CN1270166A - 三环取代异羟肟酸衍生物 - Google Patents
三环取代异羟肟酸衍生物 Download PDFInfo
- Publication number
- CN1270166A CN1270166A CN00101976A CN00101976A CN1270166A CN 1270166 A CN1270166 A CN 1270166A CN 00101976 A CN00101976 A CN 00101976A CN 00101976 A CN00101976 A CN 00101976A CN 1270166 A CN1270166 A CN 1270166A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- dioxo
- trimethylammonium
- imidazolidyl
- propionyl
- 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
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- 239000002253 acid Substances 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- -1 amino, carboxyl Chemical group 0.000 claims description 50
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
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- 239000001301 oxygen Substances 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000005907 ketalization reaction Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
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- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
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- 239000012312 sodium hydride Substances 0.000 description 4
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- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- ZNFNDZCXTPWRLQ-UHFFFAOYSA-N butane-1,1,1-tricarboxylic acid Chemical compound CCCC(C(O)=O)(C(O)=O)C(O)=O ZNFNDZCXTPWRLQ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- SSUCKKNRCOFUPT-UHFFFAOYSA-N o-[tert-butyl(dimethyl)silyl]hydroxylamine Chemical compound CC(C)(C)[Si](C)(C)ON SSUCKKNRCOFUPT-UHFFFAOYSA-N 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108010029690 procollagenase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及通式(Ⅱ)化合物及通式(Ⅳ)化合物,其中各式中R1、R2、R3、m和n的意义见说明书中所述。
Description
本发明是申请号为95104555.5、申请日为1995年4月24日、发明名称为“三环取代异羟肟酸衍生物”的发明专利申请的分案申请。
本发明涉及异羟肟酸衍生物。
R2代表一个通过N原子连接的5至8元饱和的单环或桥连的N-杂环,当它是单环时,可以任意地含有NR4、O、S、SO或SO2作为环的成员,和/或可任意地在一个或多个碳原子上被以下基团取代:羟基、低级烷基、低级烷氧基、氧基、缩酮化的氧基、氨基、单(低级烷基)氨基、二(低级烷基)氨基、羧基、低级烷氧基羰基、羟甲基、低级烷氧基甲基、氨基甲酰基、单(低级烷基)氨基甲酰基、二(低级烷基)氨基甲酰基或肟基;
R3代表一个5或6元的N-杂环,该(a)通过N原子相连接,(b)可任意地含有N、O和/或S、SO或SO2作为附加的环成员,(c)在与连接原子N相邻的一个或两个C原子上被氧基取代,和(d)可任意地苯并稠合或者任意地在一个或多个其它碳原子上被低级烷基或氧基取代,和/或在任何附加的N原子上被低级烷基或芳基取代;
R4代表氢、低级烷基、芳基、芳烷基或一个保护基团;
m代表1或2;
n代表1至4。
式I的化合物具有有价值的药理性质。具体地说,它们是胶原酶抑制剂,可以用来控制或防治诸如类风湿性关节炎和骨关节炎等关节变性病,或者用于治疗侵入性肿瘤、动脉粥样硬化或多发性硬化。
本发明的目的是式I的化合物及其药学上可接受的盐本身以及它们作为治疗活性物质的应用;制造此类化合物及其盐的方法;用于该方法的中间体;含有此类化合物及其盐的药物以及制造这些药物的方法;以及用这些化合物及其盐来控制或防治疾病或增进健康,尤其是用来控制或防治关节变性病或者治疗侵入性肿瘤或动脉粥样硬化,或者用来制造用于控制或防治关节变性病或治疗侵入性肿瘤、动脉粥样硬化或多发性硬化的药物。
本说明书中使用的“低级烷基”一词,在单独使用或组合使用时,是指含最多6个碳原子的直链或支链的烷基,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、正己基等。“低级烷氧基”一词,在单独使用或组合使用时,是指含最多6个碳原子的直链或支链的烷氧基,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基等。术语“芳基”是指可任意地被例如低级烷基、低级烷氧基和/或卤素(即,氟、氯、溴或碘)等取代的苯基,例如对甲苯基、对甲氧基苯基、对氯苯基等。术语“芳烷基”是指上面定义的低级烷基中一个或多个氢原子被上面定义的一个芳基取代,例如苄基及类似基团。缩酮化的氧基可以是例如亚乙二氧基。
R4表示的保护基团可以是任何常规的保护基团,例如在肽化学中已知的保护基团,如苄氧基羰基、叔丁氧在羰基、乙酰基等。
R2代表的单环N-杂环的实例有1-吡咯烷基、哌啶子基、1-哌嗪基、 4-芳基-1-哌嗪基、六氢-1-哒嗪基、吗啉代、四氢-1,4-噻嗪-4-基、四氢-1,4-噻嗪-4-基1-氧化物、四氢-1,4-噻嗪-4-基1,1-二氧化物、噻唑烷-3-基、六氢吖庚因基和八氢吖辛因基,它们可以接着上面给出的方式被取代,例如2-(甲基氨甲酰)-1-吡咯烷基、2-(羟甲基)-1-吡咯烷基、4-羟基哌啶子基、2-(甲基氨甲酰)哌啶子基、4-肟基哌啶子基、4-甲氧基哌啶子基、4-甲基-1-哌嗪基、4-苯基-1-哌嗪基、1,4-二氧杂-8-氮杂螺〔4,5〕癸-8-基、六氢-3-(甲基氨甲酰)-2-哒嗪基、六氢-1-(苄氧基羰基)-2-哒嗪基、5,5-二甲基-4-甲基氨甲酰噻唑烷-3-基和5,5-二甲基-4-丙基氨甲酰噻唑烷-3-基。
R2代表的桥连的N-杂环的实例有5-氮杂双环〔2,1,〕己烷、3-氮杂双环〔3,1,1〕庚烷、7-氮杂双环〔2,2,1〕庚烷、3-氮杂双环〔3,2,1〕辛烷、2-氮杂双环〔3,2,2〕壬烷和3-氮杂双环〔3,2,2〕壬烷。
R7代表氢、低级烷基或芳基;
X代表-CO-、CH2、-CH(低级烷基)-、-C(低级烷基)2-、-NH-、-N(低级烷基)-或-O-;或者,当R7代表低级烷基并且X代表-N(低级烷基)-时,这些低级烷基团可以连接成一个5、6或7元环;
