JP2014019650A - Combination of sulfonamide compound and tafluprost - Google Patents
Combination of sulfonamide compound and tafluprost Download PDFInfo
- Publication number
- JP2014019650A JP2014019650A JP2012157205A JP2012157205A JP2014019650A JP 2014019650 A JP2014019650 A JP 2014019650A JP 2012157205 A JP2012157205 A JP 2012157205A JP 2012157205 A JP2012157205 A JP 2012157205A JP 2014019650 A JP2014019650 A JP 2014019650A
- Authority
- JP
- Japan
- Prior art keywords
- intraocular pressure
- preventive
- therapeutic agent
- glaucoma
- tafluprost
- 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
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 title claims abstract description 48
- 229960004458 tafluprost Drugs 0.000 title claims abstract description 47
- -1 sulfonamide compound Chemical class 0.000 title claims abstract description 25
- 229940124530 sulfonamide Drugs 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 69
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 48
- 206010030043 Ocular hypertension Diseases 0.000 claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 32
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 50
- 230000003449 preventive effect Effects 0.000 claims description 39
- 230000004410 intraocular pressure Effects 0.000 claims description 33
- 150000003180 prostaglandins Chemical class 0.000 claims description 21
- 239000003590 rho kinase inhibitor Substances 0.000 claims description 20
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 19
- 239000002876 beta blocker Substances 0.000 claims description 14
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 claims description 10
- 239000000018 receptor agonist Substances 0.000 claims description 10
- 229940044601 receptor agonist Drugs 0.000 claims description 10
- 230000000069 prophylactic effect Effects 0.000 claims description 9
- 229940127230 sympathomimetic drug Drugs 0.000 claims description 9
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 8
- 229960002470 bimatoprost Drugs 0.000 claims description 8
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 8
- 229960001160 latanoprost Drugs 0.000 claims description 8
- 239000000734 parasympathomimetic agent Substances 0.000 claims description 8
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 8
- 229960002368 travoprost Drugs 0.000 claims description 8
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 7
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical group O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 7
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical group C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims description 7
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 claims description 7
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 7
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 claims description 7
- 229960000571 acetazolamide Drugs 0.000 claims description 7
- 229960004324 betaxolol Drugs 0.000 claims description 7
- 229960003679 brimonidine Drugs 0.000 claims description 7
- 229960001222 carteolol Drugs 0.000 claims description 7
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 claims description 7
- OCUJLLGVOUDECM-UHFFFAOYSA-N dipivefrin Chemical compound CNCC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 OCUJLLGVOUDECM-UHFFFAOYSA-N 0.000 claims description 7
- 229960000966 dipivefrine Drugs 0.000 claims description 7
- XXUPXHKCPIKWLR-JHUOEJJVSA-N isopropyl unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC(C)C XXUPXHKCPIKWLR-JHUOEJJVSA-N 0.000 claims description 7
- 229950000754 nipradilol Drugs 0.000 claims description 7
- 229940127242 parasympathomimetic drug Drugs 0.000 claims description 7
- 229960001416 pilocarpine Drugs 0.000 claims description 7
- 229960004605 timolol Drugs 0.000 claims description 7
- 229950008081 unoprostone isopropyl Drugs 0.000 claims description 7
- RHLJLALHBZGAFM-UHFFFAOYSA-N Bunazosinum Chemical group C1CN(C(=O)CCC)CCCN1C1=NC(N)=C(C=C(OC)C(OC)=C2)C2=N1 RHLJLALHBZGAFM-UHFFFAOYSA-N 0.000 claims description 6
- 229960002610 apraclonidine Drugs 0.000 claims description 6
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 claims description 6
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 claims description 6
- 229960000722 brinzolamide Drugs 0.000 claims description 6
- 229960002467 bunazosin Drugs 0.000 claims description 6
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical group CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 claims description 6
- 229960003933 dorzolamide Drugs 0.000 claims description 6
- 229960002704 metipranolol Drugs 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 102000005962 receptors Human genes 0.000 claims description 6
- 108020003175 receptors Proteins 0.000 claims description 6
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 claims description 5
- 239000000150 Sympathomimetic Substances 0.000 claims description 5
- 239000003087 receptor blocking agent Substances 0.000 claims description 5
- BDVFVCGFMNCYPV-NSHDSACASA-N 1-(5-isoquinolinesulfonyl)-2-methylpiperazine Chemical compound C[C@H]1CNCCN1S(=O)(=O)C1=CC=CC2=CN=CC=C12 BDVFVCGFMNCYPV-NSHDSACASA-N 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- ZPQPDBIHYCBNIG-UHFFFAOYSA-N befunolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1OC(C(C)=O)=C2 ZPQPDBIHYCBNIG-UHFFFAOYSA-N 0.000 claims description 4
- 229960004374 befunolol Drugs 0.000 claims description 4
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 2
- 102000003846 Carbonic anhydrases Human genes 0.000 claims 1
- 108090000209 Carbonic anhydrases Proteins 0.000 claims 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 claims 1
- BQIPXWYNLPYNHW-UHFFFAOYSA-N metipranolol Chemical compound CC(C)NCC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BQIPXWYNLPYNHW-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 19
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 45
- 239000003889 eye drop Substances 0.000 description 29
- 150000003839 salts Chemical group 0.000 description 27
- 239000002997 ophthalmic solution Substances 0.000 description 24
- 229940054534 ophthalmic solution Drugs 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 229940012356 eye drops Drugs 0.000 description 15
- 239000000203 mixture Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000001508 eye Anatomy 0.000 description 6
- 239000003885 eye ointment Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 5
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
本発明は（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとを組み合わせた緑内障若しくは高眼圧症の予防または治療剤、または眼圧下降剤に関するものである。 The present invention relates to glaucoma or ocular hypertension in which (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate isopropyl acetate and tafluprost are combined. The present invention relates to a preventive or therapeutic agent or an intraocular pressure lowering agent.
緑内障は、種々の病因により眼圧が上昇し、眼球の内部組織（網膜、視神経など）が障害を受けることで失明に至る危険性のある難治性の眼疾患である。緑内障の治療方法としては、眼圧下降療法が一般的であり、その代表的なものとして薬物療法、レーザー治療法、手術療法などがある。 Glaucoma is a refractory eye disease that has a risk of leading to blindness due to increased intraocular pressure due to various etiologies and damage to internal tissues of the eyeball (retina, optic nerve, etc.). As a method for treating glaucoma, intraocular pressure lowering therapy is generally used, and representative examples include drug therapy, laser therapy, and surgical therapy.
薬物療法には、交感神経作動薬（ジピベフリンなどの非選択性刺激薬、ブリモニジンなどのα２受容体作動薬）、交感神経遮断薬（チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロール（Ｍｅｔｉｐｒａｎｏｌｏｌ）などのβ受容体遮断薬、塩酸ブナゾシンなどのα１受容体遮断薬）、副交感神経作動薬（ピロカルピンなど）、炭酸脱水酵素阻害薬（アセタゾラミドなど）、プロスタグランジン類（イソプロピルウノプロストン、ラタノプロスト、トラボプロスト、ビマトプロストなど）などの薬物が使用されている。また、Ｒｈｏキナーゼ阻害剤（ＳＮＪ−１６５６など）、アデノシン作動薬（ＩＮＯ−８８７５など）、セロトニン遮断薬（ＢＶＴ−２８９４９）などが新たな薬物として開発中である。また、これらの他にも、プロスタグランジンＥ２受容体サブタイプ２アゴニスト（ＥＰ２アゴニスト）に眼圧下降作用があることが知られており、高いＥＰ２受容体選択性と強力なＥＰ２アゴニスト作用を有するスルホンアミド化合物が緑内障の治療薬として有望であることが国際公開第２０１０／１１３９５７号（特許文献１）に報告されている。 Drug therapy, sympathomimetics (nonselective stimulants such as dipivefrin, alpha 2 receptor agonists, such as brimonidine), sympatholytic (timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, Mechipurano roll (Metipranolol) beta receptor blockers such, alpha 1 receptor blockers such bunazosin hydrochloride), parasympathetic agonists (such as pilocarpine) and carbonic anhydrase inhibitors (acetazolamide), prostaglandins (isopropyl Uno Drugs such as prostone, latanoprost, travoprost, bimatoprost) are used. In addition, Rho kinase inhibitors (such as SNJ-1656), adenosine agonists (such as INO-8875), serotonin blockers (BVT-28949) and the like are under development as new drugs. In addition to these, it is known that prostaglandin E2 receptor subtype 2 agonist (EP2 agonist) has an intraocular pressure lowering action, and has high EP2 receptor selectivity and strong EP2 agonist action. It is reported in International Publication No. 2010/113957 (Patent Document 1) that a sulfonamide compound is promising as a therapeutic agent for glaucoma.
