TW201408297A - Sulfonamide compound combination - Google Patents

Sulfonamide compound combination Download PDF

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TW201408297A
TW201408297A TW102124846A TW102124846A TW201408297A TW 201408297 A TW201408297 A TW 201408297A TW 102124846 A TW102124846 A TW 102124846A TW 102124846 A TW102124846 A TW 102124846A TW 201408297 A TW201408297 A TW 201408297A
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prophylactic
glaucoma
therapeutic agent
ocular
agent
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TW102124846A
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TWI643619B (en
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桐原朋子
島崎敦
中村雅胤
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參天製藥股份有限公司
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Abstract

A combination of drugs for the prevention or treatment of glaucoma or ocular hypertension, said combination being useful as a prevention or treatment agent for glaucoma or ocular hypertension. Ocular tension lowering effects can be mutually complemented and/or enhanced by combining (6-{[4-(pyrazole-1-yl)benzyl](pyridine-3-ylsulfonyl)aminomethyl}pyridine-2-ylamino) isopropyl acetate and other drugs for the prevention or treatment of glaucoma or ocular hypertension. The drugs can be administered either as a combined administration or as a mixture.

Description

磺醯胺化合物之組合 Combination of sulfonamide compounds

本發明係關於一種組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它青光眼或高眼壓症之預防或治療藥的青光眼或高眼壓症之預防或治療劑、或降眼壓劑。 The present invention relates to a combination of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridin-2-ylamino)acetic acid isopropyl A preventive or therapeutic agent for glaucoma or ocular hypertension or an ocular hypotensive agent for the prevention and treatment of esters and other glaucoma or ocular hypertension.

青光眼係由於種種病因而眼壓上升、眼球的內部組織(網膜、視神經等)受到障礙而有導致失明的危險性之難治性的眼疾病。作為青光眼之治療方法，一般而言為降眼壓療法，作為其代表者有藥物療法、雷射治療法、手術療法等。 Glaucoma is an ocular disease in which the intraocular pressure rises due to various diseases, and the internal tissues of the eyeball (the omentum, the optic nerve, etc.) are impeded, and there is a risk of blindness. As a treatment method for glaucoma, it is generally an ocular hypotensive therapy, and as a representative thereof, there are a drug therapy, a laser therapy, a surgical therapy, and the like.

藥物療法係使用有交感神經促效藥(地匹福林(dipivefrine)等之非選擇性刺激藥、溴莫尼定(brimonidine)等之α2受體促效藥)、交感神經阻斷藥(噻嗎洛爾(timolol)、苯呋洛爾(befunolol)、卡替洛爾(carteolol)、尼普地洛(nipradilol)、倍他洛爾(betaxolol)、左布諾洛爾(levobunolol)或美替洛爾(Metipranolol)等之β受體阻斷藥、鹽酸布那唑嗪(bunazosin hydrochloride)等之α1受體阻斷藥)、副交感神經促效藥(毛果芸香鹼(pilocarpine)等)、碳酸酐酶抑制劑(乙醯唑胺(acetazolamide)等)、前列腺素類(異丙基烏諾前列酮 (isopropyl unoprostone)、拉坦前列腺素(latanoprost)、曲伏前列腺素(travoprost)或比馬前列腺素(bimatoprost)等)之藥物。又，Rho激酶抑制劑(SNJ-1656等)、腺核苷促效藥(INO-8875等)、血清素阻斷藥(BVT-28949)等作為新藥物開發中。又，除了該等以外，已知前列腺素E2受體亞型(subtype)2促效劑(EP2促效劑)有降眼壓作用，且於國際公開第2010/113957號(專利文獻1)報告有具有高EP2受體選擇性與強效之EP2促效劑作用之磺醯胺化合物用作為青光眼之治療藥有其希望。 The drug therapy uses a sympathetic agonist (a non-selective stimulant such as dipivefrine, an α 2 receptor agonist such as brimonidine), and a sympathetic blocker ( Timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol or beauty a β-blocker such as Metipranolol, an α 1 receptor blocker such as bunazosin hydrochloride, a parasympathetic agonist (pilocarpine, etc.), and a carbonic anhydride Enzyme inhibitors (acetazolamide, etc.), prostaglandins (isopropyl unoprostone, latanoprost, travoprost or bimatoprost) (bimatoprost), etc.). Further, Rho kinase inhibitors (such as SNJ-1656), adenosine agonists (INO-8875, etc.), and serotonin blocking drugs (BVT-28949) have been developed as new drugs. Further, in addition to these, a prostaglandin E2 receptor subtype 2 agonist (EP2 agonist) is known to have an ocular hypotensive effect, and is reported in International Publication No. 2010/113957 (Patent Document 1). A sulfonamide compound having a high EP2 receptor selectivity and a potent EP2 agonist is expected as a therapeutic drug for glaucoma.

因此，已有多數報告，以治療青光眼之目的，組合具有降眼壓作用之藥劑來使用。例如：於日本專利第2726672號公報(專利文獻2)報告有投予交感神經阻斷藥與前列腺素類之組合。又，於國際公開第2002/38158號(專利文獻3)揭示有組合數種具有降眼壓作用之藥劑而投予眼之青光眼的治療方法。進而，於國際公開第2004/019951號(專利文獻4)報告有投予Rho激酶抑制劑與前列腺素類之組合，於國際公開第2004/045644號(專利文獻5)報告有投予Rho激酶抑制劑及β受體阻斷藥之組合。 Therefore, most reports have been made for the purpose of treating glaucoma by combining agents having an ocular hypotensive effect. For example, Japanese Patent No. 2726672 (Patent Document 2) reports a combination of a sympatholytic agent and a prostaglandin. Further, Japanese Laid-Open Patent Publication No. 2002/38158 (Patent Document 3) discloses a treatment method in which a plurality of agents having an ocular hypotensive action are combined and administered to the glaucoma of the eye. Further, a combination of a Rho kinase inhibitor and a prostaglandin is reported in International Publication No. 2004/019951 (Patent Document 4), and Rho kinase inhibition is reported in International Publication No. 2004/045644 (Patent Document 5). Combination of agent and beta blocker.

然而，任一文獻中對於具有高EP2受體選擇性及強效之EP2促效劑作用之(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥的組合並未具體地揭示報告，當然，對於該等之組合針對眼壓可顯示何等效果仍是一切未知的。 However, in any literature, (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl) with a high EP2 receptor selectivity and potent EP2 agonist The combination of isopropylaminomethyl}pyridin-2-ylamino)acetate with other prophylactic or therapeutic agents for glaucoma or ocular hypertension does not specifically disclose the report, of course, for the combination of such eyes The pressure can show what effect is still unknown.

先前技術文獻 Prior technical literature 專利文獻 Patent literature

專利文獻1 國際公開第2010/113957號 Patent Document 1 International Publication No. 2010/113957

專利文獻2 日本專利第2726672號公報 Patent Document 2 Japanese Patent No. 2272672

專利文獻3 國際公開第2002/38158號 Patent Document 3 International Publication No. 2002/38158

專利文獻4 國際公開第2004/019951號 Patent Document 4 International Publication No. 2004/019951

專利文獻5 國際公開第2004/045644號 Patent Document 5 International Publication No. 2004/045644

發現作為青光眼或高眼壓症之預防或治療劑有用的青光眼或高眼壓症之預防或治療藥之組合為非常有興趣的課題。 It has been found that a combination of a prophylactic or therapeutic drug for glaucoma or ocular hypertension which is useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension is a subject of great interest.

本發明人等潛心研究由青光眼或高眼壓症之預防或治療劑之組合所帶來的效果，結果發現相較於各藥劑單獨使用時，組合(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥增強了降眼壓作用，進而完成本發明。即，本發明係關於以下。 The present inventors have diligently studied the effects brought about by the combination of prophylactic or therapeutic agents for glaucoma or ocular hypertension, and found that the combination (6-{[4-(pyrazole-1) is used in combination with each agent alone. -Base) benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridin-2-ylamino)acetic acid isopropyl ester and other glaucoma or ocular hypertension prevention or treatment drugs enhance eye drop The pressure is applied to complete the present invention. That is, the present invention relates to the following.

(1)一種青光眼或高眼壓症之預防或治療劑，其係組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中，他氟前列腺素(tafluprost)除外)。 (1) A prophylactic or therapeutic agent for glaucoma or ocular hypertension, which is combined with (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)amine A Oral isopropyl pyridyl-2-ylamino)acetate and one or more other prophylactic or therapeutic agents for glaucoma or ocular hypertension (with the exception of tafluprost).

(2)一種降眼壓劑，其係組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中，他氟前列腺素除外)。 (2) An ocular hypotensive agent which is combined with (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridin-2-yl Amino) isopropyl acetate and one or more other prophylactic or therapeutic agents for glaucoma or ocular hypertension (except for fluoroprostaglandin).

(3)如上述(1)或(2)之預防或治療劑或降眼壓劑，其中其它之青光眼或高眼壓症之預防或治療藥(其中，他氟前列腺素除外)係選自由非選擇性交感神經促效藥、α2受體促效藥、α1受體阻斷藥、β受體阻斷藥、副交感神經促效藥、碳酸酐酶抑制劑、前列腺素類及Rho激酶抑制劑所構成之群中之1或多種之預防或治療劑。 (3) The prophylactic or therapeutic agent or ocular hypotensive agent according to (1) or (2) above, wherein the other prophylactic or therapeutic agent for glaucoma or ocular hypertension (other than fluoroprostaglandin) is selected from the group consisting of Selective sympathetic agonist, α 2 receptor agonist, α 1 receptor blocker, beta blocker, parasympathetic agonist, carbonic anhydrase inhibitor, prostaglandins and Rho kinase inhibition A prophylactic or therapeutic agent for one or more of the group consisting of agents.

(4)如上述(3)之預防或治療劑或降眼壓劑，其中非選擇性交感神經促效藥為地匹福林。 (4) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the non-selective sympathetic agonist is dipivoxil.

(5)如上述(3)之預防或治療劑或降眼壓劑，其中α2受體促效藥為溴莫尼定或阿可樂定(apraclonidine)。 (5) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the α 2 receptor agonist is brimonidine or apraclonidine.

(6)如上述(3)之預防或治療劑或降眼壓劑，其中α1受體阻斷藥為布那唑嗪。 (6) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the α 1 receptor blocking drug is bunazosin.

(7)如上述(3)之預防或治療劑或降眼壓劑，其中β受體阻斷藥為噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾或美替洛爾。 (7) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the beta blocker is timolol, benfurolol, carteolol, nipudrolol, betaloc , left bunolol or metoprolol.

(8)如上述(3)之預防或治療劑或降眼壓劑，其中副交感神經促效藥為毛果芸香鹼。 (8) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the parasympathetic agonist is pilocarpine.

(9)如上述(3)之預防或治療劑或降眼壓劑，其中碳酸酐酶抑制劑為多佐胺(dorzolamide)、布林唑胺(brinzolamide)或乙醯唑胺(acetazolamide)。 (9) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the carbonic anhydrase inhibitor is dozolamide, brinzolamide or acetazolamide.

