CN1042633C - 咪唑并(1,2－a)吡啶类的氨基甲酸烷氧基烷基酯 - Google Patents
咪唑并(1,2－a)吡啶类的氨基甲酸烷氧基烷基酯 Download PDFInfo
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- CN1042633C CN1042633C CN94194070A CN94194070A CN1042633C CN 1042633 C CN1042633 C CN 1042633C CN 94194070 A CN94194070 A CN 94194070A CN 94194070 A CN94194070 A CN 94194070A CN 1042633 C CN1042633 C CN 1042633C
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- pyridine
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- -1 Alkoxy alkyl carbamates Chemical class 0.000 title claims description 23
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical class C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 150000003839 salts Chemical class 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 15
- 229940015043 glyoxal Drugs 0.000 claims description 13
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- RRASRBYOKDZZNU-UHFFFAOYSA-N 2-methoxyethyl n-[2-[[(2,3-dimethylimidazo[1,2-a]pyridin-8-yl)amino]methyl]-3-methylphenyl]carbamate Chemical compound COCCOC(=O)NC1=CC=CC(C)=C1CNC1=CC=CN2C1=NC(C)=C2C RRASRBYOKDZZNU-UHFFFAOYSA-N 0.000 claims description 2
- 208000010643 digestive system disease Diseases 0.000 claims description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
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- 229940079593 drug Drugs 0.000 description 7
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- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 7
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JIRLLKQCENXKJT-UHFFFAOYSA-N NCC1=CC=CC(NC(O)=O)=C1CCl Chemical compound NCC1=CC=CC(NC(O)=O)=C1CCl JIRLLKQCENXKJT-UHFFFAOYSA-N 0.000 description 5
- 239000011149 active material Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
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- 230000002401 inhibitory effect Effects 0.000 description 3
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- ALXRNCVIQSDJAO-KRCBVYEFSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCNC(=O)OCC(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ALXRNCVIQSDJAO-KRCBVYEFSA-N 0.000 description 3
- 229960000444 pentagastrin Drugs 0.000 description 3
- QPUMEZIFDXYGPG-UHFFFAOYSA-N piperazine 1H-pyrrole Chemical class N1CCNCC1.N1C=CC=C1 QPUMEZIFDXYGPG-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
本发明涉及式(Ⅰ)的新化合物及其在治疗上的应用。
Description
发明应用领域
本发明涉及新化合物，该化合物在制药工业中作为用于制药的活性物质使用。
背景技术
在欧洲专利申请EP-A-0 033 094中描述了咪唑并[1,2-a]吡啶类，它在8位有一个芳基取代基，该取代基优先是苯基、噻吩基、吡啶基或者是一个被氯、氟、甲基、叔丁基、三氟甲基、甲氧基或氰基取代的苯基。尤其作为感兴趣的芳基是在EP-A-0 033 094中列举的苯基、邻氟苯基或对氟苯基、对氯苯基和2,4,6-三甲基苯基，其中特别优选地是苯基、邻氟苯基或对氟苯基和2,4,6-三甲基苯基。在欧洲专利申请EP-A-0 204 285、EP-A-0 228 006、EP-A-O 268989和EP-A-0 308 917中描述了咪唑并[1,2-a]吡啶类，它在3位有一个不饱和脂族基，尤其是一个(取代)炔基。在欧洲专利申请EP-A-0 266 890中描述了咪唑并[1,2-a]吡啶类，它在8位上被一个链烯基、烷基或环烷基烷基取代。
发明的公开
现已发现，下面详细描述的化合物特别由于其在3位或8位的取代基而有别于现有技术的化合物，因而，具有出人意料的和特别有益的性能。
本发明的主题是式Ⅰ的化合物(参见所附的分子式页)及其盐，其中：
R1表示1-4C-烷基，
R2表示1-4C-烷基，
R3表示1-4C-烷氧基-2-4C-烷氧基，
R4表示1-4C-烷基或羟甲基，以及
A表示O(氧)或NH。
1-4C-烷基表示具有1-4个碳原子的直链或支链烷基。例如可举出丁基、异丁基、仲丁基、叔丁基、丙基、异丙基、乙基，而特别是甲基。
1-4C-烷氧基表示一个在其上结合一个上述的1-4C-烷基的氧原子。1-4C-烷氧基优先是甲氧基。2-4C-烷氧基表示在一个氧原子上结合一个2-4C-烷基(选自上述的1-4C-烷基)。1-4C-烷氧基-2-4C-烷氧基表示在一个2-4C-烷氧基上结合一个1-4C-烷氧基。1-4C-烷氧基-2-4C-烷氧基优先是2-甲氧基乙氧基。
作为用于式Ⅰ化合物的盐优先考虑所有的酸加成盐。特别应提及在盖伦氏制药学中常用的无机酸和有机酸的药理学相容盐。药理学不相容的盐，例如其在以工业规模生产本发明化合物时可作为过程产物首先形成，通过专业人员已知的方法转化成药理学相容的盐。用酸加成的水溶性和水不溶性酸加成盐适合作为药理学相容的盐，所述的酸例如像盐酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、柠檬酸、D-葡糖酸、苯甲酸、2-(4-羟基苯甲酰基)-苯甲酸、丁酸、磺基水杨酸、马来酸、月桂酸、苹果酸、富马酸、琥珀酸、草酸、洒石酸、双羟萘酸、硬脂酸、甲苯磺酸、甲磺酸或3-羟基-2-萘甲酸，并且在盐制造中，看是否涉及一元或多元酸和希望是哪一种盐，以等摩尔的或以一种偏离的比例使用这些酸。
可作为示范要举出的化合物是8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇、8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄基氨基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇和8-{2-[(2-甲氧基乙氧基)-羰基氨基]-6-甲基苄基氨基}-2,3-二甲基咪唑并[1,2-a]吡啶，及其盐。
应强调的是式Ⅰ这样的化合物及其盐，在这些化合物中R4表示羟甲基，A表示O(氧)，R1、R2和R3具有上述含义。
本发明的另一主题是一种制造式Ⅰ化合物及其盐的方法。该方法的特征是：
a)式Ⅱ的化合物(其中，R1、R4和A具有上述的含义)或其盐与式Ⅲ的化合物(均参见所附的分子式页)(其中，R2和R3具有上述的含义，X表示一个合适的反应活性离去基团)或其盐进行反应，或者
b)为了制备式Ⅰ的化合物(式中R4表示羟甲基)，还原式Ⅳ的化合物(参见所附的分子式页)(式中，R1、R2、R3和A具有上述的含义)。并在需要时，接着使按照a)或b)得到的化合物Ⅰ转化成其盐，或者在需要时，接着从所得化合物Ⅰ的盐中释放出化合物Ⅰ。
以一种专业人员本身相信的方法进行化合物Ⅱ和化合物Ⅲ的反应。例如一个合适的反应活性离去基团是一个卤素原子(优先是氯或溴)或一个甲磺酰氧基团。有利的方式是在一种碱(例如，一种无机氢氧化物，如氢氧化钠，或一种无机碳酸盐，如碳酸钾，或一种有机氮碱，如三乙胺、吡啶、可力丁或4-二甲氨基吡啶)存在下进行反应，同时通过添加催化剂，如碱金属碘化物或溴化四丁铵可促进反应进行
可以一种专业人员本身熟悉的方式进行化合物Ⅳ的还原。该还原在惰性溶剂，如低级脂族醇中，例如在使用合适的氢化物，如像硼氢化钠的条件下，在必要时在添加水的条件下进行。
那些反应条件对实施该方法是更为必要的，是专业人员根据其专业知识所熟知的。
以本身公知的方式进行本发明物质的离析和纯化，例如这样，即在真空下蒸馏出溶剂或者将所得的残留物从一种合适的溶剂中重结晶出来，或者经受一种普通的纯化方法，如像在合适的载体材料上的柱色谱法。
通过在一种合适的溶剂中溶解游离碱得到酸加成盐，所述的溶剂例如是氯化的烃，像二氯甲烷或氯仿；低分子脂族醇(乙醇、异丙醇)酮，如丙酮，或醚，如四氢呋喃或二异丙醚。这种盐含有所希望的酸。或者接着向盐中添加所希望的酸。
通过过滤、再沉淀和用一种用于沉积盐的非溶剂进行沉淀，或者通过蒸发溶剂而得到盐。所得的盐可通过碱化作用，例如用氨水溶液转变成游离碱，可再将其转化成酸加成盐。以这种方式允许使药理学不相容的酸加成盐转化成药理学相容的酸加成盐。
其中原始化合物Ⅱ由欧洲专利申请EP-A-0 290 003和EP-A-0299 470是已知的。原始化合物Ⅲ是新的。它用类似于文献公开的方法进行制备，通过这种方法在具有X=OH的化合物Ⅲ中使羟基基团转变成反应活性离去基团，例如通过与一种卤化剂，像亚硫酰氯、亚硫酰溴、三溴化磷或草酰氯进行反应转变成一个卤素原子，或者通过与甲磺酰氯，在必要时有碱参与下进行反应，转变成一个甲磺酰基氧基。
化合物Ⅳ是新的，并且也是本发明的对象。它的制备如式Ⅰ化合物，即通过具有R4=CHO的化合物Ⅱ与如上所述化合物Ⅲ进行类似反应来制备。
下述实施例用于详细解释制备化合物Ⅰ的方法。缩写词RT表示室温，h表示小时。
实施例
最终和中间产物
1.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醛
一种由2.0g(11.35mmol)8-羟基-2-甲基咪唑并[1,2-a]吡啶-3-甲醛、1.2g无水碳酸钠、0.17g(1.14mmol)碘化钠和3.3g(12.8mmol)[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯在30ml丙酮中形成的混合物在室温下搅拌24小时，然后倒在200ml冰水上。过滤该沉淀物并进行干燥，从甲苯/二异丙醚中重结晶出来。得到熔点为119-120℃的标题化合物3.98(86.5％)。
2.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇
在室温下，向3.7g(9.3mmol)8-{2-[(2-甲氧基乙氧基)羟基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醛在40ml甲醇中形成的悬浮液中掺入362mg(9.3mmol)97％硼氢化钠并搅拌75分钟。将其倒在冰/水上，用二氯甲烷萃取并在旋转浓缩器中浓缩。用5ml异丙醇、5ml甲苯和二异丙醚将残油进行结晶。得到熔点121-123℃的标题化合物2.7g(72.7％)。
3.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醛
将由2.0g(11.41mmol)8-氨基-2-甲基咪唑并[1,2-a]吡啶-3-甲醛、1.21g(11.41mmol)无水碳酸钠、0.17g(1.14mmol)碘化钠和3.5g(13.6mmol)[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯在30ml丙酮中形成的混合物于室温搅拌24小时，并在旋转浓缩器中浓缩。向残留物中掺入100ml水并用乙酸乙酯萃取，用硫酸镁干燥有机相，在真空中进行浓缩。从甲苯中重结晶残留物。得到熔点为153-155℃的标题化合物3.31g(73％)。
4.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇
类似实施例2，用硼氢化钠还原2.8g(7.06mmol)8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醛，在真空下蒸馏出甲醇，掺入水和乙酸乙酯，用磷酸氢钾溶液将pH调节到9。用乙酸乙酯多次萃取，然后干燥，在真空中浓缩，从甲苯/二异丙醚中进行重结晶。得到熔点为138-140℃的标题化合物2.28g(81％)。
5.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2,3-二甲基咪唑并[1,2-a]吡啶-异丙醇(1/1)
由3.0g(18.6mmol)8-氨基-2,3-二甲基咪唑并[1,2-a]吡啶、4.9g(46.2mmol)无水碳酸钠、0.28g(1.86mmol)碘化钠和5.8g(22.5mmol)[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯在30ml丙酮中形成的混合物于室温搅拌20小时。进行过滤并在真空中浓缩，掺入水和乙酸乙酯，用稀盐酸调节到pH6，用乙酸乙酯萃取。干燥有机溶液并在真空中浓缩。向残留物中掺入40ml丙酮，再掺入1.2g(10.3mmol)富马酸在80ml丙酮中形成的溶液。无结晶产生。于是向再浓缩的溶液掺入甲苯和异丙醇，在0℃下用二异丙醚沉淀出4.9g富马酸盐。向其掺入50ml乙酸乙酯和10ml水，用氢氧化钠溶液调节到pH9，用乙酸乙酯萃取游离碱。在真空中浓缩后，溶解在甲苯/异丙醇中，在0℃用石油醚(沸点40℃)进行沉淀。得到熔点85-86℃的标题化合物2.2g(26.7％)
6.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇
将178mg(1.0mmol)8-羟基-2-甲基咪唑并[1,2-a]吡啶-3-甲醇、117mg(1.1mmol)无水碳酸钠、15mg(0.1mmol)碘化钠和283mg(1.1mmol)[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯在5ml丙酮中形成的混合物在室温搅拌48小时，类似实施例2进行处理，借助乙酸乙酯/异丙醇(9∶1)进行色谱分离。得到247mg(62％)标题化合物。
7.8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2,3-二甲基咪唑并[1,2-a]吡啶
类似实施例5，使2.0g(12.4mmol)8-羟基-2,3-二甲基咪唑并[1,2-a]吡啶、3.6g(13.9mmol)[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯、0.18g碘化钠和1.3g碳酸钠在30ml丙酮中进行反应。得到熔点107-108℃的标题化合物1.07g(22.5％)。
起始产物
Aa．[2-(羟甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯
在10℃、在搅拌和冷却下向33g(0.24mol)2-氨基-6-甲基苄醇和19.4ml(0.24mol)吡啶在600ml异丙醇中形成的溶液中滴入33.2g(0.24mol)氯甲酸(2-甲氧基乙基)酯。在0℃下再搅拌2小时，掺入水和乙酸异丙酯，用乙酸异丙酯萃取多次。用硫酸镁干燥有机相，在旋转浓缩器中于50℃进行浓缩。残余物在硅胶柱上借助乙酸乙酯进行色谱分离。在真空中浓缩后得到油状的36g(68％)标题化合物。
Ab．[2-(氯甲基)-3-甲基苯基]氨基甲酸(2-甲氧基乙基)酯
在17-20℃、在搅拌和冷却下向18.0g(0.075mol)上述的化合物在80ml甲苯中形成的溶液中滴入9.4g(0.079mol)亚硫酰氯，在室温放置超过一夜。在冰浴中冷却，进行研磨，得到熔点100-102℃的11.2g(57.7％)标题化合物。通过浓缩母液和从甲苯/石油醚(沸点40℃)中结晶，得到具有类似熔点的二次沉淀物4.8g(24.7％)。
B．8-羟基-2-甲基咪唑并[1,2-a]吡啶-3-甲醛
4.77g(0.02mol)8-苄氧基-2-甲基咪唑并[1,2-a]吡啶在由20ml二甲基甲酰胺和2.3ml磷酰氯组成的Vilsmeier混合液中、于60℃搅拌2.5小时，以-般方法用冰/水和碳酸氢钾进行处理。得到105-106℃的8-苄氧基-2-甲基咪唑并[1,2-a]吡啶-3-甲醛(出自二异丙醚)。用类似Kaminski等人的方法H(J.Med.Chem.28,876(1985))使这种化合物脱苄基，形成熔点251-252℃的标题化合物。
工业实用性
式Ⅰ的化合物及其盐具有宝贵的药理学性能，这些性能是工业上可利用的。该化合物及其盐在温血动物中尤其具有突出的抑制胃酸分泌和极好的胃、肠保护作用。在此情况下，本发明的化合物除了在水介质中有良好的溶解性外，在无明显副作用下，还以高的作用选择性、较长的作用时间、好的肠生物活性和大的治疗谱而出众。
在这种关系中，“胃和肠的保护”理解为肠胃疾病的预防和治疗，尤其是肠胃炎疾病和肠胃损伤(例如像胃溃疡、十二指肠溃疡、胃炎、低酸或药物引起的胃刺激)，这些例如可通过微生物(例如Helicobacter pylori)、细菌毒素、药物(例如规定的消炎药和抗风湿药)、化学试剂(乙醇)、胃酸或应激反应进行试验。在此情况下本发明的化合物自身也具有抵抗Helicobacter pylori病菌的作用。
在测定抗溃疡和抑制分泌性能的各种模型中，本发明化合物以其卓越的性能，证明其出入意料地明显优于由现有技术已知的化合物。基于这些性能，式Ⅰ的化合物及其药理学相容的盐极适合在人用和兽用药中使用，其中它尤其用于治疗和/或预防胃和/或肠的疾病，但也用于治疗骨质疏松症。
因此本发明的另一个主题是本发明的化合物用于治疗和/或预防上面提到的疾病。
同样本发明包括本发明的化合物用于制造药物的用途，这些药物用于治疗和/或预防上面提到的疾病。
此外本发明包括本发明的化合物用于治疗和/或预防上面提到的疾病的用途。
本发明的另一个主题是药物，它含一种或多种式Ⅰ的化合物和/或药理学相容的盐。
该药物按照本身已知的且专业人员熟知的常用方法来制造。作为药物，本发明的药理学有效的化合物(=活性物质)这样使用，即，或者原样地或者最好与合适的制药助剂和/或载体材料结合、以片剂、糖衣药丸、胶囊、栓剂、膏药(如作为TTS)、乳剂、悬浮剂或溶液的形式使用，此时，活性物质含量有利地是在0.1-95％之间，并且通过选择助剂和载体材料可以得到能准确适应活性物质和/或所希望的作用进入方式的盖伦氏给药形式(例如，一种缓释式或一种抗胃液式)。
适合用于所需药物制剂的助剂或载体，是专业人员根据其专业知识所熟知的。除了溶剂、胶粘剂、栓剂基底、片剂助剂和其他的活性物质载体外，例如还可使用片剂包覆剂、抗氧化剂、分散剂、乳化剂消泡剂、校味剂、防腐剂、增溶剂、色素或者特别是渗透促进剂和络合剂(例如环糊精)。
活性物质可以口服、肠胃外或经皮给药。
大体上在人用药中已证实有利的是，在口服给药时，为了达到所希望的结果，活性物质以日剂量约0.01-20mg/kg、优选地是0.05-5mg/kg、最好是0.1-1.5mg/公斤体重，必要时以多次方式、尤其是1-4次给药方式给药。在肠胃外治疗时，可以类似的或(尤其在活性物质静脉给药时)在通常情况下低剂量使用。可以由每个专业人员根据其专业知识很容易确定每次所需的最佳剂量和使用的活性物质种类。
本发明的化合物和/或盐如果用于治疗上面提到的疾病，那么制药学的配制品也可以含有一种或多种其它药物类的药理学活性成分，像抗酸药，例如氢氧化铝、铝酸镁；安定药，像苯并二氮杂，例如安定；解痉药，像例如比他维林、卡米罗芬；抗胆碱能药，像例如羟苄克利明、苯胺硫酯；局部麻醉药，像例如丁卡因、普鲁卡因；在必要时也可含有酶、维生素或氨基酸。
应强调的是，在这些组成中本发明的化合物与抑制酸分泌的药物相结合，像例如H2阻滞剂(例如西咪替丁、糠硝烯二胺)、H+/K+-腺甙三磷酸酶抑制物质(例如，奥莫哌唑(Omeprazol)、潘妥哌唑(Pantoprazol))，或者进而与所谓次要的抗胆碱能药(例如，哌吡二氮、Telenzepin)以及与带有下述目的胃泌素拮抗药相结合，下述目的是指添加或过添加的意图在于增强主作用和/或清除或减少副作用，或者为了杀伤Helicobacter pylori进而与抗菌活性的物质(像例如头孢菌素、四环素、萘啶酮酸、青霉素或者也有铋盐)相结合。
药理学
本发明化合物的极好的胃保护作用和胃酸分泌抑制作用可以在动物试验模型检验中被证明。给下面举出的检验本发明化合物的模型加上序号，这些序号与实施例中的化合物序号一致。
对灌注大鼠胃的抑制分泌检查
在下列表1中示出本发明化合物在静脉内给药后对在体内经五肽胃泌素刺激的灌注大鼠的胃酸分泌的影响
表1序号 剂量 在3.5小时时酸分泌物的最大抑制
(μmol/kg) (相对于先前值)(％)
在体内2 1 974 1 835 1 807 1 92
方法学
已麻醉的大鼠(CD大鼠，雌性，200-250g，每公斤大鼠平均1.5g氨基甲酸乙酯)在切开气管后，经过中央上腹部截面打开腹部，并通过口在食管中固定一根聚氯乙烯光学纤维导管以及经过幽门固定另一根聚氯乙烯光学纤维导管，光学纤维导管的固定要使软管刚好突进到胃内腔。这根从幽门引出的光学纤维导管经过一个测面开口向外引入右腹部壁。
在彻底灌洗(约50-100ml)之后，使37℃的热生理NaCl溶液连续流过胃(0.5ml/min,pH6.8-6.9,Braur-Unita I)。在总是以15分钟间隔接收的(25ml量杯)流出物中，测定pH值(pH测量计632，玻璃电极EA147,φ=5mm,Metrohm)以及用新配制的0.01NNaOH滴定至pH7(剂量计655Metrohm)测定分泌的HCL。
在外科手术结束后(也就是在确定二份初馏分后)通过体内持续注入每公斤1μg(=1.65ml/h)五肽胃泌素(左股静脉)约30分钟，进行刺激胃分泌。在五肽胃泌素持续注入开始后，要检验的物质以每公斤1ml液体体积静脉给药60分钟。
动物的体温通过红外线照射和加热垫(通过直肠温度检测计自动、无级调节)保持在恒定的37.8-38℃。
分子式页
Claims (8)
1．式Ⅰ的化合物及其盐，
其中，R1表示1-4C-烷基，
R2表示1-4C-烷基，
R3表示1-4C-烷氧基-2-4C烷氧基，
R4表示1-4C-烷基，或羟甲基，以及
A表示O(氧)或NH。