ところで、緑内障を治療する目的で眼圧下降作用を有する薬剤を組み合わせて使用することが複数報告されている。例えば、特許第２７２６６７２号公報（特許文献２）には、交感神経遮断薬とプロスタグランジン類の組み合わせの投与が報告されている。また、国際公開第２００２／３８１５８号（特許文献３）には、眼圧下降作用を有する薬剤をいくつか組み合わせて眼に投与することによる緑内障の治療方法が開示されている。さらに、国際公開第２００４／０１９９５１号（特許文献４）には、Ｒｈｏキナーゼ阻害剤とプロスタグランジン類の組み合わせの投与が、国際公開第２００４／０４５６４４号（特許文献５）にはＲｈｏキナーゼ阻害剤およびβ受容体遮断薬の組み合わせの投与が報告されている。 By the way, in order to treat glaucoma, multiple reports have been made on the use of a combination of drugs having an action of lowering intraocular pressure. For example, Japanese Patent No. 2726672 (Patent Document 2) reports the administration of a combination of a sympathetic nerve blocker and a prostaglandin. In addition, International Publication No. 2002/38158 (Patent Document 3) discloses a method for treating glaucoma by administering a combination of several drugs having an action of lowering intraocular pressure to the eye. Furthermore, International Publication No. 2004/019951 (Patent Document 4) discloses administration of a combination of a Rho kinase inhibitor and prostaglandins, and International Publication No. 2004/045644 (Patent Document 5) discloses a Rho kinase inhibitor. And the combination of β receptor blockers have been reported.
しかしながら、いずれの文献にも高いＥＰ２受容体選択性および強力なＥＰ２アゴニスト作用を有する（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとの組み合わせを具体的に開示する報告はこれまでになく、当然、これらの組み合わせが眼圧に対してどのような効果を示すかについては一切知られていない。 However, in any document, (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridine- having high EP2 receptor selectivity and potent EP2 agonist activity To date, there has been no report that specifically discloses the combination of 2-ylamino) isopropyl acetate and tafluprost, and of course, there is no known at all what effect these combinations have on intraocular pressure.
緑内障若しくは高眼圧症の予防または治療剤として有用な、緑内障若しくは高眼圧症の予防または治療薬の組み合わせを見出すことは非常に興味のある課題である。 Finding combinations of prophylactic or therapeutic agents for glaucoma or ocular hypertension that are useful as preventive or therapeutic agents for glaucoma or ocular hypertension is a very interesting issue.
本発明者らは、緑内障若しくは高眼圧症の予防または治療剤との組み合わせによる効果を鋭意研究した結果、（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとを組み合わせることで各薬剤の単独使用時と比較して眼圧下降作用が増強することを見出し、本発明を完成させた。すなわち、本発明は以下に関する。 As a result of intensive studies on the effects of a combination with a preventive or therapeutic agent for glaucoma or ocular hypertension, the present inventors have found that (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) It was found that by combining) aminomethyl} pyridin-2-ylamino) isopropyl acetate and tafluprost, the action of lowering intraocular pressure was enhanced compared to when each drug was used alone, and the present invention was completed. That is, the present invention relates to the following.
（１）（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとを組み合わせた緑内障若しくは高眼圧症の予防または治療剤。 (1) (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) glaucoma or ocular hypertension in combination with isopropyl acetate and tafluprost Prophylactic or therapeutic agent.
（２）（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとを組み合わせた眼圧下降剤。 (2) An intraocular pressure lowering agent combining (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate isopropyl acetate and tafluprost.
（３）さらに他の緑内障若しくは高眼圧症の予防または治療薬を組み合わせた上記（１）または（２）に記載の予防若しくは治療剤又は眼圧下降剤。 (3) The preventive or therapeutic agent or intraocular pressure lowering agent according to the above (1) or (2), which is further combined with other preventive or therapeutic agents for glaucoma or ocular hypertension.
（４）他の緑内障若しくは高眼圧症の予防または治療薬が、非選択性交感神経作動薬、α２受容体作動薬、α１受容体遮断薬、β受容体遮断薬、副交感神経作動薬、炭酸脱水酵素阻害剤、プロスタグランジン類及びＲｈｏキナーゼ阻害剤からなる群より選択される１または複数の予防または治療剤である、上記（３）に記載の予防若しくは治療剤又は眼圧下降剤。 (4) Other preventive or therapeutic agents for glaucoma or ocular hypertension include non-selective sympathomimetic drugs, α 2 receptor agonists, α 1 receptor blockers, β receptor blockers, parasympathomimetic drugs, The prophylactic or therapeutic agent or intraocular pressure lowering agent according to (3) above, which is one or more prophylactic or therapeutic agents selected from the group consisting of carbonic anhydrase inhibitors, prostaglandins and Rho kinase inhibitors.
（５）非選択性交感神経作動薬がジピベフリンである上記（４）に記載の予防若しくは治療剤又は眼圧下降剤。 (5) The preventive or therapeutic agent or intraocular pressure lowering agent according to (4) above, wherein the non-selective sympathomimetic drug is dipivefrin.
（６）α２受容体作動薬がブリモニジンまたはアプラクロニジンである上記（４）または（５）に記載の予防若しくは治療剤又は眼圧下降剤。 (6) The preventive or therapeutic agent or intraocular pressure-lowering agent according to the above (4) or (5), wherein the α 2 receptor agonist is brimonidine or apraclonidine.
（７）α１受容体遮断薬がブナゾシンである上記（４）〜（６）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (7) The preventive or therapeutic agent or the intraocular pressure-lowering agent according to any one of (4) to (6), wherein the α 1 receptor blocker is bunazosin.
（８）β受容体遮断薬がチモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロールまたはメチプラノロールである上記（４）〜（７）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (8) The preventive or therapeutic agent or intraocular pressure-lowering agent according to any one of (4) to (7), wherein the β receptor blocker is timolol, befunolol, carteolol, nipradilol, betaxolol, levobnolol, or metipranolol. .
（９）副交感神経作動薬がピロカルピンである上記（４）〜（８）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (9) The preventive or therapeutic agent or intraocular pressure lowering agent according to any one of (4) to (8), wherein the parasympathomimetic drug is pilocarpine.
（１０）炭酸脱水酵素阻害剤がドルゾラミド、ブリンゾラミドまたはアセタゾラミドである上記（４）〜（９）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (10) The preventive or therapeutic agent or intraocular pressure lowering agent according to any one of (4) to (9), wherein the carbonic anhydrase inhibitor is dorzolamide, brinzolamide, or acetazolamide.
（１１）プロスタグランジン類がイソプロピルウノプロストン、ラタノプロスト、トラボプロストまたはビマトプロストである上記（４）〜（１０）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (11) The preventive or therapeutic agent or intraocular pressure lowering agent according to any one of (4) to (10), wherein the prostaglandins are isopropyl unoprostone, latanoprost, travoprost, or bimatoprost.