(10)如上述(3)之預防或治療劑或降眼壓劑，其中前列腺素類為異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素或比馬前列腺素。 (10) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the prostaglandin is isopropyl unoprostone, latanoprost, travoprost or bimatoprost.

(11)如上述(3)之預防或治療劑或降眼壓劑，其中Rho激酶抑制劑為(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺、1-(5-異喹啉磺醯基)高哌嗪(1-(5-isoquinolinesulfonyl)homopiperazine)或1-(5-異喹啉磺醯基)-2-甲基哌嗪。 (11) The prophylactic or therapeutic agent or ocular hypotensive agent according to (3) above, wherein the Rho kinase inhibitor is (R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl) Cyclohexanecarbamamine, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine.

再者，上述(1)至(11)之各構成係可任意地選擇1以上而組合。 Further, each of the above configurations (1) to (11) may be arbitrarily selected by combining one or more.

又，在說明書之後述中，「其它之青光眼或高眼壓症之預防或治療藥」之記載係意指除了他氟前列腺素以外之「其它之青光眼或高眼壓症之預防或治療藥」。 In addition, in the following description of the specification, the description of "other glaucoma or prevention or treatment of ocular hypertension" means "other glaucoma or ocular hypertension prevention or treatment" other than fluoroprostaglandin. .

藉由組合(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥且將其投予眼，而增強降眼壓作用。因此，本發明係作為青光眼或高眼壓症之預防或治療劑、降眼壓劑為有用。 By combining (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridin-2-ylamino)acetic acid isopropyl ester with others The prevention or treatment of glaucoma or ocular hypertension is administered to the eye to enhance the ocular hypotensive effect. Therefore, the present invention is useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension or an ocular hypotensive agent.

[實施發明之形態] [Formation of the Invention]

本發明係組合有下述式(1)所示之(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯(以下，稱為本化合物)與1或多種其它之青光眼或高眼壓症之預防或治療藥的青光眼或高眼壓症之預防或治療劑、降眼壓劑，而相互地輔助及/或增強其作用者 The present invention is a combination of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridine-2- represented by the following formula (1). A preventive or therapeutic agent for glaucoma or ocular hypertension or an ocular hypotensive agent for the prevention or treatment of one or more other glaucoma or ocular hypertension prevention or treatment drugs with isopropylamino) isopropyl acetate (hereinafter referred to as the present compound) And mutually assist and/or enhance their role

本發明中之本化合物係可藉由國際公開第2009/113600號或國際公開第2010/113957號所記載之方法來合成。 The present compound in the present invention can be synthesized by the method described in International Publication No. 2009/113600 or International Publication No. 2010/113957.

本發明之特徵在於組合本化合物與其它之青光眼或高眼壓症之預防或治療藥，來預防或治療青光眼或高眼壓症。本發明中之青光眼，例示有原發性開角型青光眼、正常眼壓青光眼、房水分泌過多性青光眼、高眼壓症、急性閉角型青光眼、慢性閉角型青光眼、混合型青光眼、類固醇性青光眼(steroid glaucoma)、類澱粉蛋白青光眼(amyloid glaucoma)、新生血管青光眼、惡性青光眼、晶狀體之囊膜性青光眼、高原型虹膜症候群(plateau iris syndrome)等。 The present invention is characterized in that the present compound and other glaucoma or ocular hypertension preventive or therapeutic agents are combined to prevent or treat glaucoma or ocular hypertension. The glaucoma of the present invention is exemplified by primary open angle glaucoma, normal intraocular pressure glaucoma, aqueous hypersecretory glaucoma, ocular hypertension, acute angle closure glaucoma, chronic angle closure glaucoma, mixed glaucoma, steroid Steroid glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, lens glaucoma of the lens, high plateau iris syndrome.

本發明中，本化合物與1或多種其它之青光眼或高眼壓症之預防或治療藥的組合，較佳為組合本化合物與1至3種其它之青光眼或高眼壓症之預防或治療藥，更佳為組合本化合物與1或2種其它之青光眼或高眼壓症之預防或治療藥。 In the present invention, the combination of the present compound and one or more other preventive or therapeutic agents for glaucoma or ocular hypertension is preferably a combination of the present compound and one to three other preventive or therapeutic agents for glaucoma or ocular hypertension. More preferably, it is a combination of the present compound and one or two other preventive or therapeutic agents for glaucoma or ocular hypertension.

本發明中之其它之青光眼或高眼壓症之預防或治療藥係具有降眼壓作用且對青光眼治療有用者即可，可舉出：非選擇性交感神經促效藥、α2受體促效藥、α1受體阻斷藥、β受體阻斷藥、副交感神經促效藥、碳酸酐酶抑制劑、前列腺素類、Rho激酶抑制劑等。組合本化合物與2種其它之青光眼或高眼壓症之預防或治療藥時，2種其它之青光眼或高眼壓症之預防或治療藥較佳為選自由β受體阻斷藥、碳酸酐酶抑制劑及前列腺素類所構成之群中之2種預防或治療藥，更佳為β受體阻斷藥及碳酸酐酶抑制劑，或β受體阻斷藥及前列腺素類。 The other preventive or therapeutic drug for glaucoma or ocular hypertension in the present invention has an ocular hypotensive effect and is useful for the treatment of glaucoma, and examples thereof include a non-selective sympathetic agonist and an α 2 receptor. Agents, α 1 receptor blockers, β receptor blockers, parasympathetic agonists, carbonic anhydrase inhibitors, prostaglandins, Rho kinase inhibitors, and the like. When combining the present compound with two other prophylactic or therapeutic agents for glaucoma or ocular hypertension, the two other preventive or therapeutic agents for glaucoma or ocular hypertension are preferably selected from the group consisting of beta blockers and carbonic anhydrides. Two kinds of prophylactic or therapeutic agents in the group consisting of enzyme inhibitors and prostaglandins are more preferably beta blockers and carbonic anhydrase inhibitors, or beta blockers and prostaglandins.

作為非選擇性交感神經促效藥之具體例，可舉出地匹福林；作為α2受體促效藥之具體例，可舉出溴莫尼定、阿可樂定；作為α1受體阻斷藥之具體例，可舉出布那唑嗪；作為β受體阻斷藥之具體例，可舉出噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾、美替洛爾；作為副交感神經促效藥之具體例，可舉出毛果芸香鹼；作為碳酸酐酶抑制劑之具體例，可舉出多佐胺、布林唑胺或乙醯唑胺。 Specific examples of the non-selective sympathetic agonist include dipivoxil; specific examples of the α 2 receptor agonist include brimonidine and aclidine; and α 1 receptor Specific examples of the blocking drug include bunazosin; and specific examples of the β receptor blocking drug include timolol, benzalol, carteolol, nipudrol, and times. Tallool, levobromol, and metoprolol; as a specific example of the parasympathetic agonist, pilocarpine; and as a specific example of the carbonic anhydrase inhibitor, dorzolamide and brinzazole are mentioned. Amine or oxazolamide.

作為前列腺素類之具體例，可舉出：揭示於日本特開昭59-1418號公報之前列腺素類(特別是如前列 腺素F2α之天然前列腺素)、揭示於日本特表平3-501025號公報之拉坦前列腺素等前列腺素類、揭示於日本特開平2-108號公報之異丙基烏諾前列酮等前列腺素類、揭示於日本特表平8-501310號公報之比馬前列腺素等前列腺素類、揭示於日本特開平10-182465號公報之曲伏前列腺素等前列腺素類、揭示於Surv Ophthalmol 47(Suppl 1)：S13-S33,2002之AL-6598等前列腺素類，揭示於Exp Eye Res.89：608-17,2009之PF-04475270等前列腺素類，其中較佳為PGF2α或PGF2α衍生物，更佳為異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素或比馬前列腺素。 Specific examples of the prostaglandins include prostaglandins disclosed in Japanese Laid-Open Patent Publication No. 59-1418 (especially as in the forefront) A prostaglandin such as a prostaglandin, which is disclosed in Japanese Laid-Open Patent Publication No. 3-510025, and a prostaglandin such as isopropyl unoprostone disclosed in JP-A No. 2-108 A prostaglandin such as bimatoprost, which is disclosed in JP-A-H05-501310, and a prostaglandin such as travoprost, disclosed in Japanese Patent Laid-Open No. Hei 10-182465, is disclosed in Surv Ophthalmol 47 ( Suppl 1): S13-S33, 2002 prostaglandins such as AL-6598, disclosed in prostaglandins such as PF-04475270 of Exp Eye Res. 89:608-17, 2009, wherein PGF2α or PGF2α derivatives are preferred, More preferred is isopropyl unoprostone, latanoprost, travoprost or bimatoprost.

本發明中之Rho激酶抑制劑，其係意指抑制伴隨著Rho之活性化而被活化之絲胺酸/蘇胺酸激酶的化合物。可舉出例如：抑制ROKα(ROCK-II)、p160ROCK(ROKβ、ROCK-I)及其它之具有絲胺酸/蘇胺酸活性之蛋白質的化合物。作為Rho激酶抑制劑之具體例，可舉例：於國際公開第98/06433號、國際公開第00/09162號揭示之(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺等Rho激酶抑制劑，或於國際公開第97/23222號、Nature,389,990-994(1997)所揭示之1-(5-異喹啉磺醯基)高哌嗪(1-(5-isoquinolinesulfonyl)homopiperazine)、1-(5-異喹啉磺醯基)-2-甲基哌嗪等Rho激酶抑制劑，國際公開第01/56988號所揭示之(1-苄基吡咯啶-3-基)-(1H-吲唑-5-基)胺等Rho激酶抑制劑，國際公開第 02/100833號所揭示之(1-苄基哌啶-4-基)-(1H-吲唑-5-基)胺等Rho激酶抑制劑，國際公開第02/076976號所揭示之N-[2-(4-氟苯基)-6,7-二甲氧基-4-喹唑啉基]-N-(1H-吲唑-5-基)胺等Rho激酶抑制劑，國際公開第02/076977號所揭示之N-4-(1H-吲唑-5-基)-6,7-二甲氧基-N-2-吡啶-4基-喹唑啉基-2,4-二胺等Rho激酶抑制劑，國際公開第99/64011號所揭示之4-甲基-5-(2-甲基-[1,4]苯甲二氮焯-1-磺醯基)異喹啉(4-methyl-5-(2-methyl-[1,4]-diazepane-1-sulfonyl)isoquinoline)等Rho激酶抑制劑。其中特佳為(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺、1-(5-異喹啉磺醯基)高哌嗪或1-(5-異喹啉磺醯基)-2-甲基哌嗪。 The Rho kinase inhibitor of the present invention means a compound which inhibits the activation of serine/threonine kinase which is activated by the activation of Rho. For example, a compound which inhibits ROKα (ROCK-II), p160ROCK (ROKβ, ROCK-I), and other proteins having a serine/threonine activity can be mentioned. Specific examples of the Rho kinase inhibitor can be exemplified by (R)-trans-N-(pyridin-4-yl)-4-(1) disclosed in International Publication No. 98/06433, International Publication No. 00/09162 -Aminoethyl)cyclohexanecarbamamine, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl) A Rho kinase inhibitor such as benzamide or a 1-(5-isoquinolinesulfonyl)-high piperazine (1-( disclosed in International Publication No. 97/23222, Nature, 389, 990-994 (1997)) 5-isoquinolinesulfonyl)homopiperazine), a Rho kinase inhibitor such as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, which is disclosed in International Publication No. 01/56988 (1-benzylpyrrolidine- Rho kinase inhibitors such as 3-yl)-(1H-carbazol-5-yl)amine, International Publication No. Rho kinase inhibitors such as (1-benzylpiperidin-4-yl)-(1H-indazol-5-yl)amine disclosed in No. 02/100833, N-[ disclosed in International Publication No. 02/076976 Rho kinase inhibitors such as 2-(4-fluorophenyl)-6,7-dimethoxy-4-quinazolinyl]-N-(1H-indazol-5-yl)amine, International Publication No. 02 N-4-(1H-carbazol-5-yl)-6,7-dimethoxy-N-2-pyridin-4-yl-quinazolinyl-2,4-diamine as disclosed in /076977 A Rho kinase inhibitor, 4-methyl-5-(2-methyl-[1,4]benzodiazepine-1-sulfonyl)isoquinoline disclosed in International Publication No. 99/64011 ( Rho kinase inhibitors such as 4-methyl-5-(2-methyl-[1,4]-diazepane-1-sulfonyl)isoquinoline). Among them, (R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarbamamine, (R)-(+)-N-(1H-pyrrole) And [2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, 1-(5-isoquinolinesulfonyl)homopiperazine or 1-(5- Isoquinolinesulfonyl)-2-methylpiperazine.

