JPH04278094A - Production of 1-hydroxy-isoquinolinesulfonamido derivative - Google Patents
Production of 1-hydroxy-isoquinolinesulfonamido derivativeInfo
- Publication number
- JPH04278094A JPH04278094A JP4151991A JP4151991A JPH04278094A JP H04278094 A JPH04278094 A JP H04278094A JP 4151991 A JP4151991 A JP 4151991A JP 4151991 A JP4151991 A JP 4151991A JP H04278094 A JPH04278094 A JP H04278094A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- derivative
- isoquinolinesulfonamido
- hydroxy
- enzyme
- 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.)
- Withdrawn
Links
- -1 1-hydroxy-isoquinolinesulfonamido Chemical class 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 102000004190 Enzymes Human genes 0.000 claims abstract description 15
- 108090000790 Enzymes Proteins 0.000 claims abstract description 15
- 241001465754 Metazoa Species 0.000 claims abstract description 6
- 244000005700 microbiome Species 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 5
- GZZCYMXZJQCAJU-UHFFFAOYSA-N isoquinoline-1-sulfonamide Chemical class C1=CC=C2C(S(=O)(=O)N)=NC=CC2=C1 GZZCYMXZJQCAJU-UHFFFAOYSA-N 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 3
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 229940124549 vasodilator Drugs 0.000 abstract description 3
- 239000003071 vasodilator agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 3
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 230000002255 enzymatic effect Effects 0.000 abstract 2
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- GCGYREODZIZPLJ-UHFFFAOYSA-N azepan-1-ium;chloride Chemical compound Cl.C1CCCNCC1 GCGYREODZIZPLJ-UHFFFAOYSA-N 0.000 abstract 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 abstract 1
- 229940126585 therapeutic drug Drugs 0.000 abstract 1
- 230000000304 vasodilatating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- FGQPVNODELDKQF-UHFFFAOYSA-N 1-chloroisoquinoline-5-sulfonic acid Chemical compound N1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1Cl FGQPVNODELDKQF-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- OREHUWJLRDJJGY-UHFFFAOYSA-N 1,4-diazepane;hydrochloride Chemical compound Cl.C1CNCCNC1 OREHUWJLRDJJGY-UHFFFAOYSA-N 0.000 description 1
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 1
- MWORFUXVBBINOC-UHFFFAOYSA-N 2-[2-[(1-oxo-2h-isoquinolin-5-yl)sulfonylamino]ethyl]guanidine Chemical compound C1=CNC(=O)C2=C1C(S(=O)(=O)NCCN=C(N)N)=CC=C2 MWORFUXVBBINOC-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- DULRUIHCLAIYAR-UHFFFAOYSA-N 4-[(1-oxo-2h-isoquinolin-5-yl)sulfonyl]-1,4-diazepane-1-carboximidamide Chemical compound C1CN(C(=N)N)CCCN1S(=O)(=O)C1=CC=CC2=C(O)N=CC=C12 DULRUIHCLAIYAR-UHFFFAOYSA-N 0.000 description 1
- KEEFYGCDFWGQNI-UHFFFAOYSA-N 4-isoquinolin-5-ylsulfonyl-1,4-diazepane-1-carboximidamide;hydrochloride Chemical compound Cl.C1CN(C(=N)N)CCCN1S(=O)(=O)C1=CC=CC2=CN=CC=C12 KEEFYGCDFWGQNI-UHFFFAOYSA-N 0.000 description 1
- MBZNIYPWRIDBOD-UHFFFAOYSA-N 5-piperazin-1-ylsulfonylisoquinoline;hydrochloride Chemical compound Cl.C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCNCC1 MBZNIYPWRIDBOD-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- LFVPBERIVUNMGV-UHFFFAOYSA-N fasudil hydrochloride Chemical compound Cl.C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 LFVPBERIVUNMGV-UHFFFAOYSA-N 0.000 description 1
- ZAVGJDAFCZAWSZ-UHFFFAOYSA-N hydroxyfasudil Chemical compound C1=CC=C2C(O)=NC=CC2=C1S(=O)(=O)N1CCCNCC1 ZAVGJDAFCZAWSZ-UHFFFAOYSA-N 0.000 description 1
- YFMJTLUPSMCTOQ-UHFFFAOYSA-N isoquinoline-5-sulfonic acid Chemical compound N1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 YFMJTLUPSMCTOQ-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は、哺乳動物の血管平滑筋
に作用し、血管拡張剤、脳循環改善剤、狭心症治療剤、
脳血管系の血栓症、高血圧症の予防治療剤などの循環器
官用薬として有用な化合物の製造方法である。[Industrial Application Field] The present invention acts on mammalian vascular smooth muscle, and is a vasodilator, a cerebral circulation improving agent, a therapeutic agent for angina pectoris,
This is a method for producing a compound useful as a circulatory organ drug such as a preventive treatment for cerebrovascular thrombosis and hypertension.
