JPH0449230A - Antagonistic agent against thromboxane az - Google Patents
Antagonistic agent against thromboxane azInfo
- Publication number
- JPH0449230A JPH0449230A JP16069990A JP16069990A JPH0449230A JP H0449230 A JPH0449230 A JP H0449230A JP 16069990 A JP16069990 A JP 16069990A JP 16069990 A JP16069990 A JP 16069990A JP H0449230 A JPH0449230 A JP H0449230A
- Authority
- JP
- Japan
- Prior art keywords
- thromboxane
- group
- antagonist
- formula
- agent
- 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.)
- Pending
Links
- 230000003042 antagnostic effect Effects 0.000 title abstract description 5
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 title abstract description 4
- 150000002332 glycine derivatives Chemical class 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- 208000007814 Unstable Angina Diseases 0.000 claims abstract description 3
- 208000006673 asthma Diseases 0.000 claims abstract description 3
- 201000008383 nephritis Diseases 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 208000005189 Embolism Diseases 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 206010002388 Angina unstable Diseases 0.000 claims description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 2
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 2
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 2
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 229940127218 antiplatelet drug Drugs 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
- 201000006370 kidney failure Diseases 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 2
- 230000035939 shock Effects 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 claims 8
- 230000003449 preventive effect Effects 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
- 206010003225 Arteriospasm coronary Diseases 0.000 claims 1
- 208000003890 Coronary Vasospasm Diseases 0.000 claims 1
- 201000011634 coronary artery vasospasm Diseases 0.000 claims 1
- 208000001286 intracranial vasospasm Diseases 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 23
- -1 (substituted) phenyl Chemical group 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 3
- 230000004520 agglutination Effects 0.000 abstract 1
- 238000013329 compounding Methods 0.000 abstract 1
- 230000008602 contraction Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 13
- 239000005557 antagonist Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000010378 Pulmonary Embolism Diseases 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 2
- GWDGBGXTKCRZPX-UHFFFAOYSA-N 2-(4-nitrophenyl)propan-1-amine;hydrochloride Chemical compound Cl.NCC(C)C1=CC=C([N+]([O-])=O)C=C1 GWDGBGXTKCRZPX-UHFFFAOYSA-N 0.000 description 1
- SXJTYYRZSKPXDX-UHFFFAOYSA-N 2-[4-[1-[(4-chlorophenyl)sulfonylamino]propan-2-yl]anilino]acetic acid Chemical compound C=1C=C(NCC(O)=O)C=CC=1C(C)CNS(=O)(=O)C1=CC=C(Cl)C=C1 SXJTYYRZSKPXDX-UHFFFAOYSA-N 0.000 description 1
- DPLJNTWBXCKJOL-UHFFFAOYSA-N 3-bromo-4,5-diethoxybenzonitrile Chemical compound CCOC1=CC(C#N)=CC(Br)=C1OCC DPLJNTWBXCKJOL-UHFFFAOYSA-N 0.000 description 1
- UXAZIFYAGDKABZ-UHFFFAOYSA-N 4-(2-aminopropyl)aniline Chemical compound CC(N)CC1=CC=C(N)C=C1 UXAZIFYAGDKABZ-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010059109 Cerebral vasoconstriction Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 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
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010072564 Peripheral artery thrombosis Diseases 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010037437 Pulmonary thrombosis Diseases 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- RGXJHXQSHFPCDZ-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC.CCCCCC RGXJHXQSHFPCDZ-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical group CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- URXRGRNWQOGSGQ-UHFFFAOYSA-N n-[1-(4-aminophenyl)propan-2-yl]-4-chlorobenzenesulfonamide Chemical compound C=1C=C(Cl)C=CC=1S(=O)(=O)NC(C)CC1=CC=C(N)C=C1 URXRGRNWQOGSGQ-UHFFFAOYSA-N 0.000 description 1
- NMSRYTBRGJAPFT-UHFFFAOYSA-N n-[2-(4-aminophenyl)propyl]benzenesulfonamide Chemical compound C=1C=C(N)C=CC=1C(C)CNS(=O)(=O)C1=CC=CC=C1 NMSRYTBRGJAPFT-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Abstract
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は優れたトロンボキサンＡ２拮抗剤に関する。[Detailed description of the invention] (Industrial application field) The present invention relates to superior thromboxane A2 antagonists.
（従来の技術）
Ｎ−（４−（２−ベンゼンスルホニルアミノエチル）フ
ェニルコグリシンが血小板凝集抑制作用を有することは
知られている（西ドイツ国特許出願公開第３６２２８６
５号）。(Prior art) It is known that N-(4-(2-benzenesulfonylaminoethyl)phenylcoglycine has an inhibitory effect on platelet aggregation (West German Patent Application No. 362286).
No. 5).
