CN1035766C - N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 - Google Patents
N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 Download PDFInfo
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- CN1035766C CN1035766C CN92109428A CN92109428A CN1035766C CN 1035766 C CN1035766 C CN 1035766C CN 92109428 A CN92109428 A CN 92109428A CN 92109428 A CN92109428 A CN 92109428A CN 1035766 C CN1035766 C CN 1035766C
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- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
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- OTGHWLKHGCENJV-UHFFFAOYSA-N glycidic acid Chemical class OC(=O)C1CO1 OTGHWLKHGCENJV-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
新的N-磺酰基-四氢-[1，3]-二庚并[5，6-b]-氮杂环丙(因在及其制备中所用中间产物的制备方法。
从顺-2-丁烯-1，4-二醇开始，通过4，7-二氢-1，3-二环庚-5-烯和反-6-酰氨基-5-氯代-1，3-二氧杂环庚烷，合成新的四氢-[1，3]-二庚并[5，6-b]-氮杂环丙因，由此得到新的具有降血糖活性的N-磺酰基-四氢-[1，3]-二庚并[5，6-b]氮杂环丙因。这些产物亦是合成其它生物活性物质的有价值的中间体。
Description
本发明是关于新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因(N-sulfonyl-tetrahydro-[1，3]-dioxepino[5，6-b]-azirines)及其制备时所用中间产物的制备方法的；这些化合物可用作降血糖剂。
已知非胰岛素依赖性II型糖尿病(非胰岛素依赖性糖尿病，NIDDM)的临床治疗目前只依靠两类降血糖化合物：磺酰尿类和双胍类。[R.SARGES，Progr.Med.Chem.18，191(1981)；A.C.ASMAL和A.MARBLE，Drugs，28，62(1984)；L.P.KRALL in：Joslin′sDiabetes Mellitus，12th Ed.，Lea & Febiger，Philadelphia，1985，p.412]。
亦已知，已对各种类型化合物中有代表性的化合物，如噻唑啉二酮(ciglitazone，pioglitazone，CP-72467)，磺酰基咪唑啉(CGP 11112)，羧基脒(linogliride)，环氧乙烷羧酸类(etomoxir)，piridyl-乙基咪唑啉(DG 5128)，多糖类(阿卡糖)等等的降血糖活性进行了临床试验，但因功效不足或其它原因，尚无一种在市场上出售[R.J.MOHRBACHER等人，Ann.Rep.Med.Chem.22，213(1987)；E.R.LARSON等人，Ann.Rep.Zed.Chem.25，205(1989)；K.E.STEINER和E.L.LIEN，Prog.Med.Chem，24，209(1987)；S.C.STINSON，Chem.Eng.News，Sept.30，1991].
据发明人对现有技术进行的检索表明，下面通式I的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因代表了一类新的杂环化合物和一类新的有效的降血糖剂。
本发明的目的是制备通式为I的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因式中R1和R2可以是氢原子，直链或支链的C1-4的烷基，或苯基，R1＋R2可以是亚烷基，如四亚甲基，五亚甲基或六亚甲基，R3可以是烷基，如甲基或三氟甲基或对位取代的苯基
式中X可以是氢原子，直链或支链的C1-4烷基，或卤原子如氟、氯、溴或碘，或硝基，氨基，或酰氨基如乙酰氨基，或烷氧基如甲氧基，
据通常公知的合成N-磺酰基-氮杂环丙因的下列反应(方案1-4)之一
其中，Z为离去基团。[O.C.Dermer，G.E.Ham，Ethyleneimine and OtherAziridines，Chemistry and Applications，AcademicPress，New York，London，1969；P.E.Fanta，in：A.Weissberger(Ed)，The Chemistry of HeterocyclicCompounds，Vol.19，Partl，Interscience Publishers，New York，London，Sydney，1964.，p.524]尤其是根据上述方案(1)，先用易于从市场上得到的顺-2-丁烯-1，4-二醇与通式II的醛或酮反应
