JPH02289515A - Inhibitor of restenosis after ptca - Google Patents
Inhibitor of restenosis after ptcaInfo
- Publication number
- JPH02289515A JPH02289515A JP2044710A JP4471090A JPH02289515A JP H02289515 A JPH02289515 A JP H02289515A JP 2044710 A JP2044710 A JP 2044710A JP 4471090 A JP4471090 A JP 4471090A JP H02289515 A JPH02289515 A JP H02289515A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- formula
- compound
- acid
- restenosis
- 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
- 208000037803 restenosis Diseases 0.000 title claims abstract description 13
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract 3
- 238000007887 coronary angioplasty Methods 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- -1 fumaric acid Chemical class 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000001530 fumaric acid Substances 0.000 abstract description 2
- 125000002883 imidazolyl group Chemical group 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 150000007522 mineralic acids Chemical class 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 abstract description 2
- 125000000335 thiazolyl group Chemical group 0.000 abstract description 2
- VDLWTJCSPSUGOA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)CCCC2=C1 VDLWTJCSPSUGOA-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract 1
- 239000002552 dosage form Substances 0.000 abstract 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 abstract 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002586 coronary angiography Methods 0.000 description 4
- 210000004351 coronary vessel Anatomy 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- JQVLCBFYULYLPO-UHFFFAOYSA-N 6-(1h-imidazol-2-ylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid;hydrochloride Chemical compound Cl.C1CC2=CC(C(=O)O)=CC=C2CC1CC1=NC=CN1 JQVLCBFYULYLPO-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine 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９式（１）
（式中５Ｒはイミダゾリル基、チアゾリル基又はピリジ
ル基を、 ｎは ｌ又は２を、ＩＩｌは １〜４の整数
を意味する。）で表わされる化合物又はその塩を有効成
分とする経皮的冠動脈形成術後の再狭窄抑制剤に関する
。Detailed Description of the Invention <Industrial Application Field> The present invention relates to formula 9 (1) (wherein 5R is an imidazolyl group, thiazolyl group or pyridyl group, n is l or 2, and IIl is 1 to 4) The present invention relates to an agent for inhibiting restenosis after percutaneous coronary angioplasty, which contains a compound represented by (meaning an integer) or a salt thereof as an active ingredient.
〈従来の技術〉
経皮的冠動脈形成術（以下、 ＰＴＣＡ）は虚血性心疾
患に対し近年開発された治療法であり、具体的には冠動
脈の狭窄部をバルーンによりｍ械的に拡張させるもので
ある。しかしながら、 ＰＴＣＡｉよ冠動脈硬化性病変
の根本的治療法ではなく、冠動脈の狭窄部を拡張しても
該部の再狭窄が術後数ケ月以内に４０％前後の頻度で生
ずることが知られている。該再狭窄を抑制する為、抗血
小板剤、抗凝固剤等が試みられてぎだが、臨床上充分な
効果を有する薬剤は未だ見い出されていない。<Conventional technology> Percutaneous coronary angioplasty (hereinafter referred to as PTCA) is a treatment method developed in recent years for ischemic heart disease, and specifically involves mechanical dilation of narrowed portions of coronary arteries using a balloon. It is. However, PTCAi is not a fundamental treatment for coronary atherosclerotic lesions, and it is known that even if the narrowed portion of the coronary artery is dilated, restenosis of the narrowed portion of the coronary artery occurs at a frequency of approximately 40% within several months after surgery. . Antiplatelet agents, anticoagulants, and the like have been tried to suppress restenosis, but no drug with clinically sufficient effects has yet been found.
式（１）の化合物及びその塩はトロンボキサンへ２合成
阻害剤として有用であることが知られているが、 ＰＴ
ＣＡ後の再狭窄の抑制効果は知られていない。The compound of formula (1) and its salts are known to be useful as thromboxane 2 synthesis inhibitors, but PT
The inhibitory effect on restenosis after CA is unknown.
