the Paget's disease, bone heavily absorb and form between normal equilibrium destroyed, all there be losing only of sclerotin in each cycle.At last, will cause bone weak, and minimum wound can cause the raising of fracture risk.
The a large amount of optionally expression of cathepsin K in osteoclast illustrate that effectively this enzyme is for the re-absorbed necessity of bone.Therefore, selectivity inhibition of histone enzyme K can provide the method for the excessive bone loss diseases of effective treatment, and described disease comprises (but being not limited thereto) osteoporosis, gingival disease (as oulitis, periodontitis), Paget's disease, malignant hypercalcemia and metabolic osteopathy.Proved also that in the chondroclast of osteoarthritis synovial membrane the level of cathepsin K raises.Therefore, selectivity inhibition of histone enzyme K also can be used for treating the disease that is caused by excessive cartilage or substrate degradation, comprises (but being not limited thereto) osteoarthritis and rheumatoid arthritis.The metastatic tumour cell is generally also expressed the high-caliber degraded proteolytic ferment of matrix on every side.Therefore, selectivity inhibition of histone enzyme K also is useful for some tumor disease of treatment.
Having now found that the new compound of a class is a protein inhibitor, is cathepsin K inhibitor the most specifically, and these compounds can be used for treatment and suppress bone heavily absorbing diseases associated for example osteoporosis and periodontal disease inflammation.
The present invention's general introduction
The purpose of this invention is to provide proteinase inhibitor, as halfcystine and serpin.Specifically, the present invention relates to suppress L-Cysteine HCL Anhydrous, more particularly suppress the compound of the L-Cysteine HCL Anhydrous of papoid superfamily.Preferably the present invention relates to the compound of the L-Cysteine HCL Anhydrous of inhibition of histone enzyme family, particularly the compound of inhibition of histone enzyme K.Can be thereby compound of the present invention can be used for treating by changing the disease that described protease activity improves treatment.
Therefore, in first aspect, the invention provides formula (I) compound:
Figure A9880479100171
On the other hand, the invention provides pharmaceutical composition, they contain formula (I) compound and pharmaceutically acceptable carrier.
Also have on the one hand, the invention provides the method for treatment disease, the pathology of wherein said disease can be by for example halfcystine and the alleviation of serine stretch protein enzyme treatment of arrestin enzyme.This method comprises that thereby by suppressing L-Cysteine HCL Anhydrous, saying especially be the L-Cysteine HCL Anhydrous treatment disease of papoid superfamily specifically.More particularly, description is to the inhibition of the L-Cysteine HCL Anhydrous such as the cathepsin K of tissue protein enzyme family.
Another aspect, compound of the present invention is disease such as the osteoporosis and the gingival disease (as oulitis and periodontitis) of feature for treatment with the bone loss, or is that the disease of feature such as osteoarthritis and rheumatoid arthritis are useful especially with excessive cartilage or substrate degradation.
The present invention describes in detail
The invention provides formula (I) compound or its pharmacy acceptable salt: Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; N is 1,2 or 3.
The present invention includes hydrate, solvate, mixture and the prodrug of all compounds of the present invention.Prodrug is the compound of covalent bonding, and it is the active parent drug of release type (I) in vivo.If there is the isomery center of chiral centre or another kind of form in compound of the present invention, the isomer of form of ownership (comprising enantiomorph and diastereomer) should be contained among the present invention so.The The compounds of this invention that contains chiral centre can be used as racemic mixture and uses, with the technology of knowing can the enantiomer separation enrichment mixture or racemic mixture, can use independent enantiomorph separately.According to the present invention, preferably the furan nucleus junction at formula (I) compound is the S-type.
If wherein compound has unsaturated carbon-to-carbon double bond, scope of the present invention should comprise cis (Z) and trans (E) two kinds of isomer.If wherein compound exists with tautomeric forms, keto-enol tautomerism body for example, so no matter being present in equilibrium state still is that a kind of form is preponderated, and the present invention all comprises every kind of tautomeric form.
Unless specialize, any substituent implication that appears at formula (I) or its inferior formula is separate with any other the substituent connotation that occurs in other cases.For formula (I): suitable R 2And R 4Be H, R 3Be C 1-6Alkyl or C 2-6Alkenyl.Preferred R 3Be different-butyl.Each R 5All be suitably for H.R 1Be suitably for R " OC (O), R " SO 2Or R " C (O), wherein R " be Ar-C 0-6Alkyl or Het-C 0-6Alkyl, more preferably R " be
Figure A9880479100202
Or
Figure A9880479100203
B wherein 2Be OH, CN, OCF 3, OC 1-6Alkyl, OAr, SO 2C 1-6Alkyl, C 1-6Alkyl or halo.N is suitably for 1 or 2.Preferred n is 1.X is suitably for O.
In a special embodiment, the present invention is formula (II) compound:
Figure A9880479100204
Preferred formula of the present invention (I) compound is formula (IIa) compound:
Figure A9880479100205
Formula perhaps of the present invention (I) compound is formula (IIb) compound:
Figure A9880479100206
In another embodiment, the present invention is formula (IIc) compound: Concrete representative compounds of the present invention is following compounds or its pharmacy acceptable salt: 4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(2-quinoline carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(8-quinoline carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(indoles-6-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(cumarone-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino benzo [b] thiophene of amino-N-[(5--2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-chloro-benzofuran-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-fluoro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-phenoxy group benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-phenyl benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-trifluoromethyl benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-ethylamino benzonitrile acyl group base)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-(tertiary butyl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-nitro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(benzo (b) thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(benzo (b) thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(2-naphthoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(2-naphthoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridin-3-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridine-2-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(cumarone-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-[6-picoline-3-yl] benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridin-4-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(2-chlorinated benzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-benzyl piepridine-1-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dichlorobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3-chlorinated benzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(4-phenoxy group benzoyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(quinoline-2-base carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; Or 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydro thiophene-3-ketone.
Also have on the other hand, the invention provides the new intermediate that is used for preparation formula (I) compound, by formula (III), (IV) and (V) representative, formula (III) or its pharmacy acceptable salt:
Figure A9880479100241
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; With n be 1,2 or 3; Or formula (IV) compound or its pharmacy acceptable salt: Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; With n be 1,2 or 3; Or formula V compound or its pharmacy acceptable salt:
Figure A9880479100252
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; With n be 1,2 or 3.
Representative intermediate of the present invention is following compounds or its salt: trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(tert-butoxycarbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(2-quinoline carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(indoles-6-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino benzo [b] thiophene of amino-N-[(5--2-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-amino-3-hydroxyl tetrahydrofuran; Trans-the 3-hydroxyl-4-benzyloxycarbonyl amino-tetrahydrofuran (THF); 4-benzyloxycarbonyl amino-tetrahydrofuran-3-one; 3,3-dimethoxy-4 '-benzyloxycarbonyl amino-tetrahydrofuran (THF); 3,3-dimethoxy-4 '-amino-tetrahydrofuran (THF); Trans-4-S-amino-3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-(S-leucine)-3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran: trans-4-S-amino-N-[(2-quinoline carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-the N-[(cumarone-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(2-naphthoyl base)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-(pyridine-2-yl) benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-(pyridin-3-yl) benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-amino-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-3-R-hydroxy tetrahydro pyrans; N-benzo [b] thiophene-2-base carbonyl-L-leucine methyl esters; N-benzo [b] thiophene-2-base carbonyl-L-leucine; N-benzo [b] thiophene-2-base carbonyl-L-leucine-S-(methoxycarbonyl methyl)-L, the D-ethycysteine; With 2-methoxycarbonyl-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-S-leucine]-tetrahydro thiophene-3-ketone.
With being similar to the method described in described similar method of flow process 1-4 and the embodiment after this, can prepare these intermediates.
The prodrug of The compounds of this invention can be ketal or hemiketal or its pharmacy acceptable salt of the prodrug, particularly formula (VI) of the ketone functionality of formula (I) compound: Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; N is 1,2 or 3; And R aAnd R A 'Independent is H or C 1-2Alkyl, prerequisite is for working as R aOr R A 'One of when being H, then another is C 1-2Alkyl; Perhaps together for forming (the CH of 5-unit or 6-unit ring 2) 2-3
The abbreviation and the symbol that generally are used for peptide and chemical field are used for this paper, are used to describe compound of the present invention.In general, amino acid abbreviations sees Eur.J.Biochem. for details, 158,9 (1984) according to IUPAC-IUB biological chemical name principle joint committee).Refer to following amino acid whose D-or L-isomer at this used term " amino acid ": L-Ala, arginine, l-asparagine, aspartic acid, halfcystine, glutamine, L-glutamic acid, glycine, Histidine, Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, proline(Pro), Serine, Threonine, tryptophane, tyrosine and Xie Ansuan.
At this used " C 1-6Alkyl " mean comprise replacement with unsubstituted following radicals and simple aliphatic isomer thereof: methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-, the tertiary butyl, amyl group, n-pentyl, isopentyl, neo-pentyl and hexyl.Any C 1-6Alkyl group can be chosen wantonly by following radicals and independently replace: one or two halogen atoms, SR ', OR ', N (R ') 2, C (O) N (R ') 2, formamyl or C 1-4Alkyl, wherein R ' is H or C 1-6Alkyl.C 0Alkyl refers to not have alkyl in this part.Therefore, Ar-C 0Alkyl equals Ar.
At this used " C 3-6Cycloalkyl " mean (being alkyl, OR, SR or halogen) and unsubstituted cyclopropane, tetramethylene, pentamethylene and the hexanaphthene that comprise replacement.
At this used " C 2-6Alkenyl " refer to have 2 to 6 carbon atoms, alkyl that one of them carbon-to-carbon singly-bound is replaced by carbon-to-carbon double bond.C 2-6Alkenyl comprises the isomer of ethene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, iso-butylene and several amylene and hexene.Also comprise cis and trans-isomer(ide).
At this used " C 2-6Alkynyl " refer to have 2 to 6 carbon atoms, alkyl that one of them carbon-to-carbon singly-bound is replaced by carbon-to-carbon triple bond.C 2-6Alkynyl comprises the simple isomer of acetylene, 1-propine, 2-propine, ethyl acetylene, 2-butyne, 3-butine and pentyne and hexin.
" halogen " or " halo " refers to F, Cl, Br, reaches I.
" Ar " or " aryl " refers to unsubstituted phenyl or naphthyl; Or the phenyl or naphthyl that replaces by one or more following radicals: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkoxyl group, Ph-C 0-6Alkoxyl group, Het-C 0-6Alkoxyl group, OH, (CH 2) 1-6NR ' R ', O (CH 2) 1-6NR ' R '; Wherein each R ' is independent is H, C 1-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Or by 1 to 3 phenyl or naphthyl that is selected from the following groups replacement: C 1-4Alkyl, OR ', N (R ') 2, SR ', CF 3, NO 2, CN, CO 2R ', CON (R ') 2, F, Cl, Br and I or the phenyl or naphthyl that replaces by methylene-dioxy.
At this used " Het " or stable 5 to 7 yuan of monocycles or 7 to the 10 yuan of stable two heterocycles of " heterocyclic radical " representative, it is saturated or unsaturated, and form by carbon atom and 1 to 4 heteroatoms that is selected from N, O and S, wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized, and nitrogen heteroatom can be chosen wantonly by quaternized, also comprises the heterocycle and the phenyl ring condensed bicyclic radicals of wherein above-mentioned definition.Heterocycle can be connected on any heteroatoms or carbon atom that produces rock steady structure, and can be by being selected from the optional replacement of 1 or 2 following part: C 1-4Alkyl, OR ', N (R ') 2, SR ＇, CF 3, NO 2, CN, CO 2R ', CON (R ') 2, F, Cl, Br and I, wherein R ' defines as the front.This type of heterocyclic example comprises piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base (pyrrolodinyl), 2-oxo azatropylidene base, azatropylidene base, thienyl, pyrryl, 4-piperidone base, pyrrolidyl; Pyrazolyl, pyrazolidyl, imidazolyl, pyridyl, pyrazinyl oxazolidinyl oxazolinyl oxazolyl isoxazolyl, morpholinyl, thiazolidyl, thiazolinyl, isothiazolyl, thiazolyl, quinuclidinyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothienyl, benzopyranyl benzoxazolyl, benzofuryl, furyl, pyranyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl benzoxazolyl, the thiomorpholine sulfoxide, thiomorpholine sulfone oxadiazole base, benzothiazolyl, the benzisothiazole base, the benzoisoxazole base, pyrimidyl, the cinnolines base, quinazolyl, quinoxalinyl, 1, the 5-phthalazinyl, 1, the 6-phthalazinyl, 1, the 7-phthalazinyl, 1, the 8-phthalazinyl, tetrazyl, 1,2,3-triazolyl and 1,2, the 4-triazolyl.