R8代表氢,低级烷基或芳基;
R9和R10各自代表氢或低级烷基;
Y代表-O-、-NH-或-N(低级烷基);
Z代表S、SO或SO2;
这些环的实例有2-氧代-1-吡咯烷基、2,5-二氧代-1-吡咯烷基、苯二甲酰亚氨基、1,2-二甲基-3,5-二氧代-1,2,4-三唑烷-4-基、3-甲基-2,5-二氧代-1-咪唑烷基、 3,4,4-三甲基-2,5-二氧代-1-咪唑烷基、2-甲基-3,5-二氧代-1,2,4-噁二唑-4-基、 3-甲基-2,4,5-三氧代-1-咪唑烷基、2,5-二氧代-3-苯基-1-咪唑烷基、2,6-二氧代哌啶子基、5,5-二甲基-2,4-二氧代-3-噁唑烷基和六氢-1,3-二氧代吡唑并〔1,2-a〕〔1,2,4〕三唑-2-基。
一组优选的式I的化合物包括其中的R2代表1-吡咯烷基、哌啶子基、4-芳基-1-哌嗪基、吗啉代、四氢-1,4-噻嗪-4-基、四氢-1,4-噻嗪-4-基1,1-二氧化物、噻嗪烷-3-基、六氢吖庚因基或八氢吖辛基的那些化合物,这些基团可任意地在一个或多个碳原子上被羟基、低级烷基、低级烷氧基、缩酮化的氧基或单(低级烷基)氨甲酰基取代,尤其是可任意地被羟基取代的哌啶子基,特别是4-羟基哌啶子基或3-氮杂双环〔3,2,2〕壬烷。优选的式I化合物还包括其中的R3代表一个式(b)、(c)基团(特别是其中的R7代表低级烷基、X代表-C(低级烷基)2-,尤其是3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)或(h)基团的那些化合物。最好是m和n都代表1。
最优选的式I化合物是:
1-〔3-环丙基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶,
1-〔3-环丙基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇,
3-〔3-环丙基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇,
3-〔3-环丁基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷,
1-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇,
3-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷,和
1-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶。
其它的优选的式I化合物有:
1-〔3-环己基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶,
4-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕四氢-1,4-噻嗪,
4-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕四氢-1,4-噻嗪S,S-二氧化物,
4-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕四氢-1,4-噻嗪,
4-〔3-环己基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕四氢-1,4-噻嗪,
3-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-5,5-二甲基-N-丙基-4(R)-噻唑烷甲酰胺,
4-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吗啉,
3-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-N,5,5-三甲基-4(R)-噻唑烷甲酰胺,
4-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-苯基哌嗪,
4-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吗啉,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吡咯烷,
8-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-1,4-二氧杂-8-氮杂螺〔4,5〕癸烷,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-甲氧基哌啶,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕八氢吖辛因,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(5,5-二甲基-2,4-二氧代-3-噁唑烷基)乙基〕丙酰〕哌啶,
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕六氢吖庚因,
1-〔3-环丁基-2(R)-〔2-(六氢-1,3-二氧代吡唑并〔1,2-a〕〔1,2,4〕三唑-2-基)-1(R或S)-(羟基氨甲酰)乙基〕丙酰〕哌啶,和
1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-苯二甲酰亚氨基乙基〕丙酰〕哌啶。
式I的化合物与诸如碱金属氢氧化物(如氢氧化钠和氢氧化钾)、碱土金属氢氧化物(如氢氧化钙和氢氧化镁)、氢氧化铵等碱类形成药学上可接受的盐。碱性的式I化合物与酸形成药学上可接受的盐。这类盐不仅包括与无机酸(例如盐酸和氢溴酸等氢卤酸、硫酸、硝酸、磷酸等)形成的盐,也包括与有机酸(例如乙酸、油石酸、丁二酸、富马酸、马来酸、苹果酸、水杨酸、柠檬酸、甲磺酸、对甲苯磺酸等)形成的盐。
式I的化合物含有至少两个不对称的碳原子,因此可以以旋光对映体、非对映异构体或外消旋体的形式存在。本发明将所有这些形式都包括在内。
根据本发明提供的方法,用以下步骤制备式I的化合物及其药学上可接受的盐:
H2N-OZ (III)式中Z代表氢、三(低级烷基)甲硅烷基或二苯基(低级烷基)甲硅烷基,
如有必要,将所得到的式I化合物转化成药学上可接受的盐。
式II的酸与式III化合物按本方法实施方案(a)的反应可以用已知的方式进行。例如,式II的酸可以与式III的化合物在惰性有机溶剂(例如,二氯甲烷、二甲基甲酰胺或类似物)中使用1-羟基苯并三唑在约0℃至约室温下进行反应,反应中有诸如1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐等缩合剂存在。或者是,可以将式II的酸转化成相应的酰基氯(例如用乙二酰氯),然后,与式III的化合物反应。优选的式III的化合物是其中Z代表叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基的那些化合物。当使用其中的Z代表三(低级烷基)甲硅烷基的式III化合物时,此基圆在反应和后处理期间被裂解掉,直接得到了式I的化合物。另一方面,当使用其中的Z代表二苯基(低级烷基)甲硅烷基的式III化合物时,此基团保留在反应产物中,并且必须随后用已知的方法裂解掉,例如,用氟离子。
根据本发明方法实施方案(b)将式IV的化合物催化加氢可以用已知的方式进行,例如,在惰性有机溶剂中于贵金属催化剂存在下用氢进行。合适的惰性有机溶剂的实例有低级链烷醇类,例如甲醇、乙醇等。关于催化剂,它们可以是承载在合适载体材料上的铂、钯或铑催化剂。钯/碳是优选的催化剂。对温度和压力无严格要求,虽然为方便起见催化加氢最好是在室温和大气压下进行。
式I化合物可以用碱处理转化成药学上可接受的盐,式I的碱性化合物则可用酸处理转化成药学上可接受的盐。这种处理可以用常规方式进行。
在本发明方法实施方案(a)中作为起始物使用的式II的酸是新化合物,它构成了本发明的另一目的。
式II的酸可以按例如下述反应示意图的说明来制备,其中R1、R2、R3、m和n具有先前给出的含义,Bz代表苄基,tBu代表叔丁基:
