CN1681770A - 氨基-丙醇衍生物 - Google Patents
氨基-丙醇衍生物 Download PDFInfo
- Publication number
- CN1681770A CN1681770A CNA038215780A CN03821578A CN1681770A CN 1681770 A CN1681770 A CN 1681770A CN A038215780 A CNA038215780 A CN A038215780A CN 03821578 A CN03821578 A CN 03821578A CN 1681770 A CN1681770 A CN 1681770A
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- China
- Prior art keywords
- compound
- alkyl
- randomly
- phenyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 44
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 150000003839 salts Chemical group 0.000 claims description 27
- -1 betanaphthyl Chemical group 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
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- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
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- 239000012044 organic layer Substances 0.000 description 11
- 229910052698 phosphorus Inorganic materials 0.000 description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
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- 239000000284 extract Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
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- SPXAJWHTGUYHOS-UHFFFAOYSA-N [O].C(CCC)[SiH](C)C Chemical group [O].C(CCC)[SiH](C)C SPXAJWHTGUYHOS-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
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- 239000012043 crude product Substances 0.000 description 6
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- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000002924 anti-infective effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 206010040070 Septic Shock Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
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- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 238000000527 sonication Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- LXJOYRVJPWDJBZ-UHFFFAOYSA-N (2-acetamido-3-hydroxyphenyl)arsonic acid Chemical compound OC=1C(=C(C=CC1)[As](O)(O)=O)NC(C)=O LXJOYRVJPWDJBZ-UHFFFAOYSA-N 0.000 description 2
- YEEFLZIZMHPFFY-UHFFFAOYSA-N 1-(2-iodoethyl)-4-phenylmethoxybenzene Chemical compound C1=CC(CCI)=CC=C1OCC1=CC=CC=C1 YEEFLZIZMHPFFY-UHFFFAOYSA-N 0.000 description 2
- JCUJAHLWCDISCC-UHFFFAOYSA-N 2-(4-phenylmethoxyphenyl)ethanol Chemical compound C1=CC(CCO)=CC=C1OCC1=CC=CC=C1 JCUJAHLWCDISCC-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及式(I)化合物:其中R1、R2、R3、R4和R5如说明书中所定义、它们的制备方法、它们的用途和包含它们的药物组合物。
Description
本发明涉及氨基-丙醇衍生物、它们的制备方法、它们的用途以及包含它们的药物组合物。
更具体而言,本发明提供了式I的化合物:
其中:
R1是任选地被OH、C1-2烷氧基或1-6个氟原子取代的C1-6烷基;C2-6链烯基;或C2-6炔基;
R2是R2’或R2”
其中R2’是X1、-O-X1、-CO-X1、-CH(OH)-X1、-C(NOR6)-X1、-S-X1、-SO-X1、-SO2-X1或-N(C1-6烷基)-X1,其中X1是被1-17个氟原子取代的且任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断的C3-8烷基;被C1-3烷基取代的且任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断的戊基;C2-8烷基-C3-6环烷基,其中C2-8烷基部分任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断,且C3-6环烷基和/或C2-8烷基被1-17个氟原子取代;且R6中的每一个独立地是H、C1-4烷基、C2-4链烯基、C2-4炔基或苄基;且
其中R2″是连接在对位上的X-CH2-CH2-R,其中X是O;CH2;或C=O;且R是式(b)的残基:
其中R7-R11中的每一个独立地是H;卤素;CN;CF3;OCF3;OCHF2;C1-6烷基;C1-6烷氧基;C3-6环烷基;C3-6环烷氧基;酰基;或任选地取代的苯基;或R9和R10一起形成3,4-[-O(CH2)rO-],其中r是1或2;或(R7和R8)或(R8和R9)与它们所连接的碳原子一起形成稠和的环或杂环,且剩余的R9-R11或R7和R10和R11分别如以上所定义;或者R是任选地被1-5个如上对R7-R11所定义的取代基取代的α-或β-萘基;是Z-X2,其中Z是CH2、CHF或CF2或CHMe且X2是OH或式(a)的残基:
其中Z1是直连键、CH2、CHF、CF2或O,且R12和R13中的每一个独立地是H或任选地被1、2或3个卤素原子取代的C1-4烷基;且R4和R5中的每一个独立地是H、任选地被1、2或3个卤素原子取代的C1-4烷基,或酰基;
其为游离形式或盐形式。