（１２）Ｒｈｏキナーゼ阻害剤が（Ｒ）−トランス−Ｎ−（ピリジン−４−イル）−４−（１−アミノエチル）シクロヘキサンカルボキサミド、（Ｒ）−（＋）−Ｎ−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−４−（１−アミノエチル）ベンズアミド、１−（５−イソキノリンスルホニル）ホモピペラジンまたは１−（５−イソキノリンスルホニル）−２−メチルピペラジンである上記（４）〜（１１）のいずれかに記載の予防若しくは治療剤又は眼圧下降剤。 (12) Rho kinase inhibitor is (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [ 2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine The preventive or therapeutic agent or intraocular pressure lowering agent according to any one of (4) to (11).
尚、上記（１）から（１２）の各構成は、任意に１以上を選択して組み合わせることができる。 Note that one or more of the configurations (1) to (12) can be arbitrarily selected and combined.
（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピルとタフルプロストとを組み合わせて眼に投与することで、眼圧下降作用が増強する。したがって、本発明は緑内障若しくは高眼圧症の予防または治療剤、眼圧下降剤として有用である。 (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate and tafluprost are administered to the eye in combination with the intraocular pressure. The descending action is enhanced. Therefore, the present invention is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension, and an intraocular pressure lowering agent.
本発明は、下記式（１）で示される（６−｛［４−（ピラゾール−１−イル）ベンジル］（ピリジン−３−イルスルホニル）アミノメチル｝ピリジン−２−イルアミノ）酢酸イソプロピル（以下、本化合物ともいう）とタフルプロストとを組み合わせた緑内障若しくは高眼圧症の予防または治療剤、眼圧下降剤であり、お互いにその作用を補完および／または増強するものである。 The present invention relates to (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate (hereinafter referred to as the following formula (1)). It is also a prophylactic or therapeutic agent for glaucoma or ocular hypertension, an intraocular pressure-lowering agent, which is a combination of tafluprost and this compound, and complements and / or enhances the action of each other.
本発明における本化合物は、国際公開第２００９／１１３６００号または国際公開第２０１０／１１３９５７号に記載された方法により合成することができる。 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.
本発明は、本化合物とタフルプロストとを組み合わせて緑内障若しくは高眼圧症を予防または治療するところに特徴がある。さらに他の緑内障若しくは高眼圧症の予防または治療薬を組み合せてもよい。本発明における緑内障としては、原発性開放隅角緑内障、正常眼圧緑内障、房水産生過多緑内障、高眼圧症、急性閉塞隅角緑内障、慢性閉塞隅角緑内障、混合型緑内障、ステロイド緑内障、アミロイド緑内障、血管新生緑内障、悪性緑内障、水晶体の嚢性緑内障、ｐｌａｔｅａｕ ｉｒｉｓ ｓｙｎｄｒｏｍｅなどが例示される。 The present invention is characterized in that glaucoma or ocular hypertension is prevented or treated by combining the present compound and tafluprost. Furthermore, other preventive or therapeutic agents for glaucoma or ocular hypertension may be combined. As glaucoma in the present invention, primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, mixed glaucoma, steroid glaucoma, amyloid glaucoma Angiogenic glaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrome, etc. are exemplified.
本発明におけるタフルプロストとは、下記式（２）で示される（５Ｚ）−７−｛（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２−［（１Ｅ）−３，３−ジフルオロ−４−フェノキシ−１−ブテニル］−３，５−ジヒドロキシシクロペンチル｝−５−ヘプテン酸 １−メチルエチルであり、既に緑内障治療薬として販売されている。 Tafluprost in the present invention is (5Z) -7-{(1R, 2R, 3R, 5S) -2-[(1E) -3,3-difluoro-4-phenoxy-1 represented by the following formula (2). -Butenyl] -3,5-dihydroxycyclopentyl} -5-heptenoic acid 1-methylethyl, which is already on the market as a glaucoma therapeutic agent.
本発明における他の緑内障若しくは高眼圧症の予防または治療薬は、眼圧下降作用を有して緑内障治療に有用なものであればよく、非選択性交感神経作動薬、α２受容体作動薬、α１受容体遮断薬、β受容体遮断薬、副交感神経作動薬、炭酸脱水酵素阻害剤、プロスタグランジン類、Ｒｈｏキナーゼ阻害剤などが挙げられる。本化合物と２種の他の緑内障若しくは高眼圧症の予防または治療薬とを組み合わせる場合、２種の他の緑内障若しくは高眼圧症の予防または治療薬は、β受容体遮断薬、炭酸脱水酵素阻害剤及びプロスタグランジン類からなる群より選択される２種の予防または治療剤である場合が好ましく、β受容体遮断及び薬炭酸脱水酵素阻害剤である場合、又はβ受容体遮断薬及びプロスタグランジン類である場合がより好ましい。 Any other glaucoma or ocular hypertension preventive or therapeutic agent in the present invention may be used as long as it has an intraocular pressure lowering effect and is useful for glaucoma treatment, and is a non-selective sympathomimetic agent or α 2 receptor agonist. , Α 1 receptor blockers, β receptor blockers, parasympathomimetic agents, carbonic anhydrase inhibitors, prostaglandins, Rho kinase inhibitors and the like. When this compound is combined with two other glaucoma or ocular hypertension prevention or treatment drugs, the other two glaucoma or ocular hypertension prevention or treatment drugs are β receptor blockers, carbonic anhydrase inhibitors It is preferably a case of two preventive or therapeutic agents selected from the group consisting of agents and prostaglandins, and is a β receptor blocker and a drug carbonic anhydrase inhibitor, or a β receptor blocker and a prostagland More preferred are gins.
非選択性交感神経作動薬の具体例としては、ジピベフリンが挙げられ、α２受容体作動薬の具体例としては、ブリモニジン、アプラクロニジンが挙げられ、α１受容体遮断薬の具体例としてはブナゾシンが挙げられ、β受容体遮断薬の具体例としては、チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロールが挙げられ、副交感神経作動薬の具体例としてはピロカルピンが挙げられ、炭酸脱水酵素阻害剤の具体例としては、ドルゾラミド、ブリンゾラミド、アセタゾラミドが挙げられる。 Specific examples of non-selective sympathomimetic drugs include dipivefrin, specific examples of α 2 receptor agonists include brimonidine and apraclonidine, and specific examples of α 1 receptor blockers include bunazosin. Specific examples of β receptor blockers include timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol, and specific examples of parasympathomimetic drugs include pilocarpine, Specific examples of the dehydrase inhibitor include dorzolamide, brinzolamide, and acetazolamide.
プロスタグランジン類の具体例としては、特開昭５９−１４１８号公報に開示されているプロスタグランジン類（特にプロスタグランジンＦ２αのような天然のプロスタグランジン）、特表平３−５０１０２５号公報に開示されているラタノプロストなどのプロスタグランジン類、特開平２−１０８号公報に開示されているイソプロピルウノプロストンなどのプロスタグランジン類、特表平８−５０１３１０号公報に開示されているビマトプロストなどのプロスタグランジン類、特開平１０−１８２４６５号公報に開示されているトラボプロストなどのプロスタグランジン類、Ｓｕｒｖ Ｏｐｈｔｈａｌｍｏｌ ４７（Ｓｕｐｐｌ １）：Ｓ１３−Ｓ３３，２００２に開示されているＡＬ−６５９８などのプロスタグランジン類、Ｅｘｐ Ｅｙｅ Ｒｅｓ．８９：６０８−１７，２００９に開示されているＰＦ−０４４７５２７０などのプロスタグランジン類などが挙げられ、中でもＰＧＦ２αまたはＰＧＦ２α誘導体であることが好ましく、イソプロピルウノプロストン、ラタノプロスト、トラボプロストまたはビマトプロストであることがより好ましい。 Specific examples of prostaglandins include prostaglandins (particularly natural prostaglandins such as prostaglandin F2α) disclosed in JP-A No. 59-1418, Japanese Patent Publication No. Hei 3-501025. Prostaglandins such as latanoprost disclosed in the publication, prostaglandins such as isopropyl unoprostone disclosed in JP-A-2-108, and disclosed in JP-A-8-501310. Prostaglandins such as bimatoprost, prostaglandins such as travoprost disclosed in JP-A-10-182465, Surv Ophthalmol 47 (Suppl 1): AL-6598 disclosed in S13-S33,2002 Prostaglandins such as Exp Eye Res. 89: 608-17, 2009, such as prostaglandins such as PF-0475270, among which PGF2α or PGF2α derivatives are preferable, and isopropyl unoprostone, latanoprost, travoprost or bimatoprost is preferred. It is more preferable.