【０００２】0002
【従来の技術】これまで、式（ＩＩ）[Prior Art] Until now, formula (II)
【０００３】0003
【化４】[C4]
【０００４】0004
【化５】[C5]
【０００５】の化合物またはその酸付加塩は、例えば、
特開昭６３−２９８０号公報に開示されている有機合成
化学的方法により、式（ＩＩＩ）に示した１−クロル−
５−イソキノリンスルホン酸を原料として製造されてい
た。The compound or its acid addition salt is, for example,
1-Chlor-
It was produced using 5-isoquinolinesulfonic acid as a raw material.
【０００６】[0006]
【化６】[C6]
【０００７】すなわち、１−クロル−５−イソキノリン
スルホン酸に、塩化チオニル、ジメチルホルムアミドを
反応させ、式（ＩＶ）That is, by reacting 1-chloro-5-isoquinolinesulfonic acid with thionyl chloride and dimethylformamide, the formula (IV) is obtained.
【０００８】[0008]
【化７】[C7]
【０００９】で示される化合物に誘導した後、式（Ｖ）
After deriving the compound of formula (V)
【００１０】0010
【化８】[Chemical formula 8]
【００１１】で示されるアミンを反応させると、式（Ｖ
Ｉ）When the amine represented by the formula (V
I)
【００１２】0012
【化９】[Chemical formula 9]
【００１３】で示される化合物が得られる。式（ＶＩ）
で示される化合物は、無機酸と加熱することにより、式
（ＩＩ）で示される化合物に誘導することができる。A compound represented by the following formula is obtained. Formula (VI)
The compound represented by formula (II) can be derived by heating with an inorganic acid.
【００１４】[0014]
【発明が解決しようとする課題】上記の従来の製造方法
は、以下の点で問題がある。
（１）式（ＩＩＩ）に示した１−クロル−５−イソキノ
リンスルホン酸の原料となる１−クロル−イソキノリン
は、イソキノリンを過酸化水素、次いでオキシ塩化リン
で処理することにより得られる。この操作には爆発性の
過酸化水素を使用し、危険が伴う。
（２）式（ＶＩ）で示される化合物から式（ＩＩ）の化
合物を得る反応は強酸性条件下、加熱を必要とする。The conventional manufacturing method described above has the following problems. (1) 1-chloro-isoquinoline, which is a raw material for 1-chloro-5-isoquinolinesulfonic acid shown in formula (III), can be obtained by treating isoquinoline with hydrogen peroxide and then with phosphorus oxychloride. This operation uses explosive hydrogen peroxide and is dangerous. (2) The reaction for obtaining the compound of formula (II) from the compound of formula (VI) requires heating under strongly acidic conditions.
【００１５】[0015]
【課題を解決するための手段】本発明者らは、上記の問
題点を解決するために鋭意研究の結果、以下に示す式（
Ｉ）の化合物に動物ならびに微生物由来の酵素もしくは
酵素源を作用させることにより、容易にかつ温和な条件
下で、式（ＩＩ）の化合物を得る方法を見出し、本発明
を完成するに至った。[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have conducted extensive research and have found the following formula (
The present inventors have discovered a method for obtaining the compound of formula (II) easily and under mild conditions by reacting the compound of formula (I) with enzymes or enzyme sources derived from animals or microorganisms, and have completed the present invention.