式中R1和R2的定义同上，生成通式III的4，7-二氢-1，3-二噁环庚-5-烯(4，7-dihydro-1，3-dioxepins)
式中R1和R2的定义同上，再使该化合物在通式IV的有机腈中与氯化腈反应
R4-CN IV式中R4表示直链或支链的C1-4烷基或苄基，使得到的通式V的反-酰氨基-氯代-二氧杂环庚烷(Trans-acylamino-chlorodioxepans)(式中R1、R2和R4的定义同上)脱卤化氢环化生成通式VI的四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因
式中R1和R2的定义同上，该化合物与通式VII的磺酰氯反应，
R3-SO2Cl VII式中R3的定义同上，生成通式I中R1和R2的定义同上，R3为4-酰氨基苯基的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因最后进行碱催化的水解反应，得到R3为4-氨基苯基如4-乙氨基苯基的通式I的新化合物，通式I中R1、R2的定义同上(方案5)。
采用文献[C.E：pawloshy，Dloxepins and Trioxepins，in：A.Weissberger，E.CTaylor(Eds.)，The Chemietry of HeterocyclicCompounds，Vol.26，Wiley Interscience New York，1972，p.319[中公开的方法，根据上述方案5，很容易得到通式III的二庚-5-烯。据文献资料]M.Dumic，M.V.Prostenik，I.Butula，Croat.Chem.Acta.51，259，(1978)；M.Dumic，Maiser Thesis，Faculy of Technology，ZagrebUniversity，1977]，很容易得到通式V的反-酰氨基-氯代二氧杂环庚烷。
据申请人的研究，通式VI的二庚并氮杂环丙(因不是公知的，但在生成氮杂环丙因的反应条件下(100℃的苏打水溶液，或氢氧化钾的热乙醇溶液)，通式V的潜在的前体(potential precursors)生成邻位的酰氨基-二烷醇[M.SOVAK，R.RANGANATHAN，US4389526(1983.6.21)，或二庚并并-唑啉(dioxepino-axozolines)(M.DUMIC等人，Org.Prep.Proc.Int.24，545(1992)inpress]。
现已意外发现，在20℃-150℃，优选50℃-100℃的范围内，在碱性氢氧化物如钠或钾的氢氧化物水溶液中，用等摩尔比反应物且碱性氢氧化物过量直到5倍摩尔，优选过量1.5-2.5摩尔条件下，可将通式V的化合物转变制成通式VI的二庚并-氮杂环丙因。
通式VI的化合物与通式VII的磺酰氯的反应可按文献中公知的条件进行，如按化学计量的摩尔比，或按磺酰氯(V)过量1.1-2.0，优选1.1-1.3摩尔，用或不用惰性有机溶剂，如选自甲苯或二甲苯的芳烃溶剂，选自二氯甲烷、氯仿或1，2-二氯乙烷的氯化烃溶剂，更进一步地在乙酸乙酯、二噁烷、二甲基甲酰胺或二甲亚砜中，在等摩尔量或过量1.1-2.0，优选1.1-1.3摩尔有机碱如吡啶，三乙胺或吗啉(morpholine)存在下，或在用作溶剂的碱中反应。该反应亦可在通式VI的氮杂环丙因过量2-5，最好2-3摩尔条件下进行，其中该通式化合物用作碱以除掉反应期间产生的氯化氢。
采用常规水解法，在碱介质中，可使通式I中R3＝4-酰氨基苯基如4-乙酰基苯基的化合物脱酰而成通式I中R3＝4-氨基苯基的化合物。
新的通式VI的四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙因适宜用作合成生物活性物质，尤其是降血糖剂的中间产物。
通式I的化合物可用作合成生物活性物质，尤其是降血糖剂的中间产物。
通式I的化合物可作为活性成份，用于制备具有降血糖活性的药剂。
意外发现按本发明得到的通式I的化合物，在阿脲诱发(alloxan-induced)小鼠和大鼠糖尿病的实验模型中，不管用药方式如静脉、皮下注射或口服，都显示出明显的，或者说甚至是非常强烈的降血糖活性。举例言之，按10mg/kg剂量给小鼠皮下用Ia 4hr后，与患糖尿病但未给药的动物相比，血中葡萄糖(糖)浓度降低37％，即血糖浓度为63％。按20mg/kg剂量给小鼠静脉用Ia 40min后，血中葡萄糖甚至降到患糖尿病但未给药的动物的血糖值的33％。按20mg/kg剂量给小鼠口服化合物Ia 6hr后，血中葡萄糖降至起始浓度的60％。在一类似实验中，按20mg/kg剂量给糖尿病患鼠(大鼠)皮下用化合物Ia 4hr后，血中葡萄糖浓度降至起始浓度的67％。
