JPH0259577A - Thiazolone derivative or salt thereof - Google Patents
Thiazolone derivative or salt thereofInfo
- Publication number
- JPH0259577A JPH0259577A JP20899388A JP20899388A JPH0259577A JP H0259577 A JPH0259577 A JP H0259577A JP 20899388 A JP20899388 A JP 20899388A JP 20899388 A JP20899388 A JP 20899388A JP H0259577 A JPH0259577 A JP H0259577A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- alkyl
- site
- thiazolone
- 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
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- IHDKBHLTKNUCCW-UHFFFAOYSA-N 1,3-thiazole 1-oxide Chemical class O=S1C=CN=C1 IHDKBHLTKNUCCW-UHFFFAOYSA-N 0.000 title claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract 2
- 238000006467 substitution reaction Methods 0.000 claims abstract 2
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 abstract description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000496 cardiotonic agent Substances 0.000 abstract description 6
- -1 cyano, carboxy Chemical group 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000037396 body weight Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 238000007911 parenteral administration Methods 0.000 abstract description 3
- 239000012442 inert solvent Substances 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 abstract 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000005245 right atrium Anatomy 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- ZBVSOJZWZUGUAY-UHFFFAOYSA-N 2-bromo-2-nitro-1-phenylethanone Chemical compound [O-][N+](=O)C(Br)C(=O)C1=CC=CC=C1 ZBVSOJZWZUGUAY-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000001008 atrial appendage Anatomy 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は強心剤として有用な新規なチアゾロン誘導体ま
たはその塩類に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to novel thiazolone derivatives or salts thereof useful as cardiotonic agents.
強心剤は心臓に直接作用してその収縮力を強める作用を
有し、従来種々の薬剤が心不全の治療に利用されている
。Cardiac inotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure.
しかしながら、これらの強心剤は安全域が極度に狭く不
整脈の原因となったシあるいはその強心作用が一過性で
かつ経口投与に適さないといった不都合を有するものが
多い。However, many of these inotropic agents have disadvantages such as extremely narrow safety margins, causing arrhythmia, or their inotropic effects being temporary and unsuitable for oral administration.
本発明者らは強心剤として活性が高くかつ効果の持続性
が十分発揮できる化合物の探索を行ない鋭意検討した結
果、本発明に到達した。The present inventors have searched for a compound that is highly active as a cardiotonic agent and can exhibit a sufficiently long-lasting effect, and as a result of intensive studies, they have arrived at the present invention.
すなわち本発明の要旨は、下記一般式（Ｉ）：Ｈ
（上記式中、Ａは１〜３個の窒素原子を含む！員環また
はｇ員環の複素環基を表わし、その環上にＣ＋％Ｃ，の
アルキル基、シアノ基、カルボキシル基、ＣＩ〜Ｃ５の
アルコキシカルボニル基、水酸基、Ｃ１〜Ｃ５のアルコ
キシ基、アミノ基、Ｃ１〜Ｃ５のアルキルアミノ基、Ｃ
２〜ｃ６のジアルキルアミノ基、０２〜Ｃ５のアシルア
ミノ基およびカルバモイル基よシ選ばれる少くとも７つ
の置換基を有してもよい。That is, the gist of the present invention is the following general formula (I): H (in the above formula, A represents a !- or g-membered heterocyclic group containing 1 to 3 nitrogen atoms, and C %C, alkyl group, cyano group, carboxyl group, CI-C5 alkoxycarbonyl group, hydroxyl group, C1-C5 alkoxy group, amino group, C1-C5 alkylamino group, C
It may have at least seven substituents selected from a 2-C6 dialkylamino group, a 02-C5 acylamino group, and a carbamoyl group.
またＲは水素原子あるいはＣ＋％Ｃ５のアルキ基が９位
のときは！位であシ、Ａ−ＮＨＧ基が！位のときは９位
である。）
で示されるチアゾロン誘導体又はその塩類に存する。Also, when R is a hydrogen atom or C+%C5 alkyl group is at the 9th position! At that position, there is an A-NHG group! 9th place. ) Thiazolone derivatives or salts thereof.