（発明が解決しようとする課題）
トロンボキサンＡＨ（Ｔｈｒｏａ＋ｂｏｘａｎ ＡＨ，
以下ＴｘＡｚと称する）は動物の各種臓器（例えば、肝
臓、腎臓、肺臓、脳等）に広く存在しているアラキドン
酸が代謝されて生成し、このＴｘＡｚが有する血小板凝
集作用に起因して、しばしば末梢動脈血栓症、肺塞栓症
、冠動脈閉塞症、心筋梗塞症、−過性脳虚血症等の各種
血栓症が引き起こされることが知られている。そこで本
発明は、優れたＴｘＡ、拮抗剤を提供するものである。(Problem to be solved by the invention) Thromboxane AH (Throa+boxan AH,
TxAz (hereinafter referred to as TxAz) is produced by the metabolism of arachidonic acid, which is widely present in various organs of animals (e.g., liver, kidneys, lungs, brain, etc.). Due to the platelet aggregation effect of TxAz, it is often It is known that various thromboses such as peripheral artery thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, and hyperactive cerebral ischemia are caused. Therefore, the present invention provides an excellent TxA antagonist.
（課題を解決するための手段）
本発明は一般式
（但し、Ｒ１は置換基を有することもあるフェニル基、
Ｒ２及びＲ３はいずれか一方が低級アルキル基、他方が
水素原子、Ｒ４は保護されていてもよいカルボキシル基
、Ｑは低級アルキレン基、ｍはＯまたは１を表す。）
で示されるグリシン誘導体またはその薬理的に許容しう
る塩を有効成分として含有するＴｘＡ ｚ拮抗剤に関す
る。(Means for Solving the Problems) The present invention is based on the general formula (wherein R1 is a phenyl group which may have a substituent,
One of R2 and R3 is a lower alkyl group, the other is a hydrogen atom, R4 is an optionally protected carboxyl group, Q is a lower alkylene group, and m is O or 1. ) The present invention relates to a TxA z antagonist containing a glycine derivative represented by the following formula or a pharmacologically acceptable salt thereof as an active ingredient.
本発明の有効成分であるグリシン誘導体の具体例として
は、−数式（１）においてＲ１がフェニル基またはハロ
ゲノフェニル基であり、Ｒ４が遊離のカルボキシル基で
あるか、または、例えば、低級アルキル基、フェニル低
級アルキル基、低級アルコキシ基置換フェニル低級アル
キル基、ニトロ基置換フェニル低級アルキル基またはベ
ンズヒドリル基などの保護基で保護されたカルボキシル
基である化合物があげられる。Specific examples of glycine derivatives that are active ingredients of the present invention include - In formula (1), R1 is a phenyl group or a halogenophenyl group, R4 is a free carboxyl group, or, for example, a lower alkyl group, Examples include compounds that are carboxyl groups protected with protecting groups such as phenyl lower alkyl groups, lower alkoxy group-substituted phenyl lower alkyl groups, nitro group-substituted phenyl lower alkyl groups, and benzhydryl groups.
このうち、薬効上好ましい化合物は、Ｒ′が遊離のカル
ボキシル基または低級アルコキシカルボニル基である化
合物である。より好ましい化合物は、低級アルキル基、
低級アルコキシ基及び低級アルキレン基がそれぞれ炭素
数１〜３のアルキル基、アルコキシ基及びアルキレン基
の化合物である。さらに好ましい化合物は、ＲＩがフェ
ニル基またはクロロフェニル基であり、Ｒｚ及びＲ３の
いずれか一方がメチル基、他方が水素原子であり、Ｒ４
が遊離のカルボキシル基の化合物である。Among these, compounds in which R' is a free carboxyl group or a lower alkoxycarbonyl group are preferred from a pharmaceutical standpoint. More preferred compounds include lower alkyl groups,
The lower alkoxy group and the lower alkylene group are compounds of an alkyl group having 1 to 3 carbon atoms, an alkoxy group, and an alkylene group, respectively. In a more preferred compound, RI is a phenyl group or a chlorophenyl group, one of Rz and R3 is a methyl group, the other is a hydrogen atom, and R4
is a compound with a free carboxyl group.
本発明の有効成分であるグリシン誘導体（１）は遊離の
形でも、またその薬理的に許容しうる塩の形でも本発明
の用途に用いることができる。薬理的に許容しうる塩と
しては、無機あるいは有機塩基との塩、例えばナトリウ
ム塩、カリウム塩の如きアルカリ金属塩、カルシウム塩
、マグネシウム塩の如きアルカリ土類金属塩、亜鉛塩の
如き重金属塩、アンモニウム塩、トリエチルアミン塩、
ピリジン塩、エタノールアミン塩、塩基性アミノ酸塩の
如き有機アミン塩が含まれる。Glycine derivative (1), which is the active ingredient of the present invention, can be used in the present invention in its free form or in its pharmacologically acceptable salt form. Pharmaceutically acceptable salts include salts with inorganic or organic bases, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, heavy metal salts such as zinc salts, ammonium salt, triethylamine salt,
Included are organic amine salts such as pyridine salts, ethanolamine salts, and basic amino acid salts.
本発明のＴｘｌｌｚ拮抗剤は経口的にも非経口的にも投
与することができ、また、常法により例えば錠剤、カプ
セル剤、散剤、注射剤のような適宜の医薬製剤として用
いることができる。The Txllz antagonist of the present invention can be administered either orally or parenterally, and can be used in the form of appropriate pharmaceutical preparations such as tablets, capsules, powders, and injections by conventional methods.