【００１６】すなわち、本発明は、式（Ｉ）That is, the present invention provides formula (I)
【００１７
】0017
]
【化１０】[Chemical formula 10]
【００１８】で示されるイソキノリンスルホンアミド誘
導体またはその酸付加塩を、動物ならびに微生物由来の
酵素もしくは酵素源を用いて酸化することによる、式（
ＩＩ）で示される１−ヒドロキシ−イソキノリンスルホ
ンアミド誘導体の製造方法に関するものである。本発明
に使用する原料、すなわち、式（Ｉ）の化合物の製造方
法は例えば、以下に示した特許公開公報に記載されてい
る。By oxidizing the isoquinoline sulfonamide derivative or its acid addition salt represented by the formula (
The present invention relates to a method for producing a 1-hydroxy-isoquinoline sulfonamide derivative represented by II). The raw material used in the present invention, ie, the method for producing the compound of formula (I), is described, for example, in the patent publication listed below.
【００１９】特開昭５７−１５６４６３号公報、特開昭
５７−２００３６６号公報、特開昭５８−１２１２７８
号公報、特開昭５８−１２１２７９号公報、特開昭５９
−９３０５４号公報、特開昭６０−８１１６８号公報、
特開昭６１−２２７５８１号公報、特開昭６２−１０３
０６６号公報。以下、本発明の製造方法について説明す
る。[0019] JP-A-57-156463, JP-A-57-200366, JP-A-58-121278
No. 1, JP-A-58-121279, JP-A-59-Sho.
-93054 publication, JP-A-60-81168 publication,
JP-A-61-227581, JP-A-62-103
Publication No. 066. The manufacturing method of the present invention will be explained below.
【００２０】本発明に用いられる動物由来の酵素源とし
ては、マウス、ラット、イヌ、モルモット、ネコ、サル
などの肝臓、腎臓などのホモジネートの中から選ばれる
。また動物由来の酵素としては上記のホモジネート中に
含まれるものから選ばれる。さらに微生物由来の酵素も
しくは酵素源としては前記のイソキノリン誘導体の１位
を選択的に酸化する能力を有するものであれば、特に限
定されない。The animal-derived enzyme source used in the present invention is selected from homogenates of liver, kidney, etc. of mice, rats, dogs, guinea pigs, cats, monkeys, etc. In addition, the animal-derived enzyme is selected from those contained in the above homogenate. Further, the microorganism-derived enzyme or enzyme source is not particularly limited as long as it has the ability to selectively oxidize the 1-position of the above-mentioned isoquinoline derivative.
【００２１】本発明における反応方法は、具体的には、
前記ホモジネートまたはそこから分離抽出した酵素なら
びに微生物由来の酵素もしくは酵素源と、式（Ｉ）で示
される化合物を接触することにより行なわれる。また、
前記の酵素もしくは酵素源を、適当な方法により担体に
、固定したものを用いてもよい。反応条件として、反応
溶媒は水、緩衝液などの水性媒体が好ましい。式（Ｉ）
で示される化合物は、粉末または液体のままで、あるい
は適当な溶媒に溶かして添加する。式（Ｉ）で示される
化合物の添加濃度は、０．０１〜１０重量％程度がよく
、反応媒体中に完全に溶解しなくてもよい。反応温度は
５〜５０℃、好ましくは２０〜３７℃、反応ｐＨは４〜
１１、好ましくは６．５〜８．０である。反応は通常１
０分間〜１００時間の範囲で適当な時間を選べばよい。
通常、反応率は１０〜１００％である。消費される式（
Ｉ）で示される化合物は、連続的にまたは間欠的に補充
して、反応液中の濃度が前記の範囲内に維持されるよう
に添加してもよい。[0021] Specifically, the reaction method in the present invention is as follows:
This is carried out by bringing the compound represented by formula (I) into contact with the homogenate, an enzyme separated and extracted therefrom, and an enzyme or enzyme source derived from a microorganism. Also,
The enzyme or enzyme source described above may be immobilized on a carrier by an appropriate method. Regarding the reaction conditions, the reaction solvent is preferably an aqueous medium such as water or a buffer solution. Formula (I)
The compound represented by is added as a powder or liquid, or dissolved in a suitable solvent. The concentration of the compound represented by formula (I) to be added is preferably about 0.01 to 10% by weight, and does not need to be completely dissolved in the reaction medium. The reaction temperature is 5-50°C, preferably 20-37°C, and the reaction pH is 4-50°C.