Some group is abbreviation in this article.T-Bu represents the tertiary butyl, and Boc or BOC represent uncle-butoxy carbonyl, and Fmoc represents the fluorenyl methoxy carbonyl, and Ph represents phenyl, and Cbz or CBZ represent benzyloxycarbonyl.
Some reagent is abbreviation in this article.DCC represents dicyclohexylcarbodiimide, and EDC or EDCI represent N-ethyl-N ' (dimethyl aminopropyl)-carbodiimide.HOBT or HOBt represent I-hydroxybenzotriazole, DMF represents dimethyl formamide, DIEA represents two-sec.-propyl ethamine, Lawesson ' s reagent represents 2, two (the 4-p-methoxy-phenyls)-1 of 4-, 3-two thiophenes-2,4-diphosphine alkane-2,4-disulphide, TFA represents trifluoroacetic acid, and THF represents tetrahydrofuran (THF).
In general, formula (I) compound can be by following preparation: (i) make the protected formula of reactive functional groups (III) compound and oxidant reaction:
Figure A9880479100311
R in formula (III) 1, R 2, R 3, R 4, R 5Identical with n with definition in the formula (I); Or (ii) make the decarboxylation of the protected formula of reactive functional groups (IV) compound:
Figure A9880479100321
R in formula (IV) 1, R 2, R 3, R 4, R 5Identical with n with definition in the formula (I); Or (iii) make protected formula V compound of reactive functional groups and acid-respons:
Figure A9880479100322
R in formula V 1, R 3, R 4, R 5Identical with n with definition in the formula (I); After this slough blocking group and the optional pharmacy acceptable salt that forms.
According to flow process 1 solution synthesis method or flow process 2 solid carrier methods or the described similar method of flow process 3 solution synthesis methods, can preparation formula (I) compound.
Flow process 1 A) NaN 3, ammonium chloride, methyl alcohol: water; B) 10%Pd/C, EtOH, H 2Ethanol system HCl; C) trimethyl-acetyl chloride, N-BOC-leucine, DIEA, CH 2Cl 2D) TFA, CH 2Cl 2E) RCOCl, sodium bicarbonate, 1,4-dioxane; F) Dess-Martin periodinane, CH 2Cl 2
Prepare general formula (I) compound according to flow process 1 described method, wherein n is 1, R 1Be R " C (O).At high temperature, in the methanol aqueous solution, handle known epoxide 1-flow process-1, obtain trinitride 2-flow process-1 with sodiumazide and ammonium chloride.As in ethanol, under hydrogen environment, using palladium charcoal reduction trinitride 2-flow process-1, after ethanol system hydrogenchloride is handled, obtain 3-flow process-1 with the methods known in the art reduction.According to methods known in the art as with acylating acid or in the presence of EDC and HOBT with sour coupling, can make amine salt 3-flow process-1 and carboxylic acid coupling, obtain acid amides 4-flow process-1.By in aprotonic solvent such as methylene dichloride, handling with strong acid such as TFA, can slough tert-butoxycarbonyl, obtain 5-flow process-1.In the presence of alkali aqueous solution such as saturated sodium bicarbonate, 1, in the 4-dioxane, make salt 5-flow process-1 acidylate with acyl chlorides, obtain 6-flow process-1.Handle oxidation alcohol 6-flow process-1 according to methods known in the art as in aprotonic solvent such as methylene dichloride, using Dess-Martin periodinane.
Flow process-2
Can prepare general formula (I) compound, wherein R according to synthetic (SPS) method of the solid carrier shown in the flow process 2 1Be C (O) R ', R 2Be H, R 4Be H, R 5Be H, X is O, and n is 1.Specifically, sodium triacetoxy borohydride is added in the dimethyl formamide solution that contains 1% acetate of Ellmans resin of stirring, add the a-amino acid methyl esters then, obtain 2-flow process-2 in the first step.As by adding carboxylic acid and EDC, make amine groups and carboxylic acid coupling according to known method, obtain acid amides 3-flow process-2.After this ester hydrolysis group, as be used in trimethyl silicane potassium alcoholate in the tetrahydrofuran (THF), then with as EDC in NMP make free acid groups and 3,3-dimethoxy-4 '-amino-tetrahydrofuran (THF) coupling obtains 4-flow process-2.Then according to cleavage method as by adding 7: 2: 1 TFA/CH 2Cl 2/ H 2O sloughs blocking group, obtains required compound 5-flow process-2.
Synthesize the compound that (SPS) method can prepare general formula (I), wherein R according to the solid carrier shown in the flow process 2 1Be C (O) R ', R 2Be H, R 4Be H, R 5Be H, X is O, and n is 2, but with 3,3-dimethoxy-4 '-amino tetrahydro pyran replaces 3,3-dimethoxy-4 '-amido tetrahydrofuran.
Flow process 3
(a) L-Leu methyl esters, iPr 2NEt, CH 2Cl 2(b) LiOH, THF/H 2O; (c) (i) ClCO 2 iPr, Et 3N, CH 2Cl 2(ii) (iii) BrCH of L-Cys ethyl ester 2CO 2Me; (d) (i) NaOMe, MeOH, (ii) AcOH/HCl, H 2O
After this flow process 4 is depicted as the preparation method of part (I) compound, is the S-diastereomer in the furan nucleus junction wherein.
Flow process 4
Figure A9880479100371
With identical method, prepare the R-diastereomer by relative 3-azido--4-hydroxyl tetrahydrofuran enantiomorph:
Can prepare intermediate of the present invention as 3,3-dimethoxy-4 '-amido tetrahydrofuran according to the method for flow process 5.
Flow process 5
The step of flow process 5 is as follows.At first, introduce nitrogen-blocking group by in containing the dioxane of aqueous sodium carbonate, making the reaction of 3-hydroxyl-4-amido tetrahydrofuran and benzyl chloroformate.After this, according to known method as in ethyl acetate, toluene and water in the presence of Sodium Bromide and TEMPO, the SYNTHETIC OPTICAL WHITNER (bleach) that contains sodium bicarbonate by adding obtains ketone with the alcohol groups oxidation.In methyl alcohol, in the presence of right-toluenesulphonic acids, above-mentioned ketone is converted into dimethyl acetal by adding trimethyl orthoformate.At last, by as in the presence of ethanol, slough blocking group with the palladium hydrogenated carbon down in hydrogen environment.
Excessive bone or cartilage are lost disease, comprise that osteoporosis, gingival disease comprise oulitis, periodontitis and sacroiliitis, more particularly are osteoarthritis and rheumatoid arthritis and Paget's disease; Malignant hypercalcemia and metabolic bone disease.
The metastatic tumour cell is generally also expressed the high-caliber degraded proteolytic ferment of matrix on every side, so some tumour and metastatic tumour cell can obtain the effective treatment with compound of the present invention.
The present invention also provides the method for the treatment of the disease that is caused by the horizontal proteolytic enzyme of pathology, in particular to halfcystine and tryptophan protease, it more particularly is L-Cysteine HCL Anhydrous, even more particularly be the cystatin of papoid superfamily, it also more particularly is the L-Cysteine HCL Anhydrous of tissue protein enzyme family, described method comprises and gives animal with compound of the present invention, particularly Mammals, the more particularly people for needing.The present invention provides the method for the disease that treatment causes by the cathepsin K of pathology level especially, and this method comprises and give animal that particularly Mammals more particularly is the human cathepsin K inhibitor (comprising compound of the present invention) of demand.The present invention provides the method for treatment and L-Cysteine HCL Anhydrous diseases associated especially, comprises the disease that is infected by Pneumocystis carinii, Ke Shi dimension worm, Bu Shi dimension worm and Crithidia; And schistosomicide, malaria, metastases, metachromatism albumin malnutrition, muscular dystrophy, myatrophy, particularly with the cathepsin K diseases associated, more particularly be that excessive bone or cartilage are lost disease, comprising that osteoporosis, gingival disease comprise oulitis and periodontitis, sacroiliitis, more particularly is osteoarthritis, rheumatoid arthritis and Paget's disease; Malignant hypercalcemia and metabolic bone disease.
The present invention further provides the treatment osteoporosis or suppress the bone loss method, this method comprises formula (I) compound that gives patient's effective dose with for oral administration, takes separately or gives jointly with other bone resorption inhibitor such as diphosphonate (Allendronate just), hormone replacement therapy, estrogen antagonist and thyrocalcitonin.In addition, can be used for stoping bone loss or improve sclerotin with compound of the present invention and anabolism medicine (as Delicious peptide and iproflavone) treatment.
According to the present invention, give the proteolytic enzyme of formula (I) compound of significant quantity with inhibition and particular disorder or disease-related.Certainly, can further adjust this dosage according to the administration type of described compound.For example for " significant quantity " of acute treatment, preferably with formula (I) compound parenteral admin.5% D/W of above-claimed cpd or the venoclysis of normal saline solution, or the similar formulations of suitable vehicle is for the most effective, although the intramuscular large bolus injection also is effective.In general, parenteral dosage is about 0.01 to about 100mg/kg; Preferred 0.1 to 20mg/kg, comes inhibition of histone enzyme K with the Plasma Concentration of remaining valid.Described compound administration every day 1 to 4 time is to reach total per daily dose of about 0.4 to about 400mg/kg/ day.Blood levels by comparative drug with have the required concentration of therapeutic action, those skilled in the art can easily determine the optimal path that the The compounds of this invention treatment is effectively accurately measured and given this compound.
The prodrug that can prepare The compounds of this invention by appropriate means.For prodrug wherein partly is those compounds of ketone functionality (particularly ketal and/or hemiketal), can transform according to conventional methods.
But compound of the present invention also per os gives the patient, and bone heavily absorbs or the mode that reaches in this disclosed other treatment index gives so that drug level is enough to suppress.Generally speaking, the medicinal compositions that contains described compound gives with about oral dosage of 0.1 to about 50mg/kg, and gives in the mode that adapts with patient disease.Preferred oral dosage is about 0.5 to about 20mg/kg.
When giving compound of the present invention, there is not unacceptable toxic action according to the present invention.
Can measure The compounds of this invention according to one of several biological assays and have the required compound concentration of given pharmacological action.The mensuration of the proteolysis catalytic activity of cathepsin K
The measuring method of all cathepsin Ks recombinase of all choosing carries out.The standard conditions that kinetic constant is measured are to use fluorescence peptide substrates (being generally Cbz-Phe-Arg-AMC), and measure in pH5.5 contains the sodium acetate solution of 100mM of 20mM halfcystine and 5mM EDTA.During these are measured the substrate stock solution concentration of preparation be 10 or the DMSO solution (substrate final concentration) of 20mM with 20 μ M in.All are measured and all contain 10% DMSO.Independent experiment finds that the level of DMSO does not influence enzymic activity or kinetic constant.All mensuration are all at room temperature carried out.Reading plate instrument monitoring product fluorescence with Perceptive Biosystems Cytofluor II fluorescence (excites at 360nM; Be transmitted in 460nM).The developed curve of product (progress curves) forms the back at the AMC product and produced in 20 to 30 minutes.Inhibiting research
The potential inhibitor is estimated by the developed curve method.Mensuration is carried out in the presence of various test compound concentration.By beginning reaction in the damping fluid that enzyme is added inhibitor and substrate.Data analysis is carried out according to one of two kinds of methods that determined by apparent developed curve in the presence of inhibitor.For its developed curve is those linear compounds, apparent inhibition constant (K i, app) calculate (Brandt etc., Biochemistry, 1989,28,140) by equation 1:
V=V mA/[K a(I+I/K i, app)+A] (1) wherein v be that maximum reaction velocity is V mSpeed of response, A is the Michaelis constant K aConcentration of substrate, I is an inhibitor concentration.
For its developed curve time-the dependence restraining effect shows those compounds be bent downwardly characteristic, data of analyzing each group according to equation 2 obtain k Obs:
[AMC]=v SsT+ (v o-v Ss) [I-exp (k ObsT)]/k Obs(2) wherein [AMC] is the production concentration that forms in the time t, v oBe initial reaction speed, and v SsBe final homeostatic reaction speed.Linear function with inhibitor concentration is analyzed k ObsValue, obtain description time-inhibiting apparent secondary velocity constant (k of dependence Obs/ inhibitor concentration or k Obs/ [I]).The complete discussion of this dynamics calculation has a detailed description (Morrison etc., Adv.Enzymol.Relat.Areas Mol.Biol., 1988,61,201).