作為組合本化合物與2種其它之青光眼或高眼壓症之預防或治療藥時之2種其它之青光眼或高眼壓症之預防或治療藥的具體例，可舉出：噻嗎洛爾及多佐胺，噻嗎洛爾及拉坦前列腺素，噻嗎洛爾及曲伏前列腺素。 Specific examples of the prophylactic or therapeutic agents for two other glaucoma or ocular hypertension in the case of combining the present compound with two other glaucoma or ocular hypertension prevention or treatment agents include timolol and Dolzamide, timolol and latanoprost, timolol and travoprost.

本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥亦包含鹽之形態。該等若為醫藥許可之鹽，則無特別限制，作為鹽可舉出：與無機酸之鹽、與有機酸之鹽、四級銨鹽、與鹵素離子之鹽、與鹼金屬之鹽、與鹼土金屬之鹽、金屬鹽、與氨之鹽、與有機胺之鹽等。作為與無機酸之鹽，可舉出：與鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等之鹽。作為與有機酸之鹽， 可舉出：與乙酸、草酸、反丁烯二酸、順丁烯二酸、琥珀酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡萄糖甲酸(glucoheptonic acid)、葡萄醣醛酸、對酞酸、甲磺酸、乳酸、馬尿酸、1,2-乙二磺酸、2-羥乙磺酸、乳糖醛酸、油酸、撲酸(pamoate)、聚半乳糖醛酸、硬脂酸、單寧酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺柳酸等之鹽。作為四級銨鹽，可舉出：與溴甲烷、碘甲烷等之鹽。作為與鹵素離子之鹽，可舉出：與氯離子、溴離子、碘離子等之鹽；作為與鹼金屬之鹽，可舉出：與鋰、鈉、鉀等之鹽。作為與鹼土金屬之鹽，可舉出：與鈣、鎂等之鹽；作為金屬之鹽，可舉出：與鐵、鋅等之鹽。作為與有機胺之鹽，可舉出：與三乙二胺、2-胺乙醇、2.2-亞胺基雙(乙醇)、1-去氧-1-(甲胺基)-2-D-山梨醇、2-胺基-2-(羥甲基)-1,3-丙二醇、普羅卡因、N,N-雙(苯基甲基)-1,2-乙二胺等之鹽。 The present compound and other prophylactic or therapeutic agents for glaucoma or ocular hypertension in the present invention also include a form of a salt. The salt to be approved by the medicine is not particularly limited, and examples of the salt include a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, a salt with an alkali metal, and A salt of an alkaline earth metal, a metal salt, a salt with ammonia, a salt with an organic amine, and the like. The salt with the inorganic acid may, for example, be a salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid. As a salt with organic acids, It can be exemplified by: acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, citric acid , methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, lactaldehyde, oleic acid, pamoate, polygalacturonic acid, stearic acid, single a salt of linonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfinic acid or the like. The quaternary ammonium salt may, for example, be a salt with methyl bromide or methyl iodide. Examples of the salt with a halogen ion include a salt with a chloride ion, a bromide ion, and an iodide ion; and the salt with an alkali metal includes a salt with lithium, sodium, potassium or the like. Examples of the salt with an alkaline earth metal include salts with calcium and magnesium, and salts of metals such as iron and zinc. Examples of the salt with an organic amine include triethylenediamine, 2-aminoethanol, 2.2-iminobis(ethanol), and 1-deoxy-1-(methylamino)-2-D-sorbenta A salt of an alcohol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(phenylmethyl)-1,2-ethanediamine or the like.

又，本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥亦包含酯、醯胺等之衍生物。作為酯之具體例，可舉例：將其它之青光眼或高眼壓症之預防或治療藥中之羥基與乙酸、丙酸、異丙酸、丁酸、異丁酸、三甲基乙酸等之羧酸縮合而成之酯，將其它之青光眼或高眼壓症之預防或治療藥中之羧基與甲醇、乙醇、丙醇、異丙醇等之醇縮合而成之酯。作為醯胺之具體例，可舉例：將本化合物及/或其它之青光眼或高眼壓症之預防或治療藥之胺基與乙酸、丙酸、異丙酸、丁酸、異丁酸、三甲基乙酸等之羧酸縮合而成之醯胺，將其它 之青光眼或高眼壓症之預防或治療藥中之羧基與甲胺、乙胺、丙胺、異丙胺等之胺縮合而成之醯胺。 Further, the present compound and other prophylactic or therapeutic agents for glaucoma or ocular hypertension of the present invention also include derivatives of esters, guanamines and the like. Specific examples of the ester include carboxy groups of a hydroxyl group in the prevention or treatment of other glaucoma or ocular hypertension and acetic acid, propionic acid, isopropyl acid, butyric acid, isobutyric acid, trimethylacetic acid or the like. An acid-condensed ester which is an ester obtained by condensing a carboxyl group in a prophylactic or therapeutic drug for glaucoma or ocular hypertension with an alcohol such as methanol, ethanol, propanol or isopropanol. Specific examples of the guanamine include, for example, an amine group of the present compound and/or other glaucoma or ocular hypertension prophylactic or therapeutic agent with acetic acid, propionic acid, isopropyl acid, butyric acid, isobutyric acid, and the like. An amide condensed with a carboxylic acid such as methyl acetate, and the other A guanamine in which a carboxyl group in a prophylactic or therapeutic drug for glaucoma or ocular hypertension is condensed with an amine such as methylamine, ethylamine, propylamine or isopropylamine.

進而，本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥，亦可為水合物或溶劑合物之形態。 Further, the present compound and other preventive or therapeutic agents for glaucoma or ocular hypertension may be in the form of a hydrate or a solvate.

作為投予形態，可將本化合物與其它之青光眼或高眼壓症之預防或治療藥以各別處方之多種製劑的形態進行投予(併用投予)，又，亦可將各別的成分調配成一種製劑的形態(合劑)進行投予。較佳為合劑的情形。進而，組合有本化合物與多種其它之青光眼或高眼壓症之預防或治療藥時，可併用投予各別的成分，亦可將本化合物與其它之青光眼或高眼壓症之預防或治療藥中任意成分調配成之合劑與殘餘成分併用投予亦可，另可將所有成分調配成合劑。 As the administration form, the present compound can be administered in the form of various preparations of the respective prescriptions for glaucoma or ocular hypertension or in the form of various preparations of the respective prescriptions, and the individual components can also be administered. The form (mixture) formulated into one preparation is administered. It is preferably a mixture. Further, when the present compound is combined with a plurality of other preventive or therapeutic agents for glaucoma or ocular hypertension, the respective components may be administered in combination, and the present compound may be prevented or treated with other glaucoma or ocular hypertension. Any component of the drug may be formulated into a mixture and a residual component, and all components may be formulated into a mixture.

本發明之製劑可為經口、亦可為非經口投予，該等之製劑化不需特別之技術，可使用廣泛使用之技術來進行製劑化。作為投予劑型，可舉出：點眼劑、眼軟膏、注射劑、錠劑、膠囊、顆粒、粉劑等。較佳為點眼劑、眼軟膏。 The preparation of the present invention may be administered orally or parenterally, and the formulation may be formulated using a widely used technique without special techniques. Examples of the administration dosage form include an eye drop, an ophthalmic ointment, an injection, a tablet, a capsule, a granule, a powder, and the like. It is preferably an eye drop or an eye ointment.

將本化合物與其它之青光眼或高眼壓症之預防或治療藥各別地製劑化時，可分別根據周知的方法來製備製劑。例如：本化合物之製劑係可參考國際公開第2009/113600號或國際公開第2010/113957號所記載之製劑例來製備。作為其它之青光眼或高眼壓症之預防或治療藥的製劑，可使用已於市面販售之地匹福林、溴莫尼 定、阿可樂定、布那唑嗪、噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾、美替洛爾、毛果芸香鹼、多佐胺、布林唑胺、乙醯唑胺、異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素、比馬前列腺素、Cosopt(註冊商標)調配點眼液、Xalacom(註冊商標)調配點眼液、DuoTrav(註冊商標)調配點眼液等製劑或根據該等者。Rho激酶抑制劑之製劑係可參考上述之國際公開第00/09162號、國際公開第97/23222號等所記載之製劑例來製備。 When the present compound is separately formulated with other prophylactic or therapeutic agents for glaucoma or ocular hypertension, the preparation can be prepared according to a known method. For example, the preparation of the present compound can be prepared by referring to the formulation examples described in International Publication No. 2009/113600 or International Publication No. 2010/113957. As a preparation for the prevention or treatment of other glaucoma or ocular hypertension, the commercially available pirimiben, brimonidine, acroleidine, bunazosin, timolol, benzene can be used. Furolol, carteolol, nipudrol, betaxolol, levobunolol, metoprolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, isopropylidene Preparation of novoprostone, latanoprost, travoprost, bimatoprost, Cosopt (registered trademark) eye drops, Xalacom (registered trademark) eye drops, DuoTrav (registered trademark) dispensing eye drops, etc. Or according to those. The preparation of the Rho kinase inhibitor can be prepared by referring to the preparation examples described in the above-mentioned International Publication No. 00/09162, International Publication No. 97/23222, and the like.

又，製備將本化合物與其它之青光眼或高眼壓症之預防或治療藥任意組合調配成之一種製劑時，可根據周知的方法來製備。 Further, when a preparation in which the present compound is formulated in any combination with other prophylactic or therapeutic agents for glaucoma or ocular hypertension is prepared, it can be prepared according to a known method.