对降血糖活性的评价实验，在体重20-25g的CBA种小鼠和体重160-200g的Fischer种大鼠身上进行。将这些鼠置于笼内，按12hr光照：12hr无光照的日程，随意喂食食物和水。将阿脲四水合物(65mg/kg；Merck)一次注入尾静脉，使诱发高血糖症(C.C.RERUP，Pharmacol.Rev.22，485(1970))。注射阿脲48hr后对受试动物进行测试。从尾静脉取出第一次血样(0.025ml)后，立即将试验药物(通式I的化合物，溶于最少量的DMSO中，且用盐水-9.0％NaCl稀释)通过皮下或静脉或通过胃饲管(经口)一次注入。根据用药剂量和给药方式，在不同时间间隔(1-24hr.)抽取其它血样。用酶法(P.TRINDER，Ann.Clin.Biochem.6，24(1969))分析血中葡萄糖。计算结果时，血糖用mmol/l全血表示。第一次血样作为对照值，表示为100％。
由小鼠所得结果示于下面表1中：
表1
s.c. 血糖 起始的百分数； 小时化合物 剂量 N*
mg/kg 1 4 24
Ia 5 5 79 99 101
10 6 - 63 -
20 13 37 53 93
Ib 2 6 94 104 -
10 5 53 57 88
Ic 10 5 76 80 113
Id 10 6 77 87 87
Ie 20 6 107 100 -
If 20 6 94 96 -
Ih 10 5 78 90 116
Ii 2 6 - 94 -
20 5 - 68 70
Im 10 6 85 93 100
Io 10 5 78 101 -*N＝实验用动物数
另一方面，通式I的化合物并未降低健康(无糖尿病的对照组)的动物的血糖浓度。Ia在健康小鼠和大鼠身上的试验结果示于下面表2。
表2化合物 动物 剂量及 N* 血糖 (mmole/L 全血)；小时
给药方式 0 1 2
20mg/kg；i.v. 12 8.83±0.58 8.82±0.91 -Ia 小鼠 20mg/kg；s.c. 6 12.43±0.69 14.41±0.75 13.15±0.72
100mg/kg；s.c. 6 11.72±2.45 12.09±1.01 13.17±0.70Ia 大鼠 20mg/kg；s.c. 7 5.52±0.19 5.44±0.18 -*N＝实验用动物数
综上所述，通式为I的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因代表了一类有效的降血糖剂，可通过常规制药技术，制成适用的、具有短期或长期活性的治疗糖尿病的药物剂型，如片剂，丸剂、粉剂、锭剂、胶囊、颗粒，溶液等等。
下面通过实施例进一步说明本发明，但决非作任何限制。实施例1
使由10.0g氯酰胺V(R1＝R2＝H，R4＝CH3)，7.2g氢氧化钾和150cm3水组成的混合物在回流冷凝器下沸腾90min，冷却到室温后用氯仿萃取。蒸出氯仿，蒸馏残余物经过硅胶柱色谱，用氯仿/甲醇混合物(25∶1)洗提，得到浅黄油状二噁庚并-氮杂环丙因VIa(R1＝R2＝H)。
B.p.90-93℃/2.1KPa。
类似地，用相应氯酰胺V制出下面的四氢-[1，3]-二噁庚并[5，6-b]氮杂环丙因VI：
表3
| VI | R1 | R2 |
| abcdefghi | HHHHHCH3 | HCH3CH2CH3CH(CH3)2PhenylCH3 |
| -(CH2)4--(CH2)5--(CH2)6- | ||
实施例2
在室温下，搅拌由0.120g二噁庚并一氮杂环丙因VIa(R1＝R2＝H)，0.260g 4-乙酰氨基苯基-磺酰氯，0.17g吡啶和5.0cm3二氯甲烷组成的混合物60min。另外加20cm3二氯甲烷后，将2×10cm3氢氧化钠溶液(1∶1)混入混合物，分离有机层，用10cm3水洗后，经稀盐酸中和至pH＝6，再用10cm3水洗一次，置无水硫酸钠上干燥。蒸出二氯甲烷，得到粗制的色谱纯(Rf＝0.57；洗提液：乙酸乙酯/甲醇＝20∶1；检测：UV254nm，硅胶板Merck 60 F254)磺酰基氮杂环丙因Ia(R1＝R2＝H，R3＝4-乙酰氨基苯基)。M.p.210-212℃(乙酸乙酯/甲醇＝1∶1)。
用相应的氮杂环丙因VI和磺酰氯VII，合成出下列磺酰基氮杂环丙因I：
表4
实施例3
使由0.313g磺酰基氮杂环丙因Ia(R1＝R2＝H，R3＝4-乙酰基-氨基苯基)，0.140g氢氧化钾和3cm3水组成的混合物回流沸腾30min，浓缩成稠浆，用氯仿提取。蒸出氯仿。蒸馏残余物经过色谱硅胶柱，用乙酸乙酯/甲醇＝20∶1混合物洗提，得到色谱纯(硅胶Merck 60F254，；洗提液：乙酸乙酯/甲醇＝20∶1；检测：UV254nm；碘蒸气：棕色；水合茚三酮溶液：仙客来属红色；Rf＝0.65)磺酰基氮杂环丙因Iv(R1＝R2＝H，R3＝4-氨基苯基)，该物为浅黄一淡红色的。
类似水解通式I的相应的N-(4-乙酰氨基-苯磺酰基)-氮杂环丙因，得到下列N-(4-氨基-苯磺酰基)-氮杂环丙因I：
表5
Claims (5)
1、一种制备通式为I的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的方法，
式中R1和R2可以是氢原子，直链或支链的C1-4的烷基，或苯基，R3可以是烷基或对位取代的苯基式中，X可选自氢原子、直链或支链的C1-4烷基、卤原子、硝基、氨基、酰氨基或烷氧基；
其特征在于按下列通常公知的合成N-磺酰基-氮杂环丙因的方案1-4之一进行制备：