本発明におけるＲｈｏキナーゼ阻害剤とは、Ｒｈｏの活性化に伴い活性化されるセリン／スレオニンキナーゼを阻害する化合物を意味する。例えば、ＲＯＫα（ＲＯＣＫ−ＩＩ）、ｐ１６０ＲＯＣＫ（ＲＯＫβ、ＲＯＣＫ−Ｉ）およびその他のセリン／スレオニンキナーゼ活性を有するタンパク質を阻害する化合物が挙げられる。Ｒｈｏキナーゼ阻害剤の具体例としては、国際公開第９８／０６４３３号、国際公開第００／０９１６２号に開示されている（Ｒ）−トランス−Ｎ−（ピリジン−４−イル）−４−（１−アミノエチル）シクロヘキサンカルボキサミド、（Ｒ）−（＋）−Ｎ−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−４−（１−アミノエチル）ベンズアミドなどのＲｈｏキナーゼ阻害剤や国際公開第９７／２３２２２号、Ｎａｔｕｒｅ，３８９，９９０−９９４（１９９７）に開示されている１−（５−イソキノリンスルホニル）ホモピペラジン、１−（５−イソキノリンスルホニル）−２−メチルピペラジンなどのＲｈｏキナーゼ阻害剤が、国際公開第０１／５６９８８号に開示されている（１−ベンジルピロリジン−３−イル）−（１Ｈ−インダゾール−５−イル）アミンなどのＲｈｏキナーゼ阻害剤が、国際公開第０２／１００８３３に号開示されている（１−ベンジルピペリジン−４−イル）−（１Ｈ−インダゾール−５−イル）アミンなどのＲｈｏキナーゼ阻害剤が、国際公開第０２／０７６９７６号に開示されているＮ−［２−（４−フルオロフェニル）−６，７−ジメトキシ−４−キナゾリニル］−Ｎ−（１Ｈ−インダゾール−５−イル）アミンなどのＲｈｏキナーゼ阻害剤、国際公開第０２／０７６９７７号に開示されているＮ−４−（１Ｈ−インダゾール−５−イル）−６，７−ジメトキシ−Ｎ−２−ピリジン−４−イル−キナゾリン−２，４−ジアミンなどのＲｈｏキナーゼ阻害剤が、国際公開第９９／６４０１１号に開示されている４−メチル−５−（２−メチル−［１，４］ジアゼパン−１−スルホニル）イソキノリンなどのＲｈｏキナーゼ阻害剤が例示される。中でも特に、（Ｒ）−トランス−Ｎ−（ピリジン−４−イル）−４−（１−アミノエチル）シクロヘキサンカルボキサミド、（Ｒ）−（＋）−Ｎ−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）−４−（１−アミノエチル）ベンズアミド、１−（５−イソキノリンスルホニル）ホモピペラジンまたは１−（５−イソキノリンスルホニル）−２−メチルピペラジンが好ましい。 The Rho kinase inhibitor in the present invention means a compound that inhibits serine / threonine kinase activated with the activation of Rho. Examples include compounds that inhibit ROKα (ROCK-II), p160ROCK (ROKβ, ROCK-I) and other proteins with serine / threonine kinase activity. Specific examples of the Rho kinase inhibitor include (R) -trans-N- (pyridin-4-yl) -4- (1) disclosed in WO 98/06433 and WO 00/09162. Rho kinase inhibitors such as -aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide 1- (5-isoquinolinesulfonyl) homopiperazine, 1- (5-isoquinolinesulfonyl) -2-methylpiperazine and the like disclosed in WO 97/22322, Nature, 389, 990-994 (1997) Rho kinase inhibitors are disclosed in WO 01/56888 (1-benzylpyrrolidin-3-yl)-(1H- Rho kinase inhibitors such as danazol-5-yl) amine are disclosed in WO 02/100833 such as (1-benzylpiperidin-4-yl)-(1H-indazol-5-yl) amine The Rho kinase inhibitor is N- [2- (4-fluorophenyl) -6,7-dimethoxy-4-quinazolinyl] -N- (1H-indazole-5- 5 disclosed in WO 02/076976. Yl) Rho kinase inhibitors such as amines, N-4- (1H-indazol-5-yl) -6,7-dimethoxy-N-2-pyridin-4-disclosed in WO 02/076977 Rho kinase inhibitors, such as yl-quinazoline-2,4-diamine, are disclosed in 4-methyl-5- (2-meso, disclosed in WO 99/64011. Le - [1,4] diazepane-1-sulfonyl) Rho kinase inhibitors such as isoquinoline and the like. Among others, (R) -trans-N- (pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (1H-pyrrolo [2,3-b Pyridin-4-yl) -4- (1-aminoethyl) benzamide, 1- (5-isoquinolinesulfonyl) homopiperazine or 1- (5-isoquinolinesulfonyl) -2-methylpiperazine is preferred.
本発明における本化合物、タフルプロストおよび他の緑内障若しくは高眼圧症の予防または治療薬は塩の形態も包含する。それらは医薬として許容される塩であれば特に制限はなく、塩としては無機酸との塩、有機酸との塩、四級アンモニウム塩、ハロゲンイオンとの塩、アルカリ金属との塩、アルカリ土類金属との塩、金属塩、アンモニアとの塩、有機アミンとの塩等が挙げられる。無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、１，２−エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。四級アンモニウム塩としては、臭化メチル、ヨウ化メチル等との塩が挙げられる。ハロゲンイオンとの塩としては、塩化物イオン、臭化物イオン、ヨウ化物イオン等との塩が挙げられ、アルカリ金属との塩としては、リチウム、ナトリウム、カリウム等との塩が挙げられ、アルカリ土類金属との塩としては、カルシウム、マグネシウム等との塩が挙げられ、金属塩としては、鉄、亜鉛等との塩が挙げられる。有機アミンとの塩としては、トリエチレンジアミン、２−アミノエタノール、２，２−イミノビス（エタノール）、１−デオキシ−１−（メチルアミノ）−２−Ｄ−ソルビトール、２−アミノ−２−（ヒドロキシメチル）−１，３−プロパンジオール、プロカイン、Ｎ，Ｎ−ビス（フェニルメチル）−１，２−エタンジアミン等との塩が挙げられる。 In the present invention, the present compound, tafluprost and other preventive or therapeutic agents for glaucoma or ocular hypertension also include salt forms. These are not particularly limited as long as they are pharmaceutically acceptable salts. The salts include salts with inorganic acids, salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, alkaline earths. Examples thereof include salts with similar metals, metal salts, salts with ammonia, and salts with organic amines. Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, sulfuric acid And salts with methyl, naphthalenesulfonic acid, sulfosalicylic acid and the like. Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like. Salts with halogen ions include salts with chloride ions, bromide ions, iodide ions, etc. Salts with alkali metals include salts with lithium, sodium, potassium, etc., alkaline earths Examples of the salt with metal include salts with calcium, magnesium and the like, and examples of the metal salt include salts with iron, zinc and the like. Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
また、本発明における本化合物、タフルプロストおよび他の緑内障若しくは高眼圧症の予防または治療薬は、エステル、アミドなどの誘導体も包含する。エステルの具体例としては、タフルプロストおよび／または他の緑内障若しくは高眼圧症の予防または治療薬中のヒドロキシル基と酢酸、プロピオン酸、イソプロピオン酸、酪酸、イソ酪酸、ピバル酸などのカルボン酸が縮合したエステル、他の緑内障若しくは高眼圧症の予防または治療薬中のカルボキシル基とメタノール、エタノール、プロパノール、イソプロピルアルコールなどのアルコールが縮合したエステルが例示される。アミドの具体例としては、本化合物および／または他の緑内障若しくは高眼圧症の予防または治療薬中のアミノ基と酢酸、プロピオン酸、イソプロピオン酸、酪酸、イソ酪酸、ピバル酸などのカルボン酸が縮合したアミド、他の緑内障若しくは高眼圧症の予防または治療薬中のカルボキシル基とメチルアミン、エチルアミン、プロピルアミン、イソプロピルアミンなどのアミンが縮合したアミドが例示される。 In addition, the present compound, tafluprost and other preventive or therapeutic agents for glaucoma or ocular hypertension in the present invention also include derivatives such as esters and amides. Specific examples of esters include condensing of hydroxyl groups in tafluprost and / or other glaucoma or ocular hypertension preventive or therapeutic agents with carboxylic acids such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid and pivalic acid. And esters obtained by condensing a carboxyl group in other preventive or therapeutic agents for glaucoma or ocular hypertension and alcohols such as methanol, ethanol, propanol and isopropyl alcohol. Specific examples of amides include amino groups and carboxylic acids such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid in the present compound and / or other glaucoma or ocular hypertension preventive or therapeutic agents. Examples include condensed amides and amides obtained by condensing carboxyl groups in other glaucoma or ocular hypertension preventive or therapeutic agents and amines such as methylamine, ethylamine, propylamine, and isopropylamine.