烷基或烷基部分可以是直链或支链,例如甲基、乙基、丙基、异丙基或丁基。链烯基可以是例如乙烯基。炔基可以是例如丙-2-炔基。环烷基可以是例如C3-6环烷基。
酰基可以是残基W-CO,其中W是C1-6烷基、C3-6环烷基、苯基或苯基C1-4烷基。对于R7、R8、R9、R10或R11,当苯基是取代的时,它可以被1-5个如上对R7-R11所定义的除苯基之外的取代基取代。
由(R7和R8)或(R8和R9)与它们所连接的碳原子一起形成的饱和或不饱和的杂环的例子包括例如包含1或2个选自N、O或S的杂原子的环,例如噻吩基、呋喃基、吡咯基、噁唑基、异噁唑基、咪唑基、噻唑基、异噻唑基、吡唑基、脱氢二氧戊环或脱氢二噁烷。由(R7和R8)或(R8和R9)与它们所连接的碳原子一起形成的环的例子包括例如环戊烯、环己烯。
卤素可以是F、Cl或Br,优选F或Cl。
优选地,R2’中的烷基或烷基部分包含至少2个氟原子,更优选地至少3个、特别是3-8个氟碳原子。氟原子优选置换R2中烷基或烷基部分的末端(即在远离苯基的末端)碳原子上存在的1、2或3个氢原子。末端碳原子意指最后一个和/或倒数第二个和/或倒数第三个等、直至最后8个碳原子。
当R2’中的环烷基部分被F取代时,环烷基部分中存在的一个直至所有氢原子均可以被F取代。
R2’优选在对位上。
优选地R2’是X1、-O-X1、-CO-X1、-CH(OH)-X1或-C(NOR6)-X1,更优选地是X1、-COX1或-O-X1。
当R2’不包含环烷基部分时,它优选为式(c)的残基:
-Y-(CH2)n-(CF2)m-CHpFq (c),
其中:
Y是直连键、O、CO、CHOH或C=NOR6,其中R6如以上所定义;
n是0、1、2、3、4或5;
m是0、1、2、3、4、5或6,条件是n+m的和是3-8;
p和q中的每一个独立地是0、1、2或3;
链(CH2)n-(CF2)m-CHpFq任选地被一个碳-碳双键或三键、一个CO或一个或两个氧原子中断。
更优选地,R2’具有下述含义之一:
-Y-CnF2n+1,其中n=3-8且Y是CH2、O或C=O;
-Y-CH2CnF2n+1,其中n=1-7且Y是CH2、O或C=O;
-Y-CH2CH2CnF2n+1,其中n=1-6且Y是CH2、O或C=O;
-Y-CH2CH2CH2CnF2n+1,其中n=1-5且Y是CH2、O或C=O;
-Y-(CH2)nF,其中n=1-7且Y是CH2、O或C=O;
-Y-(CH2)nCF3,其中n=1-6且Y是CH2、O或C=O;
-Y-(CH2)nCF2CH3,其中n=1-4且Y是CH2、O或C=O;
-Y-(CH2)n(CF2)mCHF2,其中n=0-3、m=1-6、n+m=3-7且Y是CH2、O或C=O;或
-Y-(CH2)nC(O)CF3,其中n=1-5且Y是CH2、O或C=O。
R2’的进一步优选的含义是例如:
其中n和m具有以上给出的含义之一,n+m的和是3-8,且星号*意指与苯环直接相连或通过O、CO、CHOH、C(NOR6)、S、SO、SO2或N(C1-6烷基)与苯环相连。优选地,R2’是通过O与苯环相连。
R2’的优选含义的进一步的例子是例如:
其中星号*如以上所定义。
最优选地,R2’是-O(CH2)3CF2CF3、-O(CH2)4CF2CF3、-O(CH2)2CF2CF3、-(CH2)4C2F5、-(CH2)5C2F5、-(CH2)3C2F5、-C(O)(CH2)3CF2CF3、-C(O)(CH2)4CF2CF3或-C(O)(CH2)2CF2CF3,优选在对位上。
优选地,R2”是连接在对位上的X-CH2-CH2-R,其中R是任选地被1-5个如对R7-R11所定义的取代基取代的β-萘基,或其中R是式(b)的残基,
其中:
-R7-R11中的每一个独立地是Cl、Br、F、CF3、OCF3、C1-6烷基、C1-6烷氧基或任选地取代的苯基,和/或
-残基R7-R11中的一个或两个不是H,且其它残基R7-R11是H。
优选地Z1是O。
优选地Z是CH2。
优选地X2是OH或OPO3H2。
优选地R1是甲基;乙基或被OH取代的C1-5烷基。
式I化合物可以以游离形式或以盐形式存在,例如与例如无机酸的加成盐,如盐酸盐、氢溴酸盐或硫酸盐,与有机酸的盐,如醋酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐或苯磺酸盐;当R7或R8是氢时,磷酸基团也可以以盐形式例如铵盐或与金属如钠、钾、钙、锌或镁的盐或它们的混合物形式存在。水合物或溶剂合物形式的式I化合物和它们的盐也是本发明的一部分。
当式I化合物在分子中具有不对称中心时,可获得各种旋光异构体。本发明也包括对映体、外消旋物、非对映异构体和它们的混合物。例如,带有R1、R3和NR4R5的中心碳原子可以具有R或S构型。具有以下3-维构型的化合物一般是优选的:
此外,当式I化合物包括几何异构体时,本发明包括顺式-化合物、反式-化合物和它们的混合物。关于具有如上提及的不对称碳原子或不饱和键的起始原料例如如下所述的式II、III或IV化合物,应用类似考虑。
本发明还包括制备式I化合物的方法,该方法包括:
a)对于其中R3是Z-X2、X2是OH的式I化合物,除去式II化合物中存在的保护基:
其中R1、R2和R5如以上所定义,R’3是Z-X2,其中X2是OH且R’4是氨基保护基,或者
b)对于其中R3是Z-X2、X2是式(a)的残基的式I化合物,除去式III化合物中存在的保护基:
其中R1、R2、R’4和R5如以上所定义,且R”3是Z-X2,其中Z如以上所定义且X2是式(a’)的残基:
其中Z1如以上所定义,且R’12或R’13中的每一个是可水解的或可氢解的基团或者R’12和R’13一起形成任选地稠和至环(例如苯环)上的二价桥连残基,
并且,如果需要,将获得的游离形式的式I化合物转化成所需的盐形式,或者反之亦然。
方法步骤a)可以用本领域已知的方法进行。氨基保护基的除去可以方便地用本领域已知的方法来进行,例如可通过水解、例如在酸性介质中、例如用盐酸水解来进行。氨基保护基的例子是例如″Protective Groups inOrganic Synthesis″T.W. Greene,J.Wiley & Sons NY,第2版,第7章,1991和其中的参考文献中所公开的那些,例如苄基、对甲氧基苄基、甲氧基甲基、四氢吡喃基、三烷基甲硅烷基、酰基、叔丁氧基羰基、苄氧基羰基、9-芴基甲氧基羰基、三氟乙酰基等。
在式(a’)的残基中,R’7和R’8中的每一个可以具有含义例如苯基或苄基或一起形成环体系如1,5-二氢-2,4,3-苯并二氧杂磷杂环庚三烯(benzodioxaphosphepin)中的环体系。
方法步骤(b)可以用本领域已知的方法进行,当R’7和R’8各自是可水解的基团时,例如可通过水解、例如在碱性介质中、例如用氢氧化物如氢氧化钡水解来进行。它也可以通过氢解、例如在催化剂如Pd/C存在下氢解、然后水解、例如在酸性介质如HCl中水解或通过酸处理、例如用HCl处理来进行,例如如果R12和R13均是叔丁基时。用作起始原料的式II和III的化合物和它们的盐也是新的并且构成本发明的一部分。
本发明还包括制备式II化合物的方法,其中R2是为-O-X1的R2’或者R2是为-O-CH2-CH2-R的R2”,该方法包括:
将式IV化合物烷基化:
其中R1、R3’、R4’和R5如以上所定义,
以引入所需的残基X1或-CH2-CH2-R。
式IV化合物的烷基化可以用本领域已知的方法进行,例如通过亲核取代,例如通过与烷基化剂X1-X3或R-CH2-CH2-X3反应,其中R如以上所定义且X3是甲磺酸基、甲苯磺酸基、三氟甲磺酸基、硝基苯磺酸基或卤素,例如氯化物、溴化物或碘化物。烷基化也可以按照Mitsunobu方案(例如在Hughes,Organic Preparations and Procedures International 28,127-64,1996或D.L.Hughes,Org.React.42,335,1992中公开的方案)在溶液中或在固相载体合成物上进行,例如通过将式IV化合物附着在树脂上来进行。或者,可以使用结合在树脂例如聚苯乙烯上的三苯基膦或例如偶氮甲酸二乙酯。
其中R’12和R’13形成环体系的式III化合物可以如下制备:
其中X1、R1、R’4和R5如以上所定义。
对起始原料的制备未具体进行描述,这些化合物是已知的或可以用本领域已知的方法或如下文实施例中所公开的那样类似地进行制备。
以下实施例用于举例说明本发明。熔点是未校正的。
RT =室温
DCM =二氯甲烷
Bn =苄基
THF =四氢呋喃
DMF =二甲基甲酰胺
DMSO =二甲基亚砜
MTBE =甲基叔丁基醚
AcOEt=乙酸乙酯
DEAD =偶氮二甲酸二乙酯
DBAD =叠氮二甲酸二叔丁酯
Ts =甲苯磺酸基
Ms =甲磺酸基
流程图1:氨基丙醇的制备
流程图2:氨基丙醇磷酸酯的制备
流程图3:氨基丙烷-1,3-二醇和相应磷酸酯的制备
R′=-X1或-CH2-CH2-R,其中X1和R如以上所定义
实施例1:(R)-2-氨基-2-甲基-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-1-醇盐酸盐
向{(R)-1-羟基-2-甲基-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基}氨基甲酸叔丁酯(25mg,0.055mmol)中加入4M的在干燥二噁烷中的HCl(1ml)。将该澄清的无色溶液在防潮条件下搅拌2小时。然后,将该溶液蒸发至干并将部分结晶性残余物用干燥乙醚(5ml)吸收。声波振荡10分钟,得到无色晶体沉淀。将产物滤出、用冷乙醚洗涤(3×1ml)并真空干燥,得到非吸湿性无色微晶粉末形式的标题化合物:mp.186-189℃。MS(ESI+):356(MH+),1H-NMR(400MHz,CD3OD):δ1.35(s,3H,2-Me),1.91(cm,2H,3-CH2),2.06(cm,2H,2′-CH2),2.35(cm,2H,3′-CH2),2.63(cm,2H,4-ArCH2),3.55(d,1H,2J=12.1,1-CHα),3.63(d,1H,,2J=11.9,1-CHβ),4.06(t,3H,3J=7.1,1′-OCH2),6.88(′d′,2H,J=11.0,ArH),7.18(′d′,J=10.8Hz,ArH)。
所需的起始原料可以用以下方法制备:
a)
{(R)-1-羟基-2-甲基-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基}-氨基甲 酸叔丁酯
一般操作方法A1(使用聚苯乙烯-三苯基膦的Mitsunobu反应;流程图1)
向[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酸叔丁酯(100mg,0.34mmol)和4,4,5,5,5-五氟戊-1-醇(50μl,0.37mmol,1.1当量)在干燥THF(5ml)中的溶液中加入三苯基膦-聚苯乙烯1.10mmol g-1(370mg,0.41mmol,1.2当量)。将该混悬液振摇15分钟以使树脂膨胀。然后,一次性注射加入偶氮二甲酸二乙酯(67μl,0.41mmol,1.2当量)。将获得的混悬液在氩气、RT下振摇过夜。然后,滤出聚合物并用THF(3×2ml)洗涤。蒸发合并的滤液,得到黄色半结晶性残余物。通过快速色谱法(FlashMaster II,MTBE/己烷梯度:在30分钟内0%MTBE->30%MTBE;在10分钟内30%MTBE->60%MTBE)纯化,得到无色晶体:mp.90-92℃,MS(ESI+):456(MH+),400(MH+-tBu),356(MH+-Boc),1H-NMR(400MHz,CDCl3):δ1.16(s,3H,2-Me),1.37(s,9H,tBu),1.79(cm,1H,3-CHα),1.91-2.04(m,3H,3-CHα+2′-CH2),2.12-2.28(m,2H,3′-CH2),2.51(cm,2H,4-CH2Ar),3.58(d,1H,2J=10.9,1-CHα),3.63(d,1H,,2J=11.2,1-CHβ),3.94(t,3H,3J=7.3,1′-ArOCH2),6.75(′d′,2H,J=10.2,ArH),7.05(′d′,J=10.5,ArH)。
一般操作方法A2 (在溶液中的Mitsunobu反应;流程图1)
将[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酸叔丁酯(1.48g,5mmol)、4,4,5,5,5-五氟戊-1-醇(0.74ml,5.5mmol)和三苯基膦(1.39g,5.25mmol)在无水THF(50ml)中的溶液放置在冰浴中。搅拌10分钟后,在15分钟期间内缓慢注射加入重氮二甲酸二乙酯(0.87ml,5.25mmol)。在加入完成后除去冰浴并将现在的淡黄色反应混合物在RT、氩气下搅拌过夜。然后,蒸发溶剂并将残余物用MTBE/己烷重结晶以便除去在反应中形成的大部分肼二甲酸二乙酯和三苯基膦氧化物。将母液蒸发至干。通过快速色谱法(洗脱液:MTBE/己烷1∶2)纯化,得到标题化合物,为无色晶体。
b)
[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酸叔丁酯
标题化合物可根据以下所述的流程图制备。可以使用由L-缬氨酸和丙氨酸A或由D-缬氨酸和甘氨酸B获得的Schoellkopf试剂作为起始原料。
实施例2:(R)-2-氨基-2-甲基-4-[4-(5-氟-戊氧基)-苯基]-丁-1-醇盐酸盐
如实施例1中所述将{(R)-1-羟基-2-甲基-4-[4-(5-氟-戊氧基)-苯基]-丁-2-基氨基甲酸叔丁酯进行去保护,得到标题化合物,为非吸湿性灰白色粉末:mp.143-146℃,MS(ESI+):284(MH+),1H-NMR(400MHz,DMSO-d6):δ1.19(s,3H,2-Me),1.48(cm,2H,3′-CH2),1.62-1.83(m,6H,2′,3-,4′-CH2),2.52(cm,2H,4-CH2),3.39(dd,1H,2J=10.1,3J=5.3 1-CHα),3.47(dd,1H,2J=10.1,3J=5.3,1-CHβ),3.94(t,3H,(t,3H,3J=6.6,1′-OCH2),4.45(dt,2H,2JH,F=47.4,3JH,H=7.1,5′-CH2F,5.51(t,1H,1-OH),6.85(′d′,2H,J=8.9,ArH),7.10(′d′,J=9.5Hz,ArH),7.78(br s,3H,2-NH3 +)。
所需的起始原料可以用以下方法制备:
a)
{(R)-1-羟基-2-甲基-4-[(5-氟-戊氧基)-苯基]-丁-2-基}-氨基甲酸叔丁酯 一般操作方法B1(烷基化反应;流程图1)
向[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酸叔丁酯(200mg,0.68mmol,实施例1b)和1-溴-5-氟戊烷(172mg,1.02mmol,1.5当量)在无水DMF(2.5ml)中的溶液中加入无水碳酸铯(331mg,1.02mmol,1.5当量)。将获得的混悬液在防潮、60℃下搅拌过夜。在冷却至RT后,滤出固体并用DMF(2×1ml)洗涤。将合并的滤液在高真空下蒸发,得到深橙色浆液。通过快速色谱法(FlashMaster II,实施例1a中所述的MTBE/己烷梯度)纯化,得到无色晶体:mp.91-93℃,ESI+MS:m/z=406(MNa+),384(MH+),328(MH+-tBu),1H-NMR(400MHz,CDCl3):δ1.23(s,3H,2-Me),1.46(s,9H,tBu),1.60(cm,2H,3′-CH2),1.74(cm,1H,3-CHα),1.77-1.90(m,4H,2′-&4′-CH2),2.03(cm,1H,3-CHβ),2.48-2.69(m,2H,4-CH2),3.64(br d,1H,2J=11.3,1-CHα),3.72(br d,1H,2J=11.9,1-CHβ),3.96(t,2H,J=7.1,1′-OCH2),4.03(br,1H,OH),4.48(dt,2H,2JH,F=47.8,3JH,H=7.2,5′-CH2F),4.62(br s,1H,NH),6.80(′d′,2H,J=10.1,ArH),7.08(′d′,J=10.3,ArH)。
实施例3-10:如实施例2(方法B1)中所述制备以下实施例。
实施例11-25:如实施例1(方法A1)中所述制备以下实施例。
实施例26:(R)-2-氨基-4-{4-[2-(4-甲氧基-苯基)-乙氧基]-苯基}-2-甲基-丁-1-醇
将(R)-3-{4-[2-(4-甲氧基-苯基)-乙氧基]-苯基}-1-羟甲基-1-甲基-丙基)-氨基甲酸叔丁酯(0.01mol)溶解在二噁烷(25ml)中。加入5N HCl(25ml)后,将混合物在RT下放置6小时。通过冷冻干燥小心地除去溶剂。
MS(ESI+):330(MH+)。
所需的起始原料可以用以下方法制备:
(R)-3-{4-[2-(4-甲氧基-苯基)-乙氧基]-苯基}-1-羟甲基-1-甲基-丙基)-氨基甲 酸叔丁酯,一般操作方法B2
(烷基化反应,流程图1)
向[(R)-1-羟基-4-(4-羟基-苯基)-2-甲基-丁-2-基]-氨基甲酸叔丁酯(0.1mol)和甲磺酸4-甲氧基-苯乙基酯(0.1mol)在乙醇(500ml)中的溶液中加入碳酸钾(0.3mol)。将混悬液在70℃下搅拌16小时并冷却至RT。过滤后,蒸发溶剂并使用硅胶和CH2Cl2/MeOH=20/1通过色谱法纯化残余物粗品,得到白色结晶性固体。
实施例27和28:如实施例20(方法B2)中所述制备以下实施例。
实施例29:1-[4-((R)-3-氨基-4-羟基-3-甲基-丁基)-苯基]-6,6,6-三氟-己-1-酮
分两步实现相应的N-{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-1-甲基-3-[4-(6,6,6-三氟-己酰基)-苯基]-丙基}-乙酰胺的去保护,首先将起始原料(0.1mmol)与氟化四丁铵(0.2mmol)在THF中的溶液在RT下搅拌3小时。用水使反应停止,然后用AcOEt萃取,干燥(MgSO4)有机层并蒸发溶剂。
然后将粗产物溶解在MeOH、水和THF中,并使其与LiOH(0.45mmol)在50℃下反应过夜。用AcOEt萃取,干燥(MgSO4)并蒸发溶剂,然后将产物用MeOH和乙醚结晶。MS(ESI+):332.4(MH+)。
所需的起始原料可以用以下方法制备:
a)
N-{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-1-甲基-3-[4-(6,6,6-三氟-1-羟基 -己基)-苯基]-丙基}-乙酰胺
向N-[(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-3-(4-甲酰基-苯基)-1-甲基-丙基]-乙酰胺(0.1mol)在干燥THF中的溶液中加入5-三氟戊基溴化镁(由相应的溴化物(0.45mmol)和镁转变获得)在THF中的溶液。在RT下搅拌2小时后,用水使反应混合物停止反应并用AcOEt(3×)萃取。用1N HCl、NaHCO3饱和水溶液和水洗涤有机层。干燥(MgSO4)并蒸发溶剂后,使用硅胶和AcOEt/己烷=3/7通过色谱法纯化标题化合物。
b)
N-{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-1-甲基-3-[4-(6,6,6-三氟-己酰 基)-苯基]丙基}-乙酰胺
在-78℃下,向草酰氯(0.15mmol)在CH2Cl2中的溶液中首先加入DMSO(0.2mmol),然后加入N-{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-1-甲基-3-[4-(6,6,6-三氟-1-羟基-己基)-苯基]-丙基}-乙酰胺(0.1mmol)在CH2Cl2中的溶液。在-78℃下搅拌1小时后,加入三乙胺(0.7mmol),并使混合物温热至RT。用水使反应停止,然后用AcOEt萃取。干燥(MgSO4)后,蒸发溶剂。
实施例30-32:如实施例29中所述将以下实施例去保护。
根据实施例29使用合适的格氏试剂制备所需的起始原料。
实施例33:(R)-2-氨基-2-甲基-4-[4-(7,7,7-三氟-庚基)-苯基]-丁-1-醇
如实施例29中所述将相应的N-{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-1-甲基-3-[4-(7,7,7-三氟-庚基)-苯基]-丙基}-乙酰胺进行去保护。MS(ESI+):332.4(MH+)
在步骤a)中,根据实施例29使用合适的格氏试剂制备所需的起始原料。而在步骤b)中,用醋酸酐在吡啶中将相应的醇乙酰化,然后用1巴的氢和10%披钯炭在EtOH中氢解。
实施例34:单-(R)-2-氨基-2-甲基-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基磷酸酯
一般操作方法C1(流程图2)
向{(R)-2-甲基-2-(3-氧代-1,5-二氢-3λ5-苯并[e][1,3,2]二氧杂磷杂环庚三烯-3-基氧基)-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基}-氨基甲酸叔丁酯(32mg,0.05mmol)在甲醇中的溶液中加入Pd/C 10%(50mg)。将该混悬液用氮净化,然后在大气压力、温和搅拌下氢化2小时。此后,滤除催化剂并将滤液蒸发至干,得到无色树脂。将残余物重新溶解在二噁烷(0.75ml)中并加入4M的在二噁烷中的HCl(0.25ml)。搅拌2小时后,蒸发略微混浊的溶液。将无色半固体残余物与干燥乙醚(5ml)一起进行声波振荡,得到无色沉淀。将固体滤出、用干燥乙醚洗涤并真空干燥,得到无色粉末:mp.229-231℃,MS(ESI+):434(M-H-),1H-NMR(400MHz,CD3OD):δ1.37(s,3H,2-Me),1.88(cm,1H,3-CHα),1.94-2.09(m,3H,3-CHα+2′-CH2),2.32(cm,2H,3’-CH2),2.64(cm,2H,4-CH2Ar),3.90(dd,1H,2J=10.6,3JH,P=4.5,1-CHα),4.00(dd,1H,1-CHβ),4.03(t,3H,3J=6.6Hz,1’-ArOCH2),6.88(′d′,2H,J=10.1,ArH),7.16(′d′,J=8.1,ArH)。
所需的起始原料可以用以下方法制备:
a)
{(R)-2-甲基-2-(3-氧代-1,5-二氢-3λ5-苯并[e][1,3,2]二氧杂磷杂环庚三烯 -3-基氧基)-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基}-氨基甲酸叔丁酯
向{(R)-1-羟基-2-甲基-4-[4-(4,4,5,5,5-五氟-戊氧基)-苯基]-丁-2-基}-氨基甲酸叔丁酯(40mg,0.088mmol,实施例1a)和四唑(18mg,0.26mmol,3当量,用甲苯重结晶)在干燥THF(1ml)中的溶液中加入3-二乙氨基-1,5-二氢-苯并[e][1,3,2]二氧杂磷杂环庚三烯(32μl,0.13mmol,1.5当量)。将反应混合物在氩气、RT下搅拌3小时。然后,在0℃、剧烈搅拌下注射加入H2O2(30%,90μl,0.88,10当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(1ml)。分离有机层并用乙醚(3×1ml)萃取水相。将合并的有机萃取物用盐水洗涤、用MgSO4干燥并蒸发至干。通过快速色谱法(MTBE/己烷1∶1)纯化粗产物,得到无色晶体:MS(ESI+):655(MNH4 +),638(MH+),538(MH+-Boc)。1H-NMR(400MHz,CHCl3):δ1.36(s,3H,2-Me),1.44(s,9H,tBu),1.80(cm,1H,3-CHα),2.02-2.20(m,3H,3-CHα+2′-CH2),2.27(cm,2H,3′-CH2),2.59(‘t’,2H,J=8.6,4-CH2Ar),4.02(t,3H,3J=5.9,1’-ArOCH2),4.17(dd,1H,2J=9.9,3JH,P=5.4,1-CHα),4.35(dd,1H,1-CHβ),5.17(dd,2H,ArCHαO,2J=13.6,3JH,P=15.3),5.30(ddd,2H,ArCHβO,2J=13.4,3JH,P=16.3,J=4.4),6.82(‘d’,2H,J=8.9,ArH),7.16(‘d’,J=8.7,ArH),7.29-7.35(m,2H,ArH),7.37-7.42(m,2H,ArH)。
实施例35:单-(R)-2-氨基-2-甲基-4-[4-(5-氟-戊氧基)-苯基]-丁-2-基磷酸酯
一般操作方法C2(流程图2)
向{(R)-1-(二-叔丁氧基-磷酰氧基甲基)-3-[4-(5-氟戊氧基)-苯基]-1-甲基-丙基}-氨基甲酸叔丁酯(90mg,0.16mmol)在二噁烷(0.75ml)中的溶液中加入4M的在二噁烷中的HCl(0.25ml)。搅拌2小时后,蒸发混浊的溶液。将无色蜡状残余物与干燥乙醚(5ml)一起进行声波振荡,得到米黄色沉淀。将固体滤出、用干燥乙醚洗涤并真空干燥,得到褐色粉末:mp.237-241℃,MS(ESI+):727(M2H+),364(MH+),1H-NMR(400MHz,CH3OD):δ1.37(s,3H,2-Me),1.60(cm,2H,3’-CH2),1.69-1.93(m,5H,3-CHα&2’-CH2&4’-CH2),2.01(cm,2H,3-CHβ),2.55-2.75(m,2H,4-CH2Ar),3.86(dd,1H,2J=10.3,3JH,P=4.6,1-CHα),3.97(dd,1H,1-CHβ),3.99(t,3H,3J=6.8Hz,1’-ArOCH2),4.46(dt,2H,2JH,F=46.2,3JH,H=6.9,5’-CH2F),6.84(‘d’,2H,J=10.4,ArH),7.16(‘d’,J=8.5,ArH)。
所需的起始原料可以用以下方法制备:
a)
{(R)-1-(二-叔丁氧基-磷酰氧基甲基)-3-[4-(5-氟戊氧基)-苯基]-1-甲基-丙 基}-氨基甲酸叔丁酯
向{(R)-1-羟基-2-甲基-4-[4-(5-氟-戊氧基)-苯基]-丁-2-基}-氨基甲酸叔丁酯(80mg,0.21mmol,实施例2a)和四唑(88mg,1.26mmol,6当量,用甲苯重结晶)在干燥THF(2ml)中的溶液中加入二乙基氨基磷酸二叔丁酯(174μl,0.63mmol,3当量)。将反应混合物在氩气、RT下搅拌2小时。加入三乙胺(320ml,2.3mmol,11当量)后,在0℃、剧烈搅拌下注射加入过氧化氢(30%,213μl,2.1mmol,10当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(1ml)。分离有机层并用乙醚(3×1ml)萃取水相。将合并的有机萃取物用盐水洗涤、用MgSO4干燥并蒸发至干。通过快速色谱法(MTBE/Hx 1∶1)纯化粗产物,得到无色晶体:MS(ESI+):598(MNa+),593(MNH4 +),576(MH+),1H-NMR(400MHz,CDCl3):δ1.37(s,3H,2Me),1.46(s,9H,Boc),1.52(s,18H,tBuO),1.62(cm,2H,3′-CH2),1.70-1.98(m,5H,3-CHα&2′-CH2&4′-CH2),2.08(cm,1H,3-CHβ),2.48(cm,2H,4-CH2Ar),3.88(dd,1H,2J=10.1,3JH,P=5.5,1-CHα),3.96(t,3H,3J=6.5,1′-ArOCH2),4.07(dd,1H,1-CHβ),4.44(dt,2H,2JH,F=44.2,3JH,H=6.7,5′-CH2F),6.82(′d′,2H,J=9.1,ArH),7.10(′d′,J=8.9,ArH)。
实施例36-44:如方法C2中所述制备以下实施例。
实施例45-51:如方法C1中所述制备以下实施例。
*=无色粉末
实施例52:2-氨基-2-{2-[4-(4,4,4-三氟-丁氧基)-苯基]-乙基}-丙烷-1,3-二醇
一般操作方法F(流程图3)
向2-甲基-4-{2-[4-(4,4,4-三氟-丁氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基-甲醇(200mg,0.57mmol)在乙醇(5ml)中的溶液中加入浓盐酸(5ml)。将反应混合物在85℃下搅拌4小时,然后浓缩至干。将残余物重新溶解在AcOEt中并用己烷沉淀。将固体滤出、用干燥乙醚洗涤并在真空下干燥,得到2-氨基-2-{2-[4-(4,4,4-三氟-丁氧基)-苯基]-乙基}-丙烷-1,3-二醇的盐酸盐,为白色粉末。MS(ESI+):322.2(MH+)
所需的起始原料可以用以下方法制备:
a)
2-甲基-4-{2-[4-(4,4,4-三氟-丁氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基-甲 醇
(一般操作方法D,流程图3)
在惰性气氛下,向4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚(500mg,2.12mmol)在干燥DMF(8ml)中的溶液中加入Cs2CO3(901mg,2.76mmol,1.3当量)和4-溴-1,1,1-三氟-丁烷(487.8mg,2.55mmol,1.2当量)。将反应混合物在惰性气氛下于85℃搅拌过夜。然后加入NaHCO3饱和溶液(20ml)和AcOEt(40ml)。分离有机层并用AcOEt(3×40ml)萃取水相。将合并的有机萃取物用盐水和1M HCl洗涤、用MgSO4干燥并蒸发至干。通过快速色谱法(环己烷/AcOEt(9/1)至(1/1)和(0/1))纯化,得到2-甲基-4-{2-[4-(4,4,4-三氟-丁氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基-甲醇,为无色油状物。
b)
4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚
可根据以下所述的流程图制备标题化合物。
向4-(2-羟基-乙基)-苯酚(50g,0.36mol)在乙醇(400ml)中的溶液中加入碳酸钾(75g,0.54mol,1.5当量)和苄基溴(47.2ml,0.39mol,1.1当量),将反应混合物在室温下搅拌过夜。然后经硅藻土过滤反应混合物并在真空下浓缩。用乙醚结晶后分离出2-(4-苄氧基-苯基)-乙醇。
向2-(4-苄氧基-苯基)-乙醇(78.72g,0.34mol)在二氯甲烷(400ml)中的溶液中加入三乙胺(67.3ml,0.44mol,1.4当量),然后在0℃下加入甲磺酰氯(34.8ml,0.44mol,1.3当量)。将反应混合物在0℃下搅拌30分钟,并使其升至室温。用二氯甲烷(2×300ml)萃取反应混合物,然后用盐水(2×300ml)洗涤合并的有机层并在真空下浓缩。向粗产物在AcOEt(600ml)中的溶液中加入碘化钠(67.2g,0.44mol,1.3当量)并将反应混合物在回流下搅拌6小时。过滤后,将有机层用盐水(3×400ml)洗涤、用Na2SO4干燥、过滤并在真空下浓缩。用乙醚结晶后分离出1-苄氧基-4-(2-碘-乙基)-苯。
在0℃、惰性气氛下,向乙酰氨基丙二酸酯(59.4g,0.27mol,2当量)在干燥二甲基甲酰胺(400ml)中的溶液中加入氢化钠(60%在油中)(9.94g,0.49mol,1.8当量),将反应混合物在0℃下搅拌3小时。然后,在0℃下缓慢加入1-苄氧基-4-(2-碘-乙基)-苯(46.8g,0.13mol,1当量)在干燥DMF(250ml)中的溶液,并将反应混合物在室温下搅拌过夜。用数滴甲醇使反应混合物停止反应并在真空下浓缩几乎至干,然后用AcOEt萃取,之后用1N HCl(2×500ml)、NaHCO3饱和溶液(2×500ml)和盐水(2×500ml)洗涤,用Na2SO4干燥,过滤并在真空下浓缩。用乙醚多次结晶后分离出2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙酯。
向2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙酯(44.1g,0.1mol)在乙醇水(2/1)(285ml/285ml)中的溶液中加入CaCl2(28.5g,0.26mol,2.5当量),并分份加入NaBH4(19.4g,0.52mol,5.0当量),将反应混合物在室温下搅拌过夜。在0℃下,通过滴加甲醇(10ml)小心地使反应混合物停止反应并在真空下浓缩几乎至干。用AcOEt(4×500ml)萃取混合物粗品,然后用1N HCl(2×300ml)、NaHCO3饱和溶液(2×300ml)和盐水(2×300ml)洗涤。然后,将合并的有机层用Na2SO4干燥、过滤并在真空下浓缩。N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺不经进一步纯化直接使用。
在室温下,向N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺粗品在四氢呋喃、甲醇、水(1/2/2)(450ml/900ml/900ml)混合物中的溶液中加入氢氧化锂(32.7g,1.36mol,8.0当量)。将反应混合物在55℃下搅拌5小时,然后用AcOEt(500ml)萃取并用盐水(2×300ml)洗涤,然后将合并的有机层用Na2SO4干燥、过滤并在真空下浓缩。用AcOEt结晶后分离出2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇。
向2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇(31.1g,0.10mol)在乙腈(2.38L)中的溶液中加入原乙酸三乙酯(17.1ml,0.12mol,1.2当量)和醋酸(5.48ml,0.11mol,1.1当量),然后将反应混合物在80℃下搅拌5小时。然后,在真空下浓缩反应混合物,用AcOEt结晶后分离出{4-[2-(4-苄氧基-苯基)-乙基]-2-甲基-4,5-二氢-噁唑-4-基}-甲醇。
向{4-[2-(4-苄氧基-苯基)-乙基]-2-甲基-4,5-二氢-噁唑-4-基}-甲醇(26.1g,0.08mol)在甲醇(800ml)中的溶液中加入披钯炭(2.6g,10%重量比),并将反应混合物在氢气氛、室温下搅拌5小时。然后,经硅藻土过滤反应混合物并在真空下浓缩。用AcOEt和己烷结晶后分离出4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚。
实施例53-59:如方法D和F中所述制备以下实施例。
实施例60-62:
如方法D中所述用甲磺酸酯代替溴化物作为烷基化剂和如方法F中所述制备以下实施例。
实施例63:2-氨基-2-(2-{4-[2-(4-甲氧基-3-氟-苯基)-乙氧基]-苯基}-乙基)-丙烷-1,3-二醇
一般操作方法E(流程图3)
在惰性气氛下,向4-[2-(4-羟甲基-2-甲基-4,5-二氢-噁唑-4-基)-乙基]-苯酚(300mg,1.27mmol)在干燥THF(6ml)中的溶液中加入聚苯乙烯负载的三苯基膦(负载3mmol.g-1,1.27g,3.81mmol,3当量)、2-(3-氟-4-甲氧基-苯基)-乙醇(647.7mg,3.81mmol,3当量)和DBAD(877.3mg,3.81mmol,3当量)。将反应混合物在惰性气氛、室温下搅拌过夜。然后经玻璃料过滤聚苯乙烯负载的三苯基膦,并用乙酸乙酯和甲醇洗涤。然后,将反应混合物浓缩至干,之后加入4M的在二噁烷中的HCl(3ml),将反应在室温下搅拌3小时。通过加入NaHCO3饱和溶液(10ml)和乙酸乙酯(40ml)使反应混合物停止反应。分离有机层并用乙酸乙酯(3×40ml)萃取水相。将合并的有机萃取物用盐水洗涤、用MgSO4干燥并蒸发至干。用Flashmaster(环己烷/乙酸乙酯(1/9),乙酸乙酯和乙酸乙酯/甲醇(98/2))纯化,得到[4-(2-{4-[2-(3-氟-4-甲氧基-苯基)-乙氧基]-苯基}-乙基)-2-甲基-4,5-二氢-噁唑-4-基]-甲醇,为无色油状物。MS(ESI+):364.2(MH+)
实施例64-78:如方法E和F中所述制备以下实施例。
实施例79:单-{2-氨基-2-羟甲基-4-[4-(6,6,6-三氟-己氧基)-苯基]-丁基}磷酸酯
一般操作方法G(流程图3)
向(2-甲基-4-{2-[4-(6,6,6-三氟-己氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基)-甲醇(300mg,0.80mmol)和四唑(337.4mg,4.82mmol,6当量,用甲苯重结晶)在干燥THF(6ml)中的溶液中加入3-二乙氨基-1,5-二氢-苯并[e]_[1,3,2]二氧杂磷杂环庚三烯(433.5μl,1.56mmol,1.95当量)。将反应混合物在氩气、室温下搅拌3小时。然后,在0℃、剧烈搅拌下注射加入H2O2(30%,75μl,4.0mmol,5当量)。将反应混合物再搅拌30分钟,然后加入饱和硫代硫酸钠溶液(1ml)。分离有机层并用乙醚(3×20ml)萃取水相。将合并的有机萃取物用盐水洗涤、用MgSO4干燥并蒸发至干。通过快速色谱法(AcOEt)纯化,得到磷酸二叔丁酯2-甲基-4-{2-[4-(6,6,6-三氟-己氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲酯,为无色油状物。向磷酸二叔丁酯2-甲基-4-{2-[4-(6,6,6-三氟-己氧基)-苯基]-乙基}-4,5-二氢-噁唑-4-基甲酯(33mg,0.050mmol)在乙醇(2ml)中的溶液中加入浓盐酸(2ml)。将反应混合物在85℃下搅拌2小时,然后浓缩至干。将残余物重新溶解在AcOEt中并用己烷沉淀。滤出固体,用干燥乙醚洗涤并在真空下干燥,得到磷酸单-{2-氨基-2-羟甲基-4-[4-(6,6,6-三氟-己氧基)-苯基]-丁基}酯,为无色粉末。MS(ESI-):428.2(MH-)
实施例80-95:如方法G中所述制备以下实施例。
游离形式或可药用盐形式的式I化合物具有有价值的药理学性质,例如淋巴细胞再循环调节性质,例如如在体外和体内试验中所示,因此适合用于治疗。
A.体外
式I化合物对各个人S1P受体具有结合亲和力,如在以下试验中所测定的那样:
鞘氨醇-1-磷酸(S1P)受体概况
在人S1P受体(S1P1)、(S1P3)、(S1P2)、(S1P4)和(S1P5)上试验各化合物的激动剂活性。通过定量与膜蛋白结合的化合物诱导的GTP[γ-35S]来测定功能性受体的活化,所述的膜蛋白由稳定表达合适的人S1P受体的转染CHO或RH7777细胞制备得到。所用的测定技术是SPA(闪烁亲近测定法)。简言之,将溶解在DMSO中的化合物连续地进行稀释,并于50mM Hepes、100mM NaCl、10mM MgCl2、10μM GDP、0.1%无脂肪BSA和0.2nM GTP[γ-35S](1200Ci/mmol)存在下加入SPA-珠(Amersham-Pharmacia)固定的表达膜蛋白的S1P受体中(10-20μg/孔)。在96孔微量滴定板中于RT下孵育120分钟后,通过离心步骤分离未结合的GTP[γ-35S]。用TOPcount读板仪(Packard)定量膜结合GTP[γ-35S]引发的SPA珠的发光。用标准曲线拟合软件计算EC50。例如,获得了以下结果:
实施例 | S1P1EC50[nM] | S1P2EC50[nM] | S1P3EC50[nM] | S1P4EC50[nM] | S1P5EC50[nM] |
34 | 16.1 Agon | >10000 - | >10000 - | 15.3 Agon | 0.9 Agon |
42 | 4.1 Agon | >10000 - | >10000 - | 1.8 Agon | 21.7 Agon |
49 | 0.2 Agon | >10000 - | 47 Agon | >10000 - | 10 Agon |
50 | 0.3 Agon | >10000 - | 196 Agon | >10000 - | 1.5 Agon |
87 | 23.6 Agon | >10000 - | >10000 - | >10000 - | 22 Agon |
88 | 2.5 Agon | >10000 - | 97.6 Agon | >10000 - | 40 Agon |
94 | 12.2 Agon | >10000 - | >10000 - | n.d. - | 4.9 Agon |
Agon=激动剂
B.体内:血淋巴细胞减少
将式I化合物或赋形剂通过管饲法口服施用于大鼠。在第1天获取尾部血用于血液监测以得到基线个体值,并在施用后2、6、24、48和72小时获取尾部血用于血液监测。在本测定中,当以0.03-3mg/kg的剂量施用时,式I化合物减少外周血淋巴细胞。
例如,获得了以下结果:外周血淋巴细胞减少超过50%
实施例1:0.2mg/kg口服6小时后,0.1mg/kg口服24小时后
实施例6:0.06mg/kg口服6小时后,0.05mg/kg口服24小时后
实施例14:0.03mg/kg口服6小时后,0.04mg/kg口服24小时后
实施例27:0.1mg/kg口服6小时后,0.03mg/kg口服24小时后
实施例31:0.05mg/kg口服6小时后,0.1mg/kg口服48小时后
实施例72:0.07mg/kg口服6小时后,0.03mg/kg口服48小时后
因此,式I化合物可用于治疗和/或预防由淋巴细胞相互作用介导的疾病或病症,例如在移植中,如急性或慢性细胞、组织或器官同种异体移植物或异种移植物排斥或移植物功能延迟恢复(delayed graft function)、移植物抗宿主病、自身免疫性疾病,例如类风湿性关节炎、系统性红斑狼疮、桥本甲状腺炎、多发性硬化、重症肌无力、I型糖尿病或II型糖尿病和与之相关的病症、脉管炎、恶性贫血、干燥综合征、眼色素层炎、银屑病、格雷夫斯眼病(Graves ophthalmopathy)、斑秃等、过敏性疾病例如过敏性哮喘、特应性皮炎、过敏性鼻炎/结膜炎、过敏性接触性皮炎、任选地具有潜在异常反应的炎性疾病,例如炎症性肠病、局限性回肠炎或溃疡性结肠炎、内源性哮喘、炎性肺损伤、炎性肝损伤、炎性肾小球损伤、动脉粥样硬化、骨关节炎、刺激性接触性皮炎和其它的湿疹性皮炎、脂溢性皮炎、免疫学介导的病症的皮肤表现、炎性眼病、角膜结膜炎、心肌炎或肝炎、局部缺血/再灌注损伤,例如心肌梗死、中风、肠缺血、肾衰竭或出血性休克、外伤性休克、癌,例如乳腺癌、T细胞淋巴瘤或T细胞白血病、感染性疾病,例如中毒性休克(例如超抗原诱导的中毒性休克)、败血症性休克、成人型呼吸窘迫综合征或病毒感染,例如AIDS、病毒性肝炎、慢性细菌感染或老年性痴呆。细胞、组织或固体器官移植物的例子包括例如胰岛、干细胞、骨髓、角膜组织、神经元组织、心、肺、联合心-肺、肾、肝、肠、胰腺、气管或食管。对于上述应用,所需的剂量当然根据施用方式、所治疗的具体病症和所需的效果而变化。
通常,表明在约0.03-2.5mg/kg体重的日剂量下可全身性地获得令人满意的结果。在较大的哺乳动物例如人中,适用的日剂量为约0.5mg至约100mg,可方便地例如以每天不超过4次的分剂量或以延迟形式施用。用于口服施用的合适的单元剂型包含约0.1-50mg活性成分。
式I化合物可以通过任何常规途径施用,特别是经肠施用例如口服、例如以片剂或胶囊剂形式口服施用,或经胃肠外施用例如以注射用溶液剂或混悬剂形式经胃肠外施用,局部施用例如以洗剂、凝胶剂、软膏剂或乳膏剂形式或以鼻用或栓剂形式局部施用。包含游离形式或可药用盐形式的式I化合物和至少一种可药用载体或稀释剂的药物组合物可以以常规方式通过与可药用载体或稀释剂混合来制备。
式I化合物可以以游离形式或可药用盐形式施用,例如以上所述的可药用盐。这些盐可以以常规方式制备,并且具有与游离化合物相同等级的活性。
根据上述内容,本发明还提供了:
1.1 在需要所述治疗的个体中预防或治疗由淋巴细胞介导的病症或疾病、例如以上所述的相应病症或疾病的方法,该方法包括对所述个体施用有效量的式I化合物或其可药用盐;
1.2 在需要所述治疗的个体中预防或治疗急性或慢性移植物排斥或T细胞介导的炎性或自身免疫性疾病、例如以上所述的相应疾病的方法,该方法包括对所述个体施用有效量的式I化合物或其可药用盐;
2.用作药物、例如在1.1或1.2项下所述的任何方法中用作药物的游离形式或可药用盐形式的式I化合物。
3.包含游离形式或可药用盐形式的式I化合物和适用的可药用稀释剂或载体的药物组合物,例如在以上1.1或1.2的任何方法中使用的药物组合物。
4.用于制备在以上1.1或1.2的任何方法中使用的药物组合物的式I化合物或其可药用盐。
式I化合物可以作为单独的活性成分施用,或与例如作为辅剂的其它药物例如免疫抑制剂或免疫调节剂或其它抗炎剂、例如用于治疗或预防同种异体移植物或异种移植物急性或慢性排斥或炎性或自身免疫性病症的上述药物或化疗剂例如恶性细胞抗增殖剂联合施用。例如,式I化合物可以与以下物质组合使用:钙调磷酸酶抑制剂,例如环孢菌素A或FK 506;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、CCI779、ABT578或AP23573;具有免疫抑制性质的子囊霉素,例如ABT-281、ASM981等;皮质类固醇;环磷酰胺;硫唑嘌呤;甲氨蝶呤;来氟洛米;咪唑立宾;霉酚酸;霉酚酸酯;15-去氧斯潘格宁或它们的免疫抑制同系物、类似物或衍生物;免疫抑制单克隆抗体,例如抗白细胞受体例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、CD80、CD86或它们的配体的单克隆抗体;其它免疫调节化合物,例如具有至少一部分CTLA4或其突变体的胞外结构域、例如具有至少与非-CTLA4蛋白序列结合的CTLA4或其突变体、例如CTLA4Ig(例如称为ATCC 68629)或其突变体、例如LEA29Y的胞外部分的重组结合分子;粘附分子抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂;或化疗剂,例如紫杉醇、吉西他滨、顺铂、阿霉素或5-氟尿嘧啶;或抗感染剂。
如果式I化合物与其它免疫抑制疗法/免疫调节疗法、抗炎疗法、化疗或抗感染疗法联合施用,则共同施用的免疫抑制化合物、免疫调节化合物、抗炎化合物、化疗化合物或抗感染化合物的剂量当然将根据所用的联用药物的类型(例如它是类固醇还是钙调磷酸酶抑制剂)、所用的具体药物、所治疗的状况等而变化。根据上述内容,另一方面,本发明还提供了:
5.以上所定义的方法,该方法包括共同施用、例如同时或相继施用治疗有效、非毒性量的式I化合物和至少一种第二种药物物质,例如免疫抑制药、免疫调节药、抗炎药或化疗药,例如以上所述的那些。
6.药物组合,例如成套药盒,其包含a)第一种药物,其是此处所公开的游离形式或可药用盐形式的式I化合物,和b)至少一种联用药物,例如免疫抑制剂、免疫调节剂、抗炎剂、化疗剂或抗感染剂。该成套药盒可以包含关于其施用的说明书。
此处所用的术语“共同施用”或“组合施用”或类似用语意指包括对单个患者施用所选择的治疗剂,并且旨在包括其中各药物不必须通过相同施用途径或在相同时间施用的治疗方案。
此处所用的术语“药物组合”意指将一种以上的活性成分混合或组合所得到的产品,并且包括活性成分的固体组合和非固定组合。术语“固定组合”意指活性成分、例如式I化合物和联用药物以单一实体或剂型形式被同时施用于患者。术语“非固定组合”意指活性成分、例如式I化合物和联用药物作为单独的实体被同时、并行或无具体时间限制地相继施用于患者,其中所述的施用在患者体内提供2种化合物的治疗有效水平。后者也应用于组合疗法,例如施用3种或更多种活性成分。
Claims (10)
1.式I的化合物:
其中:
R1是任选地被OH、C1-2烷氧基或1-6个氟原子取代的C1-6烷基;C2-6链烯基;或C2-6炔基;
R2是R2’或R2”,