以下、本発明の詳細な説明する。The present invention will be explained in detail below.
上記一般式（Ｉ）におけるＡの具体例としては、ピリジ
ル基、ピリダジニル基、ピリミジル基、ピラジニル基′
、δ−トリアジニル基、ω−トリアジニル基、ピロリル
基、イミダゾリル基、ピラゾリル基等の７〜３個の窒素
原子を含む夕員環またはｇ員環の複素環基が挙げられ、
該環上に少くとも１つの置換基を有していてもよい。Specific examples of A in the above general formula (I) include pyridyl group, pyridazinyl group, pyrimidyl group, pyrazinyl group'
, δ-triazinyl group, ω-triazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, and other heterocyclic groups having an evening ring or a g-membered ring containing 7 to 3 nitrogen atoms,
The ring may have at least one substituent.
該置換基としては、メチル基、エチル基、プロピル基、
ブチル基等のＣ１〜Ｃ５の直鎖または分枝したアルキル
基；シアノ基；カルボキシル基；メトキシカルボニル基
、エトキシカルボニル基、プロポキシカルボニル基、ブ
トキシカルボニル基等のＣ１〜Ｃ５の直鎖または分枝し
たアルコキシカルボニル基：水酸基；メトキシ基、エト
キシ基、プロポキシ基、ブトキシ基等のＣ１〜Ｃ５の直
鎖または分枝したアルコキシ基；アミノ基；メチルアミ
ノ基、エチルアミノ基、プロピルアミノ基、ブチルアミ
ノ基等のＣ１〜Ｃ５の直鎖または分枝したアルキルアミ
ノ基；ジメチルアミノ基、ジエチルアミノ基、ジプロピ
ルアミノ基等のＣ２〜Ｃ６の直鎖または分枝したジアル
キルアミン基ニアセチルアミノ基、プロピオニルアミノ
基、ブチリルアミノ基等のＣ２〜ｃ５の直鎖または分枝
したアシルアミノ基；およびカルバモイル基が挙げられ
る。The substituents include methyl group, ethyl group, propyl group,
C1 to C5 straight chain or branched alkyl groups such as butyl groups; cyano groups; carboxyl groups; C1 to C5 straight chain or branched alkyl groups such as methoxycarbonyl groups, ethoxycarbonyl groups, propoxycarbonyl groups, butoxycarbonyl groups Alkoxycarbonyl group: hydroxyl group; C1 to C5 straight or branched alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; amino group; methylamino group, ethylamino group, propylamino group, butylamino group C1 to C5 straight chain or branched alkylamino groups such as; C2 to C6 straight chain or branched dialkylamine groups such as dimethylamino group, diethylamino group, dipropylamino group, niacetylamino group, propionylamino group , a C2-C5 straight chain or branched acylamino group such as a butyrylamino group; and a carbamoyl group.
またＲの具体例としては水素原子およびメチル基、エチ
ル基、プロピル基、ブチル基等のＣ１〜Ｃ５の直鎖また
は分枝したアルキル基が挙げられる。Further, specific examples of R include a hydrogen atom and a C1 to C5 straight chain or branched alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and the like.
上記一般式（１）で示されるチアゾロン誘導体の具体例
としては以下のような化合物が挙げられる。Specific examples of the thiazolone derivative represented by the above general formula (1) include the following compounds.
れ
また上記化合物の薬剤的に許容さＺ得る塩類も本発明の
範囲に含まれる。上記塩類としては塩酸、リン酸等の鉱
酸の塩および乳酸、酢酸等の有機酸の塩が挙げられる。Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. Examples of the above salts include salts of mineral acids such as hydrochloric acid and phosphoric acid, and salts of organic acids such as lactic acid and acetic acid.
これらの化合物はいずれも強心剤として有用である。All of these compounds are useful as cardiotonic agents.
次に本発明の化合物の製造法について説明する０
本発明におけるチアゾロン誘導体は、例えば次の様な経
路で製造される。Next, the method for producing the compound of the present invention will be explained. The thiazolone derivative in the present invention can be produced, for example, by the following route.
（上記式中、ＡおよびＲは既に定義したとおシであシ、
Ｘは“ハロゲン原子を表わす。）すなわち、上記化合物
（Ｉｆ）と上記化合物（ＩＩＩ）をＮ、Ｎ−ジメチルホ
ルムアミド、Ｎ、Ｎ−ジメチルアセトアミドあるいはＮ
−メチルーコーピロリドン等の不活性溶媒中でｔｏ０〜
ａＯＯ℃においてｏ３〜１０時間加熱することによシ目
的とするチアゾロン誘導体（１）を合成できる。(In the above formula, A and R are as defined above,
(X represents a halogen atom.) That is, the above compound (If) and the above compound (III) are combined into
- to0~ in an inert solvent such as methyl-copyrrolidone
The desired thiazolone derivative (1) can be synthesized by heating at 00°C for 3 to 10 hours.
なお、塩基としてトリエチルアミンおよび／、♂−ジア
ザビシロ（ｚ、ｔ、ｏ ） −７−ウンデセン等の有機
塩基あるいは炭酸カリウムおよび炭酸ナトリウム等の無
機塩基を添加してもよい。In addition, as a base, an organic base such as triethylamine and/or ♂-diazabicylo(z,t,o)-7-undecene, or an inorganic base such as potassium carbonate and sodium carbonate may be added.
また触媒として銅化合物を用いてもよい。Further, a copper compound may be used as a catalyst.
出発原料として使用する上記化合物（ＩＩ）は常法に従
い、例えば以下に示すような経路によシ合成される。The above compound (II) used as a starting material is synthesized according to a conventional method, for example, by the route shown below.
（り
／′
ｈ
（■、 （ＩＩ）
（上記式中、Ｒおよび置換位置については既に定義した
とおシであシ、Ｑはベンジルオキシカルボニル基および
ｔｅｒｔ−ブトキシカルボニル基等の保護基で保護され
たアミノ基；あるいはニトロ基、シアン基およびアルコ
キシカルボニル基等のアミノ基に変換可能な置換基を表
わす。(R/' h (■, (II) or a substituent that can be converted into an amino group such as a nitro group, a cyan group, or an alkoxycarbonyl group.
またＸはハロゲン原子を表わし、Ｒ′はメチル基、エチ
ル基およびプロピル基等の低級アルキル基を表わす。）
本発明の化合物を強心剤として用いる場合は、経口、非
経口の適当な投与方法により投与することができる。Further, X represents a halogen atom, and R' represents a lower alkyl group such as a methyl group, an ethyl group, and a propyl group. ) When the compound of the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method.
この場合、提供される形態としては、経口投与用には例
えば散剤、顆粒、錠剤、糖衣錠、ピル、カプセル、液剤
等、非経口投与用には例えば廃剤、懸濁液、液剤、乳剤
、アンプルおよび注射液等が挙げられる。勿論これらを
組み合わせた形態でも提供しうる。In this case, the forms provided include, for example, powders, granules, tablets, dragees, pills, capsules, liquid preparations, etc. for oral administration, and e.g. waste tablets, suspensions, solutions, emulsions, ampoules, etc. for parenteral administration. and injection solutions. Of course, a combination of these can also be provided.
製剤化に際しては、この分野における常法によることが
できる。For formulation, conventional methods in this field can be used.
また、本発明の化合物を強心薬として投与する量は、年
令、性別、体重、感受性差、投与方法、投与の時期・間
隔、病状の程度、体調、医薬製剤の性質・調剤・種類、
有効成分の種類などを考慮して、医師によシ決定される
。In addition, the amount of the compound of the present invention to be administered as a cardiotonic drug depends on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, etc.
This will be determined by your doctor, taking into account the type of active ingredient.
例えば、経口投与の場合、体重／ｋｆ／日当り、０、／
−１０■／に９程度の投与量が選ばれるが、もちろんこ
れに制限されない。For example, in the case of oral administration, body weight/kf/day, 0, /
A dosage of approximately 9 to -10 .mu./cm is selected, but of course the dosage is not limited to this.