其中，Z为离去基团。
2、如权利要求1所述的方法，其特征在于：所述的R3可以是甲基，或对位由乙酰氨基或甲氧基取代的苯基。
3、如权利要求1或2所述的方法，其特征在于：使顺-2-丁烯-1，4-二醇与通式II的醛或酮反应，
式中，R1和R2的定义同上，生成通式III的4，7-二氢-1，3-二噁环庚-5-烯，
式中R1和R2的定义同上，再使该化合物在通式IV的有机腈中与氯化腈反应
R4-CN IV式中R4表示直链或支链的C1-4烷基或苄基，得到的通式V的反-酰氨基-氯代-二氧杂环庚烷
式中R1、R2和R4的定义同上，
在20-150℃的温度下，在碱性氢氧化物的水溶液中，用等摩尔比反应物且碱性氢氧化物过量直到5倍摩尔的条件下，使得到的通式V转变成为通式VI的四氢-[1，3]-二噁烷庚并[5，6-b]-氮杂环丙因式中R1和R2的定义同上，
该化合物与通式VII的磺酰氯反应，
R3-SO2Cl VII式中R3的定义同上，生成通式I中R1和R2的定义同上，R3为4-酰氨基苯基的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因最后进行碱催化的水解反应，得到R3为4-氨基苯基的通式I的新化合物，通式I中R1、R2的定义同上。
4、如权利要求3所述的方法，其特征在于：在50-100℃的温度下，在碱性氢氧化物的水溶液中，用等摩尔比反应物且碱性氢氧化物过量1.5-2.5倍摩尔的条件下，使得到的通式V的反-酰氨基-氯代-二氧杂环庚烷转变成为通式VI的四氢-[1，3]-二噁烷庚并[5，6-b]-氮杂环丙因。
5、如权利要求4所述的方法，其特征在于：
由通式VI与通式VII的磺酰氯反应所生成的R1和R2的定义同上，R3为4-乙酰氨基苯基的新的N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因最后进行碱催化的水解反应，得到R3为4-氨基苯基的通式I的新化合物，通式I中R1、R2的定义同上。
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9111433A SI9111433B (sl) | 1991-08-22 | 1991-08-22 | Novi N-sulfonil-tetrahidro-/1,3/-dioksepino/5,6-b/azirini, postopek priprave, intermediati za njihovo pripravo in uporaba |
| RU94043428A RU2118324C1 (ru) | 1991-08-22 | 1992-08-20 | N-сульфонилтетрагидро-[1,3]-диоксепино[5,6-b] азирины и промежуточные продукты для их получения |
| JP5504124A JPH08506565A (ja) | 1991-08-22 | 1992-08-20 | Ｎ−スルホニルテトラヒドロ−〔１，３〕−ジオキセピノ−〔５，６−ｂ〕−アジリン類、その調製のための方法と中間体および用途 |
| CS94392A CZ39294A3 (en) | 1991-08-22 | 1992-08-20 | N-SULFONYL-TETRAHYDRO-/1,3/-DIOXEPINO/5,6-b/AZIRINES, PROCESSES AND INTERMEDIATES OF THEIR PREPARATION AND THEIR USE |
| HU9402713A HUT70948A (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirine derivatives pharmaceutical compositions containing them and process for preparing them |
| EP92917719A EP0641345A1 (en) | 1991-08-22 | 1992-08-20 | Hypoglycemic n-sulfonyl-tetrahydro- 1,3]-dioxepino 5,6-b]azirines |
| PCT/EP1992/001913 WO1993004067A1 (en) | 1991-08-22 | 1992-08-20 | Hypoglycemic n-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines |
| US07/932,482 US5286744A (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-biazirines, intermediates for their preparation and their use |
| CA002115269A CA2115269A1 (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines, methods and intermediates for their preparation, and their use |