其中R2’是X1、-O-X1、-CO-X1、-CH(OH)-X1、-C(NOR6)-X1、-S-X1、-SO-X1、-SO2-X1或-N(C1-6烷基)-X1,其中X1是被1-17个氟原子取代的且任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断的C3-8烷基;被C1-3烷基取代的且任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断的戊基;C2-8烷基-C3-6环烷基,其中C2-8烷基部分任选地在碳链中被一个或多个O、C=O、CH-OH或C=NOR6和/或一个碳-碳双键或三键中断,且C3-6环烷基和/或C2-8烷基被1-17个氟原子取代;且R6中的每一个独立地是H、C1-4烷基、C2-4链烯基、C2-4炔基或苄基;且
其中R2″是连接在对位上的X-CH2-CH2-R,其中X是O;CH2;或C=O;且R是式(b)的残基:
其中R7-R11中的每一个独立地是H;Cl;Br;F;CN;CF3;OCF3;OCHF2;C1-6烷基;C1-6烷氧基;C3-6环烷基;C3-6环烷氧基;酰基;或任选地取代的苯基;或R9和R10一起形成3,4-[-O(CH2)rO-],其中r是1或2;或(R7和R8)或(R8和R9)与它们所连接的碳原子一起形成稠和的环或杂环,且剩余的R9-R11或R7和R10和R11分别如以上所定义;或者R是任选地被1-5个如上对R7-R11所定义的取代基取代的α-或β-萘基;
R3是Z-X2,其中Z是CH2、CHF或CF2或CHMe且X2是OH或式(a)的残基:
其中Z1是直连键、CH2、CHF、CF2或O,且R12和R13中的每一个独立地是H或任选地被1、2或3个卤素原子取代的C1-4烷基;且
R4和R5中的每一个独立地是H、任选地被1、2或3个卤素原子取代的C1-4烷基,或酰基;
其为游离形式或盐形式。
2.权利要求1的化合物,其中R2是为X1、-O-X1、-CO-X1、-CH(OH)-X1或-C(NOR6)-X1的R2′。
3.权利要求2的化合物,其中R2′是式(c)的残基:
-Y-(CH2)n-(CF2)m-CHpFq (c),
其中:
Y是直连键、O、CO、CHOH或C=NOR6,其中R6如以上所定义;
n是0、1、2、3、4或5;
m是0、1、2、3、4、5或6,条件是n+m的和是3-8;
p和q中的每一个独立地是0、1、2或3;
链(CH2)n-(CF2)m-CHpFq任选地被一个碳-碳双键或三键、一个CO或一个或两个氧原子中断。
4.权利要求2或3的化合物,其中R2′选自如下组成的组:
-Y-CnF2n+1,其中n=3-8且Y是CH2、O或C=O;
-Y-CH2CnF2n+1,其中n=1-7且Y是CH2、O或C=O;
-Y-CH2CH2CnF2n+1,其中n=1-6且Y是CH2、O或C=O;
-Y-CH2CH2CH2CnF2n+1,其中n=1-5且Y是CH2、O或C=O;
-Y-(CH2)nF,其中n=1-7且Y是CH2、O或C=O;
-Y-(CH2)nCF3,其中n=1-6且Y是CH2、O或C=O;
-Y-(CH2)nCF2CH3,其中n=1-4且Y是CH2、O或C=O;
-Y-(CH2)n(CF2)mCHF2,其中n=0-3、m=1-6、n+m=3-7且Y是CH2、O或C=O;和
-Y-(CH2)nC(O)CF3,其中n=1-5且Y是CH2、O或C=O。
5.权利要求1的化合物,其中R2是R2”。
6.权利要求5的化合物,其中R是任选地被1至5个取代基取代的β-萘基或者R是式(b)的残基,其中残基R7-R11中的一个或两个独立地是Cl、Br、F、CF3、OCF3、C1-6烷基、C1-6烷氧基或任选地取代的苯基,且其它残基R7-R11是H。
7.用作药物和用于制备药物的权利要求1至6中任一项的化合物或其可药用盐。
8.包含权利要求1至6中任一项的化合物或其可药用盐和适用的可药用稀释剂或载体的药物组合物。
9.包含游离形式或可药用盐形式的权利要求1至6中任一项的化合物以及至少一种联用药物的药物组合物。
10.在个体中用于预防或治疗由淋巴细胞介导的病症或疾病和用于预防或治疗急性或慢性移植物排斥或T-细胞介导的炎性或自身免疫性疾病的方法,该方法包括对需要其的个体施用有效量的权利要求1至6中任一项的化合物或其可药用盐。
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ES2126658T3 (es) | 1992-10-21 | 1999-04-01 | Yoshitomi Pharmaceutical | Compuesto de 2-amino-1,3-propanodiol e inmunosupresor. |
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CN1137086C (zh) | 1997-04-04 | 2004-02-04 | 三菱制药株式会社 | 2-氨基丙烷-1,3-二醇化合物、其作为医药的用途及其合成中间体 |
JP2004507552A (ja) | 2000-08-31 | 2004-03-11 | メルク エンド カムパニー インコーポレーテッド | 免疫調節剤としてのリン酸誘導体 |
KR20030093279A (ko) | 2001-03-26 | 2003-12-06 | 노파르티스 아게 | 2-아미노-프로판올 유도체 |
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2003
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- 2003-09-12 JP JP2004535500A patent/JP4166218B2/ja not_active Expired - Fee Related
- 2003-09-12 CA CA002497067A patent/CA2497067A1/en not_active Abandoned
- 2003-09-12 US US10/526,760 patent/US7612238B2/en not_active Expired - Fee Related
- 2003-09-12 CN CNB038215780A patent/CN100516024C/zh not_active Expired - Fee Related
- 2003-09-12 EP EP03757830A patent/EP1539674A1/en not_active Withdrawn
- 2003-09-12 WO PCT/EP2003/010175 patent/WO2004024673A1/en active Application Filing
- 2003-09-12 AU AU2003273865A patent/AU2003273865A1/en not_active Abandoned
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101768086B (zh) * | 2008-12-29 | 2014-03-26 | 北京富龙康泰生物技术有限公司 | 氨基甲醇衍生物及其盐类化合物及其合成方法和其药物用途 |
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EP1539674A1 (en) | 2005-06-15 |
CN100516024C (zh) | 2009-07-22 |
WO2004024673A1 (en) | 2004-03-25 |
US20060166940A1 (en) | 2006-07-27 |
JP2005538169A (ja) | 2005-12-15 |
CA2497067A1 (en) | 2004-03-25 |
US7612238B2 (en) | 2009-11-03 |
JP2009001567A (ja) | 2009-01-08 |
AU2003273865A1 (en) | 2004-04-30 |
JP4166218B2 (ja) | 2008-10-15 |
BR0314113A (pt) | 2005-07-12 |
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