CN1012642B - 氨磺酰苯甲酸衍生物的制备方法 - Google Patents
氨磺酰苯甲酸衍生物的制备方法Info
- Publication number
- CN1012642B CN1012642B CN85108940A CN85108940A CN1012642B CN 1012642 B CN1012642 B CN 1012642B CN 85108940 A CN85108940 A CN 85108940A CN 85108940 A CN85108940 A CN 85108940A CN 1012642 B CN1012642 B CN 1012642B
- Authority
- CN
- China
- Prior art keywords
- acid derivatives
- group
- compound
- sulfamoylbenzoic acid
- mouse
- 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.)
- Expired
Links
- KDNIOKSLVIGAAN-UHFFFAOYSA-N 2-sulfamoylbenzoic acid Chemical class NS(=O)(=O)C1=CC=CC=C1C(O)=O KDNIOKSLVIGAAN-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 7
- -1 methylenedioxy) group Chemical group 0.000 claims description 6
- 150000004885 piperazines Chemical class 0.000 claims description 4
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000003424 uricosuric effect Effects 0.000 abstract description 7
- 230000001882 diuretic effect Effects 0.000 abstract description 4
- 239000002934 diuretic Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 9
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 8
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 229940116269 uric acid Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 210000002700 urine Anatomy 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 208000004880 Polyuria Diseases 0.000 description 4
- 230000035619 diuresis Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BWSSMIJUDVUASQ-UHFFFAOYSA-N Benzylhydrochlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 BWSSMIJUDVUASQ-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229950007003 benzylhydrochlorothiazide Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 3
- 229960003081 probenecid Drugs 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229940116731 Uricosuric agent Drugs 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000003383 uricosuric agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
- C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及新的和有用的氨磺酰苯甲酸衍生物的制备方法，它具有利尿和促尿酸尿的作用。
Description
本发明涉及某些新型的氨磺酰苯甲酸（SVLFAMOYLBENZOIC ACID）衍生物及其制备方法。这些衍生物具有有效的排盐利尿作用，促尿酸尿作用以及降血压作用。因此，本发明的化合物构成了一类有价值的药剂，它们可用来对伴有肝病或心脏病特别是伴有心力衰竭的水肿进行药疗，以及用来治疗高血压、血尿酸过多等疾病。
本发明之更详细的内容是，它涉及一些新的氨磺酰苯甲酸衍生物，其化学式为