2．权利要求1所述的式Ⅰ化合物及其盐，其中，R4表示羟甲基，A表示O(氧)，而R1、R2和R3具有权利要求1给出的含义。
3．按照权利要求1所述的化合物，其中所述化合物是8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氧基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇及其盐。
4．按照权利要求1所述的化合物，其中所述化合物是8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2-甲基咪唑并[1,2-a]吡啶-3-甲醇及其盐。
5．按照权利要求1所述的化合物，其中所述化合物是8-{2-[(2-甲氧基乙氧基)羰基氨基]-6-甲基苄氨基}-2,3-二甲基咪唑并[1,2-a]吡啶及其盐。
6．权利要求1的式Ⅰ化合物及其盐的制备方法，其特征在于，
a)使式Ⅱ的化合物或其盐与式Ⅲ的化合物或其盐进行反应，
在式Ⅱ中，R1、R4和A具有权利要求1给出的含义，在式Ⅲ中，R2和R3具有权利要求1给出的含义，X表示一个合适的反应活性离去基团，
或者
b)为了制备式Ⅰ的化合物，式中R4表示羟甲基，还原式Ⅳ的化合物，式中，R1、R2、R3
和A具有权利要求1给出的含义，并且在需要时，接着使按照a)或b)所得到的化合物Ⅰ转变成它的盐，或者在需要时，接着从所得到的化合物Ⅰ的盐游离出化合物Ⅰ。
7．药物，其中含有权利要求1的一种化合物和/或其药理学相容的盐。
8．权利要求1的化合物及其药理学相容的盐在制备用于预防和治疗肠胃疾病的药物方面的用途。
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| DE19602855A1 (de) * | 1996-01-26 | 1997-07-31 | Byk Gulden Lomberg Chem Fab | Neue 3-Methylimidazopyridine |
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| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
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| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| UA80393C2 (uk) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Фармацевтична композиція, яка містить інгібітор фде 4, диспергований в матриці |
| DE10145457A1 (de) | 2001-09-14 | 2003-04-03 | Basf Ag | Substituierte Imidazo[1,2-a]-5,6,7,8-tetrahydropyridin-8-one, Verfahren zu ihrer Herstellung, sowie deren Verwendung zur Herstellung von Imidazo[1,2,-a]pyridinen |
| MY140561A (en) * | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| SI1606261T1 (sl) | 2003-03-10 | 2010-03-31 | Nycomed Gmbh | Novi postopek za pripravo roflumilasta |
| AU2004285394B2 (en) | 2003-11-03 | 2009-01-08 | Astrazeneca Ab | Imidazo (1,2-A) pyridine derivatives for the treatment of silent gastro-esophageal reflux |
| JP5383183B2 (ja) * | 2005-03-16 | 2014-01-08 | タケダ ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロフルミラストを含有する矯味された剤形 |
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| EP0033094A1 (en) * | 1980-01-23 | 1981-08-05 | Schering Corporation | Imidazo(1,2-a)pyridines, processes for their preparation and pharmaceutical compositions containing them |