作成點眼劑時，於蒸餾水、緩衝液等添加本化合物或其它之青光眼或高眼壓症之預防或治療藥且進行攪拌後，利用pH調整劑調整pH，藉此可製備所欲之點眼劑。又，視需要，可使用廣泛使用於點眼劑之添加劑，而作為添加劑，可舉出：等張劑、緩衝劑、界面活性劑、安定劑、防腐劑等。作為等張劑，可舉出氯化鈉、濃縮甘油等，作為緩衝劑，可舉出磷酸鈉、乙酸鈉、硼酸、硼砂、檸檬酸等，作為界面活性劑，可舉出聚氧乙烯去水山梨醇單油酯、聚氧乙烯硬脂酸酯、聚氧乙烯硬化蓖麻油酯等，作為安定劑，可舉出檸檬酸鈉、乙二胺四乙基二鈉等，作為防腐劑，可舉出氯化烷基二甲基苄基銨(benzalkonium chloride)、苯甲酸酯類(paraben)等之防腐劑。 When an eye drop is added, the compound or other glaucoma or ocular hypertension prevention or therapeutic agent is added to distilled water, a buffer solution or the like and stirred, and then the pH is adjusted by a pH adjuster, whereby the desired eye can be prepared. Agent. Further, an additive widely used for eye drops may be used as needed, and as an additive, an isotonic agent, a buffer, a surfactant, a stabilizer, a preservative, and the like may be mentioned. Examples of the isotonic agent include sodium chloride and concentrated glycerin. Examples of the buffering agent include sodium phosphate, sodium acetate, boric acid, borax, and citric acid. Examples of the surfactant include deoxyethylene deionized water. Sorbitol monooleate, polyoxyethylene stearate, polyoxyethylene hardened castor oil ester, etc., as a stabilizer, sodium citrate, ethylenediamine tetraethyl disodium, etc. are mentioned as a preservative. A preservative such as benzalkonium chloride or paraben is used.

點眼劑之pH值為眼科製劑之許可範圍內即可，較佳為pH4~8之範圍，更佳為pH5~7之範圍。 The pH of the eye drop agent may be within the permissible range of the ophthalmic preparation, preferably in the range of pH 4 to 8, more preferably in the range of pH 5 to 7.

作成眼軟膏時，可使用廣泛使用之基劑來製備，作為基劑可舉出白色凡士林、液態石蠟等。 When an ophthalmic ointment is prepared, it can be prepared by using a widely used base. Examples of the base include white petrolatum, liquid paraffin, and the like.

作成錠劑、膠囊、顆粒、粉劑等經口劑時，視需要可添加增量劑、潤澤劑、黏合劑、崩散劑、塗膜劑、被膜劑等而製備。作為增量劑，可舉出乳糖、結晶纖維素、澱粉、植物油等，作為潤澤劑，可舉出硬脂酸鎂、滑石等，作為黏合劑，可舉出羥丙基纖維素、聚乙烯氫吡咯酮等，作為崩散劑，可舉出羧甲基纖維素鈣、低取代羥丙基甲基纖維素等，作為塗膜劑，可舉出羥丙基甲基纖維素、聚乙二醇(macrogol)、矽樹脂等，作為被膜劑，可舉出明膠被膜等。 When an oral preparation such as a tablet, a capsule, a granule, or a powder is prepared, an extender, a moisturizer, a binder, a disintegrating agent, a coating agent, a coating agent, or the like may be added as needed. Examples of the extender include lactose, crystalline cellulose, starch, and vegetable oil. Examples of the moisturizing agent include magnesium stearate and talc. Examples of the binder include hydroxypropylcellulose and polyvinyl hydrogen. Examples of the disintegrator include pyrrolidone and the like, and carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose. Examples of the coating agent include hydroxypropylmethylcellulose and polyethylene glycol. A macrogol), an anthracene resin, etc., as a filming agent, a gelatin film etc. are mentioned.

本化合物及其它之青光眼或高眼壓症之預防或治療藥的投予量係可視劑型、應投予之患者之症狀的輕重、年齡、體重、投予途徑、醫師的判斷等適當地改變。以點眼投予為主要例而進行以下說明。 The administration amount of the present compound and other preventive or therapeutic agents for glaucoma or ocular hypertension is appropriately changed depending on the dosage form, the severity of the symptoms of the patient to be administered, the age, the body weight, the administration route, the judgment of the physician, and the like. The following description will be made with the eye drop administration as a main example.

本化合物之投予量，當為點眼劑時，通常1日的投予量在0.05~500μg之範圍，可1日1次或分成數次投予，根據患者的年齡、症狀等可適當地增減。點眼劑中本化合物的濃度並無特別限制，可將在0.00001~3w/v%之範圍內，較佳為0.0001~1w/v%之範圍內，更佳為0.001~0.1w/v%之範圍內，再更佳為0.003~0.03w/v%之範圍內之濃度的點眼劑，1日1次或數次點眼。再者，點眼劑之濃度係可將本化合物之自由體 及其之鹽之任一者的重量作為基準計算者(以下相同)又，為眼軟膏時，通常，通常1日的投予量可為在0.0001~30mg之範圍內，較佳為0.0003~10mg之範圍內，更佳為0.001~3mg之範圍內，再更佳為0.003~1mg之範圍內，1次或分為數次投予。 When the administration amount of the present compound is an eye drop, the administration amount per day is usually in the range of 0.05 to 500 μg, and may be administered once a day or several times, depending on the age, symptoms, and the like of the patient. Increase or decrease. The concentration of the present compound in the eye drop is not particularly limited and may be in the range of 0.00001 to 3 w/v%, preferably 0.0001 to 1 w/v%, more preferably 0.001 to 0.1 w/v%. In the range, it is more preferably an eye drop having a concentration in the range of 0.003 to 0.03 w/v%, and one or several eye drops per day. Furthermore, the concentration of the eye-dropping agent is a free form of the compound. The weight of any of the salts and the salt thereof is used as a reference calculator (the same applies hereinafter). In the case of an ophthalmic ointment, usually, the administration amount per day may be in the range of 0.0001 to 30 mg, preferably 0.0003 to 10 mg. In the range of 0.001 to 3 mg, more preferably 0.003 to 1 mg, once or divided into several doses.

非選擇性交感神經促效藥之投予量係根據藥物之種類而有所不同，通常1日之投予量在1~5000μg之範圍，可1日1次或分為數次投予。更具體而言，當為地匹福林時係通常使用2~3000μg作為1日量，該等之用量，視患者之年齡、症狀等可適當地增減。又，對於其它之非選擇性交感神經促效藥亦可基於同樣的基準而決定其用量。點眼液中之非選擇性交感神經促效藥之濃度並無特別限制，當為地匹福林時，可將在0.001~3w/v%之範圍內，較佳為0.04~0.1w/v%之範圍內，更佳為0.04w/v%或0.1w/v%之濃度的點眼劑，1日1次或數次點眼。 The dosage of the non-selective sympathetic agonist varies depending on the type of the drug. Usually, the dose for one day is in the range of 1 to 5000 μg, and may be administered once a day or in divided doses. More specifically, in the case of dipivoxil, 2 to 3000 μg is usually used as the amount of one day, and the amounts may be appropriately increased or decreased depending on the age, symptoms, and the like of the patient. Further, for other non-selective sympathetic agonists, the amount can be determined based on the same criteria. The concentration of the non-selective sympathetic agonist in the eye drops is not particularly limited, and may be in the range of 0.001 to 3 w/v%, preferably 0.04 to 0.1 w/v, in the case of dipivolin. In the range of %, more preferably an eye drop of a concentration of 0.04 w/v% or 0.1 w/v%, once or several times a day.

α2受體促效藥之投予量係根據藥物之種類而有所不同，通常1日之投予量在2~3000μg之範圍，可1日1次或分為數次投予。更具體而言，當為溴莫尼定時係通常使用2~1000μg作為1日量，當為阿可樂定時係通常使用20~3000μg作為1日量，該等之用量，視患者之年齡、症狀等可適當地增減。又，對於其它之α2受體促效藥亦可基於同樣的基準而決定其用量。點眼液中之α2受體促效藥之濃度並無特別限制，當為溴莫尼定時，可將在0.01~5w/v%之範圍內，較佳為0.1~0.5w/v%之範圍 內，更佳為0.1w/v%、0.15w/v%、0.2w/v%或0.5w/v%之濃度的點眼劑，1日1次或數次點眼。又，當為阿可樂定時，可將在0.01~5w/v%之範圍內，較佳為0.5~1w/v%之範圍內，更佳為0.5w/v%或1w/v%之濃度的點眼劑，1日1次或數次進行點眼。 The dose of the α 2 receptor agonist varies depending on the type of the drug, and the dose on the 1st day is usually in the range of 2 to 3000 μg, and may be administered once a day or in divided doses. More specifically, when the brimonic timing system is usually used, 2 to 1000 μg is used as the 1 day amount, and when the Alcoa timing system is used, 20 to 3000 μg is usually used as the 1 day amount, and the amount depends on the age, symptoms, and the like of the patient. It can be increased or decreased as appropriate. Further, other α 2 receptor agonists can be determined based on the same criteria. The concentration of the α 2 receptor agonist in the eye drops is not particularly limited. When it is bromoni, it may be in the range of 0.01 to 5 w/v%, preferably 0.1 to 0.5 w/v%. In the range, it is more preferably an eye drop of a concentration of 0.1 w/v%, 0.15 w/v%, 0.2 w/v% or 0.5 w/v%, once or several times a day. Further, when the time is Arcoa, it may be in the range of 0.01 to 5 w/v%, preferably 0.5 to 1 w/v%, more preferably 0.5 w/v% or 1 w/v%. Eye drops, one eye or one time on the 1st.

α1受體阻斷藥之投予量係根據藥物之種類而有所不同，通常1日之投予量在1~5000μg之範圍，可1日1次或分為數次投予。更具體而言，當為布那唑嗪時係通常使用2~3000μg作為1日量，該等之用量，視患者之年齡、症狀等可適當地增減。又，對於其它之α1受體阻斷藥亦可基於同樣的基準而決定其用量。點眼液中之α1受體阻斷藥之濃度並無特別限制，當為布那唑嗪時，可將在0.001~0.3w/v%之範圍內，較佳為0.003~0.03w/v%之範圍內，更佳為0.01w/v%之濃度的點眼劑，1日1次或數次點眼。 The dosage of the α 1 receptor blocking drug varies depending on the type of the drug, and the administration amount per day is usually in the range of 1 to 5000 μg, and may be administered once a day or in divided doses. More specifically, in the case of bunazosin, 2 to 3000 μg is usually used as the amount of one day, and the amounts may be appropriately increased or decreased depending on the age, symptoms, and the like of the patient. Further, for other α 1 receptor blocking drugs, the amount can be determined based on the same criteria. The concentration of the α 1 receptor blocking agent in the eye drops is not particularly limited, and when it is bunazosin, it may be in the range of 0.001 to 0.3 w/v%, preferably 0.003 to 0.03 w/v. Within the range of %, more preferably an eyedrop of a concentration of 0.01 w/v%, once or several times a day.