| SK210-94A SK21094A3 (en) | 1991-08-22 | 1992-08-20 | N-sulfonyl-tetrahydro-/1,3/-dioxepino/5,6-b/azirines, methods and intermediates of their preparation and use |
| CN92109428A CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
| HR930891A HRP930891A2 (en) | 1991-08-22 | 1993-05-13 | NEW N-SULFONIL-TETRAHIDRO-/1,3/-DIOKSEPINO/5,6-b/ AZYRINES, METHODS, PREPARATIONS, INTERMEDIATES AND USE |
| BG98627A BG61570B1 (en) | 1991-08-22 | 1994-03-01 | N-sulphonyl-tetrahydro-[1,3]-dioxepino[5,6-b]azirines,methods and means for their preparation and their usage |
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| YU143391 | 1991-08-22 | ||
| CN92109428A CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92109428A Expired - Fee Related CN1035766C (zh) | 1991-08-22 | 1992-08-22 | N-磺酰基-四氢-[1，3]-二噁庚并[5，6-b]-氮杂环丙因的制备方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5286744A (zh) |
| EP (1) | EP0641345A1 (zh) |
| JP (1) | JPH08506565A (zh) |
| CN (1) | CN1035766C (zh) |
| BG (1) | BG61570B1 (zh) |
| CA (1) | CA2115269A1 (zh) |
| CZ (1) | CZ39294A3 (zh) |
| HR (1) | HRP930891A2 (zh) |
| HU (1) | HUT70948A (zh) |
| RU (1) | RU2118324C1 (zh) |
| SI (1) | SI9111433B (zh) |
| SK (1) | SK21094A3 (zh) |
| WO (1) | WO1993004067A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0669335A1 (en) * | 1994-02-21 | 1995-08-30 | PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija, dionicko drustvo | N-sulfonyl-tetrahydro-[1,3]-dioxepino [5,6] azirines with hypoglycemic activity |
| HRP940123A2 (en) * | 1994-02-21 | 1997-04-30 | Sour Pliva | New hydroxylamines with hypoglycemic activity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1262315A (en) * | 1968-03-14 | 1972-02-02 | Geigy Ag J R | New benzenesulphonamide derivatives, their production ond compositions containing same |
| US4389526A (en) * | 1981-08-03 | 1983-06-21 | The Regents Of The University Of California | Intermediates and synthesis of 2-amino-2-deoxytetritols |
| EP0094595A1 (de) * | 1982-05-14 | 1983-11-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Neue Aziridin- und Phenäthanolaminderivate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3624912A1 (de) * | 1986-07-23 | 1988-02-04 | Studiengesellschaft Kohle Mbh | Optisch reine 1,3-dioxenone, verfahren zu ihrer herstellung und ihre verwendung |