关于上述反应示意图,其中的各个步骤可以根据本身已知的方法进行。例如,在第一步中,式V的氨基酸可以根据Chenault H.K,Dahmer J.和Whitesides G.M.,J.Am.Chem.Soc,1989,111,6354-6364中所述的步骤得到,将它在浓硫酸存在下用亚硝酸钠处理,转化成式VI的羟基酸,随后使其与苄基溴在有机碱(例如,三乙胺等三烷基胺)存在下反应,转化成相应的式VII苄基酯。随后通过例如与三氟甲磺酸酐反应将其活化,在强碱(例如,氢化钠等金属氢化物)存在下用苄基叔丁基丙二酸酯处理,得到式VIII化合物。后者再用强碱(例如,氢化钠等碱金属氢化物)处理,与式IX化合物反应,得到式X的二苄基叔丁基丁烷三羧酸酯,然后在钯催化剂(例如钯/碳)存在下通过催化加氢脱苄基,得到式XI的丁烷三羧酸二氢叔丁酯。将此化合物在甲苯中与三乙胺一起加热脱羧基化,此反应可以原位进行,得到式XII的丁二酸氢叔丁酯,它与式XIII的环胺按照酰基氯法或使用1-羟基苯并三唑在缩合剂(例如1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐)存在下缩合,得到式XIV化合物,将其去保护(例如用三氟乙酸处理),得到式II的酸。
在本发明方法实施方案(b)中作为起始物使用的式IV化合物是新化合物,它构成了本发明的又一目的。
式IV化合物可以用例如式II的酸与O-苄基羟胺反应来制备。此反应可以按已知方式进行,例如,在惰性有机溶剂(例如,二氯甲烷或二甲基甲酰胺)中用1-羟基苯并三唑在缩合剂(如1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐)存在下进行。
在制造式I化合物中作为中间体或反应物使用的其余化合物是已知化合物或是已知化合物的类似物,它们可以根据与已知化合物相类似的方式进行。
如上所述,式I化合物及其药学上可接受的盐是胶原酶抑制剂。这些化合物和盐的体外抑制胶原酶活性可以用根据Dayer J-M等,Proc.Natl.Acad.Sci.USA(1976),73,945中的方法由得自人类滑液纤维细胞培养物得到的胶原酶来证实,随后在适当的介质内用胰蛋白酶处理将原胶原酶活化。胶原酶活性采用Johnson-Wint,B在Anal.Biochem.(1980),104,175中所述的微量滴板分析法使用由作为底物的鼠尾腱得到的14C-乙酰化胶原I型来测定。IC50是本发明的化合物或盐在酶消化过程中将底物的裂解和加溶减少到只用酶时的50%时的浓度。
用本发明的有代表性的化合物进行的上述实验中得到的结果列在下面表1中。
表I
产物的实施例编号 | IC50(nM) |
24579161723 | 18.07.02.56.58.54.12.3534.0 |
式I化合物及其药学上可接受的盐可以作为药物使用,例如,以药物制剂的形式使用。这些药物制剂可以口服,例如,以片剂、糖衣片剂、糖衣丸剂、硬和软明胶胶囊、溶液、乳液或悬浮液的形式口服。但是也可以以例如栓剂的形式直肠用药,或者以例如注射液的形式非肠道用药。
为制造药物制剂,可以将式I化合物及其药学上可接受的盐与治疗上惰性的无机或有机载体一起配制。例如,可以用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐作为片剂、糖衣片剂、糖衣丸剂及硬明胶胶囊的载体。适合作为软明胶胶囊的有例如植物油、蜡、脂肪、半固体和液体多元醇等。但是,根据活性成分的本性,在软明胶胶囊的情形一般不需要载体。适合制造溶液和糖浆的载体实例有水、多元醇、蔗糖、反转糖、葡萄糖等。制造注射液的合适载体有水、醇、多元醇、甘油、植物油等。天然油和硬化油、蜡、脂肪、半液态的多元醇等是制造栓剂的合适载体。
药物制剂中还可以含有防腐剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、香味剂、用来调节渗适压的盐、缓冲剂、涂布剂或抗氧化剂。
含式I化合物或其药学上可接受的盐及治疗上可接受的载体的药物,以及制造这类药物的方法,也是本发明的目的。此方法包括将式I化合物或其药学上可接受的盐与治疗上惰性的载体材料混合,并将该混合物制成盖仑制剂型的服用形式。
如上所述,式I化合物及其药学上可接受的盐可以用来控制或防治疾病,尤其是控制或防治关节变性病或者治疗侵入性肿瘤、动脉粥样硬化或多发硬化症。药的剂量可以在很广的范围内变化,而且当然要随具体病例中的个别要求进行调节。一般来说,对于成人服用,日剂量从约5mg到约30mg、优选从约10mg至约15mg是适当的,但是在需要时可以超过上限。上述日剂量可以作为单次剂量或分次服用。
以下实施例更详细地说明本发明。在这些实施例中所有温度均为摄氏度。
实施例1
将0.575g的1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕哌啶(非对映异构体1)在10ml乙醇中的溶液在0.4g 5%钯/炭催化剂存在下加氢催化6小时。过滤除掉催化剂,将溶液蒸发。残余物在硅胶上用闪蒸色谱法纯化,用二氯甲烷/甲醇(96∶4)作为洗脱液,得到0.37g 1-〔3-环丙基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶(非对映异构体1),为白色泡沫体。nmr(MeOD):3.78-3.64(m,3H);3.62(dd,1H,J=15,8);3.49-3.41(m,1H);3.39(dd,1H,J=15,5);3.33-3.27(m,1H);2.95-2.87(m,1H);2.83(s,3H);1.74-1.46(m,7H);1.33(s,3H);1.31(s,3H);1.20-1.13(m,1H);0.61-0.50(m,1H);0.44-0.33(m,2H);0.06--0.05(m,2H);MS:409(M+H)+.
起始物制备如下:(i)将4.9g的2(R)-氨基-3-环丙基丙酸(用类似于ChenaultH.K.,Dahmer J.和Whitesides G.M.在J.Am.Chem.Soc.1989,111,6354-6364中所述的方法制备)在含4.05ml浓硫酸的50ml水中的溶液温热至45℃。在30分钟内逐滴加入10.5g亚硝酸钠在20ml水中的溶液。将该溶液在45℃下搅拌4小时,然后冷却至室温。该溶液用三份50ml的乙酸乙酯萃取。合并的萃取液用水洗,在无水硫酸镁上干燥。蒸走溶剂,留下3.95g含3-环丙基-2(R)-羟基丙酸的黄色油状物,不经纯化即用于下一步骤。Rf〔二氯甲烷/甲醇(9∶1)〕=0.65。(ii)将3.95g(i)中的产物在50ml乙酸乙酯中的溶液用5.32ml三乙胺和3.8ml苄基溴处理。将该混合物搅拌,在回流下搅拌加热3小时,然后冷至室温过夜。用2M盐酸、水和饱和氯化钠溶液洗该悬浮液。在用无水硫酸镁干燥后蒸走溶剂。残余物用闪蒸色谱法在硅胶上纯化,用己烷/乙酸乙酯(2∶1)作洗脱液,得到3.36g黄色油状的3-环丙基-2(R)-羟基丙酸苄酯。nmr(CDCl3):7.39-7.28(m;5H);5.19(d,1H,J=14);5.15(d,1H,J=14);4.31-4.24(m,1H);2.81(br.d,1H);1.69-1.54(m,2H);0.87-0.74(m,1H);0.45-0.34(m,2H);0.08--0.07(m,2H).(iii)在30分钟内将3.36g(ii)中的产物和1.49ml吡啶在10ml二氯甲烷中的溶液于0℃和搅拌下逐滴加到3.07ml三氟甲磺酸酐在15ml二氯甲烷中的溶液里,在0℃下搅拌该混合物2小时,然后用水和饱和氯化钠溶液洗。在用无水硫酸镁干燥后蒸走溶剂,得到5.37g橙色油状的3-环丙基-2(R)-三氟甲磺酰氧丙酸苄酯,不经纯化直接用于下一步骤。Rf〔乙烷/乙酸乙酯(4∶1)〕=0.5。(iv)将3.8g叔丁基丙二酸苄酯在50ml 1,2-二甲氧基乙烷中的溶液用0.504g氢化钠在矿物油中的80%分散体处理。将该混合物在室温下搅拌30分钟,然后冷却至0℃。在0℃下逐滴加入5.37g步骤(iii)的产物在20ml二氯甲烷中的溶液。在0℃下搅拌此混合物2小时,然后温热至室温放置过夜。