本発明のＴｘＡ、拮抗剤の投与量は投与方法、患者の年
齢、体重、状態及び治療すべき疾患の種類によっても異
なるが、通常１日当たり、有効成分化合物にして約０．
０１〜５０ｍｇ／ｋｇ、とりわけ０．０５〜２０■／ｋ
ｇ程度となるよう投与するのが好ましい。The dosage of the TxA antagonist of the present invention varies depending on the administration method, the age, weight, condition of the patient, and the type of disease to be treated, but is usually about 0.00% of the active ingredient compound per day.
01-50mg/kg, especially 0.05-20■/k
It is preferable to administer the amount to about 100 g.
本発明の有効成分であるグリシン誘導体（１）は１個の
不斉炭素原子に基づく２種の光学異性体が存在しうるが
、本発明はこれら異性体及びその混合物のいずれをも包
含するものである。The glycine derivative (1), which is the active ingredient of the present invention, may have two types of optical isomers based on one asymmetric carbon atom, but the present invention includes both these isomers and mixtures thereof. It is.
本発明の有効成分であるグリシン誘導体（Ｉ）は、例え
ば、−数式
（但し、Ｒ１，Ｒ１及びＲ３は前記と同一意味を有する
。Glycine derivative (I), which is an active ingredient of the present invention, can be expressed, for example, by the formula - (where R1, R1 and R3 have the same meanings as above).
で示される化合物またはその塩と一般式ＸＣＨｚ（ＣＯ
ＮＨ−Ｑ）ｒＲ” （ｍ ）（但し、Ｘは反応性
残基、Ｒ４１は保護されていてもよいカルボキシル基、
Ｑ及びｍは前記と同一意味を有する。）
で示される化合物とを脱酸剤（例えば炭酸水素ナトリウ
ム）の存在下に縮合反応させ、１１７４１が保護された
カルボキシル基である場合は、所望により保護基を除去
して製造することができる。The compound represented by or its salt and the general formula XCHz(CO
NH-Q)rR'' (m) (where, X is a reactive residue, R41 is an optionally protected carboxyl group,
Q and m have the same meanings as above. ) in the presence of a deoxidizing agent (for example, sodium hydrogen carbonate), and when 11741 is a protected carboxyl group, the protecting group can be removed if desired.
また、本発明の有効成分であるグリシン誘導体（Ｉ）の
うちｍ＝１の化合物は、−数式（但し、Ｒ１，Ｒ２及び
Ｒ３は前記と同一意味を有する。）で示される化合物ま
たはそのカルボキシル基における反応性誘導体と一般式
％式％（）
（但し、Ｒ４１及びＱは前記と同一意味を有する。）で
示されるアミン化合物またはその塩とを脱酸剤（例えば
カルボニルジイミダゾール）の存在下に縮合反応させ、
Ｒ４１が保護されたカルボキシル基である場合は、所望
により当該保護基を除去して製造することもできる。Furthermore, among the glycine derivatives (I) which are the active ingredients of the present invention, the compound where m=1 is a compound represented by the formula - (wherein R1, R2 and R3 have the same meanings as above) or its carboxyl group. The reactive derivative and the amine compound represented by the general formula % (where R41 and Q have the same meanings as above) or a salt thereof are combined in the presence of a deoxidizing agent (for example, carbonyldiimidazole). Condensation reaction,
When R41 is a protected carboxyl group, the protecting group can be removed if desired.
なお、本発明の有効成分であるグリシン誘導体の、原料
化合物（ｎ）は、例えば−数式（但し、Ｙはニトロ基ま
たはアミノ基を表し、ｐＸ及びＲ３は前記と同一意味を
有する。）で示される化合物と一般式
％式％
（但し、Ｒ′は前期と同一意味を有する。）で示される
スルホン酸化合物またはその反応性誘導体とを縮合反応
させて一般式
（但し、Ｙ、Ｒ’、Ｒ２及びＲ３は前記と同一意味を有
する。）
で示される化合物とし、Ｙがニトロ基である場合にはさ
らに還元してアミノ基に変換することにより製造するこ
とができる。The raw material compound (n) of the glycine derivative which is the active ingredient of the present invention is, for example, represented by the formula - (wherein, Y represents a nitro group or an amino group, and pX and R3 have the same meanings as above). A condensation reaction is carried out between a compound represented by the general formula %formula% (wherein, R' has the same meaning as in the previous term) or a reactive derivative thereof, and a compound represented by the general formula (wherein, Y, R', R2 and R3 have the same meanings as above.) When Y is a nitro group, it can be produced by further reducing it to convert it into an amino group.