| EP0268989A1 (en) * | 1986-11-26 | 1988-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
| JPH02270873A (ja) * | 1989-03-13 | 1990-11-05 | Fujisawa Pharmaceut Co Ltd | イミダゾピリジン化合物およびその製造法 |
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| US4725601A (en) * | 1985-06-04 | 1988-02-16 | Fujisawa Pharmaceutical Co., Ltd. | Certain imidazo[1,2-a]pyridines useful in the treatment of ulcers |
| EP0228006A1 (en) * | 1985-12-16 | 1987-07-08 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
| EP0266890A1 (en) * | 1986-10-07 | 1988-05-11 | Yamanouchi Pharmaceutical Co. Ltd. | Imidazopyridine derivatives, their production, and pharmaceutical compositions containing them |
| GB8722488D0 (en) * | 1987-09-24 | 1987-10-28 | Fujisawa Pharmaceutical Co | Imidazopyridine compound |
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1994
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- 1994-10-08 WO PCT/EP1994/003326 patent/WO1995010518A1/de active IP Right Grant
- 1994-10-08 DK DK94930158T patent/DK0723544T3/da active
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- 1994-10-08 ES ES94930158T patent/ES2157992T3/es not_active Expired - Lifetime
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- 1994-10-08 AU AU79372/94A patent/AU685176B2/en not_active Ceased
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1996
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1998
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2001
- 2001-05-28 GR GR20010400798T patent/GR3035943T3/el not_active IP Right Cessation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0033094A1 (en) * | 1980-01-23 | 1981-08-05 | Schering Corporation | Imidazo(1,2-a)pyridines, processes for their preparation and pharmaceutical compositions containing them |
| EP0268989A1 (en) * | 1986-11-26 | 1988-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
| JPH02270873A (ja) * | 1989-03-13 | 1990-11-05 | Fujisawa Pharmaceut Co Ltd | イミダゾピリジン化合物およびその製造法 |
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