さらに、本発明における本化合物およびタフルプロストは、水和物または溶媒和物の形態をとってもよい。 Furthermore, the present compound and tafluprost in the present invention may take the form of hydrates or solvates.
投与形態としては、本化合物とタフルプロストとを別々に処方した複数の製剤とした形態で投与（併用投与）してもよく、また、それぞれの成分を配合した１つの製剤とした形態（合剤）で投与してもよい。合剤である場合が好ましい。さらに他の緑内障若しくは高眼圧症の予防または治療薬を組み合わせる場合には、それぞれの成分を併用投与してもよく、本化合物とタフルプロストと他の緑内障若しくは高眼圧症の予防または治療薬のうち任意の成分を配合した合剤と残りの成分とを併用投与してもよく、すべての成分を配合した合剤としてもよい。 As a dosage form, it may be administered in the form of a plurality of preparations in which the present compound and tafluprost are separately prescribed (combined administration), or a single preparation in which each component is blended (mixture) May be administered. A combination is preferred. Furthermore, when other preventive or therapeutic agents for glaucoma or ocular hypertension are combined, the respective components may be administered in combination, and any of the compounds, tafluprost, and other preventive or therapeutic agents for glaucoma or ocular hypertension may be used. A mixture containing these ingredients and the remaining ingredients may be administered in combination, or a mixture containing all ingredients.
本発明の製剤は経口でも非経口でも投与することができ、これらの製剤化には特別な技術は必要なく、汎用される技術を用いて製剤化をすることができる。投与剤型としては、点眼剤、眼軟膏、注射剤、錠剤、カプセル剤、顆粒剤、散剤などが挙げられ、点眼剤または眼軟膏が好ましい。 The preparation of the present invention can be administered either orally or parenterally, and no special technique is required for the preparation, and the preparation can be prepared using a widely used technique. Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops or eye ointments are preferable.
本化合物とタフルプロストと他の緑内障若しくは高眼圧症の予防または治療薬を別々に製剤化する場合は、それぞれ公知の方法に準じて製剤を調製することができる。例えば、本化合物の製剤は、国際公開第２００９／１１３６００号または国際公開第２０１０／１１３９５７号に記載の製剤例を参考にして調製することができる。タフルプロストの製剤としては、市販の製剤またはそれに準じたものを使用することもできる。他の緑内障若しくは高眼圧症の予防または治療薬の製剤としては、既に市販されているジピベフリン、ブリモニジン、アプラクロニジン、ブナゾシン、チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロール、ピロカルピン、ドルゾラミド、ブリンゾラミド、アセタゾラミド、イソプロピルウノプロストン、ラタノプロスト、トラボプロスト、ビマトプロスト、コソプト（登録商標）配合点眼液、ザラカム（登録商標）配合点眼液、デュオトラバ（登録商標）配合点眼液などの製剤またはそれに準じたものを使用することもできる。Ｒｈｏキナーゼ阻害剤の製剤は、上述した国際公開第００／０９１６２号、国際公開第９７／２３２２２号などに記載された製剤例を参考にして調製することができる。 When this compound, tafluprost and other preventive or therapeutic agents for glaucoma or ocular hypertension are formulated separately, the formulations can be prepared according to known methods, respectively. For example, a preparation of the present compound can be prepared with reference to the preparation examples described in International Publication No. 2009/113600 or International Publication No. 2010/113957. As the preparation of tafluprost, a commercially available preparation or an equivalent thereof can also be used. As other pharmaceutical preparations for the prevention or treatment of glaucoma or ocular hypertension, dipivefrin, brimonidine, apraclonidine, bunazosin, timolol, befnolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, pilocarpine, which are already on the market Dorzolamide, Brinzolamide, Acetazolamide, Isopropylunoprostone, Latanoprost, Travoprost, Bimatoprost, Cosopt (registered trademark) ophthalmic solution, Zaracam (registered trademark) ophthalmic solution, Duotrava (registered trademark) ophthalmic solution or the like An equivalent can also be used. A Rho kinase inhibitor preparation can be prepared with reference to the preparation examples described in International Publication No. 00/09162, International Publication No. 97/22322 and the like.
また、本化合物とタフルプロストと他の緑内障若しくは高眼圧症の予防または治療薬の任意の組み合わせを配合した１つの製剤を調製する場合も、公知の方法に準じて調製することができる。 Moreover, when preparing one formulation which mix | blended arbitrary combination of this compound, tafluprost, and the other glaucoma or ocular hypertension prevention or treatment agent, it can prepare according to a well-known method.
点眼剤とする場合は、精製水、緩衝液などに本化合物やタフルプロストや他の緑内障若しくは高眼圧症の予防または治療薬を添加・攪拌した後、ｐＨ調整剤によりｐＨを調整することで所望の点眼剤を調製できる。また、必要に応じて点眼剤に汎用されている添加剤を用いることができ、添加剤としては、等張化剤、緩衝化剤、界面活性剤、安定化剤、防腐剤などが挙げられる。等張化剤としては、塩化ナトリウム、濃グリセリンなどが挙げられ、緩衝化剤としては、リン酸ナトリウム、酢酸ナトリウム、ホウ酸、ホウ砂、クエン酸などが挙げられ、界面活性剤としては、ポリオキシエチレンソルビタンモノオレート、ステアリン酸ポリオキシル、ポリオキシエチレン硬化ヒマシ油などが挙げられ、安定化剤としては、クエン酸ナトリウム、エデト酸ナトリウムなどが挙げられ、防腐剤としては、塩化ベンザルコニウム、パラベンなどの防腐剤などが挙げられる。 In the case of an eye drop, the compound, tafluprost, other glaucoma or ocular hypertension preventive or therapeutic agent is added and stirred in purified water, buffer, etc., and then adjusted to the desired pH by adjusting the pH with a pH adjuster. Eye drops can be prepared. In addition, additives that are widely used for eye drops can be used as necessary, and examples of the additives include isotonic agents, buffering agents, surfactants, stabilizers, and preservatives. Examples of the isotonic agent include sodium chloride and concentrated glycerin, examples of the buffering agent include sodium phosphate, sodium acetate, boric acid, borax, citric acid, and the like. Examples include oxyethylene sorbitan monooleate, polyoxyl stearate, and polyoxyethylene hydrogenated castor oil. Stabilizers include sodium citrate and sodium edetate. Preservatives include benzalkonium chloride and parabens. And other preservatives.
点眼剤のｐＨは眼科製剤に許容される範囲内にあればよく、ｐＨ４〜８の範囲が好ましく、ｐＨ５〜７の範囲がより好ましい。 The pH of the eye drop may be within the range acceptable for ophthalmic preparations, preferably in the range of pH 4-8, and more preferably in the range of pH 5-7.
眼軟膏とする場合は、汎用される基剤を用いて調製することができ、基剤としては、白色ワセリン、流動パラフィンなどが挙げられる。 In the case of an eye ointment, it can be prepared using a widely used base, and examples of the base include white petrolatum and liquid paraffin.
錠剤、カプセル剤、顆粒剤、散剤などの経口剤とする場合は、増量剤、滑沢剤、結合剤、崩壊剤、コーティング剤、皮膜剤などを必要に応じて加え調製することができる。増量剤としては、乳糖、結晶セルロース、デンプン、植物油などが挙げられ、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどが挙げられ、崩壊剤としては、カルボキシメチルセルロースカルシウム、低置換ヒドロキシプロピルメチルセルロースなどが挙げられ、コーティング剤としては、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂などが挙げられ、皮膜剤としては、ゼラチン皮膜などが挙げられる。 In the case of an oral preparation such as a tablet, capsule, granule, powder, etc., a bulking agent, a lubricant, a binder, a disintegrant, a coating agent, a film agent and the like can be added as necessary. Examples of the bulking agent include lactose, crystalline cellulose, starch, and vegetable oil, examples of the lubricant include magnesium stearate, talc, and the like, examples of the binder include hydroxypropyl cellulose, polyvinyl pyrrolidone, and the like. Examples of the disintegrant include carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, examples of the coating agent include hydroxypropylmethylcellulose, macrogol, and silicone resin, and examples of the filming agent include a gelatin film.
本化合物、タフルプロストおよび他の緑内障若しくは高眼圧症の予防または治療薬の投与量は、剤型、投与すべき患者の症状の軽重、年令、体重、投与経路、医師の判断などに応じて適宜変えることができる。点眼投与の場合を主に例にとり以下に説明する。 The dose of this compound, tafluprost, and other glaucoma or ocular hypertension prevention or treatment drugs should be determined appropriately according to the dosage form, the severity of the patient's symptoms, age, weight, route of administration, doctor's judgment, etc. Can be changed. The case of ophthalmic administration will be mainly described below as an example.
本化合物の投与量は、点眼剤の場合には、通常１日の投与量は０．０５〜５００μｇの範囲で、１日に１回または数回に分けて投与でき、患者の年齢、症状などにより適宜増減できる。点眼剤中の本化合物の濃度に特に制限はないが、０．００００１〜３ｗ／ｖ％の範囲内、好ましくは０．０００１〜１ｗ／ｖ％の範囲内、より好ましくは０．００１〜０．１ｗ／ｖ％の範囲内、さらに好ましくは０．００３〜０．０３ｗ／ｖ％の範囲内の濃度の点眼剤を１日１回又は数回点眼することができる。なお、点眼剤の濃度は、本化合物のフリー体及びその塩のいずれの重さを基準として計算されたものであってもよい（以下、同じ）。また、眼軟膏の場合には、通常１日の投与量は０．０００１〜３０ｍｇの範囲内、好ましくは０．０００３〜１０ｍｇの範囲内、より好ましくは０．００１〜３ｍｇの範囲内、さらに好ましくは０．００３〜１ｍｇの範囲内で１回又は数回に分けて投与することができる。 In the case of eye drops, the dose of this compound is usually in the range of 0.05 to 500 μg per day, and can be administered once or several times a day. Can be increased or decreased as appropriate. Although there is no restriction | limiting in particular in the density | concentration of this compound in eyedrops, It exists in the range of 0.00001-3 w / v%, Preferably it is in the range of 0.0001-1 w / v%, More preferably, it is 0.001-0. An ophthalmic solution having a concentration in the range of 1 w / v%, more preferably in the range of 0.003 to 0.03 w / v% can be instilled once or several times a day. The concentration of the eye drop may be calculated based on the weight of any of the free form of this compound and its salt (hereinafter the same). In the case of eye ointment, the daily dose is usually within the range of 0.0001 to 30 mg, preferably within the range of 0.0003 to 10 mg, more preferably within the range of 0.001 to 3 mg, even more preferably. Can be administered once or divided into several doses within the range of 0.003 to 1 mg.
タフルプロストの投与量は、通常１日の投与量は０．０５〜１０μｇの範囲で、１日に１回または数回に分けて投与でき、患者の年齢、症状などにより適宜増減できる。点眼剤中のタフルプロストの濃度に特に制限はないが、０．０００１〜５ｗ／ｖ％の範囲内、好ましくは０．０００５〜１ｗ／ｖ％の範囲内、より好ましくは０．００１〜０．１ｗ／ｖ％の範囲内、さらに好ましくは０．００１５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of tafluprost is usually in the range of 0.05 to 10 μg per day, and can be administered once or several times a day, and can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. Although there is no restriction | limiting in particular in the density | concentration of tafluprost in eyedrops, It exists in the range of 0.0001-5 w / v%, Preferably it is in the range of 0.0005-1 w / v%, More preferably, it is 0.001-0.1 w. An ophthalmic solution having a concentration within the range of / v%, more preferably 0.0015 w / v% can be instilled once or several times a day.
非選択性交感神経作動薬の投与量は薬物の種類によって異なるが、通常１日の投与量は１〜５０００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ジピベフリンの場合には１日量として２〜３０００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他の非選択性交感神経作動薬についても同様な基準に基づいて、その用量を定めることができる。点眼液中の非選択性交感神経作動薬の濃度に特に制限はないが、ジピベフリンの場合には、０．００１〜３ｗ／ｖ％の範囲内、好ましくは０．０４〜０．１ｗ／ｖ％の範囲内、より好ましくは０．０４ｗ／ｖ％または０．１ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of the non-selective sympathomimetic drug varies depending on the type of drug, but the daily dose is usually in the range of 1 to 5000 μg and can be administered once or several times a day. More specifically, in the case of dipivefrin, 2-3000 μg is usually used as a daily dose, and these doses can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. The doses of other non-selective sympathomimetic drugs can be determined based on the same criteria. The concentration of the non-selective sympathomimetic drug in the ophthalmic solution is not particularly limited, but in the case of dipivefrin, it is within the range of 0.001 to 3 w / v%, preferably 0.04 to 0.1 w / v%. Of ophthalmic solution at a concentration of 0.04 w / v% or 0.1 w / v%, more preferably once or several times a day.
α２受容体作動薬の投与量は薬物の種類によって異なるが、通常１日の投与量は２〜３０００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ブリモニジンの場合には１日量として２〜１０００μｇが、アプラクロニジンの場合には、１日量として２０〜３０００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他のα２受容体作動薬についても同様な基準に基づいて、その用量を定めることができる。点眼液中のα２受容体作動薬の濃度に特に制限はないが、ブリモニジンの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．１〜０．５ｗ／ｖ％の範囲内、より好ましくは０．１ｗ／ｖ％、０．１５ｗ／ｖ％、０．２ｗ／ｖ％または０．５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。またアプラクロニジンの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．５〜１ｗ／ｖ％の範囲内、より好ましくは０．５ｗ／ｖ％または１ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of the α 2 receptor agonist varies depending on the type of drug, but the daily dose is usually in the range of 2 to 3000 μg, and can be administered once or several times a day. More specifically, in the case of brimonidine, a daily dose of 2 to 1000 μg is usually used, and in the case of apraclonidine, a daily dose of 20 to 3000 μg is usually used. Can be increased or decreased as appropriate. The doses of other α 2 receptor agonists can be determined based on the same criteria. The concentration of the α 2 receptor agonist in the ophthalmic solution is not particularly limited, but in the case of brimonidine, it is in the range of 0.01 to 5 w / v%, preferably 0.1 to 0.5 w / v%. An eye drop having a concentration within a range, more preferably 0.1 w / v%, 0.15 w / v%, 0.2 w / v% or 0.5 w / v% may be instilled once or several times a day. it can. In the case of apraclonidine, the concentration is within the range of 0.01 to 5 w / v%, preferably within the range of 0.5 to 1 w / v%, more preferably 0.5 w / v% or 1 w / v%. These eye drops can be instilled once or several times a day.
α１受容体遮断薬の投与量は薬物の種類によって異なるが、通常１日の投与量は１〜５０００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ブナゾシンの場合には１日量として２〜３０００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他のα１受容体遮断薬についても同様な基準に基づいて、その用量を定めることができる。点眼液中のα１受容体遮断薬の濃度に特に制限はないが、ブナゾシンの場合には、０．００１〜０．３ｗ／ｖ％の範囲内、好ましくは０．００３〜０．０３ｗ／ｖ％の範囲内、より好ましくは０．０１ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of α 1 receptor blocker varies depending on the type of drug, but the daily dose is usually in the range of 1 to 5000 μg and can be administered once or several times a day. More specifically, in the case of bunazosin, a daily dose of 2 to 3000 μg is usually used, and these doses can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. The doses of other α 1 receptor blockers can be determined based on the same criteria. The concentration of the α 1 receptor blocker in the ophthalmic solution is not particularly limited, but in the case of bunazosin, it is within the range of 0.001 to 0.3 w / v%, preferably 0.003 to 0.03 w / v. %, More preferably 0.01% w / v% of eye drops can be instilled once or several times a day.
β受容体遮断薬の投与量は薬物の種類によって異なるが、通常１日の投与量は５〜５０００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、チモロールの場合には１日量として５〜１５００μｇが、ベフノロールの場合には、１日量として１０〜２０００μｇが、カルテオロールの場合には１日量として１０〜５０００μｇが、ニプラジロールの場合には１日量として１０〜１２５０μｇが、ベタキソロールの場合には１日量として５０〜１０００μｇが、レボブノロールの場合には１日量として５〜５０００μｇが、メチプラノロールの場合には１日量として５〜５０００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他のβ受容体遮断薬についても同様な基準に基づいて、その用量を定めることができる。点眼剤中のβ受容体遮断薬の濃度に特に制限はないが、チモロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．１〜０．５ｗ／ｖ％の範囲内、より好ましくは０．１ｗ／ｖ％、０．２５ｗ／ｖ％または０．５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。またベフノロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．２５〜１ｗ／ｖ％の範囲内、より好ましくは０．２５ｗ／ｖ％、０．５ｗ／ｖ％または１ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。カルテオロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは１〜２ｗ／ｖ％の範囲内、より好ましくは１ｗ／ｖ％または２ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。ニプラジロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．２５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。ベタキソロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．２５〜０．５ｗ／ｖ％の範囲内、より好ましくは０．２５ｗ／ｖ％または０．５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。レボブノロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．２５〜０．５ｗ／ｖ％の範囲内、より好ましくは０．２５ｗ／ｖ％または０．５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。メチプラノロールの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．３ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of β receptor blocker varies depending on the type of drug, but the daily dose is usually in the range of 5 to 5000 μg and can be administered once or divided into several times a day. More specifically, in the case of timolol, the daily dose is 5 to 1500 μg, in the case of befnolol, the daily dose is 10 to 2000 μg, and in the case of carteolol, the daily dose is 10 to 5000 μg. In the case of nipradilol, the daily dose is 10 to 1250 μg, in the case of betaxolol, the daily dose is 50 to 1000 μg, in the case of levobanolol, the daily dose is 5 to 5000 μg, and in the case of methylpranolol. A daily dose of 5 to 5000 μg is usually used, and these doses can be appropriately increased or decreased depending on the age and symptoms of the patient. The doses of other β receptor blockers can be determined based on the same criteria. The concentration of the β receptor blocker in the eye drop is not particularly limited, but in the case of timolol, it is in the range of 0.01 to 5 w / v%, preferably in the range of 0.1 to 0.5 w / v%. Among them, an ophthalmic solution having a concentration of 0.1 w / v%, 0.25 w / v% or 0.5 w / v% can be instilled once or several times a day. In the case of befnolol, it is in the range of 0.01 to 5 w / v%, preferably in the range of 0.25 to 1 w / v%, more preferably 0.25 w / v%, 0.5 w / v% or Eye drops with a concentration of 1 w / v% can be instilled once or several times a day. In the case of carteolol, an ophthalmic solution having a concentration of 0.01 to 5 w / v%, preferably 1 to 2 w / v%, more preferably 1 w / v% or 2 w / v% is used. Can be instilled once or several times a day. In the case of nipradilol, an ophthalmic solution having a concentration of 0.01 to 5 w / v%, preferably 0.25 w / v%, can be instilled once or several times a day. In the case of betaxolol, it is 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%. Eye drops at a concentration of 1 to 5 times a day. In the case of levobunolol, it is in the range of 0.01-5 w / v%, preferably in the range of 0.25-0.5 w / v%, more preferably 0.25 w / v% or 0.5 w / v%. Eye drops at a concentration of 1 to 5 times a day. In the case of metipranolol, an eye drop having a concentration of 0.01 to 5 w / v%, preferably 0.3 w / v% can be instilled once or several times a day.
副交感神経作動薬の投与量は薬物の種類によって異なるが、通常１日の投与量は５〜３０００００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ピロカルピンの場合には１日量として５〜２０００００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他の副交感神経作動薬についても同様な基準に基づいて、その用量を定めることができる。点眼液中のα１受容体遮断薬の濃度に特に制限はないが、ピロカルピンの場合には、０．０１〜２０ｗ／ｖ％の範囲内、好ましくは０．１〜５ｗ／ｖ％の範囲内、より好ましく０．５ｗ／ｖ％、１ｗ／ｖ％、２ｗ／ｖ％、３ｗ／ｖ％または４ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of the parasympathomimetic drug varies depending on the type of drug, but the daily dose is usually in the range of 5 to 300,000 μg, and can be administered once or several times a day. More specifically, in the case of pilocarpine, a daily dose of 5 to 200,000 μg is usually used, and these doses can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. The doses of other parasympathomimetic drugs can be determined based on similar criteria. The concentration of the α 1 receptor blocker in the ophthalmic solution is not particularly limited, but in the case of pilocarpine, it is within the range of 0.01 to 20 w / v%, preferably within the range of 0.1 to 5 w / v%. More preferably, an ophthalmic solution having a concentration of 0.5 w / v%, 1 w / v%, 2 w / v%, 3 w / v% or 4 w / v% can be instilled once or several times a day.