第１表
実験例
アラキドン 憬 （ｉｎ ｖｉｖｏ）−
夜絶食させたｄｄｙ系、雄性マウスに、検体のカルボキ
シメチルセルロース溶液を経口投与（２０ｄ／ｋｇ ）
Ｌ、た。３時間後、アラキドン酸（１２５ｍｇ７１０
ｄ／ ｋｇ）溶液を尾静脈内に投与して肺塞栓を誘発さ
せた。アラキドン酸投与から、歩行運動が回復するまで
の時間（回復時間二分）を測定し、検体の代わりに０．
２５χＣＭＣを投与した検体非投与群のそれと比較して
行った。検体のアラキドン酸誘発肺塞栓抑制作用は、検
体非投与群に比べ上記回復時間を１５％以上短縮させた
投与量で表した。Table 1 Experimental Examples Arachidon yin (in vivo)
A carboxymethyl cellulose solution was orally administered (20 d/kg) to male DDY mice that had been fasted overnight.
L, ta. After 3 hours, arachidonic acid (125mg710
d/kg) solution was administered intravenously into the tail vein to induce pulmonary embolism. The time from the administration of arachidonic acid to the recovery of walking movement (recovery time of 2 minutes) was measured, and 0.
This was compared with that of a group to which 25χCMC was administered but no sample was administered. The inhibitory effect of the arachidonic acid-induced pulmonary embolism of the specimen was expressed as the dose that shortened the recovery time by 15% or more compared to the group to which the specimen was not administered.
結果は第１表の通りである。The results are shown in Table 1.
注）実験に供した各検体の化合初老は次の通り。Note) The compound age of each sample used in the experiment is as follows.
□ム
Ｉ Ｎ−（４−（２−（４−クロロフェニル）ス
ルホニルアミノ−１−メチルエ
チル〕フェニル）グリシン・ナトリウ
ム塩
Ｎ−（４−（２−（（４−クロロフェ
ニル）スルホニルアミノ〕プロピル〕
フェニル）グリシン・ナトリウム塩
３− ［［［４−［２−（４−クロロフェニル）スルホ
ニルアミノ−１−メチ
ルエチル］フェニル〕アミノ］アセチ
ルアミノ） −ｎ−プロピオン酸・ナトリウム塩
４− （（［４−（２−（４−クロロフェニル）スルホ
ニルアミノ−１−メチ
ルエチル〕フェニル〕アミノ〕アセチ
ルアミノ）−ｎ−１１酸・ナトリウム塩４− （（（４
−（２−（ベンゼンスルホニルアミノ）−１−メチルエ
チル〕
フェニル〕アミノ〕アセチルアミノ）
−ｎ−酪酸・ナトリウム塩
３− （（［４−（２−（（４−クロロフェニル）スル
ホニルアミノ］プロピ
ル〕フェニル〕アミノ〕アセチルアミ
ノ）−ｎ−プロピオン酸・ナトリウム
７ ４−（（（４−（２−（（４−クロロフェニル
）スルホニルアミノ）プロピ
ル〕フェニル〕アミノ〕アセチルアミ
ノ） −ｎ−酪酸・ナトリウム塩
対照検体： Ｎ−［４−（２−ベンゼンスルホニルアミ
ノエチル）フェニルコグリシン・
ナトリウム塩
（製造例）
製造例１
１− （４−アミノフェニル）−２−ベンゼンスルホニ
ルアミノ−１−メチルエタン２．５ｇ、炭酸水素ナトリ
ウム１．０９ｇ、ヘキサメチルホスホリックトリアミド
１５ｄの混合物に、水冷下にブロモ酢酸エチル１．５１
ｇを滴下し、水冷下で１時間、さらに室温で３０分間撹
拌する。反応混合物に水を加え、酢酸エチル抽出する。□MuI N-(4-(2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl)glycine sodium salt N-(4-(2-((4-chlorophenyl)sulfonylamino]propyl) phenyl ) Glycine, sodium salt 3- [[[4-[2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl]amino]acetylamino) -n-propionic acid, sodium salt 4- (([4- (2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl]amino]acetylamino)-n-11 acid, sodium salt 4- (((4
-(2-(benzenesulfonylamino)-1-methylethyl] phenyl]amino]acetylamino) -n-butyric acid, sodium salt 3- (([4-(2-((4-chlorophenyl)sulfonylamino]propyl) phenyl]amino]acetylamino)-n-propionic acid, sodium 7 4-(((4-(2-((4-chlorophenyl)sulfonylamino)propyl]phenyl]amino]acetylamino)-n-butyric acid, sodium salt Control specimen: N-[4-(2-benzenesulfonylaminoethyl)phenylcoglycine sodium salt (Production example) Production example 1 2.5 g of 1-(4-aminophenyl)-2-benzenesulfonylamino-1-methylethane , 1.51 g of ethyl bromoacetate was added to a mixture of 1.09 g of sodium hydrogen carbonate and 15 d of hexamethylphosphoric triamide under cooling with water.
g was added dropwise, and the mixture was stirred for 1 hour under water cooling and further stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate.
抽出液を乾燥し、溶媒を留去する。残渣をシリカゲルカ
ラムクロマトグラフィー（溶出液；クロロホルム：エタ
ノール＝２０：１）にて分離精製し、さらに酢酸エチル
−ｎ−ヘキサン混液から再結晶してＮ（４−（２−ベン
ゼンスルホニルアミノ−１−メチルエチル）フェニルコ
グリシンエチル１．８９ｇを得る。The extract is dried and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (eluent; chloroform:ethanol = 20:1), and further recrystallized from a mixture of ethyl acetate and n-hexane to give N(4-(2-benzenesulfonylamino-1- 1.89 g of ethyl phenylcoglycine (methylethyl) are obtained.