-
1991
- 1991-08-22 SI SI9111433A patent/SI9111433B/sl unknown
-
1992
- 1992-08-20 RU RU94043428A patent/RU2118324C1/ru active
- 1992-08-20 JP JP5504124A patent/JPH08506565A/ja active Pending
- 1992-08-20 US US07/932,482 patent/US5286744A/en not_active Expired - Fee Related
- 1992-08-20 EP EP92917719A patent/EP0641345A1/en not_active Withdrawn
- 1992-08-20 CA CA002115269A patent/CA2115269A1/en not_active Abandoned
- 1992-08-20 WO PCT/EP1992/001913 patent/WO1993004067A1/en not_active Application Discontinuation
- 1992-08-20 HU HU9402713A patent/HUT70948A/hu unknown
- 1992-08-20 CZ CS94392A patent/CZ39294A3/cs unknown
- 1992-08-20 SK SK210-94A patent/SK21094A3/sk unknown
- 1992-08-22 CN CN92109428A patent/CN1035766C/zh not_active Expired - Fee Related
-
1993
- 1993-05-13 HR HR930891A patent/HRP930891A2/xx not_active Application Discontinuation
-
1994
- 1994-03-01 BG BG98627A patent/BG61570B1/bg unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1262315A (en) * | 1968-03-14 | 1972-02-02 | Geigy Ag J R | New benzenesulphonamide derivatives, their production ond compositions containing same |
| US4389526A (en) * | 1981-08-03 | 1983-06-21 | The Regents Of The University Of California | Intermediates and synthesis of 2-amino-2-deoxytetritols |
| EP0094595A1 (de) * | 1982-05-14 | 1983-11-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Neue Aziridin- und Phenäthanolaminderivate |
Non-Patent Citations (1)
| Title |
|---|
| J.O.C.54,16(1989)3945-52 * |
Also Published As
| Publication number | Publication date |
|---|---|
| SI9111433B (sl) | 1999-02-28 |
| CA2115269A1 (en) | 1993-03-04 |
| JPH08506565A (ja) | 1996-07-16 |
| RU2118324C1 (ru) | 1998-08-27 |
| RU94043428A (ru) | 1996-06-20 |
| BG61570B1 (en) | 1997-12-30 |
| US5286744A (en) | 1994-02-15 |
| HRP930891A2 (en) | 1996-04-30 |
| HUT70948A (en) | 1995-11-28 |
| CZ39294A3 (en) | 1995-01-18 |
| BG98627A (bg) | 1995-06-30 |
| SK21094A3 (en) | 1995-08-09 |
| EP0641345A1 (en) | 1995-03-08 |
| WO1993004067A1 (en) | 1993-03-04 |
| SI9111433A (sl) | 1998-04-30 |
| CN1083065A (zh) | 1994-03-02 |
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