Those skilled in the art considers any K iValue is potential guiding (lead) compound less than 50 micromolar compounds.Be preferred for its K of compound of the inventive method iValue is less than 1 micromole.The K of described compound most preferably iValue is less than 100 nmoles.4-(R, S)-amino-N-[(8-quinoline alkylsulfonyl)-the S-leucine]-its K of 3-tetrahydrofuran-3-one (formula (I) compound) iValue is greater than 10 micromoles.The re-absorbed quantivative approach of human osteoclast
From the liquid nitrogen storage tank, take out the osteoclastoma deutero-cell suspending liquid be divided into equal portions, heat rapidly in 37 ℃, and in the RPMI-1640 substratum, wash 1 time with centrifugal (1000rpm, 4 ℃, 5 minutes).Sucking-off substratum, and replace it with the antibody of mouse-anti-HLA-DR, again with 1: 3 ratio with the dilution of RPMI-1640 substratum, in ice bath, hatched 30 minutes.Frequent this suspension of mixing.
With cold RPMI-1640 centrifuge washing cell 2 times (1000rpm, 4 ℃, 5 minutes), cell is moved in the aseptic 15ml centrifuge tube then.Counting monocyte number in the Neubauer nucleonics of improvement.
Be coated with goat anti--the capacity magnetic bead (5/monocyte) of mouse IgG takes out from its reservoir bottle, places 5mL fresh culture (the toxic triazo-compound sanitas of flush away).Described magnetic bead is fixed on removes substratum on the magnet, and replace with fresh culture.
With magnetic bead and cytomixis, and suspension is put and is hatched 30 minutes on ice.Frequent this suspension of mixing.The cell fixation of magnetic bead bag quilt on magnet, and is poured into remaining cell (being rich in the osteoclast part) in the aseptic 50mL centrifuge tube.Add in the fresh cell of cultivation, so that remove adsorbed osteoclast based on magnetic bead bag quilt.This washing process is repeated 10 times.Discard the cell of magnetic bead bag quilt.
With wide aperture, disposable plastics pasteur pipet sample is full of cell, in the counting cell, counts osteoclast.By the centrifugation osteoclast, and be 1.5 * 10 with the concentration that the EMEM substratum that contains 10% foetal calf serum and 1.7g/L sodium bicarbonate is regulated osteoclast 4/ mL.The cell suspending liquid (each processing) of 3mL equal portions is poured in the 15mL centrifuge tube.Centrifugation cell.In every pipe, add suitable handled thing 3ml (being diluted to 50 μ M) with the EMEM substratum.Comprise suitable solvent contrast, positive control (being diluted to the 87MEM1 of 100 μ g/mL) and homotype contrast (being diluted to the IgG2a of 100 μ g/mL) simultaneously.Each pipe was hatched 30 minutes in 37 ℃.
The cell inoculation of 0.5mL equal portions to the aseptic dentine section that is arranged in 48 hole plates, was hatched 2 hours for 37 ℃.Quadruplicate each processing of screening.Replace washing slice 6 times (in 6 orifice plates, every hole 10mL) with warm PBS, then it is placed fresh processing sample or control sample, and hatched 48 hours in 37 ℃.Wash these sections with phosphate buffered saline (PBS) then, and fix 5 minutes, wash section subsequently with water, and in damping fluid, hatched 5 minutes in 37 ℃ with 2% glutaraldehyde (in the 0.2M sodium dimethylarsonate).Use the above-mentioned section of cold water washing then, and in cold acetate buffer/fast red garnet, hatching 5 minutes under 4 ℃.The damping fluid that sucking-off is excessive, and after washing with water, air-dry should the section.
By the positive osteoclast of bright field microscopy counting TRAP, by supersound process it is removed from dentin surface then.Measure the recess volume with Nikon/Lasertec ILM21W confocal microscope.
Embodiment
Unless otherwise indicated, all raw material sources in following synthetic embodiment are in commerce.Needn't further specify, believe that those skilled in the art can farthest use the present invention according to aforementioned description.The embodiment that provides is used to the present invention is described and does not limit its scope.The claim that belongs to the inventor below the reference.
Embodiment 14-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
A) trans-4-azido--3-hydroxyl tetrahydrofuran
With 3,4-epoxy tetrahydrofuran (THF) (9g, 105mmol) add to sodiumazide (27g, 415mmol) and ammonium chloride (9g, methanol aqueous solution 159mmol) (95%, in stirred solution 200ml).This reactant is heated to 75 ℃ and stirred 20 hours.Cool off this reactant, filter and reduction vaporization.The dilute with water residue is used ethyl acetate extraction, and dry and reduction vaporization obtains the target compound into colorless oil, 10g, yield 74%.
1H?NMR?δ(CDCl 3)4.32(m，1H)，4.09(dd，1H，J＝4.8，9.9Hz)，3.99(dd，1H，J＝4.3，10.1Hz)，3.94(m，1H)，3.81(dd，1H，J＝2.1，9.9Hz)，3.73(dd，1H，J＝1.8，10.1Hz)，2.72(d，1H，J＝4.6Hz)。
B) trans-4-amino-3-hydroxyl tetrahydrofuran hydrochloride
Under hydrogen environment (35psi), (10g, 77mmol) ethanol (150ml) mixed solution with 10% palladium charcoal (1g) stirred 12 hours with trans-4-azido--3-hydroxyl tetrahydrofuran.Filter this mixture, HCl handles with 100ml alcohol system, obtains the target compound into brown solid behind the reduction vaporization, 10.5g, yield 97%, m.p.132 ℃.
1H NMR δ (d 6DMSO) 8.37 (s, 3H), 4.13 (m, 1H), 3.84 (dd, 1H, J=4.9 and 14.3), 3.76 (dd, 1H, J=5.5,10.0Hz), 3.58 (dd, 1H, J=2.7,10.0Hz), 3.34 (m, 3H).
C) trans-4-(R, S)-amino-N-[(tert-butoxycarbonyl)-S-leucine]-the 3-hydroxyl tetrahydrofuran
With trimethyl-acetyl chloride (3.5ml, 29mmol) add to the N-Boc-L-leucine (7.3g, 31mmol) and diisopropylethylamine (9ml is in methylene dichloride 52mmol) (200ml) stirred solution.After 1 hour, (4g 28mmol), spends the night this mixture stirring to add trans-4-amino-3-hydroxyl tetrahydrofuran hydrochloride.This reaction mixture is inclined to water, use dichloromethane extraction.The organic layer that merges with 0.5N HCl, saturated sodium bicarbonate and salt water washing, and dry.Reduction vaporization obtains the target compound into yellow foam, 5g, yield 44%.
1H?NMRδ(CDCl 3)8.08(d，0.5H，J＝4.8Hz)，7.89(d，0.5H，J＝7.4Hz)，6.20(d，0.5H，J＝8.3Hz)，6.09(δ，0.5H，J＝8.7Hz)，4.81(d，1H，J＝16.0Hz)，4.40(m，2H)，4.20(m，2H)，3.77(m，2H)，1.60(m，3H)，1.50(s，9H)，0.92(m，6H)。
D) trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxyl tetrahydrofuran trifluoroacetate
With trans-4-(R, S)-amino-N-[(tert-butoxycarbonyl)-S-leucine]-(2.5g 8.0mmol) adds in methylene dichloride (100ml) stirred solution of 20% trifluoroacetic acid the 3-hydroxyl tetrahydrofuran.After 2 hours, this reaction mixture of reduction vaporization obtains the target compound into white jelly, 2.6g, yield 100%.
1H NMR δ (MeOD) 4.18 (m, 2H), 4.08 (m, 2H), 3.97 (m, 2H), 3.86 (tangible t, 2H, J=7.1Hz), 3.69 (dd, 2H, J=1.6,7.4Hz), 1.68 (m, 3H), 0.99 (d, 6H, J=2.1Hz).
E) trans-4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-S-leucine]-the 3-hydroxyl tetrahydrofuran
With 3,4-(methylenedioxy) Benzoyl chloride (400mg, 2.2mmol) add to trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxyl tetrahydrofuran trifluoroacetate (380mg, 1.1mmol) saturated sodium bicarbonate (10ml) and 1, in 4-dioxane (10ml) stirred solution.This reactant was stirred 1 hour, dilute with ether then.With 1N hydrochloric acid, sodium bicarbonate and salt water washing organic layer, drying.Evaporating solvent obtains the target compound into white foam shape thing, 250mg, yield 60%.
1H?NMRδ(CDCl 3)8.23(d，0.5H，J＝4.8Hz)，8.15(d，0.5H，J＝7.4Hz)，7.85(d，0.5H，J＝7.6Hz)，7.3(m，2H)，6.66(dd，1H，J＝8.1，11.5Hz)，5.92(d，2H，J＝6.2Hz)，4.78(m，1H)，4.50(s，1H)，4.2(s，1H)，4.08-3.75(m，4H)，3.74-3.48(m，3H)，1.82-1.48(m，3H)，0.90(m，6H)。(C 18H 24N 2O 5+ H) +The MS calculated value: 365.Measured value: 365.
F) 4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-S-leucine]-tetrahydrofuran-3-one
With Dess-Martin periodinane (500mg 1.2mmol) adds to trans-4-(R, S)-amino-N-[(tert-butoxycarbonyl)-S-leucine]-(220mg is in methylene dichloride 0.60mmol) (10ml) stirred solution for the 3-hydroxyl tetrahydrofuran.After 1 hour, add successively ether and Sulfothiorine (570mg, 3.6mmol).After 15 minutes, with saturated sodium bicarbonate and this reactant of salt water washing and dry.Evaporating solvent obtains the target compound into white foam shape thing.200mg, yield 100%. 1H?NMRδ(CDCl 3)8.14(d，0.5H，J＝6.2Hz)，7.90(d，0.5H，J＝5.9Hz)，7.54(d，0.5H，J＝7.3Hz)，7.46(d，0.5H，J＝5.1Hz)，7.23(d，1H，J＝6.6Hz)，7.14(s，1H)，6.67(m，1H)，5.93(s，2H)，4.73(m，1H)，437-3.71(m，5H)，1.68(m，3H)，0.85(m，6H)。(C 18H 22N 2O 6+ H) +The MS calculated value: 363.Measured value: 363.
Embodiment 2 4-(R, S)-amino-N-[(3,4-dichloro-benzoyl base)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1 (e-f), but with 3,4-dithio Benzoyl chloride replaces 3, and 4-(methylenedioxy) Benzoyl chloride prepares this target compound: 1H NMR δ (MeOD) 8.01 (d, 1H, J=2.0Hz), 7.75 (dd, 1H, J=2.0,8.3Hz), 7.61 (d, 1H, J=8.3Hz), 4.60 (m, 1H), 4.50-3.84 (m, 5H), 1.66 (m, 3H), 1.00 (m, 6H).(C 17Cl 2H 20N 2O 4+ H) +The MS calculated value: 387 and 389.Measured value: 387 and 389.
Embodiment 3
4-(R, S)-amino-N-[(2-quinoline carbonyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1 (e-f), but replace 3 with 2-quinoline carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride is prepared as the target compound of white foam shape thing: 1H NMR δ (CDCl 3) 8.57 (dd, 1H, J=1.5,5.1Hz), 8.20 (m, 3H), 7.77 (m, 2H), 7.62 (m, 1H), 7.40 (d, 1H, J=6.2Hz), 4.80 (m, 1H), 4.57 (m, 1H), 4.30 (m, 1H), 4.26-3.87 (m, 3H), 1.96-1.71 (m, 3H), 1.00 (m, 6H).(C 20H 23N 3O 4+ H) +The MS calculated value: 370.Measured value: 370.
Embodiment 4
4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1, but use N-CBZ-leucine in place N-BOC-leucine, be prepared as the target compound of white foam shape thing: 1H NMR δ (CDCl 3) 7.31 (m, 5H), 5.71 (tangible dd, 1H, J=8.4,14.8Hz), 5.06 (m, 2H), 4.50 (dd, 1H, J=8.9,18.0Hz), 4.30-3.88 (m, 4H), 3.80 (tangible t, 1H, J=9.6Hz), 1.64 (m, 3H), 0.91 (m, 6H).(C 18H 24N 2O 5+ H) +The MS calculated value: 349.Measured value: 349.
Embodiment 5 4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
According to the method for embodiment 1, but with 3,4-methylene-dioxy Benzoyl chloride replaces 3, and 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
Embodiment 6
4-(R, S)-amino-N-[(8-quinoline carbonyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1 (e-f), but replace 3 with 8-quinoline carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride is prepared as the target compound of white foam shape thing: m.p.123 ℃ (hydrochloride).