〈発明が解決しようとする問題点〉
本発明者等はＰＴＣＡ後の再狭窄に対し優れた抑制効果
を有する化合物を見い出すべく鋭意検討した結果１本発
明を完成した。<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to find a compound that has an excellent inhibitory effect on restenosis after PTCA.
〈発明の構成〉
本発明は式（１）の化合物又はその塩を有効成分とする
ＰＴＣＡ後の再狭窄抑制剤に関する。<Configuration of the Invention> The present invention relates to an agent for inhibiting restenosis after PTCA, which contains the compound of formula (1) or a salt thereof as an active ingredient.
式（１）の化合物の塩としては、塩酸、硫酸。Examples of the salt of the compound of formula (1) include hydrochloric acid and sulfuric acid.
硝酸等の無機酸及びフマル酸、酒石酸、マレイン酸、コ
ハク酸等の有機酸との酸付加塩、又、カルボキシル基の
ナトリウム塩、カリウム塩等のアルカリ金属塩及びカル
シウム塩、マグネシウム塩等のアルカリ土類金属塩等が
あげられる。Acid addition salts with inorganic acids such as nitric acid and organic acids such as fumaric acid, tartaric acid, maleic acid, and succinic acid, and alkali metal salts such as sodium salts and potassium salts of carboxyl groups, and alkali salts such as calcium salts and magnesium salts. Examples include earth metal salts.
式（Ｉ）の化合物をラットに経口投与し、急性毒性（Ｌ
Ｄ、。）を検討した結果９式（りの化合物及びその塩は
安全性が高いことが確認された。The compound of formula (I) was orally administered to rats, and acute toxicity (L
D. ), it was confirmed that the compound of formula 9 and its salts are highly safe.
式（りの化合物又はその塩は公知の製剤技術により錠剤
、散剤、カプセル剤又は注射剤等の剤型に製剤化可能で
あり１通常経ロ、皮下、筋肉内あるいは静脈内に投与さ
れる。The compound of the formula (RI) or a salt thereof can be formulated into tablets, powders, capsules, injections, etc. by known formulation techniques, and is usually administered orally, subcutaneously, intramuscularly, or intravenously.
式（１）の化合物又はその塩の投与量は経口投与におい
て成人−人あたり通常１００〜１０００ｍｇ／日の範囲
である。The dosage of the compound of formula (1) or a salt thereof is usually in the range of 100 to 1000 mg/day per adult person when administered orally.
〈発明の効果〉
式（１）の化合物又はその塩はＰＴＣＡ後の再狭窄に対
し優れた抑制効果を有することが臨床的に確認された。<Effects of the Invention> It was clinically confirmed that the compound of formula (1) or a salt thereof has an excellent inhibitory effect on restenosis after PTCA.
従って１式（Ｉ）の化合物及びその塩はＰＴＣＡ後の再
狭窄抑制剤として優れたものである。Therefore, the compound of formula (I) and its salts are excellent as agents for inhibiting restenosis after PTCA.
以下１本発明を更に実施例により説明するが。The present invention will be further explained below with reference to Examples.
本発明はこれに限定されるものではない。The present invention is not limited to this.
実施例１
６−（ｌ−イミダゾリルメチル）−５，６，７，８−テ
トラヒドロ−ナフタレン−２−カルボン酸塩酸塩・％水
和物（以下、化合物＾）を待機的ＰＴＣＡを施行した狭
心症患者１８名にＰＴＣＡを施行３日程前より施行後３
ケ月間１日 ３回毎食後２００ｍｇ（６００ｍｇ／日）
経口投与した（投与群） 、 ＰＴＣＡ施行前、 ＰＴ
ＣＡ施行直後及びＰＴＣＡ施行３ケ月後に冠動脈造影を
行い、その所見から右冠状動脈、左前下行技及び左回旋
技について病変部位別に再狭窄抑制の判定を以下の表１
の基準に基づいて行い、更にその結果に基づいて患者別
の有効性総合判定を行なった。Example 1 Angina treated with elective PTCA using 6-(l-imidazolylmethyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic hydrochloride % hydrate (hereinafter referred to as compound^) From 3 days before to 3 days after PTCA was performed on 18 patients with
200mg after each meal (600mg/day) 3 times a day for 1 month
Orally administered (administration group), before PTCA, PT
Coronary angiography was performed immediately after CA and 3 months after PTCA, and based on the findings, the inhibition of restenosis was determined by lesion location for the right coronary artery, left anterior descending maneuver, and left rotation maneuver as shown in Table 1 below.