β受體阻斷藥之投予量係根據藥物之種類而有所不同，通常1日之投予量在5~5000μg之範圍，可1日1次或分為數次投予。更具體而言，當為噻嗎洛爾時係通常使用5~1500μg作為1日量，當為苯呋洛爾時係通常使用10~2000μg作為1日量，當為卡替洛爾時係通常使用10~5000μg作為1日量，當為尼普地洛時係通常使用10~1250μg作為1日量，當為倍他洛爾時通常使用50~1000μg作為1日量，當為左布諾洛爾時係通常使用5~5000μg作為1日量，當為美替洛爾時係通常使用5~5000μg作為1日量，該等之用量，視患者之年齡、症 狀等可適當地增減。又，對於其它之β受體阻斷藥亦可基於同樣的基準而決定其用量。點眼液中之β受體阻斷藥之濃度並無特別限制，當為噻嗎洛爾時，可將在0.01~5w/v%之範圍內，較佳為0.1~0.5w/v%之範圍內，更佳為0.1w/v%、0.25w/v%或0.5w/v%之濃度的點眼劑，1日1次或數次點眼。又，當為苯呋洛爾時，可將在0.01~5w/v%之範圍內，較佳為0.25~1w/v%之範圍內，更佳為0.25w/v%、0.5w/v%或1w/v%之濃度的點眼劑，1日1次或數次點眼。當為卡替洛爾時，可將在0.01~5w/v%之範圍內，較佳為1~2w/v%之範圍內，更佳為1w/v%或2w/v%之濃度的點眼劑，1日1次或數次點眼。當為尼普地洛時，可將在0.01~5w/v%之範圍內，較佳為0.25w/v%之濃度的點眼劑，1日1次或數次點眼。當為倍他洛爾時，可將在0.01~5w/v%之範圍內，較佳為0.25~0.5w/v%之範圍內，更佳為0.25w/v%或0.5w/v%之濃度的點眼劑，1日1次或數次點眼。當為左布諾洛爾時，將在0.01~5w/v%之範圍內，較佳為0.25~0.5w/v%之範圍內，更佳為0.25w/v%或0.5w/v%之濃度的點眼劑，1日1次或數次點眼。當為美替洛爾時，將在0.01~5w/v%之範圍內，較佳為0.3w/v%之濃度的點眼劑，1日1次或數次點眼。 The dose of the β-blocker is different depending on the type of the drug, and the dose for one day is usually in the range of 5 to 5000 μg, and may be administered once a day or in divided doses. More specifically, when it is timolol, 5 to 1500 μg is usually used as the 1 day amount, and when it is benzofurol, 10 to 2000 μg is usually used as the 1 day amount, and when it is carteolol, it is usually Use 10~5000μg as the 1st day. When it is nipradil, it usually uses 10~1250μg as the 1st day. When it is betaalol, it usually uses 50~1000μg as the 1st amount, when it is the left bunolo. Usually, 5~5000μg is used as the 1st day, and when it is metoprolol, 5~5000μg is usually used as the 1st day. The dosage depends on the age and the disease of the patient. The shape or the like can be appropriately increased or decreased. Further, other β-blockers may be determined based on the same criteria. The concentration of the beta blocker in the eye drops is not particularly limited. When it is timolol, it may be in the range of 0.01 to 5 w/v%, preferably 0.1 to 0.5 w/v%. In the range, it is more preferably an eye drop of a concentration of 0.1 w/v%, 0.25 w/v% or 0.5 w/v%, once or several times a day. Further, when it is benzofurol, it may be in the range of 0.01 to 5 w/v%, preferably 0.25 to 1 w/v%, more preferably 0.25 w/v% or 0.5 w/v%. Or an eye drop of 1w/v% concentration, once or several times a day. In the case of carteolol, it may be in the range of 0.01 to 5 w/v%, preferably in the range of 1 to 2 w/v%, more preferably 1 w/v% or 2 w/v%. Eye drops, once or several times a day. In the case of nipradil, an eye drop having a concentration in the range of 0.01 to 5 w/v%, preferably 0.25 w/v%, may be applied once or several times a day. In the case of betaxolol, it may be in the range of 0.01 to 5 w/v%, preferably in the range of 0.25 to 0.5 w/v%, more preferably 0.25 w/v% or 0.5 w/v%. Concentration of eye drops, once or several times a day. In the case of levobunolol, it will be in the range of 0.01 to 5 w/v%, preferably in the range of 0.25 to 0.5 w/v%, more preferably 0.25 w/v% or 0.5 w/v%. Concentration of eye drops, once or several times a day. In the case of metoprolol, the eye drops will be in the range of 0.01 to 5 w/v%, preferably 0.3 w/v%, once or several times a day.

副交感神經促效藥之投予量係根據藥物之種類而有所不同，通常1日之投予量在5~300000μg之範圍，可1日1次或分為數次投予。更具體而言，當為毛果芸香鹼時係通常使用5~200000μg作為1日量，該等之 用量，視患者之年齡、症狀等可適當地增減。又，對於其它之副交感神經促效藥亦可基於同樣的基準而決定其用量。點眼液中之副交感神經促效藥之濃度並無特別限制，當為毛果芸香鹼時，可將在0.01~20w/v%之範圍內，較佳為0.1~5w/v%之範圍內，更佳為0.5w/v%、1w/v%、2w/v%、3w/v%或4w/v%之濃度的點眼劑，1日1次或數次點眼。 The dosage of the parasympathetic agonist varies depending on the type of the drug, and the dose on the 1st day is usually in the range of 5 to 300,000 μg, which can be administered once a day or in divided doses. More specifically, when it is pilocarpine, it is usually used in the range of 5 to 200,000 μg as the amount of one day. The dosage may be appropriately increased or decreased depending on the age, symptoms, and the like of the patient. Further, for other parasympathetic agonists, the amount can be determined based on the same criteria. The concentration of the parasympathetic agonist in the eye drops is not particularly limited. When it is pilocarpine, it may be in the range of 0.01 to 20 w/v%, preferably 0.1 to 5 w/v%, more preferably An eye drop having a concentration of 0.5 w/v%, 1 w/v%, 2 w/v%, 3 w/v% or 4 w/v%, once or several times a day.

碳酸酐酶抑制劑之投予量係根據藥物之種類而有所不同，通常1日之投予量在10~10000μg之範圍，可1日1次或分為數次投予。更具體而言，當為多佐胺時係通常使用10~10000μg作為1日量，當為布林唑胺時係通常使用20~5000μg作為1日量，該等之用量，視患者之年齡、症狀等可適當地增減。又，對於其它之碳酸酐酶抑制劑亦可基於同樣的基準而決定其用量。點眼劑中之碳酸酐酶抑制劑之濃度並無特別限制，當為多佐胺時，可將在0.01~5w/v%之範圍內，較佳為0.5~2w/v%之範圍內，更佳為0.5w/v%、1w/v%或2w/v%之濃度的點眼劑，1日1次或數次點眼。又，當為布林唑胺時，可將在0.01~5w/v%之範圍內，較佳為0.1~2w/v%之範圍內，更佳為1w/v%之濃度的點眼劑，1日1次或數次點眼。又，當為乙醯唑胺時，可使用在0.01~5w/v%之範圍內，較佳為1~5w/v%之範圍內之濃度的點眼劑。再者，乙醯唑胺經口投予時係可使用250~1000mg作為1日量。 The dosage of the carbonic anhydrase inhibitor varies depending on the type of the drug, and the dose for one day is usually in the range of 10 to 10000 μg, and may be administered once a day or in divided doses. More specifically, when it is dorzolamide, 10 to 10000 μg is usually used as the 1 day amount, and when it is the linozolamide, 20 to 5000 μg is usually used as the 1 day amount, and the amount depends on the age of the patient. Symptoms and the like can be appropriately increased or decreased. Further, other carbonic anhydrase inhibitors may be determined based on the same criteria. The concentration of the carbonic anhydrase inhibitor in the eye drop is not particularly limited, and when it is dorzolamide, it may be in the range of 0.01 to 5 w/v%, preferably 0.5 to 2 w/v%. More preferably, it is an eye drop of a concentration of 0.5 w/v%, 1 w/v% or 2 w/v%, once or several times a day. Further, in the case of brinzolamide, an eye drop having a concentration in the range of 0.01 to 5 w/v%, preferably 0.1 to 2 w/v%, more preferably 1 w/v%, may be used. One or several times on the 1st. Further, in the case of oxazolamide, an eye drop having a concentration in the range of 0.01 to 5 w/v%, preferably 1 to 5 w/v% may be used. Further, when ethazolamide is administered orally, 250 to 1000 mg can be used as the amount of one day.

前列腺素類之投予量係根據藥物之種類而有所不同，通常1日之投予量在0.1~1000μg之範圍，可1 日1次或分為數次投予。更具體而言，當為拉坦前列腺素時係通常使用1~5μg作為1日量，當為異丙基烏諾前列酮時係通常使用30~300μg作為1日量，當為比馬前列腺素素時係通常使用2~30μg作為1日量，當為曲伏前列腺素時係通常使用0.5~5μg作為1日量，該等之用量，視患者之年齡、症狀等可適當地增減。又，對於其它之前列腺素類亦可基於同樣的基準而決定其用量。點眼劑中之前列腺素類之濃度並無特別限制，當為拉坦前列腺素時，可將在0.0001~5w/v%之範圍內，較佳為0.0005~1w/v%之範圍內，更佳為0.001~0.1w/v%之範圍內，再更佳為0.005w/v%之濃度的點眼劑，1日1次或數次點眼。當為異丙基烏諾前列酮時，可將在0.001~5w/v%之範圍內，較佳為0.01~1w/v%之範圍內，更佳為0.12~0.15w/v%之範圍內，再更佳為0.12w/v%或0.15w/v%之濃度的點眼劑，1日1次或數次點眼。當為比馬前列腺素時，可將在0.0001~5w/v%之範圍內，較佳為0.001~1w/v%之範圍內，更佳為0.01~0.03w/v%之範圍內，再更佳為0.01w/v%或0.03w/v%之濃度的點眼劑，1日1次或數次點眼。當為曲伏前列腺素時，可將在0.0001~5w/v%之範圍內，較佳為0.001~1w/v%之範圍內，更佳為0.004w/v%之濃度的點眼劑，1日1次或數次點眼。 The dosage of prostaglandins varies depending on the type of the drug. Usually, the dosage for one day is in the range of 0.1 to 1000 μg. Once a day or divided into several doses. More specifically, when it is latanoprost, 1 to 5 μg is usually used as the 1 day amount, and when it is isopropyl unoprostone, 30 to 300 μg is usually used as the 1 day amount, and when it is piracetin Usually, 2 to 30 μg is used as the 1 day amount, and when it is the Trevor prostaglandin, 0.5 to 5 μg is usually used as the 1 day amount, and the amount of the dosage may be appropriately increased or decreased depending on the age, symptoms, and the like of the patient. Further, other prostaglandins may be determined based on the same criteria. The concentration of the prostaglandins in the eye drops is not particularly limited. When it is latanoprost, it may be in the range of 0.0001 to 5 w/v%, preferably 0.0005 to 1 w/v%, and more. Preferably, it is in the range of 0.001 to 0.1 w/v%, and more preferably an eyedrop of a concentration of 0.005 w/v%, once or several times a day. In the case of isopropyl unoprostone, it may be in the range of 0.001 to 5 w/v%, preferably 0.01 to 1 w/v%, more preferably 0.12 to 0.15 w/v%. More preferably, it is an eye drop of 0.12 w/v% or 0.15 w/v%, and the eye is applied once or several times a day. In the case of bimatoprost, it may be in the range of 0.0001 to 5 w/v%, preferably in the range of 0.001 to 1 w/v%, more preferably in the range of 0.01 to 0.03 w/v%, and more An eye drop agent having a concentration of 0.01 w/v% or 0.03 w/v% is preferably applied once or several times a day. In the case of trovoprosin, it may be in the range of 0.0001 to 5 w/v%, preferably in the range of 0.001 to 1 w/v%, more preferably 0.004 w/v%. One or several times a day.