其中的R1是氯原子或苯氧基团，R2是氢原子、囟素原子、低级烷基、低级烷氧基或亚甲二氧基团，本发明还涉及这些衍生物的制备方法。
本发明的化合物（Ⅰ）可通过使氨磺酰苯甲酸（Ⅱ）或它们的活性衍生物与哌嗪衍生物（Ⅲ）在缩合剂存在下进行反应而被制备出来。
这里的R1和R2具有如上所述的意义。
氨磺酰苯甲酸衍生物（Ⅱ）与哌嗪衍生物（Ⅲ）的反应是在缩合剂的存在下进行的，这类缩合剂有N，N-双环己基碳化二亚胺（N，N′-dicyclohexylcarbodiimide）、NN′-碳酰二咪唑（N、N′-carbonyldiimidazole）等等。
这一反应是通过把缩合剂加入到化合物（Ⅱ）和（Ⅲ）的混合物中而进行的。对缩合来说也方便的是在缩合剂的存在下化合物（Ⅱ）首先转化成它的酸酐，然后该酸酐与化合物（Ⅲ）进行反应，适合这一反应的溶剂是一类对质子有隋性的溶剂，例如氯仿、四氢呋喃、二甲基甲酰胺等等。
在把氨磺酰苯甲酸（Ⅱ）的活性衍生物与哌嗪衍生物（Ⅲ）进行反应的情况下，该酸的氯化物或溴化物是用作活性衍生物的。在这种情况下，三乙胺、吡啶、碳酸钠、碳酸钾或者其它这类物质被用作缩合剂，而苯、甲苯、甲酰胺、二氯甲烷、四氢呋喃或其它这类物质则被用作溶剂。
为了使本发明能被充分理解，现给出以下实施例。
实施例1 4-氯-N-[4-（2-甲氧基苯基）-1-哌嗪基]-3-氨磺酰苯甲酸胺
在室温且搅拌的条件下，把处在20毫升四氢呋喃中的2.1克4-氯-3-氨磺酰苯甲酸溶液加入到5毫升四氢呋喃中的1.8克N，N′-双环己基碳化二亚胺溶液中。完全加入之后，该混合物就在室温下进行20分钟的搅拌，然后加入0.83克的1-氨基-4-（2-甲氧基苯基）哌嗪，此后，该反应混合物再被搅拌5小时。接着，再加入5毫升10%的盐酸并在室温下搅拌10分钟。又加入250毫升2%的氢氧化钠溶液并把不溶物质过滤掉。之后，又采用2%的氢氧化钠溶液对滤液进行碱化从而获得白色的沉淀。所生成的沉淀物被过滤出来并用水冲洗，最后从乙醇中再沽晶出来，于是就获得了如本文标题所述的化合物，其生成量为0.84克（49%），这是一种无色的晶体，熔点为232～
235℃。
对C18H21CN4O4S进行分析（%）。计算的（括号中为实测的为：C，50、88（51，06）;H，4.98（5.02）;N，13，19（13.19）。
实施例2 4-氯-N-[4-（2-甲氧基苯基）-1-哌嗪基]-3-氨磺酰苯甲酰胺
在室温且搅拌的条件下，把1.25克的4-氯-3-氨磺酰基甲酰氯加入到1克1-氨基-4-（2-甲氧基苯基）哌嗪和1毫升三乙胺的混合物中。然后，在室温下对该反应混合物进行9小时的搅拌。接着，所生成的沉淀物被过滤出来并用水冲洗，最后从乙醇中再结晶出来，于是就获得了如本文标题所述的化合物，其生成量为1.20克（60%）这是一种无色的针状晶体，熔点为231～233℃。
对C18H21ClN4O4S进行分析，计算的（括号中为实测的）为：C，50，88（50，58）;H，4.98（5.19）;N.13.19（13.15）。
表1列出了用与实施例2中相同的程序而制备的其它的新化合物。（表1见文后）
（Ⅱ）
采用一些大约重300克的雄性Wistar系老鼠。每一组由5只老鼠组成。经过18小时的断粮断水之后，就把本发明的化合物和参照药物从口中引入到鼠的机体中。其结果如表2所示。实施例1和6的化合物是有效的利尿剂，并显示出自然的排盐利尿性能。（表2见文后）
Na+K+：钠和钾的总排泄量（毫克当量/公斤）。
UV：尿体积（毫升/公斤）
Behyd：苄基氢氯噻嗪类
HCT：氢氯噻嗪类
＊，＊＊：不同于对照物，分别为P（0.05，P＜0.01）
实验2 促尿酸尿效果
在出生后11～14个星期的雄性Wistar系老鼠上进行清除实验。每一组由5只老鼠组成。根据清除率（尿酸的清除/菊粉的清除）对促尿酸尿活性进行了评价。其结果如图1所示。显然，实施例1的化合物要比被称为促尿酸尿剂的丙磺舒（Probrnecid）具有更有效的促尿酸尿效果。
实验3 在剧烈地载有尿酸的老鼠中显示的降尿酸血Hypouricemic）的效果。
用生后十个重期的雄性Wistar系老鼠进行这一实验。在把药物引入老鼠机体之前先在30分钟之内以200毫克/公斤的剂量把尿酯引入到老鼠的腹膜内。实施例1的化合物和丙磺舒被引入到鼠的腹膜。30分钟之后，通过驱血法把这些老鼠弄死。把血收集起来然后测定出血清尿酸的含口量。表3已表明，实施例1的化合物也具有降尿酸血（Hypouricemic）的活性。表3剧烈被载有尿酸的老鼠中的血清尿酸含量（表3见文后）
实施例4 降血压作用
以100毫克/公斤的剂量每天口服实施例1的化合物达四天之后就降低了原来就有高血压病症的老鼠的收缩（血）压。数据列在表4中。（表4见文后）
实施例5 急性毒性
以2.500毫克/公斤的剂量让老鼠口服实施例1的化合物以后，没有一只ICR系的老鼠死亡。
图1显示了实施例1的化合物和其它药物的促尿酸尿活性。纵坐标表示了促尿酸尿活性随含盐基团对照物的变化而发生的百
表1
实施例 分析
编号 R1R2熔点（℃） 生成量（%） 计算/实测
C H N
3 Cl 2-CH3253-255 33.3 52.87 5.17 13.70
52.64 5.15 13.66
4 Cl H 255-257 30.2 51.71 4.85 14.19