1H?NMRδ(CDCl 3)11.54(m，1H)，8.84(d，1H，J＝1.5Hz)，8.65(d，1H，J＝7.2Hz)，8.17(d，1H，J＝8.0Hz)，7.86(d，1H，J＝8.0Hz)，7.7(s，1H)，7.54(t，1H，J＝7.7Hz)，7.40(dd，1H，J＝3.8，7.7Hz)，4.78(dd，1H，J＝7.5，13.6Hz)，4.47(dd，1H，J＝8.6，13.6(Hz)，4.18(m，1H)，4.16-3.79(m，3H)，1.88(m，3H)，0.88(m，6H)。(C 20H 23N 3O 4+ H) +The MS calculated value: 370.Measured value: 370.
Embodiment 7
4-(R, S)-amino-N-[(8-quinoline sulfuryl chloride)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1 (e-f), but replace 3 with the 8-quinoline sulfuryl chloride, 4-(methylenedioxy) Benzoyl chloride is prepared as the target compound of brown solid: m.p.98 ℃ (hydrochloride).
1H NMR δ (CDCl 3) 9.07 (dd, 1H, J=1.7 and 4.3Hz), 840 (m, 1H), 8.30 (m, 1H), 8.00 (m, 1H), 7.66 (m, 2H), 7.11 (d, 0.5H, J=5.9Hz), 6.96 (d, 0.5H, J=5.7Hz), 4.51 (t, 0.5H, d=8.8Hz), 4.39 (t, 0.5H, J=8.7), 4.12-3.71 (m, 4.5H), 3.53 (dd, 0.5H, J=1.0,5.9Hz), 1.43 (m, 2H), 0.64 (m, 3H), 0.33 (m, 3H).(C 19H 23N 3O 5S+H) +The MS calculated value: 406.Measured value: 406.
Embodiment 84-(R, S)-amino-N-[((4-methyl-3-pyridyl) carbonyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
According to the method for embodiment 1 (e-f), but replace 3 with (4-methyl-3-pyridyl) carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
Embodiment 94-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-one
Preparation
With sodium methylate (140mg 2.6mmol) adds to 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydrofuran-3-one (300mg, 0.9mmol) and bromotoluene (0.4ml is in methyl alcohol 3.4mmol) (5ml) stirred solution.After 12 hours, this reactant is inclined to ether (100ml), water and salt water washing are also dry.Reduction vaporization through rapid column chromatography purifying (30% ethyl acetate-hexane wash-out), obtains the target compound into colourless jelly, 250mg, yield 55%.
1H NMR δ (CDCl 3) 7.34-7.25 (m, 10H), 7.24-7.0 (brs, 5H), 6.56 (s, 0.5H), 6.37 (s, 0.5H), 5.18 (d), 1H, J=11.5Hz), 5.07 (m, 2H), 4.48-4.42 (m, 1H), 4.20-3.98 (m, 4H), 3.12 (dd, 1H, J=12.5 and 12.5Hz), 2.88 (dd, 1H, J=12.5 and 12.5Hz), 1.72-1.32 (m, 3H), 0.92-0.76 (m, 6H).
(C 32H 36N 2O 5=C 7H 7) +The MS calculated value: 439.Measured value: 439.
Embodiment 10 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
According to the method for embodiment 1 (e-f), but replace 3 with benzo [b] thiophene-2-base carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
1H?NMRδ(CDCl 3)8.33(d，0.5H，J＝6.6Hz)，8.00(m，1H)，7.78(m，4H)，7.38(m，2.5H)，4.87(m，1H)，4.63-3.88(m，5H)，1.88(m，3H)，1.00(m，6H)。
(C 19H 22N 2O 4S-H) +The MS calculated value: 373.Measured value: 373.
Embodiment 11 4-(R, S)-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
According to the method for embodiment 1 (e-f), but with 3, the 4-dimethoxy-benzoyl chloride replaces 3, and 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
1H?NMRδ(CDCl 3)7.58(d，0.5H，J＝6.7Hz)，7.47(d，0.5H，J＝6.2Hz)，7.33(m，2H)，7.04(d，0.5H，J＝8.0Hz)，6.92(d，0.5H，J＝8.0Hz)，6.83(d，0.5H，J＝8.4Hz)，4.77(m，1H)，4.53-3.67(m，5H)，1.68(m，3H)，0.85(m，6H)。
(C 19H 26N 2O 6-H) +The MS calculated value: 377.Measured value: 377.
Embodiment 12 4-(R, S)-amino-N-[(indoles-6-base carbonyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 1 (e-f), but replace 3 with indoles-6-base carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
1H?NMRδ(d 6?DMSO)8.57-7.48(m，7H)，6.43(s，1H)，4.48-3.55(m，6H)，1.80-1.48(m，3H)，0.98-0.82(m，6H)。
(C 19H 23N 3O 4-H) +The MS calculated value: 356.Measured value: 356.
Embodiment 13 4-(R, S)-amino-N-[(cumarone-2-base carbonyl)-S-leucine]-system of tetrahydrofuran-3-one
Be equipped with
According to the method for embodiment 1 (e-f), but replace 3 with cumarone-2-base carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
1H?NMRδ(CDCl 3)8.00-7.25(m，7H)，4.90-4.78(m，1H)，4.53-4.48(m，1H)，4.38-4.21(m，1H)，4.25-3.92(m，3H)，1.88(m，3H)，1.68(m，3H)，0.97(m，6H)。
(C 19H 22N 2O 5-H) +The MS calculated value: 357.Measured value: 357.
Embodiment 14 4-(R, S)-amino benzo [b] thiophene of amino-N-[(5--2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to the method for embodiment 1 (e-f), but replace 3 with amino benzo [b] thiophene of 5--2-base carbonyl chloride, 4-(methylenedioxy) Benzoyl chloride prepares this target compound.
1H NMR δ (CDCl 3) 8.00-7.71 (m, 1H), 7.60 (d, 1H, J=3.3Hz), 7.53 (dd, 1H, J=8.5 and 4.0Hz), 7.47-6.74 (m, 3H), 4.77 (m, 1H), 4.43 (m, 1H), 4.38-3.50 (m, 4H), 1.77 (m, 3H), 0.85 (m, 6H).
(C 19H 23N 3O 4S+H) +The MS calculated value: 390.Measured value: 390.
Embodiment 15
Prepare cyclic alkoxy ketone with the solid supported synthetic method
A) 3-trans-hydroxy-4-benzyloxycarbonyl amino-tetrahydrofuran (THF)
(5g is in the dioxane that contains 10% aqueous sodium carbonate (200ml) (100ml) stirred solution 20.6mmol) benzyl chloroformate (20ml) to be dropped to trans-4-amino-3-hydroxyl tetrahydrofuran.After 3 hours, concentrate this mixture and remove dioxane, use ethyl acetate extraction then.With the organic layer that saturated sodium bicarbonate and salt water washing merge, dry (sal epsom).Reduction vaporization and with residue through column chromatography purification, obtain target compound, 8.00g, 70% into white crystals.
1H?NMRδ(CDCl 3)7.35(s，5H)，5.30(s，2H)，4.91(br?s，1H)，4.32(br?s，1H)，4.12-4.00(m，3H)，3.71-3.62(m，2H)，2.72(s，1H)。
B) 4-benzyloxycarbonyl amino-tetrahydrofuran-3-one
SYNTHETIC OPTICAL WHITNER (bleach) solution (100ml) that will contain sodium bicarbonate (7.34g) drop to 3-hydroxyl-4-benzyloxycarbonyl amino-tetrahydrofuran (THF) (21g, 88mmol), in the mixed solution of the quick stirring of ethyl acetate (140ml), toluene (140ml) and the water (40ml) of Sodium Bromide (9.4g), TEMPO (50mg).After produce continuing (persistant) orange, with this mixture of ethyl acetate extraction, with the organic layer that saturated sodium bicarbonate and salt water washing merge, drying (sal epsom).Reduction vaporization and with residue through column chromatography purification, obtain target compound, 18g, 87% into white crystals.
1H NMR δ (CDCl 3) 7.35 (s, 5H), 5.30 (s, 1H), 5.11 (s, 2H), 4.70 (tangible t, 1H, J=8.9Hz), 4.36-4.17 (m, 2H), 3.96-3.76 (2H).
C) 3,3-dimethoxy-4 '-benzyloxycarbonyl amino-tetrahydrofuran (THF)
Trimethyl orthoformate (29ml) is dropped to the 4-benzyloxycarbonyl amino-tetrahydrofuran-3-one of backflow, and (18g is 78mmol) and in methyl alcohol (100ml) solution of PTSA (500mg).After 3 hours, filter this reaction mixture and concentrated, behind column chromatography, obtain target compound, 16.2g, 76% into yellow oil.
1H NMR δ (CDCl 3) 7.35 (s, 5H), 5.30 (s, 1H), 5.11 (s, 2H), 4.70 (tangible t, 1H, J=8.9Hz), 436-4.17 (m, 2H), 3.96-3.76 (2H).
D) 3,3-dimethoxy-4 '-amino-tetrahydrofuran (THF)
Under hydrogen environment (50psi), with 3, (16g, 57mmol) ethanol (200ml) mixed solution with 10% palladium charcoal (2g) stirred 12 hours 3-dimethoxy-4 '-benzyloxycarbonyl amino-tetrahydrofuran (THF).Filter this mixture and concentrated, obtain target compound, 8g, 100% into yellow oil.
1H?NMRδ(CDCl 3)7.04(s，5H)，4.22-4.04(m，5H)，3.83-3.69(m，2H)，3.36(s，3H)，333(s，3H)。
E) carry out SPS with Ellman Linker
Steps A:
Sodium triacetoxy borohydride (10 equivalent) is added to Ellmans resin (reference: C.G.Boojamra, K.M.Murow, the L.A.Thompson and the J.A.Ellman of stirring, J.Org.Chem., 1997,62,1240) in the dimethyl formamide solution that contains 1% acetate.After 5 minutes, add a-amino acid methyl esters (10 equivalent), with this mixture jolting 1 hour.Use dimethyl formamide (* 7), methylene dichloride (* 7) and ether (* 2) washing resin then and be dried to constant weight.
Step B:
NMP is added in the mixture of above-mentioned resin, carboxylic acid (10 equivalent) and EDC (10 equivalent).With this mixture jolting 3 hours, use dimethyl formamide (* 3), methylene dichloride (* 3), methyl alcohol (* 2) and ether (* 2) washing subsequently then.Make this resin experience above-mentioned reaction conditions more then, wash as mentioned above once more after 3 hours.
Step C:
Trimethyl silane potassium alcoholate (10 equivalent) is added in the jolting mixture of tetrahydrofuran (THF) of above-mentioned resin.After 18 hours, wash this resin successively with tetrahydrofuran (THF) liquid (* 2), tetrahydrofuran (THF)-water (* 2), water (* 2), tetrahydrofuran (THF)-water (* 2) and the tetrahydrofuran (THF) (* 2) of 5% citric acid.
Step D:
With 3,3-dimethoxy-4 '-amino-tetrahydrofuran (THF) (3 equivalent) adds in the NMP mixture of above-mentioned resin and EDC (3 equivalent).After 3 hours, wash this resin with dimethyl formamide (* 7), methylene dichloride (* 7) 7 and ether (* 2).Make this resin experience above-mentioned reaction conditions more then, wash as mentioned above once more after 3 hours.
Step e: cracking
Trifluoroacetic acid/dichloromethane/water mixed liquids of 7: 2: 1 are added in the above-mentioned resin.After 2 hours, filter this mixture, use the washed with dichloromethane resin again.Remove solvent and obtain required tetrahydrofuran-3-one.
Embodiment 16 4-(R, S)-amino-N-[(5-chloro-benzofuran-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-3-
The preparation of ketone
According to the universal method of embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H?NMRδ(CDCl 3)7.62-7.05(m，6H)，4.81-4.64(m，1H)，4.62-4.54(m，1H)，4.43-3.81(m，4H)，1.90-1.60(m，3H)，1.08-0.81(m，6H)。
(C 19H 21N 2O 5Cl+H) +The MS calculated value: 393.Measured value: 393.
Embodiment 17 4-(R, S)-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to the universal method of embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H?NMRδ(CDCl 3)7.65-6.84(m，6H)，4.83-4.54(m，1H)，4.53-4.48(m，1H)，4.46-3.68(m，4H)，1.90-1.62(m，3H)，1.08-0.81(m，6H)。
(C 20H 24N 2O 6+ H) +The MS calculated value: 389.Measured value: 389.
Embodiment 18 4-(R, S)-amino-N-[(4-bromobenzene formyl radical)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the universal method of embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H NMR δ (CDCl 3) 7.64 (tangible d, 2H, J=8.5Hz), 7.60 (tangible d, 2H, J=8.5Hz), 4.81-4.67 (m, 1H), 4.62-4.48 (m, 1H), 3.36-4.19 (m, 1H), 4.18-3.78 (m, 3H), 1.81-1.59 (m, 3H), 1.05-0.80 (m, 6H).
(C 17H 21N 2O 4Br) +The MS calculated value: 397.Measured value: 397.
Embodiment 19 4-(R, S)-amino-N-[(4-bromobenzene formyl radical)-S-leucine]-preparation of tetrahydrofuran-3-one
According to the universal method of embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H?NMRδ(CDCl 3)7.91(m，1H)，7.76-7.59(m，2H)，7.39-7.18(m，1H)，7.04-6.89(m，1H)，7.84-6.68(m，1H)，4.89-4.4.68(m，1H)，4.66-4.56(m，1H)，4.27-3.76(m，4H)，1.88-1.68(m，3H)，1.03-0.78(m，6H)。
(C 17H 21N 2O 4Br) +The MS calculated value: 397.Measured value: 397.
Embodiment 20 4-(R, S)-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to the universal method of embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H NMR δ (CDCl 3) 7.88-7.67 (m, 5H), 7.48-7.38 (m, 1H), 4.81 (br d, 1H, J=6.7Hz), 4.60 (tangible t, 1H, J=8.8Hz), 4.43-4.30 (m, 1), 4.28-3.84 (m, 3H), 1.86-1.62 (m, 3H), 1.05-0.82 (m, 6H).
(C 19H 21N 2O 4SCl-H) +The MS calculated value: 408.Measured value: 408.
Embodiment 21 4-(R, S)-amino-N-[(4-fluoro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to the method for embodiment 15, but use suitable amino acid methyl ester and the carboxylic acid reagent consistent, prepare this target compound with end product.
1H NMR δ (CDCl 3) 7.96 (s, 1H), 7.68-7.58 (m, 2H), 7.48-7.32 (m, 1H), 7.06 (dd, 1H, J=9.0Hz and 9.0Hz), and 4.89-4.72 (m, 1H), 4.65-4.55 (tangible t, 1H, J=8.8Hz), 4.35 (tangible q, 1H, J=8.2Hz), and 4.28-3.82 (m, 3H), 1.88-1.62 (m, 3H), and 1.05-0.82 (m, 6H).
(C 19H 21N 2O 4SF+H) +The MS calculated value: 393.Measured value: 393.
Embodiment 22-66
The preparation of cyclic alkoxy ketone
According to embodiment 1 or embodiment 15 described similar methods, use and the corresponding to suitable amino acid of end product and acid or acyl chlorides reagent the compound of preparation in the table 1. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 1.
Table 1
Figure A9880479100541
????24 The same 4-benzyl diethylenediamine-1-base Solution methods
????25 The same 4-(3, the 4-methylenedioxy benzyl) piperazine-1-base Solution methods
????26 The same 4-(tert-butoxycarbonyl) piperazine-1-base Solution methods
????27 The same Piperazine-1-base Solution methods
????28 The same Benzoglyoxaline-5-base Solution methods
????29 The same The 6-quinolyl Solution methods
????30 The same The 5-indyl Solution methods
????31 The same The 2-naphthyl Solution methods
????32 The same The 2-pyridyl Solution methods
????33 The same 4-benzyloxy phenyl Solution methods
????34 The same 3-benzyloxy phenyl Solution methods
????35 The same The 4-hydroxy phenyl Solution methods
????36 The same 5-nitro benzo [b] thiophene-2-base Solution methods
????37 The same 2-(thiophene-2-yl) ethene-1-base Solution methods
????38 The same The 4-p-methoxy-phenyl ????SPS
????39 The same The 3-p-methoxy-phenyl ????SPS
????40 The same 7-oxyethyl group benzo furans-1-base ????SPS
????41 The same 5-nitrobenzofuran-1-base ????SPS
????42 The same 4-(2-p-methoxy-phenyl) phenyl ????SPS
????43 The same 3-(2-p-methoxy-phenyl) phenyl ????SPS
????44 The same The 4-cyano-phenyl ????SPS
????45 The same The 3-nitrophenyl ????SPS
????46 The same 3-(dimethyl aminoethyl)-4-p-methoxy-phenyl ????SPS
????47 The same 2-(2-chlorophenyl) ethene-1-base ????SPS
????48 The same The 4-Trifluoromethoxyphen-l ????SPS
????49 The same 4-methylsulfonyl phenyl ????SPS
????50 The same The 4-iodine substituted phenyl ????SPS
????51 The same 4-chloro benzo [b] thiophene-2-base ????SPS
????52 The same 5,6-dimethoxy benzo [b] thiophene-2-base ????SPS
????53 The same 5,6-methylene-dioxy benzo [b] thiophene-2-base ????SPS
????54 The same 7-chloro benzo [b] thiophene-2-base ????SPS
Figure A9880479100561
Embodiment 67 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-preparation of tetrahydropyrans-3-ketone
A) trans-4-amino-3-hydroxy tetrahydro pyranium salt hydrochlorate
According to the method for embodiment 1 (a) and 1 (b), but with 3,4-epoxy tetrahydropyrans replaces 3, and 4-epoxy tetrahydrofuran (THF) prepares this target compound.
B) trans-4-(R, S)-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxyl-tetrahydropyrans
(5.28ml, (12.48g is in methylene dichloride 47mmol) (300ml) solution 43mmol) to add to N-carbonyl benzyloxy-L-leucine with pivalyl chloride.After 1 hour, add trans-4-amino-3-hydroxy tetrahydro pyranium salt hydrochlorate (6g, 39mmol) and triethylamine (10.8ml, methylene dichloride 79mmol) (100ml) mixed solution stir this mixed solution and spend the night.Wash this reaction mixture with 1N HCl and saturated sodium bicarbonate, and dry.Reduction vaporization obtains light color oily matter.Through chromatography purification (ethyl acetate/hexane is as eluent), obtain trans-4-(R, S)-N-[(benzyloxycarbonyl)-S-leucine into white pasty state]-3-hydroxyl-tetrahydropyrans, 5.5g, yield 39%:
1H?NMRδ(CDCl 3)7.35(s，5H)，5.0(m，3H)，4.16-3.89(m，4H)，3.44-3.36(m，2H)，3.13(t，1H)，1.84-1.53(m，2H)，1.28-1.22(m，3H)，0.93(m，6H)。
C) 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydropyrans-3-ketone
Method according to embodiment 1 (f); but with 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxyl-tetrahydropyrans replace 4-(R, S)-amino-N-[(3; 4-methylene-dioxy benzoyl)-the S-leucine]-3-hydroxy tetrahydro pyrans, prepare this target compound.
1H?NMRδ(d 6?DMSO)8.15(d，1H)，7.39-7.29(m，5H)，5.02(d，2H)，4.63(m，1H)，4.14-4.10(m，2H)，3.97-3.83(m，3H)，2.10(m，1H)，1.92(m，1H)，1.61(m，1H)，1.45(m，1H)，0.95(m，6H)。
(C 19H 26N 2O 5+ H) +The MS calculated value: 363.Measured value: 363.
Embodiment 68 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone
Preparation
A) trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxy tetrahydro pyranium salt hydrochlorate
Under hydrogen environment (50psi), with 4-(R, S)-amino-N-[(benzyloxycarbonyl-S-leucine]-3-hydroxy tetrahydro pyrans (2.8g, 7.75mmol) and ethanol (200ml) mixed solution of 10% palladium charcoal (300mg) stirred 12 hours.Filter this mixture and, obtain target compound behind the reduction vaporization, 1.40g, yield 68% into brown solid with ether system HCl processing.
1H?NMRδ(CDCl 3)8.30(m，2H)，8.02(m，1H)，4.06-3.92(m，4H)，3.50-3.35(m，2H)，3.12(t，1H)，1.89-1.54(m，2H)，1.23(m，3H)，0.93(m，6H)。
B) trans-4-(R, S)-amino-N-[(thionaphthene-2-carbonyl)-S-leucine]-3-hydroxy tetrahydro pyrans
With thionaphthene-2-carbonyl chloride (442mg, 2.25mmol) add to trans-4-(R, S)-(133mg is in dioxane 0.5mmol) (7ml) and saturated sodium bicarbonate (7ml) solution for amino-N-(S-leucine)-3-hydroxy tetrahydro pyrans.After 30 minutes, dilute this reaction mixture with ethyl acetate, with saturated sodium bicarbonate washing organic layer, reduction vaporization obtains white solid.Through chromatography purification (using the ethyl acetate/hexane wash-out), obtain trans-4-(R, S)-amino-N-[(thionaphthene-2-carbonyl) S-leucine into white solid]-3-hydroxy tetrahydro pyrans, 160mg, 84%.
C) 4-(R, S)-amino-N-[(thionaphthene-2-carbonyl)-S-leucine]-tetrahydropyrans-3-ketone
Method according to embodiment 1 (f); but with trans-4-(R; S)-amino-N-[(thionaphthene-2-carbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans replacement 4-(R; S)-amino-N-[(3; 4-methylene-dioxy benzoyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran, prepare this target compound.
1H?NMRδ(CDCl 3)7.84-7.76(m，2H)，7.41(m，2H)，7.05(m，1H)，4.83-4.61(m，2H)，4.18-3.77(m，4H)，2.73-2.53(m，1H)，1.98-1.75(m，2H)，1.26(m，3H)，0.92(m，6H)。
(C 20H 24N 2O 4S+H) +The MS calculated value: 389.Measured value: 389.
Embodiment 694-(R, S)-amino-N-[(4-phenoxy group benzoyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (CDCl 3, 250MHz) 7.74 (d, 2H, J=10.9Hz), 7.37 (dd, 2H, J=7.7 and 7.7Hz), 7.20 (dd, 1H, J=7.5 and 7.5Hz), 7.03 (d, 2H, J=7.7Hz), 7.0 (d, 2H, J=7.7Hz), and 6.98-6.82 (m, 2H), 4.83-4.68 (m, 1H), 4.66-4.45 (m, 1H), 4.34-3.70 (m, 4H), 1.98-1.54 (m, 3H), 1.08-0.78 (m, 6H).
(C 23H 26N 2O 5-H) +The MS calculated value: 409.Measured value: 409.
Embodiment 70 4-(R, S)-amino-N-[(4-phenyl benzoyl)-S-leucine]-preparation of tetrahydrofuran-3-one
According to being similar to embodiment 15 described methods, prepare this target compound.
1H?NMRδ(CDCl 3，250MHz)7.83(d，2H，J＝8.2Hz)，7.70-50(m，4H)，7.48-32(m，4H)，7.30-7.12(m，1H)，6.88-6.72(m，1H)，4.88-4.70(m，1H)，4.65-52(m，1H)，4.38-3.78(m，4H)，1.92-1.60(m，3H)，1.08-0.78(m，6H)。
(C 23H 26N 2O 4-H) +The MS calculated value: 393.Measured value: 393.
Embodiment 71 4-(R, S)-amino-N-[(6-trifluoromethyl benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrochysene
The preparation of furans-3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (DMSO, d 6, 250MHz) 8.82 (d, 1H, J=6.0Hz), 8.43 (s, 1H), 8.48-8.44 (m, 0.5H), 8.34 (d, 0.5Hz, J=7.8Hz), 8.23 (s, 1H), 8.04 (d, 1H, J=8.4Hz), (7.60 dd, 1H, J=1.5 and 8.5Hz), and 4.49-4.38 (m, 1H), 4.26-3.68 (m, 5H), 1.70-1.36 (m, 3H), 0.80 (d, 3H, J=6Hz), 0.76 (d, 3H, J=6.0Hz).
(C 20H 21F 3N 2O 4S-H) +The MS calculated value: 443.Measured value: 443.
Embodiment 72 4-(R, S)-amino-N-[(4-ethylamino benzonitrile acyl group)-S-leucine]-preparation of tetrahydrofuran-3-one
According to being similar to embodiment 15 described methods, prepare this target compound.
1H?NMRδ(CDCl 3，250MHz)7.76(d，2H，J＝8.0Hz)，7.62-7.42(m，1H)，7.22(d，2H，J＝7.8Hz)，7.04-6.80(m，1H)，4.91-4.73(m，1H)，4.61-4.45(m，1H)，4.36-3.72(m，4H)，2.68(q，2H，J＝7.6Hz)，1.88-1.58(m，3H)，1.23(t，3H，J＝7.6Hz)，0.98-0.88(m，6H)。
(C 19H 26N 2O 4-H) +The MS calculated value: 345.Measured value: 345.
Embodiment 73 4-(R, S)-amino-N-[(4-(tertiary butyl) benzoyl)-S-leucine]-system of tetrahydrofuran-3-one
Be equipped with
According to being similar to embodiment 15 described methods, prepare this target compound.
1H?NMRδ(CDCl 3，250MHz)7.76(brd，2H，J＝7.5Hz)，7.46(brd，2H，J＝7.5Hz)，6.92-6.76(m，2H)，4.88-4.68(m，1H)，4.58-4.43(m，1H)，4.43-3.71(m，4H)，1.82-1.57(m，3H)，1.32(s，9H)，1.00-0.82(m，6H)。
(C 21H 30N 2O 4+ H) +The MS calculated value: 375.Measured value: 375.
Embodiment 74 4-(R, S)-amino-N-[(5-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the tetrahydrochysene furan
Mutter-preparation of 3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (CDCl 3, 250MHz) 7.84-7.54 (m, 2H), 7.20 (d, 1H, J=2.0Hz), 7.10 (d, 1H, J=2.3Hz), 7.06 (d, 1H, J=2.3Hz), 6.78 (d, 1H, J=8.1Hz), 4.82-4.68 (m, 1H), 4.59 (tangible t, 1H, J=8.8Hz), 4.49-3.61 (m, 4H), 3.84 (s, 3H), 1.82-1.58 (m, 3H), 1.08-0.72 (m, 6H).
(C 20H 24N 2O 5S-H) +The MS calculated value: 403.Measured value: 403.
Embodiment 75 4-(R, S)-amino-N-[(4-nitro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (CDCl 3, 250MHz) 8.31 (s, 1H), 7.96 (d, 1H, J=7.2Hz), 7.62-7.18 (m, 4H), 4.84 (tangible d, 1H, J=7.5Hz), 4.70-3.72 (m, 5H), 1.94-1.60 (m, 3H), 1.11-0.80 (m, 6H).
(C 19H 21N 3O 6S-NO 2) +The MS calculated value: 373.Measured value: 373.
Embodiment 76 4-(R, S)-amino-N-[(6-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (CDCl 3, 250MHz) 8.03 (s, 1H), 7.81-7.58 (m, 2H), and 7.54-7.40 (m, 1H), 7.22-6.98 (m, 2H), 4.74 (tangible d, 1H, J=7.5Hz), (4.59 tangible q, 1H, J=7.5 and 14.0Hz), 4.48-3.74 (m, 4H), 1.85-1.58 (m, 3H), and 1.10-0.78 (m, 6H).
(C 19H 21BrN 2O 4S-H) +The MS calculated value: 452.Measured value: 452.
Embodiment 77 4-(R, S)-amino-N-[(5-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran (THF)-
The preparation of 3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H?NMRδ(CDCl 3，250MHz)8.04-7.90(m，1H)，7.88-7.18(m，5H)，4.88-4.68(m，1H)，4.68-4.52(m，1H)，4.46-3.88(m，4H)，1.92-1.52(m，3H)，1.08-0.80(m，6H)。
(C 19H 21BrN 2O 4S-H) +The MS calculated value: 452.Measured value: 452.
Embodiment 78 4-(R, S)-amino-N-[(6-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the tetrahydrochysene furan
Mutter-preparation of 3-ketone
According to being similar to embodiment 15 described methods, prepare this target compound.
1H NMR δ (CDCl 3, 250MHz) 7.79-7.61 (m, 2H), 7.32-7.14 (m, 2H), 7.00 (dd, 1H, J=1.5 and 8.8Hz), 6.86-6.67 (m, 1H), 4.75 (tangible q, 1H, J=8.2 and 16.2Hz), 4.57 (tangible t, 1H, J=8.6 and 17.4Hz), 4.49-3.71 (m, 4H), 3.85 (s, 3H), 1.92-1.52 (m, 3H), 1.08-0.78 (m, 6H).
(C 20H 24N 2O 5S-H) +The MS calculated value: 403.Measured value: 403.
Embodiment 79-93
According to embodiment 15 described similar methods, use and the corresponding to suitable amino acid of end product and acid or acyl chlorides reagent, also prepare the compound in the table 2. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 2.
Table 2
Figure A9880479100621
Embodiment 944-S-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-preparation of tetrahydrofuran-3-one
(a) trans-4-S-amino-3-R-hydroxyl tetrahydrofuran hydrochloride
Under hydrogen environment (50psi), with trans-4-S-azido--3-R-hydroxyl tetrahydrofuran (reference: L.E.Martinez, J.L.Leighton, D.E.Carsten and E.N.Jacobsen, J.Amer Chem.Soc, 1995,117,5897) (10g, 77mmol) ethanol (150ml) mixed solution with 10% palladium charcoal (1g) stirred 12 hours.Filter this mixture and, obtain target compound behind the reduction vaporization, 10.5g, yield 97%, m.p.132 ℃ into brown solid with 100ml ether system HCl processing.
1H?NMRδ(D 2O)4.54-4.52(m，1H)，4.24-4.13(m，2H)，3.98-3.61(m，3H)。
(b) trans-4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran
With trimethyl-acetyl chloride (5.4ml, 44mmol) add to stirring the N-Cbz-L-leucine (12.7g, 48mmol) and triethylamine (14ml is in tetrahydrofuran (THF) 52mmol) (200ml) solution.After 1 hour, (5.58g 40mmol), stirs this mixture 16 hours under refluxing to add trans-4-S-amino-3-R-hydroxyl tetrahydrofuran hydrochloride.Filter this reaction mixture, reduction vaporization.Rapid column chromatography (80% ethyl acetate-hexane) obtains the target compound into white foam shape thing, 10.6g, yield 84%.
1H NMR δ (CDCl 3) 7.76 (d, 1H, J=5.3Hz), 7.33-7.20 (m, 5H), 6.43 (d, 1H, J=8.9Hz), 5.01 (tangible d, 2H, J=3.0Hz), 4.60-3.65 (m, 6H), 1.61-1.42 (m, 3H), 0.93-0.88 (m, 6H).
(c) trans-4-S-amino-N-(S-leucine)-3-R-hydroxyl tetrahydrofuran hydrochloride
Under hydrogen environment (50psi), with trans-4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-(2.0g, 5.7mmol) ethanol (100ml) mixed solution with 10% palladium charcoal (500mg) stirred 12 hours the 3-R-hydroxyl tetrahydrofuran.Filter this mixture and, obtain target compound behind the reduction vaporization, 1.5g, yield 100% into white foam shape thing with ether system HCl (100ml, 1 mole) dilution.
1H?NMRδ(D 2O)4.20-4.05(m，2H)，4.06-4.00(m，1H)，3.90-3.83(m，2H)，3.68-3.52(m，2H)，1.65-1.47(m，3H)，0.86-0.78(m，6H)。
(d) trans-4-S-amino-N-[(2-benzo (b) thiophene carbonyl)-S-leucine-3-R-hydroxyl tetrahydrofuran
With N, (0.4ml, (380mg is in methylene dichloride 1.1mmol) (10ml) stirred solution 2.0mmol) to add to trans-4-S-amino-N-(S-leucine)-3-R-hydroxyl tetrahydrofuran hydrochloride for the N-diisopropylethylamine.After 5 minutes, (196mg 1.0mmol), stirs this mixture 1 hour, then reduction vaporization to add benzo [b] thiophene-2-carbonyl chloride.Rapid column chromatography (40% acetone-hexane) obtains the target compound into white foam shape thing, 271mg, yield 75%.
1H NMR δ (d 6DMSO, and 400MHz) 8.72 (d, 1H, J=8.5Hz), 8.25 (s, 1H), 8.04 (d, 1H, J=8.5Hz), 7.95 (d, 1H, J=8.5Hz), 7.46-7.43 (m, 2H), 5.23 (d, 1H, J=3.94Hz), and 4.54-4.47 (m, 1H), 4.03-4.00 (m, 2H), 3.90 (dd, 1H, J=5.4 and 8.9Hz), (3.82 dd, 1H, J=4.4 and 9.3Hz), 3.53-3.48 (m, 2H), and 1.72-1.66 (m, 2H), 1.52-1.48 (m, 1H), 0.91 (d, 3H, J=6.4Hz), 0.88 (d, 3H, J=6.4Hz).
(C 18H 24N 2O 5+ H) +The MS calculated value: 365.Measured value: 365.
(e) 4S-amino-N-[(2-benzo (b) thiophene carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone
(200mg 0.5mmol) adds to trans-4-S-amino-N-[(2-benzo (b) thiophene carbonyl)-(150mg is in methylene dichloride 0.40mmol) (10ml) stirred solution for S-leucine-3-R-hydroxyl tetrahydrofuran with Dess-Martin periodinane.After 1 hour, add ether (20ml) and Sulfothiorine (1g) successively.After 15 minutes, with saturated sodium bicarbonate and this reactant of salt water washing, drying.Evaporating solvent obtains the target compound into white foam shape thing, 147mg, yield 100%.
1H?NMRδ(d 6?DMSO，400MHz)8.82(d，1H，J＝4.0Hz)，8.46(d，1H，J＝4.0Hz)，8.28(s，1H)，8.05(d，1H，J＝4.0Hz)，7.98(d，1H，J＝4.0Hz)，7.47-7.44(m，2H)，4.54-4.51(m，1H)，4.33-4.18(m，3H)，4.08-3.80(m，3H)，1.74-1.67(m，2H)，1.58-1.56(m，1H)，0.92(d，3H，J＝6.4Hz)，0.88(d，3H，J＝6.4Hz)。
(C 19H 22N 2O 4-H) +The MS calculated value: 373.Measured value: 373.
Embodiment 95 4-R-amino-N-[(2-benzo (b) thiophene carbonyl)-the S-leucine]-preparation of tetrahydrofuran-3-one
According to the described method of embodiment 94 (a-e), but in embodiment 94 (a) method, use trans-4-R-azido--3-S-hydroxyl tetrahydrofuran (reference: L.E.Martinez, J.L.Leighton, D.E.Carsten and E.N.Jacobsen, J.Amer Chem.Soc, 1995,117,5897), prepare this target compound.
1H NMR δ (d 6DMSO, and 400MHz) 8.82 (d, 1H, J=4.0Hz), 8.52 (d, 1H, J=4.0Hz), 8.28 (s, 1H), 8.01 (d, 1H, J=4.0Hz), 7.95 (d, 1H, J=4.0Hz), 7.47-7.44 (m, 2H), 4.54-4.51 (m, 1H), 4.33-4.18 (m, 3H), 4.33 (tangible t, 1H, J=8.5Hz), 4.22 (dd, 1H, J=8.7 and 16.0Hz), 4.07 (tangible d, 1H, J=16.6Hz), 3.90 (tangible d, 1H, J=16.6Hz), 3.81 (tangible t, 1H, J=8.5Hz), 1.74-1.67 (m, 2H), 1.58-1.56 (m, 1H), 0.92 (d, 3H, J=6.4Hz), 0.88 (d, 3H, J=6.4Hz).
(C 19H 22N 2O 4-H) +The MS calculated value: 373.Measured value: 373.
Embodiment 96
4-S-amino-N-[(2-naphthoyl base)-the S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the following compound of preparation.
1H NMR δ (d 6DMSO, and 400MHz) 8.64 (d, 1H, J=3.8Hz), 8.54 (s, 1H), 8.42 (d, 1H, J=3.8Hz), 8.03 (d, 1H, J=3.8Hz), 8.02-7.95 (m, 3H), 7.62-7.58 (m, 2H), 4.63-4.60 (m, 1H), 4.35-4.27 (m, 2H), 4.08 (tangible d, 1H, J=16.8Hz), 3.86 (tangible d, 1H, J=16.8Hz), 3.82 (tangible t, 1H, J=8.0Hz), and 1.75-1.64 (m, 2H), 1.62-1.55 (m, 1H), 0.92 (d, 3H, J=6.0Hz), 0.88 (d, 3H, J=6.0Hz).
(C 21H 24N 2O 4-H) +The MS calculated value: 367.Measured value: 367.
Embodiment 97
4-R-N-[(2-naphthoyl base)-the S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the following compound of preparation.
1H NMR δ (d 6DMSO, and 400MHz) 8.62 (d, 1H, J=3.8Hz), 8.52 (s, 1H), 8.50 (d, 1H, J=3.8Hz), 8.04 (d, 1H, J=3.8Hz), 8.02-7.95 (m, 3H), 7.62-7.58 (m, 2H), and 4.63-4.60 (m, 1H), 4.32 (tangible t, 1H, J=8.8Hz), 4.23 (ddd, 1H, J=8.8 and 16.0Hz), 4.04 (tangible d, 1H, J=16.4Hz), 3.86 (tangible d, 1H, J=16.4Hz), 3.81 (tangible t, 1H, J=8.0Hz), 1.75-1.64 (m, 2H), 1.62-1.55 (m, 1H), 0.92 (d, 3H, J=6.0Hz), 0.88 (d, 3H, J=6.0Hz).
(C 21H 24N 2O 4-H) +The MS calculated value: 367.Measured value: 367.
Embodiment 98
4-S-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the following compound of preparation.
1H NMR δ (d 6DMSO, and 400MHz) 8.80 (d, 1H, J=9.0Hz), 8.70 (d, 1H, J=6.9Hz), 8.63 (d, 1H, J=8.5Hz), 8.39 (d, 1H, J=2.5Hz), 8.27 (d, 1H, J=2.5Hz), 8.21 (d, 1H, J=7.9Hz), 7.95 (tangible t, 1H, J=8.2Hz), 7.77 (tangible t, 1H, J=7.1Hz), and 4.75-4.66 (m, 1H), 4.41-4.26 (m, 2H), 4.16-3.79 (m, 3H), and 1.82-1.63 (m, 3H), 0.97-0.88 (m, 6H).
(C 20H 23N 3O 4+ H) +The MS calculated value: 370.Measured value: 370.
Embodiment 99
4-R-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-preparation of tetrahydrofuran-3-one
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the following compound of preparation.
1H NMR δ (d 6DMSO, and 400MHz) 8.88 (d, 1H, J=9.0Hz), 8.82 (d, 1H, J=6.7Hz), 8.70 (d, 1H, J=8.5Hz), 8.30 (d, 1H, J=2.5Hz), 8.27 (d, 1H, J=2.5Hz), 8.21 (d, 1H, J=7.9Hz), 8.02 (tangible t, 1H, J=7.0Hz), 7.87 (tangible t, 1H, J=7.0Hz), 4.82-4.73 (m, 1H), 4.48-3.88 (m, 5H), and 1.88-1.70 (m, 3H), 1.05-1.02 (m, 6H).
(C 20H 23N 3O 4+ H) +The MS calculated value: 370.Measured value: 370.
Embodiment 100 4-S-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one
Preparation
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the following compound of preparation.
1H NMR δ (d 6DMSO, and 400MHz) 8.73 (d, 1H, J=8.4Hz), 8.52 (d, 1H, J=7.0Hz), 7.65-7.62 (m, 2H), 7.33 (d, 1H, J=2.6Hz), 7.12 (dd, 1H, J=2.6 and 9.2Hz), 4.64-4.55 (m, 1H), 4.42-4.30 (m, 2H), 4.18-3.87 (m, 3H), 3.86 (s, 3H), 1.84-1.57 (m, 3H), 0.98-0.87 (m, 6H).
(C 20H 24N 2O 6+ H) +The MS calculated value: 389.Measured value: 389.
Embodiment 101-108
According to embodiment 15 described similar methods, use and the corresponding to suitable amino acid of end product and acid or acyl chlorides reagent, also prepare the compound in the table 3. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 3.
Table 3
Figure A9880479100671
Figure A9880479100672
Embodiment 109-126
According to the method for embodiment 94, use and the corresponding to suitable acyl chlorides of end product and required stereochemical 4-azido--3-hydroxyl tetrahydrofuran the compound of preparation embodiment 109-126. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 4.
Table 4
Figure A9880479100681
Figure A9880479100682
Embodiment 127-129
SPS method according to embodiment 15, but with 3,4-dimethoxy-4 '-amino tetrahydro pyran replaces 3,3-dimethoxy-4 '-amido tetrahydrofuran, and use and end product corresponding to suitable suitable amino acid and carboxylic acid reagent the compound of preparation embodiment 127-129. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 5.
Table 5
Figure A9880479100691
Figure A9880479100692
Embodiment 130
4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetramethylene sulfide-3-
The preparation of ketone
(a) N-benzo [b] thiophene-2-base carbonyl-L-leucine methyl esters
With benzo [b] thiophene-2-carbonyl chloride (4.9g, 25mmol) add to L-leucine methyl esters (4.5g, 25mmol) and diisopropylethylamine (9ml is in DCM 5lmmol) (200ml) stirred solution.After stirring 2 hours under the room temperature, this mixture is inclined to water, with salt water washing and dry (sal epsom).Reduction vaporization obtains the target compound into white solid, 7.6g, yield 100%.
1H NMR δ (CDCl 3, 250MHz) 7.88-7.78 (m, 3H), 7.44-7.38 (m, 2H), 6.53 (d, 1H, J=7.6Hz), 4.91-4.82 (m, 1H), 3.78 (s, 3H), 1.82-1.60 (m, 3H), 1.00 (tangible t, 6H, J=5.9Hz).
(b) N-benzo [b] thiophene-2-base carbonyl chloride-L-leucine
With lithium hydroxide (1.41g, 59mmol) disposable add to N-benzo [b] thiophene-2-base carbonyl-L-leucine methyl esters (8.99g, tetrahydrofuran (THF)/water 29.4mmol) (1/1,300ml) in the stirred solution.After stirring 12 hours under the room temperature, this mixture is inclined to water, being acidified to pH with concentrated hydrochloric acid is 1, with ether (* 2) extracting twice.Reduction vaporization obtains the target compound into yellow solid, 6.1g, yield 71%.
1H?NMRδ(d 6?DMSO，250MHz)8.78(d，1H，J＝9.1Hz)，8.12(s，1H)，7.92-7.83(m，2H)，7.36-7.30(m，2H)，4.37-4.28(m，1H)，1.88-1.47(m，3H)，0.82(d，3H，J＝6.0Hz)，0.78(d，3H，J＝6.0Hz)。
(c) N-benzo [b] thiophene-2-base carbonyl-L-leucine-S-(methoxycarbonyl methyl)-L, the D-ethycysteine
With carbonochloridic acid isopropyl ester (5.9ml, 1.0M toluene solution) add to N-benzo [b] thiophene-2-base carbonyl-L-leucine (1.65g, 5.7mmol) and triethylamine (1.6ml is in DCM 11.8mmol) (20ml) stirred solution.In room temperature after following 1 hour, add L-ethycysteine and triethylamine (1.6ml, 11.8mmol), with this mixture restir 6 hours.(0.6ml 6.3mmol), inclines this mixture to water after 0.5 hour again, with ethyl acetate (* 3) extraction to add the monobromo-acetic acid methyl esters.With the organic layer that the salt water washing merges, dry (sal epsom), reduction vaporization.Rapid column chromatography (40% hexane-ether wash-out) obtains the target compound into white solid, 1.6g, yield 70%.
1H?NMRδ(CDCl 3，250MHz)7.84-7.77(m，3H)，7.65(d，0.5H，J＝8.4Hz)，7.52(d，0.5H，J＝8.4Hz)，7.40-7.35(m，2H)，7.24(d，0.5H，J＝8.4Hz)，7.16(d，0.5H，J＝8.4Hz)，4.88-4.82(m，2H)，4.23-4.15(m，2H)，3.70(s，1.5H)，3.69(s，1H)，3.36-3.22(m，2H)，3.15-3.08(m，2H)，1.82-1.75(m，3H)，1.28(t，1.5H，J＝4.5Hz)，1.23(t，1.5H，J＝4.5Hz)，0.98-0.95(m，6H)。
(d) 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-S-leucine]-tetrahydro thiophene-3-ketone
Under room temperature, sodium methylate (deriving from 75mg sodium and the 2ml methyl alcohol) solution of prepared fresh is added to N-benzo [b] thiophene-2-base carbonyl-L-leucine-S-(carbonyl methoxymethyl)-L, (1.5g is in methyl alcohol 3.2mmol) (2ml) liquid for the D-ethycysteine.After 1 hour, add ether (80ml), this solution is cooled to 0 ℃, filter the white solid that produces.This solid is dissolved in 15ml glacial acetic acid, 10ml concentrated hydrochloric acid and the 15ml water.Under refluxing, this mixture was stirred 0.5 hour, be cooled to room temperature then, with chloroform (* 5) extraction.With the organic layer that sodium bicarbonate and salt water washing merge, dry (sal epsom) and reduction vaporization.Rapid column chromatography (40% hexane-ether wash-out) obtains the target compound into white solid, 120mg, yield 10%.
1H?NMRδ(CDCl 3，400MHz)7.88-7.78(m，3H)，7.58(d，0.5H，J＝6.4Hz)，7.54(d，0.5H，J＝6.4Hz)，7.42-7.35(m，3H)，4.85-4.80(m，1H)，4.43-4.34(m，1H)，3.34-3.23(m，3H)，3.02-2.91(m，1H)，1.76-1.74(m，3H)，0.98-0.85(m，6H)。
(C 19H 22N 2O 3S+H) +The MS calculated value: 391.Measured value: 391.
Embodiment 131
4-amino-N-[(benzo [b] thiophene-2-base carbonyl)-and the S-leucine]-3,3-dimethoxy tetrahydrochysene
Furans, the preparation of diastereomer 1
(a) 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3, the 3-dimethoxy-tetrahydrofuran
Under room temperature, with 4-(R, S)-amino-3,3-dimethoxy-tetrahydrofuran (2.2g, 15mmol), N-benzyloxycarbonyl-L-leucine (3.98g, 15mmol), EDC (3.17g, 16.5mmol) and hydroxyl amino benzotriazole (0.45g, 3.3mmol) together methylene dichloride and tetrahydrofuran (THF) (1: 1,100ml) stirred 12 hours in the mixed solution.This mixture is added in the ethyl acetate (300ml), and (2 * 100ml) washings, dry (sal epsom) also is evaporated to dried water.The oily matter that produces obtains the target compound (5.27g, 89%) into oily matter through silica gel column chromatography (1: 3 to 1: 1 gradient elution of ethyl acetate/hexane).
1H?NMRδ(CDCl 3)7.34(s，5H)，6.55(d，1H)，5.11(m，3H)，4.34(q，1H，J＝6.7Hz)，4.20(m，2H)，3.77(s，2H)，3.51(m，1H)，3.26(d，3H，J＝2.3Hz)，3.20(d，3H，J＝4.7Hz)，1.54(m，3H)，0.95(s，3H)，0.93(s，3H)。
B) 4-amino-N-(S-leucine)-3, the separation of 3-dimethoxy-tetrahydrofuran diastereomer
Under 50psi, make 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3,3-dimethoxy-tetrahydrofuran (5.27g, 13.4mmol) hydrogenation in the methyl alcohol that contains 10% palladium charcoal.3.5 after hour, by this mixture of diatomite filtration, solvent is removed in decompression.The oily matter (3.5g) that produces is separated into two pure single diastereomers through silica gel column chromatography (methylene dichloride that contains methyl alcohol, 0-4% gradient elution) with target compound: diastereomer 1 (it is fast to flow) (0.63g). 1H?NMRδ(CDCl 3)7.76(d，1H，J＝7.3Hz)，4.36(dd，1H，J＝6.3，7.2Hz)，4.21(dd，1H，J＝6.4，9.0Hz)，3.80(s，2H)，3.57(dd，1H，J＝5.3，9.1Hz)，3.41(dd，1H，J＝3.8，10.1Hz)，3.30(s，3H)，3.24(s，3H)，1.73(m，2H)，1.35(m，1H)，0.96(d，3H，J＝6.7Hz)，0.94(d，3H，J＝6.6Hz)。
C) 4-amino-N-[(benzo [b] thiophene-2-base carbonyl)-and the S-leucine]-3,3-dimethoxy-tetrahydrofuran, diastereomer 1
Saturated sodium hydrogen carbonate solution (5ml) is added to 4-amino-N-(S-leucine)-3,3-dimethoxy-tetrahydrofuran, diastereomer 1 (0.13g, 0.5mmol) 1, in 4-dioxane (5ml) solution, then add benzo [b] thiophene-2-base carbonyl chloride (0.39g, 2mmol).After 45 minutes, this mixture is added in the ethyl acetate water, sodium hydrogen carbonate solution and water washing.Dry then (sal epsom) organic solution, evaporation obtains white solid (0.47g).Silica gel column chromatography (the dichloromethane gradient wash-out that contains methyl alcohol 0-5%) obtains the target compound (0.18g, 89%) into white solid. 1H?NMRδ(CDCl 3)7.88(s，1H)，7.74(m，3H)，7.34(m，2H)，7.18(d，1H，J＝7.1Hz)，4.82(m，1H)，4.38(dd，1H，J＝6.4，12.3Hz)，4.21(dd，1H，J＝6.5，9.2Hz)，3.78(ABq，2H，J＝3.8，9.8Hz)，3.62(dd，1H，J＝5.2，9.1Hz)，1.78(m，3H)，0.99(s，3H)，0.96(s，3H)。
Embodiment 132-142
According to embodiment 131 described similar methods, but use and the corresponding to suitable suitable 4-amino-N-(S-leucine)-3 of end product 3-dimethoxy-tetrahydrofuran diastereomer and carboxylic acid halides reagent, the compound of preparation table 6. 1H NMR spectrum and/or mass spectrum are consistent with structure in the table 6.