Rho激酶抑制劑之投予量係根據藥物之種類而有所不同，通常1日之投予量在0.025~10000μg之範圍，可1日1次或分為數次投予，該等之用量，視患者 之年齡、症狀等可適當地增減。點眼液中之Rho激酶抑制劑之濃度並無特別限制，可將在0.001~5w/v%之範圍內，較佳為0.001~1w/v%之範圍內之濃度的點眼劑，1日1次或數次點眼。 The dosage of the Rho kinase inhibitor varies depending on the type of the drug, and the dosage for the first day is usually in the range of 0.025 to 10000 μg, and may be administered once a day or in divided doses. patient The age, symptoms, and the like can be appropriately increased or decreased. The concentration of the Rho kinase inhibitor in the eye drops is not particularly limited, and may be in the range of 0.001 to 5 w/v%, preferably in the range of 0.001 to 1 w/v%, on the 1st day. 1 or several times.

該等之投予量適用於將本化合物與其它之青光眼或高眼壓症之預防或治療藥併用投予時，當將本化合物與其它之青光眼或高眼壓症之預防或治療藥之任意組合的合劑進行投予時，以使1日之投予量成為上述之各成分之投予量的範圍內的方式，製備經適當地選擇調配比例之製劑，而其調配製劑可1日1次或分為數次投予。 These administration amounts are suitable for the administration of the present compound together with other prophylactic or therapeutic agents for glaucoma or ocular hypertension when the compound is combined with other glaucoma or ocular hypertension prevention or treatment drugs. When the combined mixture is administered, the preparation is appropriately selected so that the dosage of one day is within the range of the above-mentioned dosage of each component, and the preparation can be formulated once a day. Or divided into several doses.

以下表示製劑例及藥理測試，惟該等係用於更了解本發明者，本發明之範圍並不限定於此。 The formulation examples and pharmacological tests are shown below, but these are used to better understand the present invention, and the scope of the present invention is not limited thereto.

[製劑例] [Formulation Example]

以下表示將本發明中之本化合物與其它之青光眼或高眼壓症之預防或治療藥所調配而成之點眼劑及眼軟膏的具體製劑例。 Specific examples of the ophthalmic preparations and ophthalmic ointments prepared by combining the present compound of the present invention with other prophylactic or therapeutic agents for glaucoma or ocular hypertension are shown below.

[製劑例1] [Formulation Example 1]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例2] [Formulation Example 2]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例3] [Formulation Example 3]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例4] [Formulation Example 4]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例5] [Formulation Example 5]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例6] [Formulation Example 6]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例7] [Formulation Example 7]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例8] [Formulation Example 8]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例9] [Formulation Example 9]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例10] [Formulation Example 10]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例11] [Formulation Example 11]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例12] [Formulation Example 12]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例13] [Formulation Example 13]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例14] [Formulation Example 14]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例15] [Formulation Example 15]

點眼劑(100mL中) Eye drops (in 100mL)

[製劑例16] [Formulation Example 16]

眼軟膏(100g中) Eye ointment (100g)

[製劑例17] [Formulation Example 17]

眼軟膏(100g中) Eye ointment (100g)

[製劑例18] [Formulation Example 18]

眼軟膏(100g中) Eye ointment (100g)

上述處方中，將本化合物之量變更為0.001g、0.003g、0.03g、0.1g等，又，變更其它之青光眼或高眼壓症之預防或治療藥，或添加劑之種類及量，而可製備所欲之組合及所欲之濃度的點演劑及眼軟膏。 In the above prescription, the amount of the present compound is changed to 0.001 g, 0.003 g, 0.03 g, 0.1 g, etc., and the type or amount of the preventive or therapeutic drug for glaucoma or ocular hypertension or the additive may be changed. Preparation of the desired combination and desired concentration of the dot lotion and eye ointment.

[藥理測試] [Pharmacological test] [實施例1] [Example 1]

為了調查本化合物與β受體阻斷藥之組合的有用性，而研究於實驗動物(正常眼壓兔)併用投予本化合物與噻嗎洛爾時之降眼壓效果。 In order to investigate the usefulness of the combination of the present compound and the beta blocker, the experimental animals (normal intraocular rabbits) were studied and the intraocular pressure lowering effect was administered by administering the compound and timolol.

(被驗化合物溶液之製備) (Preparation of test compound solution) (1)基劑之製備 (1) Preparation of base

於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 1.7 g of polyoxyethylene (35) castor oil to 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution, 30 mL of distilled water, 50 mL of 2% Boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(2)本化合物溶液之製備 (2) Preparation of the solution of the compound

於0.8g聚氧乙烯(35)蓖麻油加入0.001g本化合物，且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 0.001 g of this compound was added to 0.8 g of polyoxyethylene (35) castor oil, and 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution and 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution were added. 30 mL of distilled water, 50 mL of 2% boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(3)生理食鹽液之製備 (3) Preparation of physiological salt solution

直接使用市售之生理食鹽液(商品名：大塚生食注、由大塚製藥工廠(股)取得)。 The commercially available physiological saline solution (trade name: Otsuka Health Food Co., Ltd., obtained from Otsuka Pharmaceutical Factory Co., Ltd.) is used as it is.

(4)噻嗎洛爾溶液之製備 (4) Preparation of timolol solution

直接使用市售之噻嗎洛爾點眼液。 Commercially available timolol eye drops are used directly.

(測試方法) (testing method)

研究將本化合物與噻嗎洛爾併用投予時之降眼壓效果。作為比較對象，亦研究單獨投予本化合物或單獨投予噻嗎洛爾時之降眼壓效果。對照組係投予基劑及生理食鹽水。 The effect of reducing the intraocular pressure when the compound was administered in combination with timolol was studied. As a comparison object, the intraocular pressure lowering effect when the present compound was administered alone or when timolol was administered alone was also investigated. The control group was administered with a base and physiological saline.

(測試所使用之藥劑及動物) (testing the drugs and animals used)

本化合物溶液：0.001w/v%本化合物溶液(點眼量：50μL) Solution of the compound: 0.001 w/v% of the compound solution (eye volume: 50 μL)

噻嗎洛爾溶液：噻嗎洛爾點眼液(商品名：Timoptol(註冊商標)點眼液0.5%，點眼量：50μL) Thiololol solution: timolol eye drops (trade name: Timoptol (registered trademark) eye drops 0.5%, eye volume: 50 μL)

實驗動物：日本白色兔(系統：JW、性別：雄性、一群6隻) Experimental animals: Japanese white rabbits (system: JW, gender: male, group of 6)

(投予方法及測定方法) (injection method and measurement method) [1]本化合物與噻嗎洛爾併用投予 [1] This compound is administered in combination with timolol

(1)將0.4%鹽酸丁氧普鲁卡因(oxybuprocaine hydrochloride)點眼液(商品名：Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。 (1) 0.4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benoxil (registered trademark) eye drops 0.4%) was spotted on the eyes of the experimental animals for local anesthesia.

(2)於被驗化合物溶液投予前測定眼壓，設為初期眼壓。 (2) The intraocular pressure was measured before administration of the test compound solution, and it was set as the initial intraocular pressure.

(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將噻嗎洛爾溶液點眼於同一眼。 (3) The present compound solution was spotted on one eye of the experimental animal (no treatment on the contralateral eye). Leave the timolol solution in the same eye for a while.

(4)本化合物溶液點眼後2小時、4小時及6小時，將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後，測定眼壓。又，眼壓係測定3次而以其平均值表示結果。 (4) The intraocular pressure was measured at 2 hours, 4 hours, and 6 hours after the eye point of the present compound solution, and 0.4% hydrochloric acid butoxyprocaine eye drops were intraocularly anesthetized by eye drops. Further, the intraocular pressure was measured three times and the results were expressed as the average value.

[2]本化合物之單獨投予 [2] Separate administration of the compound

將噻嗎洛爾溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 The timolol solution was replaced with physiological saline, and the other tests were carried out in the same manner as the above-mentioned administration test.

[3]噻嗎洛爾之單獨投予 [3] Separate administration of timolol

將本化合物以基劑代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the other tests were carried out in the same manner as described above in the case of the administration test.

[4]對照組 [4] Control group

將本化合物以基劑代替，噻嗎洛爾溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the timolol solution was replaced with physiological saline, and the other test was carried out in the same manner as the above-mentioned administration test.

(結果及考察) (Results and investigation)

各投予群之點眼後4小時之降眼壓幅度(對對照群平均值)表示於表1。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示基於各群之6隻的平均值。 The amplitude of intraocular pressure (average of the control group) at 4 hours after the eye of each of the administered groups is shown in Table 1. The intraocular pressure reduction amplitude (the average value of the control group) is based on the difference between the average value of the intraocular pressure value (ΔIOP) of the initial intraocular pressure value of the control group and the ΔIOP of each body, and is based on 6 of each group. average value.

由表1可以明白，本化合物與噻嗎洛爾之併用投予群之點眼後4小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群，即，大於本化合物投予群及噻嗎洛爾投予群之點眼後4小時的降眼壓幅度(對對照群平均值)，且大於由各藥劑單獨投予所引起之點眼後4小時的降眼壓幅度(對對照群平均值)合併計算之和，本化合物與噻嗎洛爾之併用效果為加乘者。 It can be understood from Table 1 that the amplitude of intraocular pressure reduction (average of the control group) at 4 hours after administration of the compound and timolol together with the eye of the group is greater than that of the drug alone, that is, greater than the compound administration. The intraocular pressure reduction amplitude (average of the control group) at 4 hours after administration of the group and timolol to the eye of the group, and greater than the amplitude of intraocular pressure decreased 4 hours after the eye caused by the separate administration of each agent (To the average of the control group) The sum of the combined calculations, the combined effect of the present compound and timolol is the additive.

由以上可知，藉由組合本化合物與β受體阻斷藥，可獲得加乘之降眼壓效果。 From the above, it can be seen that by combining the present compound with a β-blocker, an effect of increasing the intraocular pressure can be obtained.

[實施例2] [Embodiment 2]

為了調查本化合物與前列腺素之組合的有用性，而研究於實驗動物(正常眼壓猴)併用投予本化合物與拉坦前列腺素時之降眼壓效果。 In order to investigate the usefulness of the combination of the present compound and prostaglandin, it was studied in experimental animals (normal intraocular monkeys) and the intraocular pressure lowering effect was administered when the present compound and latanoprost were administered.