11, preferably 6.5 to 8.0. The reaction is usually 1
An appropriate time may be selected within the range of 0 minutes to 100 hours. Usually, the reaction rate is 10-100%. The expression that is consumed (
The compound represented by I) may be added continuously or intermittently so that the concentration in the reaction solution is maintained within the above range.
【００２２】本発明における目的生成物、すなわち式（
ＩＩ）の化合物の回収は、次のようにして行なわれる。
反応終了液にメタノールなどの有機溶媒を加え、除タン
パクした後、逆相系の液体クロマトグラフィーにより分
取して、容易に精製することができる。The desired product of the present invention, namely the formula (
Recovery of the compound II) is carried out as follows. It can be easily purified by adding an organic solvent such as methanol to the reaction-completed solution to remove proteins, and then fractionating it by reverse-phase liquid chromatography.
【００２３】[0023]
【実施例】以下、本発明を実施例により、さらに詳細に
説明するが、実施例によって本発明が何ら限定されるも
のではない。[Examples] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to the Examples in any way.
【００２４】[0024]
【実施例１】ラット（ウィスター系雄性、１６０〜２０
０ｇ、７週令）を断頭後、直ちに開腹し、門脈より氷冷
した０．１５ＭＫＣｌで還流した後、肝臓を摘出した。
肝湿重量を秤量した後、４倍量の０．１５ＭＫＣｌを含
む０．０１ＭＴｒｉｓ−ＨＣｌ緩衝液（ｐＨ７．４）を
加え、Ｐｏｔｔｅｒ−Ｅｌｖｅｈｊｅｍ型ホモジナイザ
ー（池本理化工業株式会社製、Ｎｏ．１０−０８２型）
を用いてホモジナイズした。この操作は４℃以下で行な
った。得られたホモジネートに１−（５−イソキノリン
スルホニル）ホモピペラジン塩酸塩１ｍｇを添加し、３
７℃で２時間インキュベートした。反応終了液にメタノ
ール１０ｍｌを加え、１０分間、３０００ｒ．ｐ．ｍで
遠心分離した後、上清を以下の条件でＨＰＬＣ分析し、
１−（１−ヒドロキシ−５−イソキノリンスルホニル）
ホモピペラジンの生成率を求めた。なお１−（１−ヒド
ロキシ−５−イソキノリンスルホニル）ホモピペラジン
の同定は、前記の特開昭６３−２９８０号公報に記載さ
れた方法により合成した標品との重ね打ちにより行なっ
た。[Example 1] Rat (Wistar male, 160-20
Immediately after decapitation, the liver was removed from the liver after perfusion with ice-cold 0.15 M KCl from the portal vein. After weighing the liver wet weight, 0.01 M Tris-HCl buffer (pH 7.4) containing 4 times the amount of 0.15 M KCl was added, and the mixture was heated using a Potter-Elvehjem type homogenizer (manufactured by Ikemoto Rika Kogyo Co., Ltd., No. 10-082). type)
Homogenized using. This operation was performed at a temperature below 4°C. 1 mg of 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride was added to the obtained homogenate, and 3
Incubate for 2 hours at 7°C. 10 ml of methanol was added to the reaction completed solution, and the mixture was heated at 3000 r.p.m. for 10 minutes. p. After centrifugation at m, the supernatant was analyzed by HPLC under the following conditions,
1-(1-hydroxy-5-isoquinolinesulfonyl)
The production rate of homopiperazine was determined. Note that 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine was identified by overprinting with a standard product synthesized by the method described in JP-A No. 63-2980.