51.78 4.76 14.15
5 Cl 2-iso-Pr 190-192 22.5 53.39 5.91 12.46
53.22 5.63 12.34
6 Cl 3-OCH3267-269 30.0 50.88 4.98 13.19
50.79 4.97 13.08
7＊Cl 2-Cl 149-151 40.0 46.94 4.41 12.86
46.91 4.32 12.87
8＊＊Cl 2-F 245-247 34.1 49.49 4.02 13.58
49.38 4.46 13.31
9 Cl 3，4-OCH2O- 270 50.8 49.26 4.36 12.77
49.13 4.30 12.65
10＊＊＊o-Ph 2-OCH3211-214 3.6 58.86 5.51 11.44
59.17 5.39 11.06
11 Cl 4-OCH3245-247 62.7 48.82 5.45 12.65
49.10 5.17 12.66
＊：1/3 H2O，＊＊：1/9 H2O，＊＊＊：2/5H2O。
为证实该类化合物之用途所进行的实验如下所述。
实验1 利尿和排盐利尿的效果
表2
利尿和排盐利尿的效果
0-5小时 0-24小时
对照物 Na+1.43±0.18 2.89±0.25
（含盐的） K+1.15±0.15 4.01±0.09
UV 23.8±±1.78 41.8±1.78
实施例1 Na+3.85±0.28＊＊＊6.66±0.29＊＊
（25毫克/公斤，P.O.） K+1.33±0.07 4.88±0.22＊＊
UV 36.1±4.14＊63.1±2.13＊＊
Behyd Na+4.48±0.53＊＊7.98±0.87＊＊
（25毫克/公斤，P.O）′ K+1.57±0.19 5.62±0.43＊
UV 42.5±4.51＊72.0±6.71＊＊
HCT Na+5.24±0.47＊＊7.75±0.60＊＊
（25毫克/公斤，P.O） K+1.69±0.20 5.45±0.55
UV 42.9±3.31＊＊66.6±4.31＊＊
对照物 Na+0.56±0.14 2.67±0.07
（含盐的） K+0.31±0.05 1.72±0.12
UV 19.8±2.03 28.7±1.97
实施例6 Na+1.52±0.18＊＊4.15±0.25＊＊
（10毫克/公斤，P.O.） K+0.65±0.06＊＊2.12±0.11＊
UV 26.6±2.74 38.9±2.00＊＊
表3
剂量 血清尿酸 比率 N
（毫克/公斤，i.p.） （毫克/分升）
盐水 1.27±0.11 1 8
丙磺舒 10 1.88±0.31 1.45 5
100 0.79±0.14＊0.62 4
Behyd 10 1.15±0.16 0.91 5
实施例1 10 0.90±0.08＊0.71 5
＊：不同于盐水，P＜0.05。
表4 降血压效果
收缩（血）压 心率 N
（mmHg） （次/分钟）
盐水 178±3.5 403±13 3
实施例1 158±3.9＊417±9 3
（100毫克/公斤，P.O.×4天）
＊：不同于含盐基团，P＜0.05。
Claims (1)
1、一种氨磺酰苯甲酸衍生物的制备方法，其化学式为
的氨磺酰苯甲酸衍生物，其中的R1是选自氯原子或苯氧基团中的一种，R2是选自氢原子、卤素原子、低级烷基团、低级烷氧基团或亚甲二氧基团中的一种，该方法包括采用N，N-双环已基碳化二亚胺，使化学式为：
的哌嗪衍生物与化学式为
的氨磺酰苯甲酸衍生物进行反应，或者与化学式为Ⅱ的化合物的活性衍生物进行反应。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59256877A JPS61134382A (ja) | 1984-12-04 | 1984-12-04 | 新規なスルファモイル安息香酸誘導体およびその製造法 |
| JP59-256877 | 1984-12-04 | ||
| JP256877/84 | 1984-12-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85108940A CN85108940A (zh) | 1986-10-22 |
| CN1012642B true CN1012642B (zh) | 1991-05-22 |
Family
ID=17298651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85108940A Expired CN1012642B (zh) | 1984-12-04 | 1985-12-03 | 氨磺酰苯甲酸衍生物的制备方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4650871A (zh) |
| EP (1) | EP0186796B1 (zh) |
| JP (1) | JPS61134382A (zh) |
| KR (1) | KR900003371B1 (zh) |
| CN (1) | CN1012642B (zh) |
| AU (1) | AU569812B2 (zh) |