蒸走溶剂,将残余物溶在乙酸乙酯中。用水和饱和氯化钠溶液洗此溶液。在用无水硫酸镁干燥之后,蒸走溶剂,得到6.54g2,3-二苄基3-叔丁基1-环丙基-2(R),3(R,S),3-丙烷三羧酸酯,为橙色油状的1∶1非对映异构体混合物。nmr(CDCl3):7.46-7.36(m,20H);5.19-5.07(m,8.H);3.89(d,1H,J=10);3.85(d,1H,J=10)3.37-3.26(m,2H);1.68-1.52(m,2H);1.52-1.38(m,2H);1.41(s,9H);1.39(s,9H);0.79-0.63(m,2H);0.49-0.38(m,4H);0.12-0.07(m,4H).(v)将6.4g步骤(iv)的产物在30ml 1,2-二甲氧基乙烷中的溶液用0.446g的80%氢化钠/矿物油分散体处理。将该混合物在室温下搅拌30分钟。在15分钟内逐滴加入3.84g 1-(溴甲基)-3,4,4-三甲基-2,5-咪唑烷二酮在20ml 1,2-二甲氧基乙烷中的溶液。在室温下搅拌该混合物36小时,蒸走溶剂,将残余物溶在乙酸乙酯中,用水和饱和氯化钠溶液洗。在用无水硫酸镁干燥之后,蒸走溶剂。残余物在硅胶上用闪蒸色谱法纯化,依次用乙烷/乙酯乙酯(7∶3)和己烷/乙酸乙酯(6∶4)洗脱,得到6.4g 2,3-二苄基3-叔丁基1-环丙基-4-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)-2(R),3(R,S),3-丁烷三羧酯酯,为透明油状的1∶1非对映异构体混合物。nmr(CDCl3):7.47-7.28(m,20H);5.31-5.03(m,8H);4.32-4.18(m,4H);3.19-3.15(m,1H);3.16-3.12(m,1H);2.86(s,6H);2.00-1.90(m,1H);1.89-1.79(m,1H);1.64-1.49(m,1H);1.48-1.38(m,1H);1.37(s,12H);1.36(s,9H);1.32(s,9H);0.9-0.8(m,2H);0.41-0.3(m,4H);0.15-0.05(m,2H);0.04--0.04(m,2H).(vi)将3.0g步骤(V)的产物在30ml2-丙醇中的溶液于0.3g 5%钯/炭催化剂存在下催化加氢2小时。过滤除掉催化剂,蒸发溶液。残余物从20ml甲苯中再蒸发,然后溶在50ml甲苯中。将溶液用0.693ml三乙胺处理,该混合物回流加热2小时。将该溶液冷至室温,用2M盐酸、水和饱和氯化钠溶液洗。在用无水硫酸镁干燥后,蒸走溶剂,得到1.85g 2(R)-(环丙基甲基)-3(R或S)-〔(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)甲基〕丁二酸氢4-叔丁酯,为黄色油状的非对映异构体6∶1混合物。MS:383(M+H)+,Rf〔二氯甲烷/甲醇(9∶1)〕=0.41。(vii)将1.0g步骤(vi)产物在10ml二氯甲烷中的溶液冷却到0℃,依次用0.665ml N-乙基吗啉、0.481g 1-羟基苯并三唑和0.602g1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐处理。将该混合物在0℃下搅拌30分钟,然后用0.517ml派啶处理。将溶液温热到室温,搅拌过夜。用5%碳酸氢钠溶液、2M盐酸和饱和氯化钠溶液洗该溶液。在用无水硫酸镁干燥之后,蒸走溶剂,得到1.01g 1-(2(R)-〔1(R或S)-(叔丁氧基羰基)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕哌啶,为黄色胶状物,是大约6∶1的非对映异构体混合物。MS:450(M+H)+,Rf〔二氯甲烷/甲醇(95∶5)〕=0.51。(viii)将1.0g步骤(vii)的产物在2ml三氟乙酸中的溶液在室温下搅拌2.5小时。蒸走溶剂,残余物再从甲苯中蒸发。将残余物溶在乙醚中。该溶液用2份5%的碳酸氢钠水溶液萃取。将合并的萃取液用浓盐酸酸化至pH 2,该产物用2份二氯甲烷萃取。将合并的有机萃取相用水和饱和氯化钠溶液洗,用无水硫酸镁干燥。蒸走溶剂,得到0.634g含1-〔2(R)-〔1(R或S)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕哌啶的白色泡沫状物,为6∶1的非对映异构体混合物,不经纯化直接用于下一步骤中。Rf〔二氯甲烷/甲醇(9∶1)〕=0.31。(ix)将0.634g步骤(viii)的产物在10ml二氯甲烷中的溶液冷却到0℃。将该溶液依次用0.41ml N-乙基吗啉、0.296g 1-羟基苯并三唑和0.371g 1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐处理。将该混合物在0℃下搅拌30分钟。加入0.238g 0-苄基羟胺在2ml二氯甲烷中的溶液。将该混合物温热至室温,搅拌过夜。依次用2份5%的碳酸氢钠水溶液、2M盐酸、水和饱和氯化钠溶液洗该溶液。在用无水硫酸镁干燥之后,蒸走溶剂。残余物在硅胶上用闪蒸色谱法纯化,使用二氯甲烷/甲醇(98∶2)洗脱,得到0.592g 1-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕哌啶(非对映异构体1),为白色泡沫状物。nmr(MeOD):7.45-7.31(m, 5H);4.87(d,1H,J=13);4.79(d,1H,J=13);3.78-3.65(m,3H);3.63(dd,1H,J=15,8);3.53-3.45(m,1H);3.44(dd,1H,J=15,5);3.34-3.27(m,1H);2.87(s,3H);2.84-2.78(m,1H);1.78-1.49(m,7H);1.49-1.40(m,1H);1.36(s,3H);1.32,(s,3H);1.12-1.04(m,1H);0.61-0.50(m,1H);0.48-0.37(m,2H);0.07--0.06(m,2H).MS:499(M+H)+.
实施例2
按照与实施例1的第一段所述的类似方式,由用实施例1(i)-(ix)中所述的类似方法制得的0.391g 1-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕-4-哌啶醇(非对映异构体1)得到0.33g 1-〔3-环丙基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇(非对映异构体1),为白色泡沫状物。nmr(MeOD):4.22-4.02(m,2H);3.90-3.81(m,1H);3.69-3.56(m,1H);3.49-3.38(m,2H);3.37-3.18(m,2H);3.11-3.01(m,1H);2.97-2.86(m,1H);2.83(d,3H,J=5);2.01-1.78(m,2H);1.68-1.36(m,3H);1.33(s,3H);1.31(d,3H,J=5);1.24-1.13(m,1H);0.62-0.50(m,1H);0.49-0.33(m,2H);0.09--0.05(m,2H);MS:425(M+H)+
实施例3
按照与实施例1第一段中所述的类似方式,由用与实施例1(i)-(ix)中所述的类似方法制得的0.822g 3-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1)得到0.496g 3-〔3-环丙基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1),为白色泡沫状物。nmr(MeOD):4.0-3.1(m,5H);3.48-3.31(m,2H);2.96-2.86(m,1H);2.82(s,3H);2.14-2.03(m,2H);1.80-1.68(m,4H);1.68-1.53(m,5H);1.32(s,3H);1.31(s,3H);1.21-1.12(m,1H),0.64-0.52(m,1H);0.45-0.33(m,2H);0.08--0.05(m,2H);MS:449(M+H)+.
实施例4
按照与实施例1第一段中所述的类似方式,由用与实施例1(i)-(ix)中所述的类似方法制得的0.6g 1-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕哌啶(非对映异构体1)得到0.5g1-〔3-环丁基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶(非对映异构体1),为白色泡沫状物。nmr(MeOD):3.67(dd,1H,J=15,10);3.64-3.46(m,4H);3.34(dd,1H,J=15,8);3.12(td,1H,J=13,3);2.92-2.84(m,1H);2.82(s,3H);2.22-2.09(m,1H);2.07-1.93(m,2H);1.90-1.42(m,12H);1.33(s,3H);1.32(s,3H);MS:423(M+H)+.
实施例5
按照与实施例1第1段中所述的类似方式,由按照类似于实施例1(i)-(ix)中所述的方法制得的0.4g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-哌啶醇(非对映异构体1)得到0.294g 1-〔3-环丁基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇,为白色泡沫状物。nmr(MeOD):4.15-4.05(m,1H);4.04-3.90(m,1H);3.90-3.80(m,1H);3.72-3.57(m,1H);3.45-3.30(m,2H);3.18-3.06(m,2H);2.94-2.85(m,1H);2.84(d,3H,J=5);2.21-1.36(m,13H);1.33(d,3H,J=3);1.31(d,3H,J=6);MS:439(M+H)+.
实施例6
按照与实施例1第1段中所述的类似方式,由按照与实施例1(i)-(ix)中所述的类似方法制得的0.642g 3-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1)得到0.348g 3-〔3-环丁基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1),为白色泡沫状。nmr(MeOD):3.92 3.83(m,2H);3.76(dd,H,J=15,13);3.67-3.57(m,2H);3.34(dd,1H,J=15,5);3.28-3.21(m,1H);2.96-2.87(m,1H);2.83(s,3H);2.23-2.13(m,1H);2.12-1.92(m,4H);1.91-1.48(m,14H);1.35(s,3H);1.34(s,3H).MS:463(M+H)+.
实施例7
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)类似的方法制得的0.5g 1-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-4-哌啶醇(非对映异构体1)得到0.4g1-〔3-环戊基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-哌啶醇(非对映异构体1),为白色泡沫状。nmr(MeOD):4.20-4.02(m,2H);3.91-3.83(m,1H);3.76-3.64(m,1H);3.48-3.32(m,2H);3.26-3.08(m,3H);2.05-1.42(m,12H);1.38-1.25(m,7H);1.18-1.01(m,3H);MS:453(M+H)+.
实施例8
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)类似的方法制得的0.57g 3-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1)得到0.48g 3-〔3-环戊基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-3-氮杂双环〔3,2,2〕壬烷(非对映异构体1),为白色泡沫状物。nmr(MeOD):3.88-3.67(m,5H);3.39-3.31(m,2H);2.92-2.85(m,4H);2.15-2.06(m,2H);1.83-1.45(m,16H);1.36-1.28(m,7H;1.16-1.02(m,2H).MS:477(M+H)+.
实施例9
按照与实施例1(i)-(viii)中所述的类似的方式制备的0.421g1-〔2(R)-〔1(R或S)-羟基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕哌啶的非对映异构体1与非对映异构体2的6∶1混合物在10ml二氯甲烷中的溶液冷却到0℃。用0.211g 1-羟基苯并三唑、0.24g 1-乙基-3-(3-二甲基氨丙基)碳化二亚胺盐酸盐和0.22ml N-甲基吗啉处理该溶液。将该混合物在0℃下搅拌15分钟。加入0.295g O-(叔丁基二甲基甲硅烷基)羟胺和0.22ml N-甲基吗啉在5ml二氯甲烷中的溶液。将该混合物温热至室温,搅拌过夜。用2份5%碳酸氢钠水溶液洗上述溶液,随后用2M盐酸和饱和氯化钠溶液洗。在用无水硫酸镁干燥后,蒸走溶剂。残余物在硅胶上用闪蒸色谱法纯化,使用二氯甲烷/甲醇(96∶4)洗脱,得到0.123g白色泡沫状的1-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶(非对映异构体1)。nmr(MeOD):3.74-3.66(m,3H);3.53-3.45(m,2H);3.34(dd,J=14,7,1H);3.23(dt,J=4,14,1H);2.90-2.84(m,4H);1.80-1.45(m,14H);1.38-1.23(m, 7H);1.15-1.01(m,2H);MS:427(M+H)+.
实施例10
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)类似的方法制得的0.328g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环己基丙酰〕哌啶(非对映异构体1)出发,得到0.269g1-〔3-环己基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕哌啶(非对映异构体1),为白色泡沫状。nmr(MeOD):3.87-3.77(m,2H);3.7(dd,J=14,9,1H);3.64-3.56(m,2H);3.38-3.28(m,2H);2.9-2.83(m,4H);1.84-1.45(m,12H);1.35(s,3H);1.33(s,3H);1.25-1.05(m,5H);0.98-0.78(m,2H).MS:451(M+H)+.
实施例11
按照与实施例9中所述的类似方式,由用与实施例1(i)-(ix)相似的方法制得的0.8g 1-〔2(R)-〔1(R或S)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-四氢-1,4-噻嗪(非对映异构体1)出发,得到0.3g 4-〔3-环戊基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-四氢-1,4-噻嗪(非对映异构体1),为白色泡沫状物。nmr(MeOD):4.02-3.96(m,2H);3.92-3.85(m,2H);3.7(dd,J=13,9,1H);3.37(dd,J=13,6,1H);3.25-3.18(m,1H);2.9-2.84(m,4H);2.82-2.75(m,1H);2.7-2.55(m,3H);1.78-1.45(m,8H);1.35(s,3H);1.34(s,3H);1.18-1.04(m,2H).MS:455(M+H)+.
实施例12
按照与实施例1中所述的类似方式,由用与实施例1(i)-(ix)类似的方法制得的0.3g 4-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-四氢-1,4-噻嗪S,S-二氧化物(非对映异构体1)出发,得到0.2g 4-〔3-环戊基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-四氢-1,4-噻嗪S,S-二氧化物(非对映异构体1),为白色固体。nmr(MeOD):4.45-4.3(m,2H);4.0-3.93(m,1H);3.78-3.65(m,2H);3.55-3.39(m,2H);3.30-3.21(m,2H);3.14-3.03(m,2H);2.9-2.85(m,4H);1.78-1.45(m,9H);1.36(s,3H);1.34(s,3H);1.18-1.0(m,2H).MS:487(M+H)+.
实施例13
按照与实施例9中所述的类似方式,由用与实施例1(i)-(viii)类似的方法制得的0.8g 1-〔2(R)-〔1(R或S)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-四氢-1,4-噻嗪(非对映异构体1)出发,得到0.24g 4-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-四氢-1,4-噻嗪(非对映异构体1),为白色固体。nmr(MeOD):3.98-3.75(m,4H);3.64(dd,J=13,8,1H);3.35(dd,J=15,6,1H);3.07(td,J=10,4,1H);2.9-2.83(m,1H);2.82(s,3H);2.78-2.72(m,1H);2.66-2.52(m,3H);2.18-2.08(m,1H);2.05-1.93(m,2H);1.85-1.45(m,6H);1.13(s,3H);1.11(s,3H).MS:441(M+H)+.
实施例14
按照与实施例9中所述的类似方式,由用与实施例1(i)-(viii)相似的方法制得的1.22g 1-〔2(R)-〔1(R或S)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环己基丙酰〕-四氢-1,4-噻嗪(非对映异构体1)出发,得到0.45g 4-〔3-环己基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-四氢-1,4-噻嗪(非对映异构体1),为白色固体。nmr(MeOD):4.12-4.03(m,2H);3.95-3.88(m,1H);3.75-3.65(m,2H);3.38(dd,J=14,6,1H);2.88-2.82(m,4H);2.78-2.72(m,1H);2.68-2.55(m,3H);1.82-1.53(m,7H);1.35(s,3H);1.34(s,3H);1.26-0.8(m,8H);MS:469(M+H)+.
实施例15
按照与实施例9中所述的类似方式,由用与实施例1(i)-(viii)相似的方法制得的1.164g 3-〔2(R)-〔1(R或S)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-5,5-二甲基-N-丙基-4(R)-噻唑烷甲酰胺的非对映异构体混合物出发,得到0.329g 3-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-5,5-二甲基-N-丙基-4(R)-噻唑烷甲酰胺(非对映异构体1),为白色固体。nmr(MeOD):5.09-4.72(m,2H);4.51 and 4.46(both s,total 1H);3.84 and 3.64(both dd,J=14,8,1H);3.40-3.05(m,4H);2.90-2.73(m,4H);1.94-1.25(m,23H);1.23-1.01(m.2H);0.99-0.85(m,3H);MS:554(M+H)+.
实施例16
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)中所述的类似的方法制得的0.223g 4-〔2(R)-〔(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-吗啉(非对映异构体1)出发,得到0.112g白色固体状的4-〔3-环戊基-2-(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吗啉(非对映异构体1)。nmr(MeOD):3.83-3.56(m,9H);3.41(dd,J=14,6,1H);3.19(dt,J=4,11,1H);2.91-2.81(m,4H);1.77-1.42(m,8H);1.38-1.23(m,7H);1.19-0.99(m,2H);MS:439(M+H)+.
实施例17
按照与实施例9中所述的类似方式,由用与实施例1(i)-(viii)中所述的相似方法制得的1.289g 3-〔2(R)-〔1(RS)-羧基-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环戊基丙酰〕-N,5,5-三甲基-4(R)-噻唑烷甲酰胺的非对映体混合物(非对映异构体1)出发,得到0.629g白色固体状的3-〔3-环戊基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-N,5,5-三甲基-4(R)-噻唑烷甲酰胺(非对映异构体1)。nmr(MeOD):4.09-4.51(m,2H);4.47 and 4.43(both s,total 1H);3.82 and 3.62(both dd,J=14,10,total 1H);3.37 and 3.17(both dd,J=14,5,total 1H);3.13-2.70(m,8H);1.96-1.25(m,21H);1.23-0.99(m,2H);MS:526(M+H)+.
实施例18
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)相似的方法制得的0.289g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-苯基哌嗪(非对映异构体1)出发,得到0.121g白色固体状的1-〔3-环丁基-2(R)-〔1(R或S)-〔(羟基氨甲酰)甲基〕-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-苯基哌嗪(非对映异构体1)。nmr(MeOD):7.25(m,2H);7.00(m,2H);6.85(m,1H);3.94-3.73(m,4H);3.66(dd,J=14,7,1H);3.43(dd,J=14,6,1H);3.23-3.09(m,4H);2.96-2.84(m,1H);2.84(s,3H);2.27-2.13(m,1H);2.09-1.95(m,2H);1.90-1.48(m,6H);1.35(s,3H);1.34(s,3H);MS:499(M)+.
实施例19
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)中所述的类似方法制得的0.455g 4-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕吗啉(非对映异构体1)出发,得到0.194g白色固体状的4-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吗啉(非对映异构体1)。nmr(MeOD):3.80-3.51(m,9H);3.42(dd,J=14,6,1H);3.14-3.06(dt,J=4,11,1H);3.04-2.86(m,1H);2.85(s,3H);2.23-2.11(m,1H);2.06-1.95(m,2H);1.91-1.73(m,2H);1.71-1.46(m,4H);1.35(s,3H);1.34(s,3H);MS:425(M)+.
实施例20
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)中所述的类似方法制得的0.625g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕吡咯烷(非对映异构体1)出发,得到0.384g白色固体状1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕吗啉(非对映异构体1)。nmr(MeOD):3.77-3.69(m,1H);3.61(dd,J=14,6,1H);3.53-3.44(m,2H);3.39-3.31(m,2H);2.93-2.85(m,2H);2.84(s,3H);2.26-2.13(m,1H);2.07-1.71(m,8H);1.69-1.46(m,4H);1.36(s,3H);1.33(s,3H);MS:409(M+H)+.
实施例21
按照与实施例1第1段中所述的类似方式,由用与实施例1(i)-(ix)中所述的相似方法制得的0.176g 8-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-1,4-二氧杂-8-氮杂螺〔4,5〕癸烷(非对映异构体1)出发,得到0.084g白色固体状8-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-1,4-二氧杂-8-氮杂螺〔4,5〕癸烷(非对映异构体1)。nmr(MeOD):4.02(s,4H);3.81-3.60(m,5H);3.99(dd,J=14,6,1H);3.20-3.10(m,1H);2.93-2.85(m,1H);2.84(s,3H);2.21-2.09(m,1H);2.06-1.93(m,2H);1.80-1.46(m,10H);1.35(s,3H);1.33(s,3H);MS:481(M+H)+.
实施例22
按照与实施例1第1段中所述的类似方式,由0.443g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-甲氧基哌啶(非对映异构体1)得到0.319g白色固体状的1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕-4-甲氧基哌啶(非对映异构体1)。nmr(MeOD):3.96-3.80(m,2H);3.69-3.59(m,1H);3.54-3.23(m, 7H);3.18-3.09(m,1H);2.93-2.80(m,4H);2.21-2.09 (m,1H);2.07-1.41(m,12H);1.41-1.38(m,6H);MS:453(M+H)+.
起始物制备如下:
(i)将0.925g 1-〔2(R)-〔1(R或S)-(叔丁氧基羰基)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丙基丙酰〕-4-羟基哌啶在8ml二甲基甲酰胺中的溶液用1.08g甲基碘和1.79g氧化银处理。将该混合物在室温于暗处搅拌2天。然后加入补加的0.54g甲基碘和0.895g氧化银,该混合物再搅拌3天。蒸走溶剂,残余物悬浮在乙酸乙酯中,过滤。将乙酸乙酯溶液浓缩,残余物在硅胶上用闪蒸色谱法纯化,用乙酸乙酯洗脱。得到0.61g无色胶状的1-〔2(R)-〔1(R或S)-(叔丁氧基羰基)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-甲氧基哌啶。
(ii)按照与实施例1(vii)-(ix)中所述的类似方式,由0.61g 1-〔2(R)-〔1(R或S)-(叔丁氧基羰基)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-甲氧基哌啶出发,得到0.443g无色胶状的1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕-4-甲氧基哌啶(非对映异构体1)。
实施例23
按照与实施例1第1段中所述的类似方式,由按照实施例1(i)-(ix)中所述的相似方法制得的0.94g 1-〔2(R)-〔1(RS)-(苄氧基羰基)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕八氢吖辛因(非对映异构体1)出发,得到0.663g白色固体状的1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕八氢吖辛因(非对映异构体1)。nmr(MeOD):3.77(dd,J=14,10,1H);3.66-3.43(m,4H);3.33(dd,J=14,5,1H);3.07(dt,J=10,4,1H);2.91-2.81(m,4H);2.29-2.16(m,1H);2.10-1.95(m,2H);1.90-1.46(m,16H);1.34(s,6H);MS:451(M+H)+.
实施例24
按照与实施例1第1段中所述的类似方式,由按照实施例1(v)-(ix)中所述的类似方法用3-(溴甲基)-5,5-二甲基噁唑烷-2,4-二酮代替1-(溴甲基)-3,4,4-三甲基-2,5-咪唑烷二酮制得的0.37g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(5,5-二甲基-2,4-二氧代-3-噁唑烷基)乙基〕-3-环丁基丙酰〕哌啶(非对映异构体1)出发,得到0.13 1g 1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(5,5-二甲基-2,4-二氧代-3-噁唑烷基)乙基〕丙酰〕哌啶(非对映异构体1),为白色固体:nmr(MeOD):3.72-3.53(m,5H):3.39(dd,J=14,6,1H),3.14(dt,J=10,4,1H);2.95-2.86(m,1H);2.23-2.11(m,1H);2.08-1.94(m,2H);1.90-1.44(m,18H);MS:410(M+H)+.
实施例25
按照与实施例1第1段中所述的类似方式,由按照实施例1(i)-(ix)中所述的类似方法制得的0.42g 1-〔2(R)-〔1(R或S)-(苄氧基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕-3-环丁基丙酰〕六氢吖庚因(非对映异构体1)出发,得到0.197g白色固体状的1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-(3,4,4-三甲基-2,5-二氧代-1-咪唑烷基)乙基〕丙酰〕六氢吖庚因(非对映异构体1):nmr(MeOD):3.77-3.64(m,2H);3.62-3.45(m,3H);3.33(dd,J=14,5,1H);3.07(dt,J=10,4,1H);2.91-2.81(m,4H);2.24-2.13(m,1H);2.09-1.95(m,2H);1.90-1.47(m,14H);1.35(s,3H);1.34(s,3H);MS:437(M+H)+.
实施例26
按照与实施例1第1段中所述的类似方式,由按照实施例1(i)-(ix)中所述的类似方法用2-(溴甲基)-六氢-1,3-二氧代吡唑并〔1,2-a〕〔1,2,4〕三唑制得的0.37g 1-〔2(R)-〔1(R或S)-(苄氧基氨基甲酰)-2-(六氢-1,3-二氧代吡唑〔1,2-a〕〔1,2,4〕三唑-2-基)乙基〕-3-环丁基丙酰〕哌啶(非对映异构体1)出发,得到0.118g白色固体状的1-〔3-环丁基-2(R)-〔2-(六氢-1,3-二氧代吡唑并〔1,2-a〕〔1,2,4〕三唑-2-基)-1-(R或S)-(羟基氨甲酰)乙基〕丙酰〕哌啶。nmr(MeOD):3.68-3.56(m,8H);3.52-3.39(m,2H);3.17-3.09(m,1H);2.97-2.90(m,1H);2.35-2.27(m,2H);2.21-2.11(m,1H);2.07-1.95(M,2H);1.88-1.44(m,12H)MS:422(M+H)+.
实施例27
按照与实施例1第1段中所述的类似方式,由按照实施例1(i)-(ix)中所述的类似方法用N-(溴甲基)苯二甲酰亚胺制得的0.222g 1-〔2(R或S)-(苄氧基氨甲酰)-2-苯二甲酰亚氨基乙基〕-3-环丁基丙酰〕哌啶出发,得到0.013g白色固体状的1-〔3-环丁基-2(R)-〔1(R或S)-(羟基氨甲酰)-2-苯二甲酰亚氨基乙基〕丙酰〕哌啶(非对映异构体1)。nmr(MeOD):7.87-7.75(m.4H);3.83(dd,J=14.8,1H);3.66-3.58(m,3H);3.53-3.45(m,1H);3.35-3.25(m,1H);3.20-3.12(m,1H);3.04-2.97(m,1H);2.23-2.11(m,1H);2.08-1.95(m,2H);1.89-1.41(m,12H);MS:428 (M+H)+
以下实施例示例说明了含有本发明提供的异羟肟酸衍生物的药物制剂。
实施例A
含以下成分的片剂可以用常规方式制造:
成分 每片
异羟肟酸衍生物 10.0mg
乳糖 125.0mg
玉米淀粉 75.0mg
滑石粉 4.0mg
硬脂酸镁 1.0mg
总重 215.0mg
实施例B
含以下成分的胶囊可以用常规方式制造:
成分 每只胶囊
异羟肟酸衍生物 10.0mg
乳糖 165.0mg
玉米淀粉 20.0mg
滑石粉 5.0mg
胶囊内含物重量 200.0mg
Claims (2)
1.通式II化合物其中R1代表环丙基、环丁基、环戊基或环己基;
R2代表一个通过N原子连接的5至8元饱和的单环的或桥连的N-杂环,当它是单环时,可以任意地含有NR4、O、S、SO或SO2作为环的成员,和/或可任意地在一个或多个碳原子上被以下基团取代:羟基、C1-6烷基、C1-6烷氧基、氧基、缩酮化的氧基、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、羧基、C1-6烷氧基羰基、羟甲基、C1-6烷氧基甲基、氨基甲酰基、单(C1-6烷基)氨基甲酰基、二(C1-6烷基)氨基甲酰基或肟基;
R3代表一个5或6元的N-杂环,该(a)通过N原子相连接,(b)可任意地含有N、O和/或S、SO或SO2作为附加的环成员,(c)在与连接原子N相邻的一个或两个C原子上被氧基取代,和(d)可任意地苯并稠合或者任意地在一个或多个其它碳原子上被C1-6烷基或氧基取代,和/或在任何附加的N原子上被C1-6烷基或芳基取代;
m代表1或2;
n代表1至4;其中所述的芳基是任选被C1-6烷基、C1-6烷氧基和/或卤素取代的苯基。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9601042D0 (en) * | 1996-01-17 | 1996-03-20 | Smithkline Beecham Plc | Medical use |
EP0816341A1 (de) | 1996-07-04 | 1998-01-07 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von chiralen Bernsteinsäurederivaten |
GB9621814D0 (en) * | 1996-10-19 | 1996-12-11 | British Biotech Pharm | Metalloproteinase inhibitors |
US5840974A (en) * | 1996-12-04 | 1998-11-24 | Britisch Biotech Pharmaceuticals, Ltd. | Metalloproteinase inhibitors |
AU5577498A (en) * | 1997-01-31 | 1998-08-25 | Shionogi & Co., Ltd. | Compounds having metalloprotease inhibitory activity |
EP0911324A1 (de) * | 1997-10-03 | 1999-04-28 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von chiralen Bernsteinsäurederivaten |
CA2247580A1 (en) * | 1997-10-03 | 1999-04-03 | F. Hoffmann-La Roche Ag | Process for preparing chiral succinic acid derivatives |