(被驗化合物溶液之製備) (Preparation of test compound solution) (1)基劑之製備 (1) Preparation of base

於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 1.7 g of polyoxyethylene (35) castor oil to 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution, 30 mL of distilled water, 50 mL of 2% Boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(2)本化合物溶液之製備 (2) Preparation of the solution of the compound

於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物，且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 0.0006 g of this compound to 0.8 g of polyoxyethylene (35) castor oil, and add 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution. 30 mL of distilled water, 50 mL of 2% boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(3)生理食鹽液之製備 (3) Preparation of physiological salt solution

直接使用市售之生理食鹽液(商品名：大塚生食注、由大塚製藥工廠(股)取得)。 The commercially available physiological saline solution (trade name: Otsuka Health Food Co., Ltd., obtained from Otsuka Pharmaceutical Factory Co., Ltd.) is used as it is.

(4)拉坦前列腺素溶液之製備 (4) Preparation of latanoprost solution

直接使用市售之拉坦前列腺素點眼液。 Commercially available latanoprost eye drops are used directly.

(測試方法) (testing method)

研究將本化合物與拉坦前列腺素併用投予時之降眼壓效果。作為比較對象，亦研究單獨投予本化合物或單獨投予拉坦前列腺素時之降眼壓效果。對照組係投予基劑及生理食鹽水。 The effect of reducing the intraocular pressure when the compound was administered in combination with latanoprost was studied. As a comparison object, the intraocular pressure lowering effect when the present compound was administered alone or when latanoprost was administered alone was also examined. The control group was administered with a base and physiological saline.

(測試所使用之藥劑及動物) (testing the drugs and animals used)

本化合物溶液：0.0006w/v%本化合物溶液(點眼量：20μL) Solution of the compound: 0.0006 w/v% of the compound solution (eye volume: 20 μL)

拉坦前列腺素溶液：拉坦前列腺素點眼液(商品名：Xalatan(註冊商標)點眼液0.005%，點眼量：20μL) Latant prostaglandin solution: latanoprost eye drops (trade name: Xalatan (registered trademark) eye drops 0.005%, eye volume: 20 μL)

實驗動物：石蟹獼猴(Macaca fascicularis)(性別：雄性、一群6頭) Experimental animals: Macaca fascicularis (sex: male, group of 6)

(投予方法及測定方法) (injection method and measurement method) [1]本化合物與拉坦前列腺素併用投予 [1] The compound is administered in combination with latanoprost.

(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名：Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。 (1) Local anesthesia was performed by spotting 0.4% of butoxyprocaine hydrochloride eye drops (trade name: Benoxil (registered trademark) eye drops 0.4%) on the eyes of the experimental animals.

(2)於被驗化合物溶液投予前測定眼壓，設為初期眼壓。 (2) The intraocular pressure was measured before administration of the test compound solution, and it was set as the initial intraocular pressure.

(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將拉坦前列腺素溶液點眼於同一眼。 (3) The present compound solution was spotted on one eye of the experimental animal (no treatment on the contralateral eye). Leave the latanoprost solution in the same eye for a while.

(4)本化合物溶液點眼後2小時、4小時、6小時及8小時，將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後，測定眼壓。又，眼壓係測定3次而以其平均值表示結果。 (4) After the compound solution was spotted at 2 hours, 4 hours, 6 hours and 8 hours, 0.4% of the solution of butoxyprocaine eye drops was applied to the eye by eye drop and local anesthesia was performed. intraocular pressure. Further, the intraocular pressure was measured three times and the results were expressed as the average value.

[2]本化合物之單獨投予 [2] Separate administration of the compound

將拉坦前列腺素溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 The latanoprost solution was replaced with physiological saline, and the other tests were carried out in the same manner as the above-mentioned administration test.

[3]拉坦前列腺素之單獨投予 [3] Alcoholic administration of latanoprost

將本化合物以基劑代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the other tests were carried out in the same manner as described above in the case of the administration test.

[4]對照組 [4] Control group

將本化合物以基劑代替，拉坦前列腺素溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 The compound was replaced with a base, and the latanoprost solution was replaced with physiological saline, and the other test was carried out in the same manner as the above-mentioned administration test.

(結果及考察) (Results and investigation)

各投予群之點眼後8小時之降眼壓幅度(對對照群平均值)表示於表2。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群6頭之平均值。 The amplitude of intraocular pressure (eighth of the control group) after 8 hours after the eye of each group was shown in Table 2. The intraocular pressure reduction amplitude (the average value of the control group) is the average value of the six heads of each group from the difference between the average value of the intraocular pressure value (ΔIOP) of the initial intraocular pressure value of the control group and the ΔIOP of each body. .

由表2可以明白，本化合物與拉坦前列腺素之併用投予群之點眼後8小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群，即，大於本化合物投予群及拉坦前列腺素投予群之點眼後8小時的降眼壓幅度(對對照群平均值)，且大於由各藥劑單獨投予所引起之點眼 後8小時的降眼壓幅度(對對照群平均值)合併計算之和，本化合物與拉坦前列腺素之併用效果為加乘者。 It can be understood from Table 2 that the amplitude of intraocular pressure reduction (average of the control group) 8 hours after the administration of the compound and latanoprost in combination with the eye of the group is greater than that of the drug alone, that is, greater than the compound administration. The intraocular pressure reduction amplitude (average of the control group) at 8 hours after administration of the group and latanoprosts to the eye of the group, and greater than the eyedrop caused by the separate administration of each agent The amplitude of the intraocular pressure reduction in the last 8 hours (average of the control group) is the sum of the combined calculations, and the combined effect of the present compound and latanoprost is the additive.

由以上可知，藉由組合本化合物與前列腺素類，可獲得加乘之降眼壓效果。 From the above, it can be seen that by combining the present compound with prostaglandins, an effect of increasing the intraocular pressure can be obtained.

[實施例3] [Example 3]

為了調查本化合物與α2受體促效藥之組合的有用性，而研究於實驗動物(正常眼壓猴)併用投予本化合物與溴莫尼定時之降眼壓效果。 In order to investigate the usefulness of the combination of the present compound and the α 2 receptor agonist, the experimental animal (normal intraocular monkey) was studied and the intraocular pressure-lowering effect of the present compound and bromoni was administered.

(被驗化合物溶液之製備) (Preparation of test compound solution) (1)基劑之製備 (1) Preparation of base

於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 1.7 g of polyoxyethylene (35) castor oil to 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution, 30 mL of distilled water, 50 mL of 2% Boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(2)本化合物溶液之製備 (2) Preparation of the solution of the compound

於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物，且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 0.0006 g of this compound to 0.8 g of polyoxyethylene (35) castor oil, and add 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution. 30 mL of distilled water, 50 mL of 2% boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(3)生理食鹽液之製備 (3) Preparation of physiological salt solution

直接使用市售之生理食鹽液(商品名：大塚生食注、由大塚製藥工廠(股)取得)。 The commercially available physiological saline solution (trade name: Otsuka Health Food Co., Ltd., obtained from Otsuka Pharmaceutical Factory Co., Ltd.) is used as it is.

(4)溴莫尼定溶液之製備 (4) Preparation of brimonidine solution

直接使用市售之溴莫尼定點眼液。 Commercially available brimonidine eye drops are used directly.

(測試方法) (testing method)

研究將本化合物與溴莫尼定併用投予時之降眼壓效果。作為比較對象，亦研究單獨投予本化合物或單獨投予溴莫尼定時之降眼壓效果。對照組係投予基劑及生理食鹽水。 The effect of reducing the intraocular pressure when the compound was administered in combination with brimonidine was studied. As a comparison object, the effect of administering the compound alone or the administration of brimoni alone to reduce the intraocular pressure was also investigated. The control group was administered with a base and physiological saline.

(測試所使用之藥劑及動物) (testing the drugs and animals used)

本化合物溶液：0.0006w/v%本化合物溶液(點眼量：20μL) Solution of the compound: 0.0006 w/v% of the compound solution (eye volume: 20 μL)

溴莫尼定溶液：溴莫尼定點眼液(商品名：ALPHAGAN(註冊商標)P 0.15%，點眼量：20μL) Brimonidine solution: Brimonidine eye drops (trade name: ALPHAGAN (registered trademark) P 0.15%, eye volume: 20 μL)

實驗動物：石蟹獼猴(性別：雄性、一群6頭) Experimental animals: stone crab macaque (sex: male, a group of 6)

(投予方法及測定方法) (injection method and measurement method) [1]本化合物與溴莫尼定併用投予 [1] This compound is administered in combination with brimonidine

(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名：Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。 (1) Local anesthesia was performed by spotting 0.4% of butoxyprocaine hydrochloride eye drops (trade name: Benoxil (registered trademark) eye drops 0.4%) on the eyes of the experimental animals.

(2)於被驗化合物溶液投予前測定眼壓，設為初期眼壓。 (2) The intraocular pressure was measured before administration of the test compound solution, and it was set as the initial intraocular pressure.

(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將溴莫尼定溶液點眼於同一眼。 (3) The present compound solution was spotted on one eye of the experimental animal (no treatment on the contralateral eye). Leave the brimonidine solution in the same eye for a while.

(4)本化合物溶液點眼後2小時、4小時、6小時及8小時，將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後，測定眼壓。又，眼壓係測定3次而以其平均值表示結果。 (4) After the compound solution was spotted at 2 hours, 4 hours, 6 hours and 8 hours, 0.4% of the solution of butoxyprocaine eye drops was applied to the eye by eye drop and local anesthesia was performed. intraocular pressure. Further, the intraocular pressure was measured three times and the results were expressed as the average value.

[2]本化合物之單獨投予 [2] Separate administration of the compound

將溴莫尼定溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 The brimonidine solution was replaced with physiological saline, and the other tests were carried out in the same manner as the above-mentioned administration test.

[3]溴莫尼定之單獨投予 [3] Separate administration of brimonidine

將本化合物以基劑代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the other tests were carried out in the same manner as described above in the case of the administration test.

[4]對照組 [4] Control group

將本化合物以基劑代替，溴莫尼定溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the brimonidine solution was replaced with physiological saline, and the other test was carried out in the same manner as the above-mentioned administration test.

(結果及考察) (Results and investigation)

各投予群之點眼後2小時之降眼壓幅度(對對照組平均值)表示於表3。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群6頭之平均值。 The amplitude of intraocular pressure (average of the control group) at 2 hours after each eye of each group was shown in Table 3. The intraocular pressure reduction amplitude (the average value of the control group) is the average value of the six heads of each group from the difference between the average value of the intraocular pressure value (ΔIOP) of the initial intraocular pressure value of the control group and the ΔIOP of each body. .

由表3可以明白，本化合物與溴莫尼定之併用投予群之點眼後2小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群，即，大於本化合物投予群及溴莫尼定投予群之點眼後2小時的降眼壓幅度(對對照群平均值)，且大於由各藥劑單獨投予所引起之點眼後2小時的降眼壓幅度(對對照群平均值)合併計算之和，本化合物與溴莫尼定之併用效果為加乘者。 It can be understood from Table 3 that the amplitude of intraocular pressure reduction (average of the control group) 2 hours after the administration of the present compound and brimonidine in combination with the eye of the group is greater than the administration of the drug alone, that is, greater than the administration of the compound. The amplitude of intraocular pressure reduction (average of the control group) at 2 hours after administration of the group and brimonidine to the eye of the group, and greater than the amplitude of intraocular pressure decreased 2 hours after the eye caused by the separate administration of each agent (right) The average of the control group is the sum of the combined calculations, and the combined effect of the present compound and brimonidine is the additive.