Table 6
Embodiment 143
4-amino-N-[(benzo [b] thiophene-2-base carbonyl)-and the S-leucine]-3,3-dimethoxy tetrahydrochysene
Pyrans, the preparation of diastereomer 1
(a) 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3,3-dimethoxy tetrahydropyrans
In refluxing down, with 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine] (embodiment 67c, 3.1g 8.6mmol) heated 12 hours in methyl alcohol (50ml) with trimethyl orthoformate (2.8ml) and right-toluenesulphonic acids (0.080g) tetrahydropyrans-3-ketone.After solvent was removed in decompression, gained oily matter obtained the target compound (2.89g, 80%) into white solid through silica gel column chromatography (ethyl acetate/hexane gradient elution).
1H?NMRδ(CDCl 3)7.29(s，5H)，6.99(m，1H)，6.15(m，1H)，5.07(s，2H)，4.28(m，1H)，4.18(m，1H)，3.52(m，4H)，3.19(s，3H)，3.14(s，3H)，1.85(m，1H)，1.63(m，4H)，0.93(s，6H)。
B) 4-amino-N-(S-leucine)-3, the separation of 3-dimethoxy tetrahydropyrans diastereomer
According to embodiment 131b, with 4-(R, S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3, the hydrogenation of 3-dimethoxy tetrahydropyrans behind the chromatography, obtains the pure single diastereomer of target compound:
Diastereomer 1: 1H NMR δ (CDCl 3) 7.75 (d, 1H, J=8.1Hz), 4.17 (m, 1H), 3.58 (m, 3H), 3.41 (dd, 1H, J=3.5,9.7Hz), 3.28 (s, 3H), 3.24 (s, 3H), 1.92 (m, 1H), 1.71 (m, 4H), 1.30 (m, 1H), 0.97 (d, 3H, J=6.4Hz), 0.94 (d, 3H, J=6.3Hz).
Diastereomer 2: 1H NMR δ (CDCl 3) 7.8 (s, 1H), 4.16 (m, 1H), 3.59 (m, 3H), 3.49 (m, 1H), 3.28 (s, 3H), 3.24 (s, 3H), 1.92 (m, 1H), 1.72 (m, 4H), 1.41 (m, 1H), 0.97 (d, 3H, J=6.1Hz), 0.95 (d, 3H, J=6.0Hz).
C) 4-amino-N-[(benzo [b] thiophene-2-base carbonyl)-and the S-leucine]-3,3-dimethoxy tetrahydropyrans, diastereomer 1
According to embodiment 131c, make 4-amino-N-(S-leucine)-3,3-dimethoxy tetrahydropyrans, diastereomer 1 and benzo [b] thiophene-2-base carbonyl chloride reaction obtain target compound: 1HNMR δ (CDCl 3) 7.98 (d, 1H, J=8.3Hz), 7.93 (s, 1H), 7.78 (d, 1H, J=7.7Hz), 7.71 (d, 1H, J=8.3Hz), 7.33 (m, 3H), 4.83 (m, 1H), 4.19 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.40 (d, 1H, J=13Hz), 3.23 (s, 3H), 3.13 (s, 3H), 1.85 (m, 5H), 0.98 (d, 3H, J=4.8Hz), 0.96 (d, 3H, J=5.2Hz).
Embodiment 144
4-amino-N-[(benzo [b] thiophene-2-base carbonyl)-and the S-leucine]-3,3-dimethoxy tetrahydrochysene
Pyrans, the preparation of diastereomer 2
In embodiment 143c method, with 4-amino-N-(S-leucine)-3, the diastereomer 2 of 3-dimethoxy tetrahydropyrans prepares this target compound.
Above-mentioned explanation and embodiment full disclosure how to prepare and use compound of the present invention.Yet, the invention is not restricted to specific embodiment described above, but comprise its all change in the following claim scope.Quoting various periodicals, patent documentation and other disclosed reference has herein comprised prior art and has been attached to herein by quoting fully.

Claims (36)

1. formula (I) compound or its pharmacy acceptable salt:
Figure A9880479100021
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; N is 1,2 or 3.
2. the compound of claim 1, wherein R 2And R 4H respectively does for oneself.
3. the compound of claim 1, wherein R 3Be C 1-6Alkyl or C 2-6Alkenyl.
4. the compound of claim 3, wherein R 3Be isobutyl-.
5. the compound of claim 1, wherein R 1Be R " OC (O), R " SO 2Or R " C (O), and R wherein " be Ar-C 0-6Alkyl or Het-C 0-6Alkyl.
6. the compound of claim 5, wherein R " group is Or
Figure A9880479100033
B wherein 2Be OH, CN, OCF 3, OC 1-6Alkyl, OAr, SO 2C 1-6Alkyl, C 1-6Alkyl or halo.
7. the compound of claim 1, wherein n is 1 or 2.
8. the compound of claim 7, wherein n is 1.
9. the compound of claim 1, wherein X is O.
10. the compound of claim 1, wherein each R 5Be H.
11. the compound of the claim 1 of formula (IIa):
Figure A9880479100034
12. the compound of the claim 1 of formula (IIb):
13. the compound of the claim 1 of formula (IIc):
14. the compound of claim 1 is following compounds or its pharmacy acceptable salt: 4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(2-quinoline carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(8-quinoline carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(indoles-6-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(cumarone-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino benzo [b] thiophene of amino-N-[(5--2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-chloro-benzofuran-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-fluoro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-phenoxy group benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-phenyl benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-trifluoromethyl benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-ethylamino benzonitrile acyl group base)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-(tertiary butyl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(4-nitro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(5-bromo benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(6-methoxyl group benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(benzo (b) thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(benzo (b) thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(2-naphthoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(2-naphthoyl base)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-R-amino-N-[(quinoline-2-carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridin-3-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridine-2-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(cumarone-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-[6-picoline-3-yl] benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyridin-4-yl) benzoyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(2-chlorinated benzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(4-benzyl piepridine-1-base carbonyl)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dichlorobenzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-S-amino-N-[(3-chlorinated benzene formyl radical)-the S-leucine]-tetrahydrofuran-3-one; 4-(R, S)-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(4-phenoxy group benzoyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(quinoline-2-base carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydropyrans-3-ketone; Or 4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydro thiophene-3-ketone.
15. medicinal compositions, it comprises among the claim 1-14 any one compound and pharmaceutically acceptable carrier.
16. suppress the method for L-Cysteine HCL Anhydrous, this method comprises the compound of the claim 1 of the patient's significant quantity that needs.
17. the method for claim 16, wherein said L-Cysteine HCL Anhydrous are cathepsin K.
18. suppress the method for bone loss, this method comprises the compound of the claim 1 of the patient's significant quantity that needs.
19. treat osteoporotic method, this method comprises the compound of the claim 1 of the patient's significant quantity that needs.
20. the method for treatment gingival disease or periodontopathy, this method comprises the compound of the claim 1 of the patient's significant quantity that needs.
21. treatment is the method for the disease of feature with excessive cartilage or substrate degradation, this method comprises the compound of the claim 1 of the patient's significant quantity that needs.
22. the method for claim 21, wherein said disease are osteoarthritis or rheumatoid arthritis.
23. the compound of any one is as medicine among the claim 1-14.
24. it is purposes in the medicine of disease of a factor that the defined formula of claim 1 (I) compound is used for the treatment of in production that L-Cysteine HCL Anhydrous wherein suppresses.
25. the purposes of the compound of claim 24, wherein said L-Cysteine HCL Anhydrous are cathepsin K.
26. the defined formula of claim 1 (I) compound is used for suppressing the purposes of the medicine of bone loss in production.
27. the defined formula of claim 1 (I) compound is used for the treatment of purposes in the osteoporotic medicine in production.
28. the defined formula of claim 1 (I) compound is used for the treatment of purposes in the medicine of gingival disease or periodontopathy in production.
29. it is purposes in the medicine of disease of feature that the defined formula of claim 1 (I) compound is used for the treatment of with excessive cartilage or substrate degradation in production.
30. the purposes of the compound of claim 29, wherein said is that the disease of feature is osteoarthritis or rheumatoid arthritis with excessive cartilage or substrate degradation.
31. prepare the method for the defined formula of claim 1 (I) compound, this method comprises: (i) make the protected formula of reactive functional groups (III) compound and oxidant reaction:
Figure A9880479100081
R in formula (III) 1, R 2, R 3, R 4, R 5Identical with n with definition in claim 1 formula (I); Or (ii) make the decarboxylation of the protected formula of reactive functional groups (IV) compound: R in formula (IV) 1, R 2, R 3, R 4, R 5Identical with n with definition in claim 1 formula (I); Or (iii) make protected formula V compound of reactive functional groups and acid-respons: R in formula V 1, R 3, R 4, R 5Identical with n with definition in claim 1 formula (I); After this slough blocking group and the optional pharmacy acceptable salt that forms.
32. formula (III) compound or its pharmacy acceptable salt:
Figure A9880479100092
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; With n be 1,2 or 3.
33. formula (IV) compound or its pharmacy acceptable salt:
Figure A9880479100101
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; With n be 1,2 or 3.
34. formula V compound or its pharmacy acceptable salt: Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; With n be 1,2 or 3.
35. be selected from the compound of following compounds or its salt: trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(tert-butoxycarbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(3,4-methylene-dioxy benzoyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(2-quinoline carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino-N-[(indoles-6-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-(R, S)-amino benzo [b] thiophene of amino-N-[(5--2-base carbonyl)-the S-leucine]-the 3-hydroxyl tetrahydrofuran; Trans-4-amino-3-hydroxyl tetrahydrofuran; Trans-the 3-hydroxyl-4-benzyloxycarbonyl amino-tetrahydrofuran (THF); 4-benzyloxycarbonyl amino-tetrahydrofuran-3-one; 3,3-dimethoxy-4 '-benzyloxycarbonyl amino-tetrahydrofuran (THF); 3,3-dimethoxy-4 '-amino-tetrahydrofuran (THF); Trans-4-S-amino-3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(benzyloxycarbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-(S-leucine)-3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(3,4-dichloro-benzoyl base)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(2-quinoline carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-the N-[(cumarone-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(2-naphthoyl base)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(5-methoxyl group benzo furans-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans 4-S-amino-N-[(5-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans 4-S-amino-N-[(4-chloro benzo [b] thiophene-2-base carbonyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-bromobenzene formyl radical)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-(pyridine-2-yl) benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(4-(pyridin-3-yl) benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-S-amino-N-[(3,4-dimethoxy benzoyl)-the S-leucine]-the 3-R-hydroxyl tetrahydrofuran; Trans-4-amino-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzyloxycarbonyl)-the S-leucine]-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-(S-leucine)-3-hydroxy tetrahydro pyrans; Trans-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-3-R-hydroxy tetrahydro pyrans; N-benzo [b] thiophene-2-base carbonyl-L-leucine methyl esters; N-benzo [b] thiophene-2-base carbonyl-L-leucine; N-benzo [b] thiophene-2-base carbonyl-L-leucine-S-(methoxycarbonyl methyl)-L, the D-ethycysteine; Or 2-methoxycarbonyl-4-(R, S)-amino-N-[(benzo [b] thiophene-2-base carbonyl)-the S-leucine]-tetrahydro thiophene-3-ketone.
36. formula (VI) compound or its pharmacy acceptable salt:
Figure A9880479100131
Wherein: R 1Be R ", R " C (O), R " C (S), R " SO 2, R " OC (O), R " R ' NC (O) or R " OC (O) NR ' CH (R 6) C (O); R 2Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be H, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4Be H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; Each R 5Independent is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6Be H, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl; R ' is H, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R " be C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, Ar-C 2-6Alkenyl or Het-C 2-6Alkenyl; X is O or S; N is 1,2 or 3; And R aAnd R A 'Independent is H or C 1-2Alkyl, prerequisite is for working as R aOr R A 'One of when being H, then another is C 1-2Alkyl; Perhaps together for forming (the CH of 5-unit or 6-unit ring 2) 2-3
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ZA983762B (en) 1998-11-06

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