| CA (1) | CA1241960A (zh) |
| DE (1) | DE3573253D1 (zh) |
| DK (1) | DK167760B1 (zh) |
| ES (1) | ES8702394A1 (zh) |
| FI (1) | FI80686C (zh) |
| HU (1) | HU194200B (zh) |
| NO (1) | NO168245C (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2027898A6 (es) * | 1991-01-24 | 1992-06-16 | Espanola Prod Quimicos | Procedimiento de preparacion de nuevos derivados de la 2-metoxifenilpiperacina. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2663707A (en) * | 1951-06-22 | 1953-12-22 | American Cyanamid Co | Amino piperazines and methods of preparing the same |
| FR1448711A (fr) * | 1960-11-09 | 1966-03-18 | Sandoz Sa | Nouveaux dérivés de l'hydrazine et leur préparation |
| US3200121A (en) * | 1964-08-05 | 1965-08-10 | Searle & Co | Disubstituted-alkanoyl hydrazides of 1-aminopiperazines |
| FR2104930B1 (zh) * | 1970-09-08 | 1974-08-30 | Ferlux | |
| DE2611705A1 (de) * | 1976-03-18 | 1977-09-22 | Josef Dipl Chem Dr Rer N Klosa | N-5-(nitrofurfuryliden-)-1-amino- hydantoin enthaltende kristalloesungsmittel |
| CA1082181A (en) * | 1976-06-03 | 1980-07-22 | Eric A. Watts | Benzamide derivatives |
| GB8303946D0 (en) * | 1983-02-12 | 1983-03-16 | Recordati Chem Pharm | Antihypertensive n-piperazinylalkanoylanilides |
-
1984
- 1984-12-04 JP JP59256877A patent/JPS61134382A/ja active Granted
-
1985
- 1985-11-27 AU AU50431/85A patent/AU569812B2/en not_active Ceased
- 1985-11-29 FI FI854745A patent/FI80686C/fi not_active IP Right Cessation
- 1985-12-02 CA CA000496626A patent/CA1241960A/en not_active Expired
- 1985-12-03 KR KR1019850009043A patent/KR900003371B1/ko not_active IP Right Cessation
- 1985-12-03 CN CN85108940A patent/CN1012642B/zh not_active Expired
- 1985-12-03 DK DK559185A patent/DK167760B1/da not_active IP Right Cessation
- 1985-12-03 EP EP85115296A patent/EP0186796B1/en not_active Expired
- 1985-12-03 DE DE8585115296T patent/DE3573253D1/de not_active Expired
- 1985-12-03 US US06/804,123 patent/US4650871A/en not_active Expired - Fee Related
- 1985-12-03 NO NO854872A patent/NO168245C/no unknown
- 1985-12-04 HU HU854643A patent/HU194200B/hu not_active IP Right Cessation
- 1985-12-04 ES ES549559A patent/ES8702394A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| KR900003371B1 (ko) | 1990-05-16 |
| KR860004864A (ko) | 1986-07-14 |