由以上可知，藉由組合本化合物與α2受體促效藥，可獲得加乘之降眼壓效果。 From the above, it can be seen that by combining the present compound with the α 2 receptor agonist, an effect of increasing the intraocular pressure can be obtained.

[實施例4] [Example 4]

為了調查本化合物與碳酸酐酶抑制劑之組合的有用性，而研究於實驗動物(正常眼壓猴)併用投予本化合物與布林唑胺時之降眼壓效果。 In order to investigate the usefulness of the combination of the present compound and a carbonic anhydrase inhibitor, it was studied in an experimental animal (normal intraocular monkey) and the intraocular pressure lowering effect was administered when the present compound and brinzolamide were administered.

(被驗化合物溶液之製備) (Preparation of test compound solution) (1)基劑之製備 (1) Preparation of base

於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 1.7 g of polyoxyethylene (35) castor oil to 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution, 30 mL of distilled water, 50 mL of 2% Boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(2)本化合物溶液之製備 (2) Preparation of the solution of the compound

於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物，且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾 水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後，於其加入適量氫氧化鈉溶液或稀鹽酸，而製劑之pH成為6.5前後之後，加入適量蒸餾水而使總量成為100mL。 Add 0.0006 g of this compound to 0.8 g of polyoxyethylene (35) castor oil, and add 10 mL of 0.5% ethylenediamine tetraethyl disodium/10% glycerol solution, 1 mL of 1% alkyl dimethyl benzyl ammonium chloride solution. , 30mL distillation Water, 50 mL of 2% boric acid / 0.2% sorbic acid solution and dissolved. After confirming the solution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto, and after the pH of the preparation became 6.5 or so, an appropriate amount of distilled water was added to make the total amount 100 mL.

(3)生理食鹽液之製備 (3) Preparation of physiological salt solution

直接使用市售之生理食鹽液(商品名：大塚生食注、由大塚製藥工廠(股)取得)。 The commercially available physiological saline solution (trade name: Otsuka Health Food Co., Ltd., obtained from Otsuka Pharmaceutical Factory Co., Ltd.) is used as it is.

(4)布林唑胺懸浮液之製備 (4) Preparation of Brinzolamide Suspension

直接使用市售之布林唑胺點眼液。 Commercially available brinzolamide eye drops are used directly.

(測試方法) (testing method)

研究將本化合物與布林唑胺併用投予時之降眼壓效果。作為比較對象，亦研究單獨投予本化合物或單獨投予布林唑胺時之降眼壓效果。對照組係投予基劑及生理食鹽水。 The effect of reducing the intraocular pressure when the compound was combined with brinzolamide was studied. As a comparison object, the intraocular pressure lowering effect when the present compound was administered alone or when linazolamide was administered alone was also examined. The control group was administered with a base and physiological saline.

(測試所使用之藥劑及動物) (testing the drugs and animals used)

本化合物溶液：0.0006w/v%本化合物溶液(點眼量：20μL) Solution of the compound: 0.0006 w/v% of the compound solution (eye volume: 20 μL)

布林唑胺懸浮液：布林唑胺懸浮性點眼液(商品名：Azopt(註冊商標)懸浮性點眼液1%，點眼量：20μL) Brinzolamide suspension: Brinzolamide suspension eye drops (trade name: Azopt (registered trademark) suspension eye drops 1%, eye volume: 20 μL)

實驗動物：石蟹獼猴(Macaca fascicularis)(性別：雄性、一群5或6頭) Experimental animals: Macaca fascicularis (sex: male, a group of 5 or 6)

(投予方法及測定方法) (injection method and measurement method) [1]本化合物與布林唑胺併用投予 [1] This compound is administered in combination with brinzolamide

(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名：Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。 (1) Local anesthesia was performed by spotting 0.4% of butoxyprocaine hydrochloride eye drops (trade name: Benoxil (registered trademark) eye drops 0.4%) on the eyes of the experimental animals.

(2)於被驗化合物溶液投予前測定眼壓，設為初期眼壓。 (2) The intraocular pressure was measured before administration of the test compound solution, and it was set as the initial intraocular pressure.

(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將布林唑胺懸浮液點眼於同一眼。 (3) The present compound solution was spotted on one eye of the experimental animal (no treatment on the contralateral eye). Leave the Brinzolamide suspension in the same eye for a little longer.

(4)本化合物溶液點眼後2小時、4小時、6小時及8小時，將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後，測定眼壓。又，眼壓係測定3次而以其平均值表示結果。 (4) After the compound solution was spotted at 2 hours, 4 hours, 6 hours and 8 hours, 0.4% of the solution of butoxyprocaine eye drops was applied to the eye by eye drop and local anesthesia was performed. intraocular pressure. Further, the intraocular pressure was measured three times and the results were expressed as the average value.

[2]本化合物之單獨投予 [2] Separate administration of the compound

將布林唑胺懸浮液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試 The brinzolamide suspension was replaced with physiological saline, and the other methods were tested in the same manner as described above.

[3]布林唑胺之單獨投予 [3] Separate administration of brinzolamide

將本化合物以基劑代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the other tests were carried out in the same manner as described above in the case of the administration test.

[4]對照組 [4] Control group

將本化合物以基劑代替，布林唑胺溶液以生理食鹽水代替，其它與上述併用投予測試同樣之方法進行測試。 This compound was replaced with a base, and the brinzolamide solution was replaced with physiological saline, and the other test was carried out in the same manner as the above-mentioned administration test.

(結果及考察) (Results and investigation)

各投予群之點眼後4小時之降眼壓幅度(對對照群平均值)表示於表4。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群5或6頭之平均值。 The amplitude of intraocular pressure (the average value of the control group) at 4 hours after the eye of each of the administered groups is shown in Table 4. The intraocular pressure reduction amplitude (the average value of the control group) is the difference between the average value of the intraocular pressure value (ΔIOP) of the initial intraocular pressure value of the control group and the ΔIOP of each body to indicate the 5 or 6 heads of each group. average value.

由表4可以明白，本化合物與布林唑胺之併用投予群之點眼後4小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群，即，大於本化合物投予群及布林唑胺投予群之點眼後4小時的降眼壓幅度(對對照群平均值)。 It can be understood from Table 4 that the amplitude of intraocular pressure reduction (average of the control group) at 4 hours after the administration of the present compound and burinzamide is higher than that of the drug alone, that is, greater than the compound administration. The amplitude of intraocular pressure reduction (average of the control group) at 4 hours after the administration of the group and the body of the linazolamide group.

由以上可知，藉由組合本化合物與碳酸酐酶抑制劑，可獲得強力之降眼壓效果。 From the above, it can be seen that a strong anti-ocular hypotensive effect can be obtained by combining the present compound with a carbonic anhydrase inhibitor.

Claims (11)

一種青光眼或高眼壓症之預防或治療劑，其組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中，他氟前列腺素(tafluprost)除外)。 A prophylactic or therapeutic agent for glaucoma or ocular hypertension, which is a combination of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridine- Isopropyl 2-aminoamido) acetate and one or more other prophylactic or therapeutic agents for glaucoma or ocular hypertension (with the exception of tafluprost). 一種降眼壓劑，其組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中，他氟前列腺素除外)。 An ocular hypotensive agent combined with (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminemethyl}pyridin-2-ylamino)acetic acid A preventive or therapeutic drug for isopropyl ester and one or more other glaucoma or ocular hypertension (except for fluoroprostaglandin). 如申請專利範圍第1或2項之預防或治療劑或降眼壓劑，其中其它之青光眼或高眼壓症之預防或治療藥係選自由非選擇性交感神經促效藥、α2受體促效藥、α1受體阻斷藥、β受體阻斷藥、副交感神經促效藥、碳酸酐酶抑制劑、前列腺素類及Rho激酶抑制劑所構成之群中之1或多種之預防或治療劑。 The prophylactic or therapeutic agent or ocular hypotensive agent according to claim 1 or 2, wherein the other preventive or therapeutic agent for glaucoma or ocular hypertension is selected from the group consisting of non-selective sympathetic agonists, α 2 receptor Prevention of one or more of a group consisting of a agonist, an alpha 1 blocker, a beta blocker, a parasympathetic agonist, a carbonic anhydrase inhibitor, a prostaglandin, and a Rho kinase inhibitor Or a therapeutic agent. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中非選擇性交感神經促效藥為地匹福林(dipivefrine)。 For example, the prophylactic or therapeutic agent or ocular hypotensive agent of claim 3, wherein the non-selective sympathetic agonist is dipivefrine. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中α2受體促效藥為溴莫尼定(brimonidine)或阿可樂定(apraclonidine)。 A prophylactic or therapeutic agent or an ocular hypotensive agent according to claim 3, wherein the α 2 receptor agonist is brimonidine or apraclonidine. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中α1受體阻斷藥為布那唑嗪(bunazosin)。 A prophylactic or therapeutic agent or an ocular hypotensive agent according to claim 3, wherein the α 1 receptor blocking drug is bunazosin. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中β受體阻斷藥為噻嗎洛爾(timolol)、苯呋洛爾(befunolol)、卡替洛爾(carteolol)、尼普地洛(nipradilol)、倍他洛爾(betaxolol)、左布諾洛爾(levobunolol)或美替洛爾(metipranolol)。 For example, the prophylactic or therapeutic agent or ocular hypotensive agent of claim 3, wherein the beta blocker is timolol, befunolol, carteolol, Nipradiol, betaxolol, levobunolol or metipranolol. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中副交感神經促效藥為毛果芸香鹼(pilocarpine)。 For example, the prophylactic or therapeutic agent or the ocular hypotensive agent of claim 3, wherein the parasympathetic agonist is pilocarpine. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中碳酸酐酶抑制劑為多佐胺(dorzolamide)、布林唑胺(brinzolamide)或乙醯唑胺(acetazolamide)。 A prophylactic or therapeutic agent or an ocular hypotensive agent according to claim 3, wherein the carbonic anhydrase inhibitor is dozolamide, brinzolamide or acetazolamide. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中前列腺素類為異丙基烏諾前列酮(isopropyl unoprostone)、拉坦前列腺素(latanoprost)、曲伏前列腺素(travoprost)或比馬前列腺素(bimatoprost)。 For example, the prophylactic or therapeutic agent or the ocular hypotensive agent of claim 3, wherein the prostaglandins are isopropyl unoprostone, latanoprost, and travoprost. Or bimatoprost. 如申請專利範圍第3項之預防或治療劑或降眼壓劑，其中Rho激酶抑制劑為(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺、1-(5-異喹啉磺醯基)高哌嗪(1-(5-isoquinolinesulfonyl)homopiperazine)或1-(5-異喹啉磺醯基)-2-甲基哌嗪。 A prophylactic or therapeutic agent or ocular hypotensive agent according to claim 3, wherein the Rho kinase inhibitor is (R)-trans-N-(pyridin-4-yl)-4-(1-aminoethyl) ring Hexanecarbamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, 1 -(5-isoquinolinesulfonyl)homopiperazine or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine.
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