Based on the criteria of
表１
表２
尚、化合物＾に代えてブラセボを投与して待機的ＰＴＣ
＾を施行した狭心症患者１５名についても上記と同様の
冠動脈造影所見を行い、これを対照群とした。Table 1 Table 2 In addition, elective PTC was performed by administering bracebo instead of compound^.
Coronary angiography findings similar to those described above were also performed on 15 patients with angina who underwent ^, and these were used as a control group.
又、上記の投与群及び対照群の両群についてはカルシウ
ム拮抗剤であるニフェジピン、ジルチアゼアム、狭心症
用剤であるｌ５ＤＮ、ニコランジル。In addition, for both the above-mentioned administration group and control group, calcium antagonists such as nifedipine and diltiazeam, and angina drugs such as 15DN and nicorandil were used.
動脈硬化用剤であるエラスターゼ等を以下の表２に示す
ように適宜併用したが６両群の患者背景のうち併用薬剤
の使用に関しては両群間にχ二乗検定による差はなかっ
た。Arteriosclerotic agents such as elastase were used in combination as appropriate as shown in Table 2 below, but among the patient backgrounds of the six groups, there was no difference in the use of concomitant drugs between the two groups according to a chi-square test.
結果を表３及び４に示した。The results are shown in Tables 3 and 4.
表 冠動脈造影所見に対する判定−病変別一鴎） 累積 零 ■ ＷＩＬＣＯＸＯＮ検定Ｐ−０，１００ 表 患者別に見た有効性総合判定 （冠動脈造影 所見より） 鴎）：累積＊ ＷＩＬＣＯＸＯＮ検定 Ｐ−０，０１０ 上表から明らかなように。table Judgment based on coronary angiography findings - Ichiro by lesion) Accumulation zero ■ WILCOXON test P-0,100 table Overall evaluation of effectiveness by patient (coronary angiography Based on the findings) Seagull): Cumulative* WILCOXON test P-0,010 As is clear from the table above.
病変別及び患者別の
判定のいづれにおいても投与群では対照群に比べＰＴＣ
＾後の再狭窄について優れた抑制効果が臨床的に確認さ
れた。In both lesion-specific and patient-specific evaluations, PTC was lower in the treated group than in the control group.
An excellent suppressive effect on restenosis after ^^ was clinically confirmed.
実施例２ 化合物＾ の経口投与による急性毒性値を表 ５に 示した。Example 2 compound ^ Acute toxicity values after oral administration of to 5 Indicated.
Claims (1)
ル基を、ｎは１又は２を、ｍは１〜４の整数を意味する
。）で表わされる化合物又はその塩を有効成分とする経
皮的冠動脈形成術後の再狭窄抑制剤[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. An agent for suppressing restenosis after percutaneous coronary angioplasty, containing a compound represented by (.) or a salt thereof as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2044710A JPH02289515A (en) | 1989-02-27 | 1990-02-26 | Inhibitor of restenosis after ptca |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4609389 | 1989-02-27 | ||
| JP1-46093 | 1989-02-27 | ||
| JP2044710A JPH02289515A (en) | 1989-02-27 | 1990-02-26 | Inhibitor of restenosis after ptca |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02289515A true JPH02289515A (en) | 1990-11-29 |
Family
ID=26384673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2044710A Pending JPH02289515A (en) | 1989-02-27 | 1990-02-26 | Inhibitor of restenosis after ptca |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02289515A (en) |
-
1990
- 1990-02-26 JP JP2044710A patent/JPH02289515A/en active Pending
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