以下、実施例により本発明をさらに詳細に説明するが、
本発明はその要旨を越えない限シ、以下の実施例によっ
て限定されるものではない。Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist thereof.
＝／”、／ ２θ０ｄに溶解後、塩基性アルミナのシ
ョートカ′ラム処理し、炉液にｎ−へブタン１００ｒｘ
ｌを加え、テトラヒドロフランとメタノチオカルバミン
酸〇−エチルエステルコ、夕０ｔをＮ、Ｎ−ジメチルホ
ルムアミド３０−に溶解シ、ついで、グーニトロフェナ
シルプロマイドグ、♂？グを加えた後、ｇｏ℃油浴上で
２．５時間加熱攪拌した。反応混合物を氷水２００ ａ
ｔに注ぎＩＮ−水酸化ナトリウム水溶液で中和し、析出
した固体をＦ取した。=/'', / After dissolving in 2θ0d, it was treated with a short column of basic alumina, and 100rx of n-hebutane was added to the furnace solution.
1 of tetrahydrofuran and methanothiocarbamic acid 〇-ethyl ester, dissolved 0 t in N,N-dimethylformamide, and then nitrophenacyl bromide, ♂? After adding the ingredients, the mixture was heated and stirred for 2.5 hours on a goC oil bath. Pour the reaction mixture into ice water at 200 a
The mixture was poured into a filtrate and neutralized with an aqueous IN-sodium hydroxide solution, and the precipitated solid was collected as F.
塩化第１スズ、・コ水和物／ｒｔの濃塩酸、２５ａｔ溶
液に上で戸数した固体を乾燥することなく加え、１１０
℃油浴上で２時間加熱攪拌した。Add the solid obtained above without drying to a solution of stannous chloride, cohydrate/rt in concentrated hydrochloric acid, 25at;
The mixture was heated and stirred on a °C oil bath for 2 hours.
反応終了後、反応混合物を氷冷し析出した結晶を戸数し
、冷濃塩酸で洗浄した。After the reaction was completed, the reaction mixture was cooled on ice, and the precipitated crystals were collected and washed with cold concentrated hydrochloric acid.
結晶を温水２夕ＯｒｔｔｌとエタノールｊＯｔｔｔｌの
混合溶媒に溶解し、氷冷しながらＩＮ−水酸化ナトリウ
ム水溶液で中和した。析出した結晶を戸数し、水洗後テ
トラヒドロンラン：メタノール率乙？チ）を得た。The crystals were dissolved in a mixed solvent of Orttl and ethanol (jOtttl) for two nights in warm water, and neutralized with an IN-sodium hydroxide aqueous solution while cooling on ice. Quantify the precipitated crystals, wash with water, and then add tetrahydrone to methanol ratio. h) was obtained.
参考例−２，４−−（４ｔ−アミノフェニル）−Ｘ−メ
チル−２（、？）（）−チアゾロン
参考例１と同様な処理によｐ／−クロロ−７−（４ｔ−
二トロフェニル）アセトン ３．９６１トチオカルハミ
ン酸〇−エチルエステル八７２から上記目的カム２７ｆ
（収率＠４％）を得た。Reference Example -2,4--(4t-aminophenyl)-X-methyl-2(,?)()-thiazolone By the same treatment as in Reference Example 1, p/-chloro-7-(4t-
Nitrophenyl)acetone 3.961 tothiocarhamic acid 〇-ethyl ester 872 to the above objective cam 27f
(Yield @4%) was obtained.
実施例１，４ｔ−（グー（４ｔ−ピリジルアミン）フェ
ニル）−−２（ｊＨ）−チアゾロングー（４ｔ−アミノ
フェニル）−２（ｊＨ）−チアゾロン０．９ｇ１をＮ−
メチルーコーピロリドン３ｒｄに溶解し、９０℃油浴上
で加熱攪拌下、トリエチルアミン０．３ｊｒｔｔｌとグ
ークロルピリジン、・塩酸塩０．７ｊｆとを順次添加し
た。９０℃で２時間攪拌を続けた後、反応混合物を冷却
し、アセトンＩＯ，ｌを加え析出した固体を戸数した。Example 1 0.9 g of 4t-(gu(4t-pyridylamine)phenyl)--2(jH)-thiazolone-2(jH)-thiazolone was converted into N-
It was dissolved in methyl-copyrrolidone 3rd, and 0.3jrttl of triethylamine and 0.7jf of goochlorpyridine and hydrochloride were sequentially added thereto while heating and stirring on a 90°C oil bath. After continuing to stir at 90° C. for 2 hours, the reaction mixture was cooled, and IO,1 acetone was added to remove the precipitated solid.
その固体を温水Ｊ ｊ ＯｍＡ！に溶解し、氷冷しなが
ら／Ｎ−水酸化ナトリウムで中和した。析出した固体を
戸数し、シリカゲルカラムクロマト処理（溶媒：クロロ
ホルム／メタノール／酢酸＝！０／／１０，１→３／／
１０．１ ） シ、目的物を含む分画を集め濃縮した。Pour the solid into warm water J j OmA! and neutralized with /N-sodium hydroxide while cooling on ice. The precipitated solid was separated and subjected to silica gel column chromatography (solvent: chloroform/methanol/acetic acid =!0//10,1→3//
10.1) Fractions containing the target product were collected and concentrated.
残渣を３Ｎ−塩酸２ ｒｔｔｌを含む温水１００ｍ１Ｋ
溶解し、ｎ−ブタノールで共沸脱水しなから３θｄまで
濃縮した。ついで物性の白色固体である上記目的物の塩
酸塩を得たＯ
収量：θ、に２１（収率グｌチ）、融点： ＞ｓｏｏ℃
ＩＲ： ／ごｊｒｃｍ−’
実施例コ、ター（ｇ−（４ｔ−ビリジルナミノ）フェニ
ル〕′−グーメチル−２（３Ｈ）−チア実施例／と同様
な処理によりｓ’−Ｃ”−アミノフェニル）−グーメチ
ル−，２（ｊＨ）−チアゾロンθ、ご２１とグークロル
ピリジン・塩酸塩０．４ｔり２から、下記物性の白色固
体である上記目的物の塩酸塩を得た。Pour the residue into 100 ml of warm water containing 2 rttl of 3N hydrochloric acid.
The solution was dissolved, azeotropically dehydrated with n-butanol, and then concentrated to 3θd. Next, a hydrochloride salt of the target product, which is a white solid with physical properties, was obtained. Yield: θ, 21 (yield), melting point: >soo°C
IR: /Jrcm-' Example ter(g-(4t-biridylnamino)phenyl)'-gumethyl-2(3H)-thia/s'-C''-aminophenyl)- From goomethyl-,2(jH)-thiazolone θ, 21 and 0.4 t of goochlorpyridine hydrochloride 2, the hydrochloride of the above-mentioned target product, which is a white solid with the following physical properties, was obtained.
収量：０．７４ｔｒ（収率２７％）、融点：〉３θθ℃
ＩＲ： ＃ダＯ画 、／４ＩＯロー１
試験例
本発明の化合物の強心剤としての有用性を、モルモット
摘出右心房の収縮力の有意な増強を引き起すことにより
実証した。Yield: 0.74tr (yield 27%), melting point: 〉3θθ℃
IR: #DAO, /4IORho1 Test Example The usefulness of the compounds of the present invention as cardiotonic agents was demonstrated by causing a significant increase in the contractile force of isolated right atria of guinea pigs.
以下にモルモット摘出右心房を用いた試験方法とその結
果を記載する。The test method using isolated guinea pig right atrium and its results are described below.
Ｏ試験方法
体重−〇〇〜３θ０ｆの雄性モルモットの後頭部を殴打
し、ただちに右心房を摘出した。O Test Method A male guinea pig weighing -00 to 3θ0f was hit on the back of the head, and the right atrium was immediately removed.
右心房室口の部分を、３ｊ℃に保温したクレプス−ヘン
スライド液３０ｍｅを満した臓器浴の底部に固定した。The right atrium ostium was fixed at the bottom of an organ bath filled with 30ml of Krebs-Henslide solution kept at 3j°C.
臓器浴中のクレプス−ヘンスライド液にはワタチの０２
とｊ％のＣＯ２とからなる混合ガスを通気した。右心房
の心耳に糸をとシつけその糸の他端をトランスデー−サ
ーにつなぎ、等尺性張力を測定した。標本にはθ、！１
の静止張力をかけた。標本作製表１
反応を記録した。The Krebs-Henslide solution in the organ bath contains my 02
A mixed gas consisting of and j% CO2 was bubbled through. A thread was attached to the atrial appendage of the right atrium, the other end of the thread was connected to a transducer, and the isometric tension was measured. The sample has θ,! 1
A static tension of . Specimen Preparation Table 1 Reactions were recorded.
・試験結果 モルモット右心房の収縮力の増加率を下記表１に示す。·Test results The rate of increase in the contractile force of the guinea pig right atrium is shown in Table 1 below.
Claims (1)
は６員環の複素環基を表わし、その環上にＣ＿１〜Ｃ＿
５のアルキル基、シアノ基、カルボキシル基、Ｃ＿１〜
Ｃ＿５のアルコキシカルボニル基、水酸基、Ｃ＿１〜Ｃ
＿５のアルコキシ基、アミノ基、Ｃ＿１〜Ｃ＿５のアル
キルアミノ基、Ｃ＿２〜Ｃ＿６のジアルキルアミノ基、
Ｃ＿２〜Ｃ＿５のアシルアミノ基およびカルバモイル基
より選ばれる少くとも１つの置換基を有してもよい。 またＲは水素原子あるいはＣ＿１〜Ｃ＿５のアルキル基
を表わし、その置換位置は、 ▲数式、化学式、表等があります▼基が４位のときは５
位であり、 ▲数式、化学式、表等があります▼基が５位のときは４
位である。） で示されるチアゾロン誘導体又はその塩類。(1) The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms. and C_1 to C_ on the ring
5 alkyl group, cyano group, carboxyl group, C_1~
C_5 alkoxycarbonyl group, hydroxyl group, C_1 to C
_5 alkoxy group, amino group, C_1 to C_5 alkylamino group, C_2 to C_6 dialkylamino group,
It may have at least one substituent selected from C_2 to C_5 acylamino groups and carbamoyl groups. In addition, R represents a hydrogen atom or an alkyl group of C_1 to C_5, and the substitution position is ▲ Numerical formula, chemical formula, table, etc. ▼ When the group is at the 4th position, it is 5
▲There are mathematical formulas, chemical formulas, tables, etc. ▼When the group is in the 5th position, it is 4
It is the rank. ) Thiazolone derivatives or salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20899388A JPH0259577A (en) | 1988-08-23 | 1988-08-23 | Thiazolone derivative or salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20899388A JPH0259577A (en) | 1988-08-23 | 1988-08-23 | Thiazolone derivative or salt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0259577A true JPH0259577A (en) | 1990-02-28 |
Family
ID=16565547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20899388A Pending JPH0259577A (en) | 1988-08-23 | 1988-08-23 | Thiazolone derivative or salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0259577A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5567699A (en) * | 1994-04-26 | 1996-10-22 | Mitsubishi Chemical Corporation | Thiadiazinone derivatives |
| JP2009531321A (en) * | 2006-03-22 | 2009-09-03 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of the interaction between MDM2 and p53 |
| CN103833671A (en) * | 2012-11-27 | 2014-06-04 | 中国科学院上海药物研究所 | Thiazoline compounds and pharmaceutical composition and application thereof |
-
1988
- 1988-08-23 JP JP20899388A patent/JPH0259577A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5567699A (en) * | 1994-04-26 | 1996-10-22 | Mitsubishi Chemical Corporation | Thiadiazinone derivatives |
| JP2009531321A (en) * | 2006-03-22 | 2009-09-03 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Inhibitors of the interaction between MDM2 and p53 |
| CN103833671A (en) * | 2012-11-27 | 2014-06-04 | 中国科学院上海药物研究所 | Thiazoline compounds and pharmaceutical composition and application thereof |
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