| EP0186796A1 (en) | 1986-07-09 |
| JPS61134382A (ja) | 1986-06-21 |
| FI854745A (fi) | 1986-06-05 |
| HU194200B (en) | 1988-01-28 |
| FI80686B (fi) | 1990-03-30 |
| AU5043185A (en) | 1986-06-12 |
| ES8702394A1 (es) | 1987-01-01 |
| NO168245B (no) | 1991-10-21 |
| DK559185D0 (da) | 1985-12-03 |
| AU569812B2 (en) | 1988-02-18 |
| DK167760B1 (da) | 1993-12-13 |
| US4650871A (en) | 1987-03-17 |
| CN85108940A (zh) | 1986-10-22 |
| CA1241960A (en) | 1988-09-13 |
| ES549559A0 (es) | 1987-01-01 |
| JPH0434997B2 (zh) | 1992-06-09 |
| NO854872L (no) | 1986-06-05 |
| NO168245C (no) | 1992-01-29 |
| EP0186796B1 (en) | 1989-09-27 |
| DE3573253D1 (en) | 1989-11-02 |
| HUT40428A (en) | 1986-12-28 |
| DK559185A (da) | 1986-06-05 |
| FI80686C (fi) | 1990-07-10 |
| FI854745A0 (fi) | 1985-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1032750C (zh) | 新的聚4-氨基-2-羟基-1-甲基化合物脲基衍生物的制备方法 | |
| US4125620A (en) | 2-[(2',6'-Disubstituted-phenyl)-imino]-imidazolidines and salts thereof | |
| CN1016061B (zh) | 制备芳族2-氨烷基-1，2-苯并异噻唑-3(2h)酮-1，1-二氧化物衍生物的方法 | |
| CN1134146A (zh) | 新的苯甲酰胍衍生物及其制备方法和在药物组合物中的应用 | |
| EP0124476B1 (de) | Carboxamide, Verfahren zur Herstellung und pharmazeutische Präparate, die diese enthalten | |
| JP2556722B2 (ja) | 新規なスルホンアミド化合物 | |
| CN1205689A (zh) | 新的2,3,5－三甲基－4－羟基－n－酰苯胺衍生物及其制备方法与应用 | |
| CN1065459A (zh) | 哌啶衍生物及其制备方法和治疗应用 | |
| CN1031060C (zh) | 新颖酯类的制造方法 | |
| CN87101183A (zh) | 抗肿瘤试剂活性的增进剂及其制备方法 | |
| CN1119338C (zh) | 用作抗糖尿病剂的α－(1－哌嗪基)乙酰氨基芳烃羧酸衍生物 | |
| CN87106996A (zh) | 喹啉基化合物，它们的制备方法和以其作为有效药物组分的抗癌剂 | |
| CN1019911C (zh) | 新的苯并嗪衍生物的制备方法 | |
| CN1067885A (zh) | 2-氨基嘧啶-4-甲酰胺衍生物及其制法和医疗应用 | |
| CN1012642B (zh) | 氨磺酰苯甲酸衍生物的制备方法 | |
| CN87105612A (zh) | 嘧啶衍生物 | |
| JPS6323191B2 (zh) | ||
| US3894033A (en) | 5-Aryltetrazoles | |
| CN87105791A (zh) | 喹唑啉二酮和吡啶并嘧啶二酮及其制备方法 | |
| CN1019889C (zh) | 脲衍生物的制备方法 | |
| EP0084292B1 (en) | N,n-disubstituted alkenamides and phenylalkenamides, processes for their production and their use as pharmaceuticals | |
| CN1046281C (zh) | 药理活性的对映体及其制备方法 | |
| US3689657A (en) | Indole derivatives in the treatment of skeletal muscle fatigability | |
| CN1019196B (zh) | 2-噻唑烷酮类衍生物的制备方法 | |
| CN1015452B (zh) | 丁烯酰胺及其盐的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |