JPH0676326B2 - Cardiovascular drug - Google Patents
Cardiovascular drugInfo
- Publication number
- JPH0676326B2 JPH0676326B2 JP63127674A JP12767488A JPH0676326B2 JP H0676326 B2 JPH0676326 B2 JP H0676326B2 JP 63127674 A JP63127674 A JP 63127674A JP 12767488 A JP12767488 A JP 12767488A JP H0676326 B2 JPH0676326 B2 JP H0676326B2
- Authority
- JP
- Japan
- Prior art keywords
- carbon atoms
- chain
- branched
- straight
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002327 cardiovascular agent Substances 0.000 title 1
- 229940125692 cardiovascular agent Drugs 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 230000002490 cerebral effect Effects 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229940124549 vasodilator Drugs 0.000 claims description 5
- 239000003071 vasodilator agent Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003218 coronary vasodilator agent Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229940126585 therapeutic drug Drugs 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 37
- -1 methoxy, ethoxy Chemical group 0.000 description 34
- 238000012360 testing method Methods 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 11
- 102000000584 Calmodulin Human genes 0.000 description 10
- 108010041952 Calmodulin Proteins 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 102000010856 Type 1 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 6
- 108010037572 Type 1 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 4
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 4
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 229960000744 vinpocetine Drugs 0.000 description 4
- FGNAJWFZOBYZLR-UHFFFAOYSA-N 3h-[1,2,4]triazolo[4,3-a][1,4]diazepine Chemical class N1=CC=CN2CN=NC2=C1 FGNAJWFZOBYZLR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 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 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010022998 Irritability Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000017531 blood circulation 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
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UNRYNEUZUOGHCV-UHFFFAOYSA-N 4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6h-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine Chemical compound C1=CC(CC(C)C)=CC=C1CCC1=CC(C(=NCC2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 UNRYNEUZUOGHCV-UHFFFAOYSA-N 0.000 description 1
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
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- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
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- 229940126062 Compound A Drugs 0.000 description 1
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- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- HNDGEYCCZGRMTN-UHFFFAOYSA-N thieno[3,2-f:4,5-f]bis[1]benzothiophene Chemical compound S1C2=CC=3SC=CC=3C=C2C2=C1C=C(SC=C1)C1=C2 HNDGEYCCZGRMTN-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明はチエノトリアゾロジアゼピン誘導体およびその
薬理学的に許容される酸付加塩を有効成分として含有す
る冠血管拡張剤、心不全治療薬または脳血管拡張剤など
の循環器系疾患治療薬に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a coronary vasodilator containing a thienotriazolodiazepine derivative and a pharmaceutically acceptable acid addition salt thereof as an active ingredient, a therapeutic agent for heart failure, or a therapeutic agent for heart failure. The present invention relates to therapeutic agents for cardiovascular diseases such as cerebral vasodilators.
ある種のチエノトリアゾロジアゼピン化合物が抗不安活
性、抗痙攣活性などの中枢神経作用を有することは、た
とえばArzneim.Forsch.（Drug Res.）第28巻（II）、第
1165頁、1978年により知られている。また、特開昭61-8
7684号公報などには、同種の化合物が血小板活性化因子
拮抗作用を有することが開示されている。The fact that certain thienotriazolodiazepine compounds have central nervous effects such as anxiolytic activity and anticonvulsant activity is described in, for example, Arzneim. Forsch. (Drug Res.) Vol. 28 (II),
Known by page 1165, 1978. In addition, JP-A-61-8
7684 and the like disclose that the same type of compound has a platelet activating factor antagonistic action.
さらに、特願昭62-289983号明細書には経口投与に有効
で、作用持続が長く、さらに鎮静作用、筋弛緩作用など
の中枢抑制的作用が少ない、２位にアラルキル側鎖が置
換したPAF拮抗作用を有する一連の新規チエノ〔3,2−
ｆ〕〔1,2,4〕トリアゾロ〔4,3−ａ〕〔1,4〕ジアゼピ
ン化合物が開示されている。Further, Japanese Patent Application No. 62-289983 discloses a PAF which is effective for oral administration, has a long duration of action, and has little central depressant action such as sedative action and muscle relaxant action, in which the aralkyl side chain is substituted at the 2-position. A series of novel thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,4] diazepine compounds are disclosed.
ところで、近年の循環器系諸疾患による死亡率の増大
は、有効な薬剤の研究開発が焦眉の問題であることを認
識させるに至っているが、これら先行のチエノトリアゾ
ロジアゼピン化合物は、PAF由来の作用に拮抗すること
以外には、直接的な循環器系に対する有用な作用につい
ては知られていない。By the way, the recent increase in mortality due to various diseases of the circulatory system has led to the recognition that research and development of effective drugs is a problem of irritability, but these preceding thienotriazolodiazepine compounds are derived from PAF. Other than antagonizing the action of, the useful effects on the direct cardiovascular system are not known.
そこで、本発明者らは、循環器系疾患に対する有用な作
用を有する医薬を開発することを目的として、鋭意研究
を重ねた結果、次の一般式（Ｉ）で表わされる化合物お
よびその薬理学的に許容される酸付加塩が、強力なカル
モジュリン阻害作用、カルシウム／カルモジュリン依存
性ホスホジエステラーゼ阻害作用、赤血球変形能改善作
用などを有し、カルモジュリンが関与する細胞内カルシ
ウム生理作用抑制剤としてそれに基づく種々の疾患に有
用であり、さらに冠血管拡張作用、椎骨血流増加作用を
併せて有することにより、心不全、虚血性心疾患または
脳循環障害もしくはそれに基づく種々の循環器系疾患の
治療に有用であること、さらに、これらの作用が経口投
与においても有効であり、持続的であることも見出し、
本発明を完成させるに至った。Therefore, the inventors of the present invention have conducted extensive studies for the purpose of developing a drug having a useful action on cardiovascular diseases, and as a result, have found that a compound represented by the following general formula (I) and a pharmacological agent thereof. Acid-Accepting Salts Accepted by Alcohol have a Strong Calmodulin Inhibitory Action, Calcium / Calmodulin-Dependent Phosphodiesterase Inhibitory Action, Erythrocyte Deformability Improving Action, etc. It is useful for treating diseases such as heart failure, ischemic heart disease, cerebral circulation disorder, or various cardiovascular diseases based on the coronary vasodilatory effect and vertebral blood flow increasing effect. Furthermore, it was found that these effects are effective even in oral administration and are persistent,
The present invention has been completed.
すなわち、本発明は （１）一般式 （式中、Arはピリジル、フェニルまたは置換基としてハ
ロゲン、水酸基、炭素数１〜５個の直鎖または分枝鎖状
アルキルおよび炭素数１〜５個の直鎖または分枝鎖状ア
ルコキシから任意に選ばれる１〜３個を有するフェニル
を、Ａは炭素数１〜８個のアルキレンまたは炭素数１〜
５個の直鎖または分枝鎖状アルキルで置換された炭素数
１〜８個のアルキレンを、R1,R2,R3は同一または異なっ
て、水素または炭素数１〜５個の直鎖または分枝鎖状ア
ルキルを、R4,R5,R6は同一または異なって、水素、ハロ
ゲン、水酸基、炭素数１〜８個の直鎖または分枝鎖状ア
ルキル、炭素数１〜８個の直鎖または分枝鎖状アルコキ
シ、フェニル、フェノキシ、アラルキル、アラルキルオ
キシまたは芳香環上にハロゲン、水酸基、炭素数１〜５
個の直鎖または分枝鎖状アルキルおよび炭素数１〜５個
の直鎖または分枝鎖状アルコキシから任意に選ばれる１
〜３個の置換基を有しているフェニル、フェノキシ、ア
ラルキルまたはアラルキルオキシを示す。） で表わされるチエノトリアゾロジアゼピン誘導体および
その薬理学的に許容される酸付加塩を有効成分として含
有する冠血管拡張剤、心不全治療薬または脳血管拡張剤
である循環器系疾患治療薬に関する。That is, the present invention provides (1) the general formula (In the formula, Ar is any of pyridyl, phenyl or halogen as a substituent, a hydroxyl group, a linear or branched alkyl having 1 to 5 carbon atoms and a linear or branched alkoxy having 1 to 5 carbon atoms. Is a phenyl having 1 to 3 carbon atoms, A is an alkylene having 1 to 8 carbon atoms or 1 to 1 carbon atoms.
An alkylene group having 1 to 8 carbon atoms substituted with 5 straight chain or branched alkyl groups, R 1 , R 2 and R 3 are the same or different and each is hydrogen or a straight chain group having 1 to 5 carbon atoms. Or branched alkyl, R 4 , R 5 and R 6 are the same or different, and are hydrogen, halogen, hydroxyl group, straight or branched alkyl having 1 to 8 carbons and 1 to 8 carbons. Linear or branched alkoxy, phenyl, phenoxy, aralkyl, aralkyloxy or halogen, hydroxyl group, and 1 to 5 carbon atoms on the aromatic ring.
1 selected from straight-chain or branched-chain alkyl and straight-chain or branched-chain alkoxy having 1 to 5 carbon atoms
Represents phenyl, phenoxy, aralkyl or aralkyloxy having ~ 3 substituents. ) Relating to a coronary vasodilator, a therapeutic agent for heart failure or a cerebral vasodilator which is a therapeutic agent for cerebral vasodilator, which contains a thienotriazolodiazepine derivative represented by the formula (1) and a pharmacologically acceptable acid addition salt thereof as an active ingredient .
本発明化合物（Ｉ）の上記各記号の定義中、ハロゲンと
は塩素、臭素、フッ素、ヨウ素を、炭素数１〜５個の直
鎖または分枝鎖状アルキルとはメチル、エチル、ｎ−プ
ロピル、イソプロピル、ｎ−ブチル、イソブチル、第３
級ブチル、ｎ−ペンチル、イソペンチル、第３級ペンチ
ル、１−メチルブチルなどを、炭素数１〜５個の直鎖ま
たは分枝鎖状アルコキシとはメトキシ、エトキシ、ｎ−
プロポキシ、イソプロポキシ、ｎ−ブトキシ、イソブト
キシ、第３級ブトキシ、ｎ−ペンチルオキシ、イソペン
チルオキシ、第３級ペンチルオキシ、１−メチルブチル
オキシなどを、ピリジルとは２−ピリジル、３−ピリジ
ル、４−ピリジルを、炭素数１〜８個のアルキレンとは
直鎖状アルキレンを意味し、メチレン、エチレン、トリ
メチレン、テトラメチレン、ペンタメチレン、ヘキサメ
チレン、ヘプタメチレン、オクタメチレンを、炭素数１
〜５個の直鎖または分枝鎖状アルキルで置換された炭素
数１〜８個のアルキレンとは同一炭素上もしくは異なる
炭素上に炭素数１〜５個のアルキルで置換されたアルキ
レンを意味し、メチルメチレン、プロピレン、メチルト
リメチレン、ジメチルエチレン、ジメチルテトラメチレ
ン、エチルエチレン、ジメチルトリメチレンなどを、炭
素数１〜８個の直鎖または分枝鎖状アルキルとはメチ
ル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチ
ル、イソブチル、第３級ブチル、ｎ−ペンチル、イソペ
ンチル、１−メチルブチル、ｎ−ヘキシル、１−メチル
ペンチル、ｎ−ヘプチル、４−メチルヘキシル、１−エ
チルペンチル、1,4−ジメチルペンチル、ｎ−オクチ
ル、６−メチルヘプチル、２−エチルヘキシルなどを、
炭素数１〜８個の直鎖または分枝鎖状アルコキシとはメ
トキシ、エトキシ、ｎ−プロポキシ、イソプロポキシ、
ｎ−ブトキシ、イソブトキシ、第３級ブトキシ、ｎ−ペ
ンチルオキシ、イソペンチルオキシ、ｎ−ヘキシルオキ
シ、ｎ−ヘプチルオキシ、１−プロピルブトキシ、ｎ−
オクチルオキシ、５−メチルヘキシルオキシ、２−エチ
ルヘキシルオキシ、1,6−ジメチルヘキシルオキシなど
を、アラルキルとはベンジル、１−フェニルエチル、２
−フェニルエチル、３−フェニルプロピル、４−フェニ
ルブチルなどを、アラルキルオキシとはベンジルオキ
シ、２−フェニルエトキシ、３−フェニルプロポキシ、
４−フェニルブトキシなどを、芳香環上にハロゲン、水
酸基、炭素数１〜５個の直鎖または分枝鎖状アルキルお
よび炭素数１〜５個の直鎖または分枝鎖状アルコキシか
ら任意に選ばれる１〜３個の置換基を有しているフェニ
ル、フェノキシ、アラルキルまたはアラルキルオキシと
は２−クロロフェニル、２−ブロモフェニル、３−フル
オロフェニル、2,3−ジクロロフェニル、４−ヒドロキ
シフェニル、２−メチルフェニル、４−メチルフェニ
ル、３−エチルフェニル、４−プロピルフェニル、４−
イソプロピルフェニル、４−ブチルフェニル、４−第３
級ブチルフェニル、４−ペンチルフェニル、2,4−ジメ
チルフェニル、２−メトキシフェニル、４−メトキシフ
ェニル、３−エトキシフェニル、２−プロポキシフェニ
ル、４−ブトキシフェニル、2,4−ジメトキシフェニ
ル、3,4,5−トリメトキシフェニル、２−クロロフェノ
キシ、2,3−ジクロロフェノキシ、４−ヒドロキシフェ
ノキシ、２−メチルフェノキシ、４−ブチルフェノキ
シ、2,4−ジメチルフェノキシ、２−メトキシフェノキ
シ、４−メトキシフェノキシ、2,4−ジメトキシフェノ
キシ、3,4,5−トリメトキシフェノキシ、２−クロロベ
ンジル、2,3−ジクロロベンジル、４−ヒドロキシベン
ジル、２−メチルベンジル、４−メトキシベンジル、3,
4,5−トリメトキシベンジル、２−（２−クロロフェニ
ル）エチル、２−クロロベンジルオキシ、2,4−ジメチ
ルベンジルオキシ3,4,5−トリメトキシベンジルオキ
シ、２−（２−クロロフェニル）エトキシ、２−（2,4
−ジメチルフェニル）エトキシなどを示す。In the definition of each symbol of the compound (I) of the present invention, halogen is chlorine, bromine, fluorine or iodine, and linear or branched alkyl having 1 to 5 carbon atoms is methyl, ethyl or n-propyl. , Isopropyl, n-butyl, isobutyl, tertiary
Primary butyl, n-pentyl, isopentyl, tertiary pentyl, 1-methylbutyl and the like are methoxy, ethoxy, n-, and C1-C5 linear or branched alkoxy.
Propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, 1-methylbutyloxy and the like, and pyridyl is 2-pyridyl, 3-pyridyl, 4-Pyridyl is an alkylene having 1 to 8 carbon atoms, which means a straight-chain alkylene, and methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene has 1 carbon atom.
~ 5 straight-chain or branched alkyl substituted alkylene having 1 to 8 carbon atoms means alkylene substituted on the same carbon or different carbons with 1 to 5 carbon alkyls. , Methylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltetramethylene, ethylethylene, dimethyltrimethylene and the like, and straight-chain or branched alkyl having 1 to 8 carbon atoms is methyl, ethyl, n-propyl. , Isopropyl, n-butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, n-heptyl, 4-methylhexyl, 1-ethylpentyl, 1,4 -Dimethylpentyl, n-octyl, 6-methylheptyl, 2-ethylhexyl and the like,
The straight-chain or branched-chain alkoxy having 1 to 8 carbon atoms is methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tertiary butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, n-heptyloxy, 1-propylbutoxy, n-
Octyloxy, 5-methylhexyloxy, 2-ethylhexyloxy, 1,6-dimethylhexyloxy and the like, aralkyl is benzyl, 1-phenylethyl, 2
-Phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like, aralkyloxy and benzyloxy, 2-phenylethoxy, 3-phenylpropoxy,
4-phenylbutoxy or the like is arbitrarily selected from halogen, hydroxyl group, linear or branched alkyl having 1 to 5 carbon atoms and linear or branched alkoxy having 1 to 5 carbon atoms on the aromatic ring. Phenyl having 1 to 3 substituents, phenoxy, aralkyl or aralkyloxy is 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2- Methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-
Isopropylphenyl, 4-butylphenyl, 4-third
Tert-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3, 4,5-Trimethoxyphenyl, 2-chlorophenoxy, 2,3-dichlorophenoxy, 4-hydroxyphenoxy, 2-methylphenoxy, 4-butylphenoxy, 2,4-dimethylphenoxy, 2-methoxyphenoxy, 4-methoxy Phenoxy, 2,4-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-chlorobenzyl, 2,3-dichlorobenzyl, 4-hydroxybenzyl, 2-methylbenzyl, 4-methoxybenzyl, 3,
4,5-trimethoxybenzyl, 2- (2-chlorophenyl) ethyl, 2-chlorobenzyloxy, 2,4-dimethylbenzyloxy 3,4,5-trimethoxybenzyloxy, 2- (2-chlorophenyl) ethoxy, 2- (2,4
-Dimethylphenyl) ethoxy and the like.
一般式（Ｉ）の化合物の薬理学的に許容しうる酸付加塩
としては塩酸、硫酸、リン酸、臭化水素酸、硝酸などの
無機酸との塩、またはマレイン酸、フマール酸、リンゴ
酸、酒石酸、コハク酸、クエン酸、酢酸、乳酸、メタン
スルホン酸、パラトルエンスルホン酸、パモ酸などの有
機酸との塩があげられる。The pharmacologically acceptable acid addition salt of the compound of the general formula (I) is a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or maleic acid, fumaric acid, malic acid. , Salts of tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, paratoluenesulfonic acid, pamoic acid and the like.
本発明化合物が１個またはそれ以上の不斉炭素原子を有
する場合にはラセミ体、ジアステレオ異性体および個々
の光学異性体が存在し得るが、本発明はそれらすべてを
包含する。When the compound of the present invention has one or more asymmetric carbon atoms, racemates, diastereoisomers and individual optical isomers may exist, and the present invention includes all of them.
一般式（Ｉ）の化合物およびその薬理学的に許容される
酸付加塩としては、以下の表に例示したような化合物が
挙げられる。Examples of the compound of the general formula (I) and a pharmaceutically acceptable acid addition salt thereof include the compounds exemplified in the following table.
これらの化合物は上記の先行技術文献に記載の化合物で
ある。These compounds are the compounds described in the above-mentioned prior art documents.
〔作用および発明の効果〕 本発明化合物（Ｉ）およびその薬理学的に許容される酸
付加塩のカルモジュリン阻害作用、カルシウム／カルモ
ジュリン依存性ホスホジエステラーゼ阻害作用につい
て、以下の薬理実験例により詳細に示す。なお、用いた
試験化合物および対照化合物は以下の通りである。 [Action and Effect of the Invention] The calmodulin-inhibiting action and the calcium / calmodulin-dependent phosphodiesterase-inhibiting action of the compound (I) of the present invention and a pharmaceutically acceptable acid addition salt thereof will be described in detail by the following pharmacological experimental examples. The test compounds and control compounds used are as follows.
試験化合物A:4−（２−クロロフェニル）−２−〔２−
（４−イソブチルフェニル）エチル〕−９−メチル−6H
−チエノ〔3,2−ｆ〕〔1,2,4〕トリアゾロ〔4,3−ａ〕
〔1,4〕ジアゼピン 試験化合物B:4−（２−クロロフェニル）−２−〔２−
（４−ｎ−ブチルフェニル）エチル〕−９−メチル−6H
−チエノ〔3,2−ｆ〕〔1,2,4〕トリアゾロ〔4,3−ａ〕
〔1,4〕ジアゼピン 試験化合物C:2−〔２−（４−ｎ−ブチルフェニル）エ
チル〕−９−メチル−４−（２−メチルフェニル）−6H
−チエノ〔3,2−ｆ〕〔1,2,4〕トリアゾロ〔4,3−ａ〕
〔1,4〕ジアゼピン 試験化合物D:4−（２−クロロフェニル）−２−〔２−
（４−イソブチルフェニル）エチル〕−6,9−ジメチル
−6H−エチノ〔3,2−ｆ〕〔1,2,4〕トリアゾロ〔4,3−
ａ〕〔1,4〕ジアゼピン 試験化合物E:2−〔２−（４−イソブチルフェニル）エ
チル〕−４−（3,4,5−トリメトキシフェニル）−6,9−
ジメチル−6H−エチノ〔3,2−ｆ〕〔1,2,4〕トリアゾロ
〔4,3−ａ〕〔1,4〕ジアゼピン 対照化合物:14−エトキシカルボニル−（３α,16α−エ
チル）−14,15−エブルナメニン〔ビンポセチン〕 薬理実験例１ カルモジュリン阻害作用 （NPN螢光ポローブ法） カルモジュリン阻害作用の測定はエプシュタン（Epstei
n）らの方法〔バイオケミカル・アンド・バイオフィジ
カル・リサーチ・コミュニケーションズ（Biochem.Biop
hys.Res.Commun.）、第105巻、1142頁、1982年〕を改変
して用いた。すなわち、25mMトリス−塩酸緩衝液（pH7.
0）に最終濃度塩化カルシウム1mM、Ｎ−フェノール−１
−ナフチルアミン（NPN）５μＭ、カルモジュリン（牛
脳）1000unitおよび各試験化合物を加え、3mlになるよ
うに調製した。室温に１時間放置したのち、螢光光度計
で螢光強度を測定した（ex.350nm、em.440nm）。カルモ
ジュリンの代わりに水を加えたものをブランクとした。
各試験化合物はジメチルスルホキシドあるいは2.5％ジ
メチルスルホキシドに溶解させ、ジメチルスルホキシド
の最終濃度は0.25％とした。Test compound A: 4- (2-chlorophenyl) -2- [2-
(4-Isobutylphenyl) ethyl] -9-methyl-6H
-Thieno [3,2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine test compound B: 4- (2-chlorophenyl) -2- [2-
(4-n-Butylphenyl) ethyl] -9-methyl-6H
-Thieno [3,2-f] [1,2,4] triazolo [4,3-a]
[1,4] Diazepine Test compound C: 2- [2- (4-n-butylphenyl) ethyl] -9-methyl-4- (2-methylphenyl) -6H
-Thieno [3,2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepine test compound D: 4- (2-chlorophenyl) -2- [2-
(4-Isobutylphenyl) ethyl] -6,9-dimethyl-6H-ethino [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepine Test compound E: 2- [2- (4-isobutylphenyl) ethyl] -4- (3,4,5-trimethoxyphenyl) -6,9-
Dimethyl-6H-ethino [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine Reference compound: 14-ethoxycarbonyl- (3α, 16α-ethyl) -14 , 15-Ebrunamenine [Vinpocetine] Pharmacological Experimental Example 1 Calmodulin Inhibitory Action (NPN Fluorescent Prorobe Method) The calmodulin inhibitory action was measured by Epstein.
n) et al. [Biochemical and Biophysical Research Communications (Biochem.Biop
hys.Res.Commun.), 105, 1142, 1982]. That is, 25 mM Tris-HCl buffer (pH 7.
0) final concentration calcium chloride 1 mM, N-phenol-1
-Naphthylamine (NPN) 5 µM, calmodulin (bovine brain) 1000 unit and each test compound were added to prepare 3 ml. After left at room temperature for 1 hour, the fluorescence intensity was measured with a fluorometer (ex.350 nm, em.440 nm). A blank was prepared by adding water instead of calmodulin.
Each test compound was dissolved in dimethyl sulfoxide or 2.5% dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide was 0.25%.
その結果をIC50値（50％阻害濃度、μＭ）として表わし
たところ、用いた試験化合物Ａ、ＢおよびＤはそれぞれ
1.0、0.85および1.3μＭであった。一方、対照化合物で
あるビンポセチンは3.5μＭであった。The results were expressed as an IC 50 value (50% inhibitory concentration, μM). The test compounds A, B and D used were each
It was 1.0, 0.85 and 1.3 μM. On the other hand, the reference compound, vinpocetine, was 3.5 μM.
薬理実験例２ カルシウム／カルモジュリン依存性ホス
ホジエステラーゼ阻害作用 実験はトンプソンらの方法〔アドバンシイズ・イン・サ
イクリック・ヌクレオタイド・リサーチ（Advances in
Cyclic Nucleotide Research）第10巻、69頁、1979年〕
に準じて行なった。すなわち、40μｌの200mMトリス−
塩酸緩衝液〔pH8.0、25mM塩化マグネシウム、0.5mMエチ
レングリコール−ビス（β−アミノエチルエーテル）−
N,N'−テトラ酢酸（EGTA）含有〕、20μｌの10μＭ
〔3H〕−cAMP（250nCi）、試験化合物およびカルシウム
／カルモジュリン依存性ホスホジエステラーゼ（PDE）
酵素液を加え、最終液量200μｌとした。なお、試験化
合物はジメチルスルホキシドに溶解し、最終濃度１％と
した。反応は37℃で20分間行なった。沸騰水浴中で１分
間加熱することにより反応を停止したのち、蛇毒（snak
e venom,1mg/ml）を50μｌ加え、30℃、10分間反応させ
ることにより、生成した5'−AMPをアデノシンに変換し
た。続いて500μｌのAGI−X8（メタノール：樹脂＝3:
2）を加え、氷冷下にときどき振動させながら、15分間
放置することにより未反応のcAMPを吸着させた。その
後、遠心分離を行ない、上清の放射活性を液体シンチレ
ーションカウンターで測定した。Pharmacological Experiment 2 Calcium / Calmodulin-Dependent Phosphodiesterase Inhibitory Action The experiment was conducted by the method of Thompson et al. [Advances in Cyclic Nucleotide Research (Advances in
Cyclic Nucleotide Research) Volume 10, p. 69, 1979)
Was carried out according to. That is, 40 μl of 200 mM Tris-
Hydrochloric acid buffer solution [pH 8.0, 25 mM magnesium chloride, 0.5 mM ethylene glycol-bis (β-aminoethyl ether)-
Containing N, N'-tetraacetic acid (EGTA)], 20 μl of 10 μM
[ 3 H] -cAMP (250 nCi), test compound and calcium / calmodulin-dependent phosphodiesterase (PDE)
The enzyme solution was added to make a final volume of 200 μl. The test compound was dissolved in dimethyl sulfoxide to give a final concentration of 1%. The reaction was carried out at 37 ° C for 20 minutes. After stopping the reaction by heating in a boiling water bath for 1 minute, snake poison (snak
e venom, 1 mg / ml) was added thereto and reacted at 30 ° C. for 10 minutes to convert the produced 5′-AMP into adenosine. Then 500 μl of AGI-X8 (methanol: resin = 3:
2) was added, and unreacted cAMP was adsorbed by leaving it for 15 minutes while shaking it under ice cooling occasionally. Then, centrifugation was performed and the radioactivity of the supernatant was measured by a liquid scintillation counter.
試験化合物のPDE活性に対する作用はカルシウム／カル
モジュリン非添加時の障害率を下記の式により算出し
た。The effect of the test compound on the PDE activity was calculated by the following formula as the injury rate when calcium / calmodulin was not added.
a:試験化合物存在、カルモジュリン非存在下でのPDE活
性 b:試験化合物、カルモジュリン非存在下でのPDE活性 その結果をIC50値として求めたところ、用いた試験化合
物A,B,CおよびＥは、それぞれ10,12,8および11μＭであ
った。一方、対照化合物であるビンポセチンは88μＭで
あった。 a: PDE activity in the presence of a test compound, in the absence of calmodulin b: PDE activity in the absence of a test compound, calmodulin When the results were determined as IC 50 values, the test compounds A, B, C and E used were: , 10, 12, 8 and 11 μM, respectively. On the other hand, the control compound, vinpocetine, was 88 μM.
また、本発明化合物の急性毒性を６匹の雄性マウスを用
いて検討した。試験化合物を経口投与して５日間観察し
たところ、1000mg/kgの投与量で何ら死亡例はみられな
かった。Further, the acute toxicity of the compound of the present invention was examined using 6 male mice. When the test compound was orally administered and observed for 5 days, no deaths were observed at the dose of 1000 mg / kg.
以上の薬理実験例および各種薬理実験から明らかなよう
に本発明化合物（Ｉ）およびその薬理学的に許容される
酸付加塩は強力なカルモジュリン阻害作用、カルシウム
／カルモジュリン依存性ホスホジエステラーゼ阻害作用
の他に赤血球変形能改善作用、冠血管拡張作用、椎骨血
流増加作用を示し、経口投与でも持続的で強い活性を示
す。As is clear from the above-mentioned examples of pharmacological experiments and various pharmacological experiments, the compound (I) of the present invention and its pharmacologically acceptable acid addition salts have a strong calmodulin inhibitory action and a calcium / calmodulin-dependent phosphodiesterase inhibitory action. It shows erythrocyte deformability-improving action, coronary vasodilatory action, and vertebral blood flow increasing action, and shows persistent and strong activity even after oral administration.
また、この活性は対照として用いたビンポセチンと比較
しても、カルシウム／カルモジュリン依存性ホスホジエ
ステラーゼ阻害作用では、はるかに強力であることがわ
かる。Further, it can be seen that this activity is far more potent in the calcium / calmodulin-dependent phosphodiesterase inhibitory action as compared with vinpocetine used as a control.
したがって、本発明化合物（Ｉ）およびその薬理学的に
許容される酸付加塩は、カルモジュリンが関与する細胞
内カルシウム生理作用抑制剤として、さらに、冠血管拡
張剤、心不全治療薬、脳血管拡張剤として心不全、虚血
性心疾患（狭心症、心筋梗塞など）または脳循環障害
（脳梗塞、脳動脈硬化症、脳出血、頭部障害など）もし
くはそれに基づく疾病（自発性低下、うつ状態、記憶障
害など）などの循環器系疾患の治療薬として有用であ
る。Therefore, the compound (I) of the present invention and a pharmacologically acceptable acid addition salt thereof can be further used as a calmodulin-involved intracellular calcium physiological inhibitor, as well as a coronary vasodilator, a therapeutic agent for heart failure, and a cerebral vasodilator. As heart failure, ischemic heart disease (angina, myocardial infarction, etc.) or cerebral circulatory disorder (cerebral infarction, cerebral arteriosclerosis, cerebral hemorrhage, head disorder, etc.) or its related diseases (spontaneous decline, depression, memory impairment) Etc.) and the like are useful as therapeutic agents for cardiovascular diseases.
本発明の化合物（Ｉ）およびその薬理学的に許容される
酸付加塩は、その治療上の有効量と賦形剤、増量剤、希
釈剤、溶解補助剤などの医薬用添加剤とを適宜混合し、
錠剤、丸剤、散剤、カプセル剤、顆粒剤、液剤、吸入
剤、坐剤、経皮吸収剤または注射剤として経口的または
非経口的に安全に投与することができる。投与量は選択
する化合物、疾病の重症度、年齢などにより異なるが、
通常成人１日当り0.1〜100mgを１回または数回に分けて
投与することができる。The compound (I) of the present invention and a pharmaceutically acceptable acid addition salt thereof are appropriately treated in a therapeutically effective amount with pharmaceutical additives such as an excipient, a bulking agent, a diluent and a solubilizing agent. Mix and
It can be safely administered orally or parenterally as tablets, pills, powders, capsules, granules, solutions, inhalants, suppositories, transdermal agents or injections. The dose varies depending on the compound selected, the severity of the disease, the age, etc.
Usually, 0.1 to 100 mg per day for an adult can be administered once or in several divided doses.
本発明化合物を有効成分とする医薬組成物について以下
に例示する。The pharmaceutical composition containing the compound of the present invention as an active ingredient is exemplified below.
製剤処方例１ 錠剤 本発明化合物（Ｉ）を１部、乳糖30部、結晶セルロース
40部およびコーンスターチ５部とをよく混和したのち、
コーンスターチ２部で製した結合剤とよく練合した。こ
の練合物を16メッシュで篩過し、オーブン中、50℃で乾
燥後、24メッシュで篩過した。ここで得た練合粉体とコ
ーンスターチ10部、結晶セルロース13部およびタルク９
部とをよく混合した後、圧搾打錠し、１錠当り重量110m
gの錠剤を得た。Pharmaceutical Formulation Example 1 Tablet 1 part of the compound (I) of the present invention, 30 parts lactose, crystalline cellulose
After thoroughly mixing 40 parts and 5 parts of corn starch,
Kneaded well with the binder made from 2 parts of corn starch. The kneaded product was sieved with 16 mesh, dried in an oven at 50 ° C., and then sieved with 24 mesh. The kneaded powder obtained here, 10 parts of corn starch, 13 parts of crystalline cellulose and 9 talc
After mixing well with the parts, press tableting, weight per tablet 110m
A tablet of g was obtained.
製剤処方例２ １％散剤 本発明化合物（Ｉ）を１部と乳糖90部をよく混和し、適
当量のメチルセルロースより製した結合剤とよく練合す
る。これを16メッシュで篩過し、オーブン中、50℃で乾
燥する。乾燥顆粒末を32メッシュで圧篩過し、適量のシ
リコンジオキシドとよく混和して、１％散剤を得た。Pharmaceutical Formulation Example 2 1% Powder 1 part of the compound (I) of the present invention and 90 parts of lactose are mixed well and kneaded well with a binder made of an appropriate amount of methylcellulose. It is sieved through 16 mesh and dried in an oven at 50 ° C. The dried granule powder was sieved with 32 mesh and mixed well with an appropriate amount of silicon dioxide to obtain a 1% powder.
本発明を上述の明細書およびそれに包含される実施例で
十分に説明したが、これらは本発明の精神と範囲に反す
ることなく種々に変更、修飾することができる。While the present invention has been fully described in the above specification and examples included therein, it is possible to make various changes and modifications without departing from the spirit and scope of the invention.
Claims (1)
ロゲン、水酸基、炭素数１〜５個の直鎖または分枝鎖状
アルキルおよび炭素数１〜５個の直鎖または分枝鎖状ア
ルコキシから任意に選ばれる１〜３個を有するフェニル
を、Ａは炭素数１〜８個のアルキレンまたは炭素数１〜
５個の直鎖または分枝鎖状アルキルで置換された炭素数
１〜８個のアルキレンを、R1,R2,R3は同一または異なっ
て、水素または炭素数１〜５個の直鎖または分枝鎖状ア
ルキルを、R4,R5,R6は同一または異なって、水素、ハロ
ゲン、水酸基、炭素数１〜８個の直鎖または分枝鎖状ア
ルキル、炭素数１〜８個の直鎖または分枝鎖状アルコキ
シ、フェニル、フェノキシ、アラルキル、アラルキルオ
キシまたは芳香環上にハロゲン、水酸基、炭素数１〜５
個の直鎖または分枝鎖状アルキルおよび炭素数１〜５個
の直鎖または分枝鎖状アルコキシから任意に選ばれる１
〜３個の置換基を有しているフェニル、フェノキシ、ア
ラルキルまたはアラルキルオキシを示す。） で表わされるチエノトリアゾロジアゼピン誘導体および
その薬理学的に許容される酸付加塩を有効成分として含
有する冠血管拡張剤、心不全治療薬または脳血管拡張剤
である循環器系疾患治療薬。1. A general formula (In the formula, Ar is any of pyridyl, phenyl or halogen as a substituent, a hydroxyl group, a linear or branched alkyl having 1 to 5 carbon atoms and a linear or branched alkoxy having 1 to 5 carbon atoms. Is a phenyl having 1 to 3 carbon atoms, A is an alkylene having 1 to 8 carbon atoms or 1 to 1 carbon atoms.
An alkylene group having 1 to 8 carbon atoms substituted with 5 straight chain or branched alkyl groups, R 1 , R 2 and R 3 are the same or different and each is hydrogen or a straight chain group having 1 to 5 carbon atoms. Or branched alkyl, R 4 , R 5 and R 6 are the same or different, and are hydrogen, halogen, hydroxyl group, straight or branched alkyl having 1 to 8 carbons and 1 to 8 carbons. Linear or branched alkoxy, phenyl, phenoxy, aralkyl, aralkyloxy or halogen, hydroxyl group, and 1 to 5 carbon atoms on the aromatic ring.
1 selected from straight-chain or branched-chain alkyl and straight-chain or branched-chain alkoxy having 1 to 5 carbon atoms
Represents phenyl, phenoxy, aralkyl or aralkyloxy having ~ 3 substituents. ) A thienotriazolodiazepine derivative represented by the following formula and a pharmacologically acceptable acid addition salt thereof as an active ingredient, a coronary vasodilator, a heart failure therapeutic drug, or a cerebral vasodilator therapeutic drug for cardiovascular disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63127674A JPH0676326B2 (en) | 1988-05-24 | 1988-05-24 | Cardiovascular drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63127674A JPH0676326B2 (en) | 1988-05-24 | 1988-05-24 | Cardiovascular drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01299231A JPH01299231A (en) | 1989-12-04 |
| JPH0676326B2 true JPH0676326B2 (en) | 1994-09-28 |
Family
ID=14965910
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63127674A Expired - Lifetime JPH0676326B2 (en) | 1988-05-24 | 1988-05-24 | Cardiovascular drug |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0676326B2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119160B (en) * | 2010-05-14 | 2016-06-01 | 达那-法伯癌症研究所 | For regulating compositions and the method for metabolism |
| MX354217B (en) | 2010-05-14 | 2018-02-19 | Dana Farber Cancer Inst Inc | Compositions and methods for treating leukemia. |
| EP2571875A4 (en) | 2010-05-14 | 2013-10-30 | Dana Farber Cancer Inst Inc | Male contraceptive compositions and methods of use |
| PL2902030T3 (en) | 2010-05-14 | 2017-07-31 | Dana-Farber Cancer Institute, Inc. | Thienotriazolodiazepine compounds for treating neoplasia |
| US9975896B2 (en) | 2013-07-25 | 2018-05-22 | Dana-Farber Cancer Institute, Inc. | Inhibitors of transcription factors and uses thereof |
| RU2016122654A (en) | 2013-11-08 | 2017-12-14 | Дана-Фарбер Кэнсер Инститьют, Инк. | COMBINED THERAPY OF A MALIGNANT TUMOR USING BRODOMODOMENE AND EXTRATERMINAL (BET) PROTEIN INHIBITORS |
| US10793571B2 (en) | 2014-01-31 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
| EP3099677A4 (en) | 2014-01-31 | 2017-07-26 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
| JP2017506666A (en) | 2014-02-28 | 2017-03-09 | テンシャ セラピューティクス，インコーポレイテッド | Treatment of symptoms related to hyperinsulinemia |
| CN106715437A (en) | 2014-08-08 | 2017-05-24 | 达纳-法伯癌症研究所股份有限公司 | Diazepane derivatives and uses thereof |
| CN106793775B (en) | 2014-08-08 | 2020-06-02 | 达纳-法伯癌症研究所股份有限公司 | Dihydropyrazinone derivatives and uses thereof |
| KR20170068597A (en) | 2014-10-27 | 2017-06-19 | 텐샤 세러퓨틱스 인코포레이티드 | Bromodomain inhibitors |
| WO2016201370A1 (en) | 2015-06-12 | 2016-12-15 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| EP3347021A4 (en) | 2015-09-11 | 2019-07-24 | Dana-Farber Cancer Institute, Inc. | CYANO-THIENOTRIAZOLOAZEPINES AND THEIR USES |
| RU2018112953A (en) | 2015-09-11 | 2019-10-14 | Дана-Фарбер Кэнсер Инститьют, Инк. | ACETAMIDTIENOTRIAZOLODIAZODEPINE AND WAYS OF THEIR APPLICATION |
| MX2018006499A (en) | 2015-11-25 | 2018-08-01 | Dana Farber Cancer Inst Inc | Bivalent bromodomain inhibtors and uses thereof. |
-
1988
- 1988-05-24 JP JP63127674A patent/JPH0676326B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01299231A (en) | 1989-12-04 |
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