JPH0259573A - 2(1h)-pyrimidinone derivative or salts thereof - Google Patents
2(1h)-pyrimidinone derivative or salts thereofInfo
- Publication number
- JPH0259573A JPH0259573A JP20899188A JP20899188A JPH0259573A JP H0259573 A JPH0259573 A JP H0259573A JP 20899188 A JP20899188 A JP 20899188A JP 20899188 A JP20899188 A JP 20899188A JP H0259573 A JPH0259573 A JP H0259573A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- pyrimidinone
- salts
- alkyl
- 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
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000003282 alkyl amino 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
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000003277 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
- 239000000126 substance Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 239000000496 cardiotonic agent Substances 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- -1 cyano, carboxy Chemical group 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 210000005245 right atrium Anatomy 0.000 description 8
- 230000002861 ventricular Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000003540 papillary muscle Anatomy 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 241000700198 Cavia Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 230000037396 body weight Effects 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004041 inotropic agent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- XGAFCCUNHIMIRV-UHFFFAOYSA-N 4-chloropyridine;hydron;chloride Chemical compound Cl.ClC1=CC=NC=C1 XGAFCCUNHIMIRV-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000000709 aorta Anatomy 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
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 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
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 210000003205 muscle Anatomy 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 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
- 238000000746 purification Methods 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
- 230000000284 resting effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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２（ＩＨ）−ピリミ
ジノン誘導体またはその塩類に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel 2(IH)-pyrimidinone derivatives or salts thereof useful as cardiotonic agents.
〔従来の技術および発明が解決しようとする課題〕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。[Prior Art and Problems to be Solved by the Invention] Cardiotropic agents have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used in the past for the treatment of 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り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 having an extremely narrow safety margin, causing arrhythmia, or having a transient inotropic effect, making them 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（■）：Ｒ′
（上記式中、Ａは１〜３個の窒素原子を含む５員環また
は６員環の複素環基を表わし、その環上にＣ，−ＣＳの
アルキル基、シアノ基、カルボキシ基。That is, the gist of the present invention is the following general formula (■): R' (In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, and on the ring C, -CS alkyl group, cyano group, carboxy group.
０１〜Ｃ９のアルコキシカルボニル基、 水ＷＩＬ Ｃ
＋〜Ｃ１のアルコキシ基、アミノ基＋ＣＩ〜Ｃ６のアル
キルアミノ基＋Ｃ２〜Ｃ６のジアルキルアミノ基、０２
〜Ｃ６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。01-C9 alkoxycarbonyl group, water WIL C
+ ~ C1 alkoxy group, amino group + CI ~ C6 alkylamino group + C2 ~ C6 dialkylamino group, 02
It may have at least one substituent selected from -C6 acylamino, groups and carbamoyl groups.
Ｒ１およびｐＺは、それぞれ独立して水素原子またはＣ
Ｉ”” Ｃｓのアルキル基を表わす。）で示される２（
ＩＨ）−ピリミジノン誘導体又はその塩類に存する。R1 and pZ are each independently a hydrogen atom or C
I"" represents an alkyl group of Cs. ) denoted by 2(
IH)-pyrimidinone derivatives or salts thereof.
以下、具体例を示し本発明の詳細な説明する。Hereinafter, the present invention will be explained in detail with reference to specific examples.
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１〜３個の窒素原
子を含む５員環または６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。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０１〜Ｃ％の直鎖または分校したアルキル基；
シアノ基；カルボキシ基：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〜Ｃ１の直鎖または分校したアル
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
は分校したアルコキシ基；アミノ基；メチルアミノ基、
エチルアミノ基。Specific examples of A in the above general formula (I) include a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group,
Examples include 5- or 6-membered heterocyclic groups containing 1 to 3 nitrogen atoms, such as δ-triazinyl group, ω-triazinyl group, pyrrolyl group, imidazolyl group, and pyrazolyl group, and at least It may have one substituent. As the substituent, 01 to C% straight chain or branched alkyl groups such as methyl group, ethyl group, propyl group, butyl group;
Cyano group; Carboxy group: C1-C1 linear or branched alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group; Hydroxyl group: methoxy group, ethoxy group, propoxy group, butoxy group, etc. C1 to C5 linear or branched alkoxy group; amino group; methylamino group,
ethylamino group.
プロピルアミノ基、ブチルアミノ基等のＣＩ” Ｃｓ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０２〜
Ｃ５の直鎖または分校したジアルキルアミノ基；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〜Ｃ６の直鎖または分校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。Straight-chain or branched alkylamino groups of CI"Cs such as propylamino groups and butylamino groups; 02-2 such as dimethylamino groups, diethylamino groups and dipropylamino groups
C5 straight chain or branched dialkylamino group; C2 to C6 straight chain or branched acylamino group such as acetylamino group, propionylamino group, butyrylamino group;
and a carbamoyl group.
また、Ｒ１およびＲ２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、ブチル基のＣＩ”
”” Ｃｓの直鎖または分校したアルキル基が挙げられ
る。Specific examples of R1 and R2 include hydrogen atoms and CI'' of methyl, ethyl, propyl, and butyl groups.
"" A straight chain or branched alkyl group of Cs can be mentioned.
上記一般式（１）で示される２（ＬＨ）−ピリミジノン
誘導体の具体例としては以下に示すような化合物が挙げ
られる。Specific examples of the 2(LH)-pyrimidinone derivative represented by the above general formula (1) include the compounds shown below.
Ｈ３ 体は、例えば次の様な経路で製造される。H3 The body is manufactured, for example, by the following route.
Ｒ１
Ｒ′
（ｎ）
（Ｉｎ＞
また上記化合物の薬剤的に許容され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。R1 R' (n) (In> Pharmaceutically acceptable salts of the above compounds are also included within the scope of the present invention. Examples of the above salts include hydrochloric acid.
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。これらの化合物はいずれも強心剤として有
用である。Examples include salts of mineral acids such as phosphoric acid and salts of organic acids such as lactic acid and acetic acid. 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。Next, a method for producing the compound of the present invention will be explained.
本発明における２（ＩＨ）−ピリミジノン誘導Ｒ′
（上記式中、Ａ、 Ｒ’およびＲ２は既に定義したとお
りであり、Ｘはハロゲン原子を表わす。）すなわち、上
記化合物（ＩＩ）と化合物（Ｉ［Ｉ）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−２−ピロリドン等の不活性溶媒中で５０
’〜２００℃において０．５〜１０時間加熱することに
より口約とする２（ＩＨ）−ピリミジノン誘導体（１）
を合成できる。なお、塩基としてトリエチルアミンおよ
び１．８−ジアザビシロ（５，４，０）−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。2(IH)-pyrimidinone derivative R' in the present invention (in the above formula, A, R' and R2 are as defined above, and X represents a halogen atom), that is, the above compound (II) and the compound (I [I) in an inert solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone for 50 minutes.
2(IH)-pyrimidinone derivative (1) which is softened by heating at ~200°C for 0.5 to 10 hours
can be synthesized. In addition, as a base, organic bases such as triethylamine and 1,8-diazabicylo(5,4,0)-7-undecene, or inorganic bases 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（ｎ）はＴ。The above compound (n) used as a starting material is T.
セラトスキー（Ｔ、 ５ｈｅｒａｄｓｋｙ ）らにより
ジャーナル・オブ・ザ・ケミカル・ソサエティ、パーキ
ン・トランザクションＩ （Ｊ、 Ｃ，Ｓ、 Ｐｅｒ
ｋｉｎＩ）、第１２９６〜１２９９ページ（１９７７年
）に記載された方法により、以下の経路で製造される。Journal of the Chemical Society, Perkin Transactions I (J, C, S, Per
kinI), pages 1296 to 1299 (1977), by the following route.
２皿
Ｒ’
（ｒＶ）
（Ｖ）
Ｒ′
Ｒ′
（ｎ）
（上記式中、Ｒ１，Ｒ２およびＸは既に定義したとおり
であり、Ｑはアセチル基、プロピオニル基等のアシル基
あるいはベンジルオキシカルボニル基。2 plates R' (rV) (V) R'R' (n) (In the above formula, R1, R2 and Base.
ｔｅｒｔ−ブトキシカルボニル基等のアルコキシカルボ
ニル基を表わす。）
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。It represents an alkoxycarbonyl group such as a tert-butoxycarbonyl 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、カプセル剤、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, sugar-coated tablets, pills, capsules, liquids, etc. for oral administration, and wastes, suspensions, liquids, emulsions, etc. for parenteral administration. Examples include ampoules 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（Ｖｌ） ることができる。When formulating, use the conventional method in this field (Vl) can be done.
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、−医師により決定され
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.
-Determined by the physician, taking into account the type of active ingredient, etc.
例えば、経口投与の場合、体重／ｋｇ／日当り、０．１
〜１０■／ｋｇ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, 0.1 per body weight/kg/day
The dosage is selected to be approximately 10 μg/kg, but 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り、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.
参考例
５−（４−アミノフェニル）−２（ＩＨ）−（ａ）５−
（４−アセチルアミノフェニル）−２（ＩＨ）−ピリミ
ジノン
Ｎ−アセチル−Ｎ−フェニルヒドロキシルアミン３．７
８ ｇをＮ、Ｎ−ジメチルホルムアミド２５ＩＩｌｌに
溶解し、水冷撹拌下、６０％水素化ナトリウム１．０ｇ
を一時に添加した。添加後、同温度で５分間撹拌した後
、２−クロロピリミジン２．８６ ｇを固体で加えた。Reference example 5-(4-aminophenyl)-2(IH)-(a)5-
(4-acetylaminophenyl)-2(IH)-pyrimidinone N-acetyl-N-phenylhydroxylamine 3.7
Dissolve 8 g in 25IIll of N,N-dimethylformamide, and add 1.0 g of 60% sodium hydride while stirring under water cooling.
was added all at once. After the addition, the mixture was stirred at the same temperature for 5 minutes, and then 2.86 g of 2-chloropyrimidine was added as a solid.
水冷下で１０分間撹拌後、反応溶液を４０℃水浴上に移
し更に２時間反応を行った。反応終了後、反応混合物を
氷冷し水１２５ｎｊ！。After stirring for 10 minutes under water cooling, the reaction solution was transferred to a 40° C. water bath and the reaction was further carried out for 2 hours. After the reaction is complete, the reaction mixture is cooled with ice and poured with 125 nj of water. .
エーテル３０ｍβと酢酸２＋１１１を加え、析出した沈
澱を炉取し、３．５６ ｇの上記粗生成物を得た。この
粗生成物は精製せずに、次工程で使用しした。Ether 30 mβ and acetic acid 2+111 were added, and the precipitate precipitated was collected in a furnace to obtain 3.56 g of the above crude product. This crude product was used in the next step without purification.
（ｂ）５−（４−アミノフェニル） −２（１８） −
上記合成反応（ａ）で得た粗生成物３ｇに水９０ｍ１と
濃塩酸１０ｍ１２を加え、１０５°Ｃ油浴上で３゜５時
間加熱攪拌した。反応混合物に活性炭０．２ｇを加え更
に５分間攪拌後、熱時濾過により活性炭を除去した。炉
液に、氷冷しながらＩＮ−水酸ナトリウムを加え中和し
、析出した結晶を炉取した。(b) 5-(4-aminophenyl) -2(18) -
90 ml of water and 10 ml of concentrated hydrochloric acid were added to 3 g of the crude product obtained in the above synthesis reaction (a), and the mixture was heated and stirred on a 105° C. oil bath for 3.5 hours. 0.2 g of activated carbon was added to the reaction mixture, and after further stirring for 5 minutes, the activated carbon was removed by filtration while hot. The furnace solution was neutralized by adding IN-sodium hydroxide while cooling on ice, and the precipitated crystals were collected from the furnace.
水洗後、乾燥し、上記目的物２．３０ ｇを得た。After washing with water and drying, 2.30 g of the above-mentioned target product was obtained.
実施例
５− ［４−（４−ピリジルアミノ）フェニル〕−２（
ＩＨ）−ピリミジノン
５−（４−アミノフェニル）−２（ＬＨ）−ピリミジノ
ン０．９４ ｇをＮ−メチル−２−ピロリドン１５ｍ２
に溶解し、９０°Ｃ油浴上で加熱攪拌下、トリエチルア
ミン０．３５＋／！と４−クロルピリジン・塩酸塩０．
７５ ｇを順次加えた。同温度で２時間攪拌後、反応混
合物を氷冷し、アセトン２０ｔａｆｌを加え析出した固
体を炉取した。その固体を温水３００ｍｌに溶解し、氷
冷しながらＩＮ−水酸化ナトリウムを加え中和した。析
出した沈澱を炉取し、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Ｍ＝２０／１１０
゜１→１／１１０．０１）により精製した。目的物を含
む分画を集め濃縮し、残渣をメタノール４０ｒｍｌに溶
解し、水冷下、４Ｎ−塩酸／ジオキサン１．３ｍｆｆ１
．アセトン５０／！とエーテル１００ｍｊ２を加え析出
した固体を炉取し、エーテル洗浄後、乾燥し、下記物性
の淡褐色固体である上記目的物の塩酸塩を得た。Example 5 - [4-(4-pyridylamino)phenyl]-2(
IH)-pyrimidinone 0.94 g of 5-(4-aminophenyl)-2(LH)-pyrimidinone was dissolved in 15 m2 of N-methyl-2-pyrrolidone.
Dissolved in triethylamine 0.35+/! under heating and stirring on a 90°C oil bath. and 4-chlorpyridine hydrochloride 0.
75 g were added sequentially. After stirring at the same temperature for 2 hours, the reaction mixture was ice-cooled, 20 tafl of acetone was added, and the precipitated solid was collected in a furnace. The solid was dissolved in 300 ml of warm water and neutralized by adding IN-sodium hydroxide while cooling on ice. The precipitate was collected in a furnace and subjected to silica gel column chromatography (
Solvent; Chloroform/methanol/vinegar M=20/110
1/110.01). Fractions containing the target product were collected and concentrated, the residue was dissolved in 40 rml of methanol, and 1.3 mff1 of 4N-hydrochloric acid/dioxane was added under water cooling.
．． Acetone 50/! and 100 mj2 of ether were added, and the precipitated solid was collected in a furnace, washed with ether, and dried to obtain the above-mentioned hydrochloride of the target product as a pale brown solid with the following physical properties.
収１：１．１４ｇ （収率７６％）、融点？ ＞ ３０
０°ＣＩ Ｒ： １６４５ｃｍ−’
試験例
本発明の化合物の強心剤としての有用性を、インビトロ
およびインビボ双方の試験において、心臓収縮力の有意
な増加を引き起すことにより実証した。Yield 1: 1.14g (yield 76%), melting point? > 30
0° CI R: 1645 cm-' Test Examples The usefulness of the compounds of the invention as cardiotonic agents was demonstrated by causing a significant increase in cardiac contractile force in both in vitro and in vivo tests.
（１）インビトロ試験
インビトロ試験は、モルモットの摘出右心房および摘出
乳頭筋の双方の系につき、以下に記載する方法を用いて
行なわれた。(1) In vitro test In vitro tests were conducted using the method described below on both the isolated right atrium and isolated papillary muscle systems of guinea pigs.
（ａ） モルモット摘出右心房を用いる方法体重２０
０〜３００ｇ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。右心房室口の部分を、３５℃に
保温したタレブスーヘンスライト液３０ｍ１を満した臓
器浴の底部に固定した。臓器浴中のタレブスーヘンスラ
イド液には９５％の０２と５％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りつけその糸の
他端をトランスデユーサ−につなぎ、等尺性張力を測定
した。標本には０．５ｇの静止張力をかけた。(a) Method using isolated right atrium of guinea pig Weight 20
A male guinea pig weighing 0 to 300 g was hit on the back of the head, and the right atrium was immediately removed. The right atrium ostium was fixed at the bottom of an organ bath filled with 30 ml of Taleb-Sugensreit solution kept at 35°C. A mixed gas consisting of 95% 02 and 5% CO2 was bubbled through the Taleb-Suchen slide solution in the organ bath. 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. A resting tension of 0.5 g was applied to the specimen.
標本作製後３０分間安定させた後、溶媒に溶解した前記
実施例で得られた化合物を臓器浴中に加え、反応を記録
した。After stabilizing for 30 minutes after specimen preparation, the compound obtained in the above example dissolved in a solvent was added into the organ bath and the reaction was recorded.
（ｂ） モルモット摘出乳頭筋を用いる方法上記（ａ
）のモルモット摘出右心房を用いる方法と同様にして、
モルモット右心室乳頭筋を用い、薬物を添加したときの
反応を記録した。ただし、この場合標本は２本の白金電
極を介して持続１ミリ秒、闇値の１．５倍の電圧の矩形
波により１秒間に２回の割合で電気的に駆動した。(b) Method using isolated guinea pig papillary muscle (a)
) using a guinea pig isolated right atrium,
Using guinea pig right ventricular papillary muscle, the response when a drug was added was recorded. However, in this case, the specimen was electrically driven via two platinum electrodes with a square wave of voltage 1.5 times the dark value, lasting 1 millisecond, twice per second.
（２） インビボ試験
インビボ試験では、体重８〜１５ｋｇの雌雄雑犬を用い
た。犬は３０ ｍｇ／）ｃｇ （静注）のベントパルビ
タールナトリウムで麻酔し、人工呼吸を行った。(2) In-vivo test In the in-vivo test, male and female mixed dogs weighing 8 to 15 kg were used. The dog was anesthetized with 30 mg/)cg (intravenously) bentoparbital sodium and artificially ventilated.
左第四および第五肋間を開胸し、第五肋骨は切除した。A thoracotomy was made between the fourth and fifth left ribs, and the fifth rib was removed.
心のう膜を切開し、心臓を露出した。上行大動脈に電磁
流量計のプローブをとりつけ大動脈血流量を測定し、そ
れを心拍出量（ＣＯ）の概指数として使用した。左心室
にポリエチレンカニユーレを挿入し、左心室内圧を測定
し、それより電気−的に左心室内圧の変化率（ｄｐ／ｄ
ｔ）を求めた。右心室壁に歪測定ゲージをとりつけ、右
心室筋の収縮力（Ｃｏｎｔ）を測定した。全身血圧は左
大腿動脈から測定した。心拍数は心電図（第■誘導）よ
り測定した。溶媒に溶解した前記実施例で得られた化合
物は、左大腿静脈より静脈内投与した。The heart sac was incised and the heart exposed. An electromagnetic flowmeter probe was attached to the ascending aorta to measure the aortic blood flow, which was used as an approximate index of cardiac output (CO). A polyethylene cannula is inserted into the left ventricle, the left ventricular pressure is measured, and the rate of change in left ventricular pressure (dp/d) is measured electrically.
t) was calculated. A strain measurement gauge was attached to the right ventricular wall, and the contractile force (Cont) of the right ventricular muscle was measured. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured by electrocardiogram (Lead ■). The compound obtained in the above example dissolved in a solvent was intravenously administered through the left femoral vein.
上記の薬理試験を行ったとき、本発明の化合物はモルモ
ット右心房および乳頭筋の収縮力を増加させ、また麻酔
犬の左心室内圧変化率の最大値（ｄｐ／ｄｔ ｍａｘ）
、右心室の収縮力（Ｃｏｎｔ）および心拍比ｉｔ （
ＣＯ）の増加、すなわち心臓収縮性の増加を引き起した
。When the above pharmacological test was conducted, the compound of the present invention increased the contractile force of the right atrium and papillary muscles of guinea pigs, and also increased the maximum rate of change in left ventricular pressure (dp/dt max) in anesthetized dogs.
, right ventricular contractile force (Cont) and heart rate ratio it (
CO), which caused an increase in cardiac contractility.
モルモット右心房および乳頭筋収縮力の増加率、および
麻酔大のｄｐ／ｄｔ １１ａｘ、 Ｃｏｎｔ、 Ｃｏの
増加率を下記表１に示す。Table 1 below shows the rate of increase in guinea pig right atrium and papillary muscle contractile force, and the rate of increase in dp/dt 11ax, Cont, and Co during anesthesia.
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。 Ｒ＾１およびＲ＾２は、それぞれ独立して水素原子また
はＣ＿１〜Ｃ＿５のアルキル基を表わす。）で示される
２（１Ｈ）−ピリミジノ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, carboxy group, C_1 to 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, C
It may have at least one substituent selected from acylamino groups and carbamoyl groups of_2 to C_5. R^1 and R^2 each independently represent a hydrogen atom or an alkyl group of C_1 to C_5. ) A 2(1H)-pyrimidinone derivative or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20899188A JPH0259573A (en) | 1988-08-23 | 1988-08-23 | 2(1h)-pyrimidinone derivative or salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20899188A JPH0259573A (en) | 1988-08-23 | 1988-08-23 | 2(1h)-pyrimidinone derivative or salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0259573A true JPH0259573A (en) | 1990-02-28 |
Family
ID=16565516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20899188A Pending JPH0259573A (en) | 1988-08-23 | 1988-08-23 | 2(1h)-pyrimidinone derivative or salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0259573A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5567699A (en) * | 1994-04-26 | 1996-10-22 | Mitsubishi Chemical Corporation | Thiadiazinone derivatives |
| US9107923B2 (en) | 2013-06-27 | 2015-08-18 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
-
1988
- 1988-08-23 JP JP20899188A patent/JPH0259573A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5567699A (en) * | 1994-04-26 | 1996-10-22 | Mitsubishi Chemical Corporation | Thiadiazinone derivatives |
| US9107923B2 (en) | 2013-06-27 | 2015-08-18 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US9139561B2 (en) | 2013-06-27 | 2015-09-22 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US9527831B2 (en) | 2013-06-27 | 2016-12-27 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US9822097B2 (en) | 2013-06-27 | 2017-11-21 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US10093655B2 (en) | 2013-06-27 | 2018-10-09 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US10421744B2 (en) | 2013-06-27 | 2019-09-24 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US10696658B2 (en) | 2013-06-27 | 2020-06-30 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
| US11014909B2 (en) | 2013-06-27 | 2021-05-25 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
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