US6329418B1 (en) | 1998-04-14 | 2001-12-11 | The Procter & Gamble Company | Substituted pyrrolidine hydroxamate metalloprotease inhibitors |
US6239151B1 (en) * | 1998-06-26 | 2001-05-29 | Hoffmann-La Roche Inc. | Compounds as inhibitor of tumor necrosis factor alpha release |
FR2780402B1 (fr) | 1998-06-30 | 2001-04-27 | Adir | Nouveaux composes acides carboxyliques et hydroxamiques inhibiteurs de metalloproteases, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP0974590A1 (en) * | 1998-07-13 | 2000-01-26 | F. Hoffmann-La Roche Ag | Process for the preparation of chiral lactones by asymetrical hydrogenation |
US6222039B1 (en) | 1998-07-13 | 2001-04-24 | Hoffman-La Roche Inc. | Process for the preparation of chiral lactones |
US6316633B1 (en) | 1998-09-15 | 2001-11-13 | Hoffman-La Roche Inc. | Process for manufacture of chiral succinic acid derivatives |
JO2258B1 (en) * | 1999-05-11 | 2004-10-07 | اف . هوفمان لاروش ايه جي | Method for preparing hydroxamic acids |
WO2000068205A1 (en) * | 1999-05-11 | 2000-11-16 | F. Hoffmann-La Roche Ag | Process for obtaining a hydroxamic acid |
US6696456B1 (en) | 1999-10-14 | 2004-02-24 | The Procter & Gamble Company | Beta disubstituted metalloprotease inhibitors |
US6797820B2 (en) | 1999-12-17 | 2004-09-28 | Vicuron Pharmaceuticals Inc. | Succinate compounds, compositions and methods of use and preparation |
AU2001245862A1 (en) * | 2000-03-21 | 2001-10-03 | The Procter & Gamble Company | Difluorobutyric acid metalloprotease inhibitors |
BR0109354A (pt) * | 2000-03-21 | 2003-04-15 | Procter & Gamble | Inibidores de metaloproteases os quais contêm cadeias laterais carbocìclicas |
BR0109328A (pt) | 2000-03-21 | 2003-06-10 | Procter & Gamble | Inibidores de metaloprotease n-substituìdos, contendo cadeia lateral heterocìclica |
DE60219630T2 (de) * | 2001-06-15 | 2007-12-27 | Vicuron Pharmaceuticals, Inc., Fremont | Bicyclische pyrrolidinverbindungen |
AR036053A1 (es) | 2001-06-15 | 2004-08-04 | Versicor Inc | Compuestos de n-formil-hidroxilamina, un proceso para su preparacion y composiciones farmaceuticas |
PE20030701A1 (es) | 2001-12-20 | 2003-08-21 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
AU2003229883B2 (en) | 2002-04-03 | 2009-06-11 | Topotarget Uk Limited | Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors |
CA2513246A1 (en) | 2003-01-17 | 2004-08-05 | Topotarget Uk Limited | Carbamic acid compounds comprising an ester or ketone linkage as hdac inhibitors |
KR20060037446A (ko) * | 2003-08-23 | 2006-05-03 | 베르날리스(옥스포드)엘티디 | 금속 단백질 분해효소로서의 히드록삼산 유도체 |
GB0319917D0 (en) * | 2003-08-23 | 2003-09-24 | British Biotech Pharm | Metalloproteinase inhibitors |
DE102004025901A1 (de) | 2004-05-27 | 2005-12-22 | Consortium für elektrochemische Industrie GmbH | Verfahren zur Herstellung optisch aktiver 3-Alkylcarbonsäuren |
EP2234608A2 (en) | 2007-12-11 | 2010-10-06 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
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FR2572072B1 (fr) * | 1984-10-18 | 1989-04-14 | Basf Ag | Procede de preparation de derives d'indole |
US4743587A (en) * | 1985-09-10 | 1988-05-10 | G. D. Searle & Co. | Hydroxamic acid based collagenase inhibitors |
IT1230595B (it) * | 1988-10-24 | 1991-10-28 | Ausimont Srl | Perossiacidi immido derivati |
GB8827308D0 (en) * | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
JP3065636B2 (ja) * | 1989-06-29 | 2000-07-17 | 塩野義製薬株式会社 | [ジ―tert―ブチル(ヒドロキシ)フェニルチオ]置換ヒドロキサム酸誘導体 |
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JPH05125029A (ja) * | 1991-11-06 | 1993-05-21 | Yamanouchi Pharmaceut Co Ltd | 新規なアミド化合物又はその塩 |
US5318964A (en) * | 1992-06-11 | 1994-06-07 | Hoffmann-La Roche Inc. | Hydroxamic derivatives and pharmaceutical compositions |
AU666727B2 (en) * | 1992-06-25 | 1996-02-22 | F. Hoffmann-La Roche Ag | Hydroxamic acid derivatives |
WO1994022309A1 (en) * | 1993-04-07 | 1994-10-13 | Glycomed Incorporated | Synthetic matrix metalloprotease inhibitors and uses thereof |
WO1995004715A1 (fr) * | 1993-08-09 | 1995-02-16 | Kanebo, Ltd. | Derive d'acylphenylglycine et agent preventif et curatif, concernant des maladies causees par une activite collagenase accrue, contenant un tel compose comme ingredient actif |
CA2172049C (en) * | 1993-10-15 | 1999-11-30 | David Joseph Kenneth Goulait | Elastically extensible mechanical fastening system |
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