【００２５】生成率 １００％
ＨＰＬＣ分析条件
カラム ：ＹＭＣ ＯＤＳ Ａ−３１２（山村化
学研究所製）
移動相 ：０．５ＭＮＨ４ Ｃｌ（ｐＨ３．１）／Ｃ
Ｈ３ ＣＮ＝８／１
検出波長：３２３ｎｍ
流速 ：１．５ｍｌ／ｍｉｎ．
温度 ：２５℃Production rate: 100% HPLC analysis conditions Column: YMC ODS A-312 (manufactured by Yamamura Kagaku Kenkyusho) Mobile phase: 0.5M NH4Cl (pH 3.1)/C
H3 CN=8/1 Detection wavelength: 323nm Flow rate: 1.5ml/min. Temperature: 25℃
【００２６】[0026]
【実施例２〜５】１−（５−イソキノリンスルホニル）
ホモピペラジン塩酸塩のかわりに、１−（５−イソキノ
リンスルホニル）ピペラジン塩酸塩（１）、Ｎ−（２−
グアニジノエチル）−５−イソキノリンスルホンアミド
塩酸塩（２）、４−アミジノ−１−（５−イソキノリン
スルホニル）ホモピペラジン塩酸塩（３）、４−ヘキシ
ル−１−（５−イソキノリンスルホニル）エチレンジア
ミン塩酸塩（４）を用いた以外は、実施例１と同様にし
て１−（１−ヒドロキシ−５−イソキノリンスルホニル
）ピペラジン、Ｎ−（２−グアニジノエチル）−１−ヒ
ドロキシ−５−イソキノリンスルホンアミド、４−アミ
ジノ−１−（１−ヒドロキシ−５−イソキノリンスルホ
ニル）ホモピペラジン、４−ヘキシル−１−（１−ヒド
ロキシ−５−イソキノリンスルホニル）エチレンジアミ
ンを得た。反応条件ならびに生成率を表１に示す。[Examples 2 to 5] 1-(5-isoquinolinesulfonyl)
Instead of homopiperazine hydrochloride, 1-(5-isoquinolinesulfonyl)piperazine hydrochloride (1), N-(2-
(guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride (2), 4-amidino-1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride (3), 4-hexyl-1-(5-isoquinolinesulfonyl)ethylenediamine hydrochloride 1-(1-hydroxy-5-isoquinolinesulfonyl)piperazine, N-(2-guanidinoethyl)-1-hydroxy-5-isoquinolinesulfonamide, 4 -amidino-1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine and 4-hexyl-1-(1-hydroxy-5-isoquinolinesulfonyl)ethylenediamine were obtained. Table 1 shows the reaction conditions and production rate.
【００２７】[0027]
【表１】[Table 1]
【００２８】[0028]
【発明の効果】本発明により、例えば特開昭６１−１５
２６５８号公報に開示されているような血管拡張剤、脳
循環改善剤、狭心症治療剤、脳血管系の血栓症、高血圧
症の予防治療剤などの循環器官用薬として有用な化合物
を、常温常圧の反応条件下、容易に得ることができる。Effects of the Invention According to the present invention, for example, JP-A-61-15
Compounds useful as circulatory organ drugs such as vasodilators, cerebral circulation improving agents, angina treatment agents, cerebrovascular thrombosis, hypertension prevention and treatment agents as disclosed in Japanese Patent No. 2658, It can be easily obtained under reaction conditions of room temperature and normal pressure.
Claims (1)
の酸付加塩を、動物ならびに微生物由来の酵素もしくは
酵素源を用いて酸化することによる、式（ＩＩ）【化３
】 で示される１−ヒドロキシ−イソキノリンスルホンアミ
ド誘導体の製造方法。Claim 1: The isoquinoline sulfonamide derivative represented by formula (I) [Chemical 1] [Chemical 2] or its acid addition salt is oxidized using an enzyme or an enzyme source derived from an animal or a microorganism to obtain a compound of the formula ( II) [Chem.3
] A method for producing a 1-hydroxy-isoquinoline sulfonamide derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4151991A JPH04278094A (en) | 1991-03-07 | 1991-03-07 | Production of 1-hydroxy-isoquinolinesulfonamido derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4151991A JPH04278094A (en) | 1991-03-07 | 1991-03-07 | Production of 1-hydroxy-isoquinolinesulfonamido derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04278094A true JPH04278094A (en) | 1992-10-02 |
Family
ID=12610631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4151991A Withdrawn JPH04278094A (en) | 1991-03-07 | 1991-03-07 | Production of 1-hydroxy-isoquinolinesulfonamido derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04278094A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997002260A1 (en) * | 1995-07-03 | 1997-01-23 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
-
1991
- 1991-03-07 JP JP4151991A patent/JPH04278094A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997002260A1 (en) * | 1995-07-03 | 1997-01-23 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
| US5942505A (en) * | 1995-07-03 | 1999-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
| CN1080721C (en) * | 1995-07-03 | 2002-03-13 | 旭化成株式会社 | 1 -(5 -isoquinolinesulfonyl) homopiperazine hydrochloride hydrates |
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