収率 ５８％
Ｍ、ｐ、７０−７１°Ｃ
Ｉ ＲＶ ｍａｘ （ｃｍ−’） ： １７４
０製造例２〜１２
対応原料化合物を製造例１と同様に処理して、上記第２
及び３表記載の化合物を得る。Yield 58% M, p, 70-71°C I RV max (cm-'): 174
0 Production Examples 2 to 12 The corresponding raw material compounds were treated in the same manner as Production Example 1 to produce the second
and the compounds listed in Table 3 are obtained.
ＩＲ” ：
■
Ｒνｎ＊ｘ （Ｃｍ
を表す
（以下、
同様）
第３表
製造例１３
Ｎ−（４−（２−（４−クロロフェニル）スルホニルア
ミノ−１−メチルエチル〕フェニル）グリシンエチル１
．８ｇのエタノール３０ｄ！溶ｉにＩＮ−水酸化ナトリ
ウム水溶液５．３１１を加え、室温で１７時間攪拌する
０反応後溶媒を留去し、残渣をイソプロピルアルコール
−水混液から再結晶してＮ−（４−（２−（４−クロロ
フェニル）スルホニルアミノ−１−メチルエチル〕フェ
ニル）グリシン・ナトリウム塩１．１１ｇを無色結晶と
して得る。IR”: ■ Rνn*x (Represents Cm (hereinafter the same) Table 3 Production Example 13 N-(4-(2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl)glycineethyl 1
．． 8g of ethanol 30d! Add 5.31 l of IN-sodium hydroxide aqueous solution to the solution and stir at room temperature for 17 hours. After the reaction, the solvent was distilled off, and the residue was recrystallized from an isopropyl alcohol-water mixture to give N-(4-(2- 1.11 g of (4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl)glycine sodium salt is obtained as colorless crystals.
収率 ６３％ Ｍ、ｐ、２４２−２４４°Ｃ（分解） ＩＲｖ、、Ｘ （。ｍ−１） ： ３１００゜ ＩＲ’″’： ＩＲｖ、、、（ｃｍ−’）を表す。Yield 63% M, p, 242-244°C (decomposition) IRv,,X (.m-1): 3100° IR''': represents IRv, , (cm-').
遊離カルボン酸：
製造例１４〜１６
対応原料化合物を製造例１３と同様に処理して、下記第
４表記載の化合物を得る。Free Carboxylic Acid: Production Examples 14 to 16 The corresponding starting compounds were treated in the same manner as in Production Example 13 to obtain the compounds listed in Table 4 below.
第４表
製造例１７
Ｎ−（４−［２−（４−クロロフェニル）スルホニルア
ミノ−１−メチルエチル］フェニル）グリシン １．９
６ｇを塩化メチレン３０ｄ及びテトラヒドロフラン３０
１１ｊ！の乾燥混合溶媒に溶解し、水冷下カルボニルジ
イミダゾール０．８３ｇを加え、室温で１．５時間攪拌
する。次いで３−アミノプロピオン酸メチル塩酸塩７１
４ｍｇ及びトリエチルアミン５２０■を加え、室温で１
時間反応させた後、メタノール１ ｍｌを加え、溶媒を
留去する。残渣を酢酸エチル抽出し、抽出液を洗浄、乾
燥後、溶媒を留去し、さらに残渣をシリカゲルカラムク
ロマトグラフィー（溶出液；クロロホルム：酢酸エチル
−４＝１）にて分離精製して３−（［（４−（２−（４
−クロロフェニル）スルホニルアミノ−１−メチルエチ
ル〕フェニル〕アミノ〕アセチルアミノ） −ｎ−プロ
ピオン酸メチルを得る。Table 4 Production Example 17 N-(4-[2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl)glycine 1.9
6g of methylene chloride 30d and tetrahydrofuran 30d
11j! 0.83 g of carbonyldiimidazole was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Then methyl 3-aminopropionate hydrochloride 71
Add 4 mg and 520 μm of triethylamine, and stir at room temperature.
After reacting for an hour, 1 ml of methanol is added and the solvent is distilled off. The residue was extracted with ethyl acetate, the extract was washed and dried, the solvent was distilled off, and the residue was separated and purified using silica gel column chromatography (eluent: chloroform:ethyl acetate -4=1) to obtain 3-( [(4-(2-(4
-chlorophenyl)sulfonylamino-1-methylethyl]phenyl]amino]acetylamino)-methyl propionate is obtained.
本島の物理恒数は製造例５の目的物のそれと一敗した。The physical constants of the main island were completely inferior to those of the target in Production Example 5.
製造例１８〜２５
製造例５〜１２の生成物を製造例１３と同様に処理して
下記第５表記載化合物を得る。Preparation Examples 18-25 The products of Preparation Examples 5-12 are treated in the same manner as in Preparation Example 13 to obtain the compounds listed in Table 5 below.
（原料化合物の製造）
参考例１
（１）２−アミノ−１−メチル−１−（４−ニトロフェ
ニル）エタン・塩酸塩３．０ｇを炭酸水素ナトリウム３
．４８ｇ、水２０ｍ及び酢酸エチル３０ｄの混合物に水
冷攪拌下で加え、ついでベンゼンスルホニルクロリド２
．６９ｇを加える。水冷下で２０分間、さらに室温で４
０分間攪拌した後、酢酸エチル層を分取し、洗浄後乾燥
する。溶媒を留去し、残渣をシリカゲルカラムクロマト
グラフィー（溶出液；クロロホルム二〇−へキサン：酢
酸エチル−７：２：１）にて分離精製し、さらにクロロ
ホルムートヘキサン混液がら再結晶して２ベンゼンスル
ホニルアミノ−１−メチル−１−（４−ニトロフェニル
）エタン３．５４ｇをＩる。(Production of raw material compound) Reference example 1 (1) 3.0 g of 2-amino-1-methyl-1-(4-nitrophenyl)ethane hydrochloride was mixed with 3.0 g of sodium hydrogen carbonate.
．． 48 g of benzenesulfonyl chloride, added to a mixture of 20 m of water and 30 d of ethyl acetate under stirring under water cooling, and then added 2 ml of benzenesulfonyl chloride.
．． Add 69g. 20 minutes under water cooling, then 4 minutes at room temperature.
After stirring for 0 minutes, the ethyl acetate layer is separated, washed, and dried. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (eluent: chloroform di-hexane: ethyl acetate - 7:2:1), and then recrystallized from a chloroform-meth-hexane mixture to obtain 2 3.54 g of benzenesulfonylamino-1-methyl-1-(4-nitrophenyl)ethane are added.
ＩＲＩ／ｍａＸ（ｃｍ−’） ： ３３００＋
３２８０． １５９０（２）本島３．５ｇのエタノール
１５０ｄ溶液に１０％パラジウム−炭素０．３５ｇを加
え、常温常圧下、接触還元する。反応終了後、触媒をろ
去し、溶媒を留去する。残渣をクロロホルム−ｎ−ヘキ
サン混液から再結晶して、１−（４−アミノフェニル）
−２−ベンゼンスルホニルアミノ−ｌメチルエタン２．
６２ｇを得る。IRI/maX (cm-'): 3300+
3280. 1590 (2) Main Island Add 0.35 g of 10% palladium-carbon to a solution of 3.5 g of ethanol 150d and perform catalytic reduction at room temperature and pressure. After the reaction is complete, the catalyst is filtered off and the solvent is distilled off. The residue was recrystallized from a chloroform-n-hexane mixture to give 1-(4-aminophenyl).
-2-benzenesulfonylamino-l methylethane2.
Obtain 62g.
Ｍ、ｐ、１３Ｂ−１４１°Ｃ
Ｔ Ｒｖ ｍｉｘ （ｃｍ−リ ： ３４４０．３
３６０．１６２０参考例２
（１）対応原料化合物を参考例１−（１）と同様に処理
して１−（４〜ニトロフエニル）−２−（４−クロロツ
ユニル）スルホニルアミノ−１−メチルエタンを得る。M, p, 13B-141°C T Rv mix (cm-re: 3440.3
360.1620 Reference Example 2 (1) The corresponding raw material compound is treated in the same manner as in Reference Example 1-(1) to obtain 1-(4-nitrophenyl)-2-(4-chlorotuunyl)sulfonylamino-1-methylethane.
Ｍ、ｐ、１１４−１１６℃（クロロホルム−ｎヘキサン
混液から再結晶）
（２）本島３．１ｇをエタノール２０−に加犬、ついで
撹拌下７０゛Ｃで塩化第二スズ２水和物９．８６ｇを５
分間かけて加える。同温で３時間撹拌後、氷１００ｇに
反応混合物を注ぐ。１０％水酸化ナトリウム水溶液でア
ルカリ性にし、析出物をろ別する。ろ液を塩化メチレン
抽出し、抽出液を乾燥後、溶媒を留去し、残渣をクロロ
ホルム−ｎ−ヘキサン混液で結晶化して１−（４−アミ
ノフェニル）〜２−（４−１０ロフエニル）スルホニル
アミノル１−メチルエタン２．０６ｇを得る。M, p, 114-116°C (recrystallized from a chloroform-n-hexane mixture) (2) 3.1 g of Honjima was added to 20°C of ethanol, and then stannic chloride dihydrate 9. was added at 70°C with stirring. 86g 5
Add over a minute. After stirring at the same temperature for 3 hours, pour the reaction mixture onto 100 g of ice. The mixture is made alkaline with a 10% aqueous sodium hydroxide solution, and the precipitate is filtered off. The filtrate was extracted with methylene chloride, the extract was dried, the solvent was distilled off, and the residue was crystallized from a chloroform-n-hexane mixture to give 1-(4-aminophenyl) to 2-(4-10 lophenyl)sulfonyl. 2.06 g of aminol 1-methylethane are obtained.
Ｍ、ｐ、１Ｂ２−１８３℃
参考例３
２−アミノ〜１−（４−アミノフェニル）プロパン・２
塩酸塩６．６９ｇ、ピリジン５０Ｉｎｌ及び塩化メチレ
ン３０戚の懸濁液に室温下ジアザビシクロ（５，４，０
）ランデカルツーエン１８ｄを加よる。ついで−５０°
Ｃにてベンゼンスルホニルクロリド５．５６ｇの塩化メ
チレン４０−溶液を滴下し、同温で２時間攪拌する０反
応混合物を室温にもどし、溶媒を留去し、残渣を酢酸エ
チル抽出する。抽出液を洗浄後乾燥し、溶媒を留去する
。残渣をシリカゲルカラムクロマトグラフィー（溶出液
；クロロホルム：酢酸エチル＝４：１）にて分離精製し
、ジエチルエーテルで結晶化して１（４−アミノフェニ
ル）−２−ベンゼンスルホニルアミノプロパン４．６６
ｇを淡黄色結晶として得る。M, p, 1B2-183°C Reference example 3 2-amino-1-(4-aminophenyl)propane 2
Diazabicyclo (5,4,0
) Add Landekaltuen 18d. Then -50°
At C, a solution of 5.56 g of benzenesulfonyl chloride in 40% methylene chloride was added dropwise and stirred at the same temperature for 2 hours. The reaction mixture was returned to room temperature, the solvent was distilled off, and the residue was extracted with ethyl acetate. The extract is washed and dried, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (eluent; chloroform:ethyl acetate = 4:1) and crystallized from diethyl ether to give 1(4-aminophenyl)-2-benzenesulfonylaminopropane (4.66%).
g as pale yellow crystals.
Ｍ、ｐ、８９−９１°Ｃ
参考例４
対応原料化合物を参考例３と同様に処理して１−（４−
アミノフェニル）−２−（４−クロロフェニル）スルホ
ニルアミノプロパンヲ得る。M, p, 89-91°C Reference Example 4 The corresponding raw material compound was treated in the same manner as Reference Example 3 to obtain 1-(4-
Aminophenyl)-2-(4-chlorophenyl)sulfonylaminopropane is obtained.
Ｍ、ｐ、１２９−１３０°Ｃ
（発明の効果）
従来公知のＴｘＡ、拮抗剤の中には、ＴｘＡ、拮抗作用
を有する反面、一過性のＴｘＡ、様作用をも示し、血小
板凝集作用、気管支収縮作用、血管収縮作用等の副作用
を生じるものもあるが、本発明のＴｘｌｈ拮抗剤は、経
口投与及び非経口投与に際して、この様な副作用を実質
的に伴わないという特長を有する。また、有効成分であ
るグリシン誘導体（１）は、毒性も低く、例えば、３−
（（［４−（２−（４−クロロフェニル）スルホニルア
ミノ−１−メチルエチル〕フェニル〕アミノ〕アセチル
アミノ） −ｎ−プロピオン酸・ナトリウム塩を１００
０■／ｋｇ経口投与し、３日間観察しても死亡例は認め
られず、体重増加の抑制も観察されなかった。M, p, 129-130°C (Effect of the invention) Some conventionally known TxA antagonists have TxA antagonistic effects, but also exhibit transient TxA-like effects, platelet aggregation effects, Although some drugs cause side effects such as bronchoconstriction and vasoconstriction, the Txlh antagonist of the present invention has the advantage of being substantially free of such side effects when administered orally or parenterally. In addition, the active ingredient glycine derivative (1) has low toxicity, for example, 3-
(([4-(2-(4-chlorophenyl)sulfonylamino-1-methylethyl]phenyl]amino]acetylamino)-n-propionic acid sodium salt at 100%
No deaths were observed even after oral administration of 0.5 kg/kg and observation for 3 days, and no suppression of weight gain was observed.
従って、本発明のＴｘＡ、拮抗剤は、その優れた拮抗作
用に基づき、ＴｘＡ、に起因する各種疾患の治療、症状
の緩和及び予防に使用することができる。例えば、本発
明のＴｘＡ、拮抗剤は、血小板凝集抑制剤として有用で
あり、脳血栓症、冠状動脈血栓症、肺血栓症、末梢血管
塞栓症、血栓脈管炎などの各種血栓症、塞栓症の治療、
予防に好適に用いることができる。また、本発明のＴｘ
Ａ、拮抗剤は、心筋虚血、不安定狭心症、冠状動脈彎縮
、クモ膜下出血後の脳血管ｆ縮、脳溢血、喘息、腎炎、
腎不全、ショック等の治療・緩和及び予防に効果的に用
いることもできる。更に、体外循環時の血栓予防や臓器
（例えば、腎臓）移植時にも使用することができる。Therefore, the TxA antagonist of the present invention can be used to treat, alleviate symptoms of, and prevent various diseases caused by TxA based on its excellent antagonistic effect. For example, the TxA antagonist of the present invention is useful as a platelet aggregation inhibitor, and can inhibit various thromboses and embolisms such as cerebral thrombosis, coronary artery thrombosis, pulmonary thrombosis, peripheral vascular embolism, and thrombovasculitis. treatment,
It can be suitably used for prevention. Moreover, the Tx of the present invention
A. Antagonist can be used to treat myocardial ischemia, unstable angina, coronary artery curvature, cerebral vasoconstriction after subarachnoid hemorrhage, cerebral hemorrhage, asthma, nephritis,
It can also be effectively used for the treatment, alleviation, and prevention of renal failure, shock, and the like. Furthermore, it can be used to prevent blood clots during extracorporeal circulation and during organ (eg, kidney) transplantation.
Claims (1)
、Ｒ＾２及びＲ＾３はいずれか一方が低級アルキル基、
他方が水素原子、Ｒ＾４は保護されていてもよいカルボ
キシル基、Ｑは低級アルキレン基、ｍは０または１を表
す。） で示されるグリシン誘導体またはその薬理的に許容しう
る塩を有効成分として含有するトロンボキサンＡ＿２拮
抗剤。 ２、Ｒ＾１がフェニル基またはハロゲノフェニル基であ
る請求項１記載のトロンボキサンＡ＿２拮抗剤。 ３、Ｒ＾４が遊離のカルボキシル基または低級アルコキ
シカルボニル基である請求項１または２記載のトロンボ
キサンＡ＿２拮抗剤。 ４、Ｒ＾１がフェニル基またはクロロフェニル基であり
、Ｒ＾２及びＲ＾３のいずれか一方がメチル基、他方が
水素原子であり、Ｒ＾４が遊離のカルボキシル基である
請求項３記載のトロンボキサンＡ＿２拮抗剤。 ５、血小板凝集抑制剤である請求項１、２、３または４
記載のトロンボキサンＡ＿２拮抗剤。 ６、血栓症又は塞栓症の治療、予防剤である請求項１、
２、３または４記載のトロンボキサンＡ＿２拮抗剤。 ７、心筋虚血、不安定狭心症、冠動脈攣縮、クモ膜下出
血後の脳血管攣縮、脳溢血、喘息、腎炎、腎不全、ショ
ックの治療、予防剤である請求項１、２、３または４記
載のトロンボキサンＡ＿２拮抗剤。 ８、体外循環時または臓器移植時の血栓予防剤である請
求項１、２、３または４記載のトロンボキサンＡ＿２拮
抗剤。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is a phenyl group that may have a substituent, and R^2 and R^3 are either One is a lower alkyl group,
The other is a hydrogen atom, R^4 is an optionally protected carboxyl group, Q is a lower alkylene group, and m is 0 or 1. ) A thromboxane A_2 antagonist containing a glycine derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2. The thromboxane A_2 antagonist according to claim 1, wherein R^1 is a phenyl group or a halogenophenyl group. 3. The thromboxane A_2 antagonist according to claim 1 or 2, wherein R^4 is a free carboxyl group or a lower alkoxycarbonyl group. 4. According to claim 3, R^1 is a phenyl group or a chlorophenyl group, one of R^2 and R^3 is a methyl group and the other is a hydrogen atom, and R^4 is a free carboxyl group. thromboxane A_2 antagonist. 5. Claim 1, 2, 3 or 4, which is a platelet aggregation inhibitor.
Thromboxane A_2 antagonist as described. 6. Claim 1, which is a therapeutic or preventive agent for thrombosis or embolism.
Thromboxane A_2 antagonist according to 2, 3 or 4. 7. Claims 1, 2, 3, or 7, which is a therapeutic or preventive agent for myocardial ischemia, unstable angina, coronary artery spasm, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma, nephritis, renal failure, and shock. Thromboxane A_2 antagonist according to 4. 8. The thromboxane A_2 antagonist according to claim 1, 2, 3 or 4, which is an agent for preventing thrombosis during extracorporeal circulation or organ transplantation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16069990A JPH0449230A (en) | 1990-06-19 | 1990-06-19 | Antagonistic agent against thromboxane az |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16069990A JPH0449230A (en) | 1990-06-19 | 1990-06-19 | Antagonistic agent against thromboxane az |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0449230A true JPH0449230A (en) | 1992-02-18 |
Family
ID=15720561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16069990A Pending JPH0449230A (en) | 1990-06-19 | 1990-06-19 | Antagonistic agent against thromboxane az |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0449230A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0860428A3 (en) * | 1997-02-04 | 2000-07-19 | Eli Lilly And Company | Sulphonamide derivatives |
-
1990
- 1990-06-19 JP JP16069990A patent/JPH0449230A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0860428A3 (en) * | 1997-02-04 | 2000-07-19 | Eli Lilly And Company | Sulphonamide derivatives |
| US6303816B1 (en) | 1997-02-04 | 2001-10-16 | Eli Lilly And Company | Sulphonamide derivatives |
| US6596716B2 (en) | 1997-02-04 | 2003-07-22 | Eli Lilly And Company | 2-propane-sulphonamide derivatives |
| US7135487B2 (en) | 1997-02-04 | 2006-11-14 | Eli Lilly And Company | Sulphonamide derivatives |
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