炭酸脱水酵素阻害剤の投与量は薬物の種類によって異なるが、通常１日の投与量は１０〜１００００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ドルゾラミドの場合には１日量として１０〜１００００μｇが、ブリンゾラミドの場合には、１日量として２０〜５０００μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他の炭酸脱水酵素阻害剤についても同様な基準に基づいて、その用量を定めることができる。点眼剤中の炭酸脱水酵素阻害剤の濃度に特に制限はないが、ドルゾラミドの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．５〜２ｗ／ｖ％の範囲内、より好ましくは０．５ｗ／ｖ％、１ｗ／ｖ％または２ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。またブリンゾラミドの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは０．１〜２ｗ／ｖ％の範囲内、よりい好ましくは１ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。また、アセタゾラミドの場合には、０．０１〜５ｗ／ｖ％の範囲内、好ましくは１〜５ｗ／ｖ％の範囲内の濃度の点眼剤を用いることができる。なお、アセタゾラミドを経口投与する場合には、１日量として２５０〜１０００ｍｇを使用することができる。 The dose of the carbonic anhydrase inhibitor varies depending on the type of drug, but the daily dose is usually in the range of 10 to 10,000 μg, and can be administered once or divided into several times a day. More specifically, in the case of dorzolamide, a daily dose of 10 to 10000 μg is usually used, and in the case of brinzolamide, a daily dose of 20 to 5000 μg is usually used. Increase or decrease as appropriate. In addition, doses of other carbonic anhydrase inhibitors can be determined based on similar criteria. The concentration of the carbonic anhydrase inhibitor in the eye drop is not particularly limited, but in the case of dorzolamide, it is in the range of 0.01 to 5 w / v%, preferably in the range of 0.5 to 2 w / v%. More preferably, an ophthalmic solution having a concentration of 0.5 w / v%, 1 w / v% or 2 w / v% can be instilled once or several times a day. In the case of brinzolamide, an eye drop having a concentration of 0.01 to 5 w / v%, preferably 0.1 to 2 w / v%, more preferably 1 w / v% is applied daily. Can be instilled several times or several times. In the case of acetazolamide, an eye drop having a concentration in the range of 0.01 to 5 w / v%, preferably in the range of 1 to 5 w / v% can be used. In addition, when acetazolamide is orally administered, 250 to 1000 mg can be used as a daily dose.
プロスタグランジン類の投与量は薬物の種類によって異なるが、通常１日の投与量は０．１〜１０００μｇの範囲で、１日に１回または数回に分けて投与できる。より具体的に言えば、ラタノプロストの場合には１日量として１〜５μｇが、イソプロピルウノプロストンの場合には１日量として３０〜３００μｇが、ビマトプロストの場合には１日量として２〜３０μｇが、トラボプロストの場合には１日量として０．５〜５μｇが通常使用され、それらの用量は患者の年齢、症状などにより適宜増減できる。また、他のプロスタグランジン類についても同様な基準に基づいて、その用量を定めることができる。点眼剤中のプロスタグランジン類の濃度に特に制限はないが、ラタノプロストの場合には、０．０００１〜５ｗ／ｖ％の範囲内、好ましくは０．０００５〜１ｗ／ｖ％の範囲内、より好ましくは０．００１〜０．１ｗ／ｖ％の範囲内、さらに好ましくは０．００５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。イソプロピルウノプロストンの場合には、０．００１〜５ｗ／ｖ％の範囲内、好ましくは０．０１〜１ｗ／ｖ％の範囲内、より好ましくは０．１２〜０．１５ｗ／ｖ％の範囲内、さらに好ましくは０．１２ｗ／ｖ％または０．１５ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。ビマトプロストの場合には、０．０００１〜５ｗ／ｖ％の範囲内、好ましくは０．００１〜１ｗ／ｖ％の範囲内、より好ましくは０．０１〜０．０３ｗ／ｖ％の範囲内、さらに好ましくは０．０１ｗ／ｖ％または０．０３ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。トラボプロストの場合には、０．０００１〜５ｗ／ｖ％の範囲内、好ましくは０．００１〜１ｗ／ｖ％の範囲内、より好ましくは０．００４ｗ／ｖ％の濃度の点眼剤を１日１回または数回点眼することができる。 The dose of prostaglandins varies depending on the type of drug, but the daily dose is usually in the range of 0.1 to 1000 μg and can be administered once or divided into several times a day. More specifically, in the case of latanoprost, the daily dose is 1 to 5 μg, in the case of isopropyl unoprostone, the daily dose is 30 to 300 μg, and in the case of bimatoprost, the daily dose is 2 to 30 μg. However, in the case of travoprost, a daily dose of 0.5 to 5 μg is usually used, and these doses can be appropriately increased or decreased depending on the age and symptoms of the patient. The doses of other prostaglandins can be determined based on the same criteria. The concentration of prostaglandins in the eye drop is not particularly limited, but in the case of latanoprost, it is within the range of 0.0001 to 5 w / v%, preferably within the range of 0.0005 to 1 w / v%, more An eye drop having a concentration of preferably 0.001 to 0.1 w / v%, more preferably 0.005 w / v% can be instilled once or several times a day. In the case of isopropyl unoprostone, it is in the range of 0.001 to 5 w / v%, preferably in the range of 0.01 to 1 w / v%, more preferably in the range of 0.12 to 0.15 w / v%. Of these, an ophthalmic solution having a concentration of 0.12 w / v% or 0.15 w / v% can be instilled once or several times a day. In the case of bimatoprost, it is within the range of 0.0001-5 w / v%, preferably within the range of 0.001-1 w / v%, more preferably within the range of 0.01-0.03 w / v%, Preferably, an ophthalmic solution having a concentration of 0.01 w / v% or 0.03 w / v% can be applied once or several times a day. In the case of travoprost, an ophthalmic solution having a concentration of 0.0001 to 5 w / v%, preferably 0.001 to 1 w / v%, more preferably 0.004 w / v% Can be instilled once or several times.
Ｒｈｏキナーゼ阻害剤の投与量は薬物の種類によって異なるが、通常１日の投与量は０．０２５〜１００００μｇの範囲で、１日に１回または数回に分けて投与することができ、それらの用量は患者の年齢、症状等により適宜増減できる。点眼液中のＲｈｏキナーゼ阻害剤の濃度に特に制限はないが、０．０００１〜５ｗ／ｖ％、好ましくは０．００１〜１ｗ／ｖ％の範囲内の濃度の点眼剤を１日１回または数回点眼することができる。 The dosage of the Rho kinase inhibitor varies depending on the type of drug, but the daily dosage is usually in the range of 0.025 to 10,000 μg, and can be administered once or divided into several times a day. The dose can be appropriately increased or decreased depending on the age and symptoms of the patient. The concentration of the Rho kinase inhibitor in the ophthalmic solution is not particularly limited, but an ophthalmic solution having a concentration in the range of 0.0001 to 5 w / v%, preferably 0.001 to 1 w / v% is once a day or Can be instilled several times.
これらの投与量は本化合物とタフルプロストと他の緑内障若しくは高眼圧症の予防または治療薬を併用投与するときに適用されるが、本化合物とタフルプロストと他の緑内障若しくは高眼圧症の予防または治療薬の任意の組み合わせの合剤を投与する場合には、１日の投与量が上記の各成分の投与量の範囲内になるように、配合割合を適宜選択した製剤を調製して、その配合製剤を１日１回または数回に分けて投与できる。 These doses are applied when this compound and tafluprost are used in combination with other glaucoma or ocular hypertension preventive or therapeutic agents, but this compound and tafluprost and other glaucoma or ocular hypertension preventive or therapeutic agents are applied. In the case of administering a combination of any of the above preparations, a preparation having an appropriately selected blending ratio is prepared so that the daily dose falls within the range of the dose of each of the above components. Can be administered once or several times a day.
以下に製剤例および薬理試験を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Formulation examples and pharmacological tests are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.
［製剤例］
本発明における本化合物とタフルプロストとを配合した点眼剤の具体的な製剤例を以下に示す。
[Formulation example]
Specific formulation examples of eye drops containing the present compound and tafluprost in the present invention are shown below.
［製剤例１］
点眼剤（１００ｍＬ中）
本化合物 ０．０１ｇ
タフルプロスト ０．００１５ｇ
リン酸二水素ナトリウム ０．１５ｇ
グリセリン 適量
ポリオキシル３５ヒマシ油 １．７ｇ
エデト酸ナトリウム ０．０５ｇ
塩化ベンザルコニウム ０．００５ｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
[Formulation Example 1]
Eye drops (in 100 mL)
0.01 g of this compound
Tafluprost 0.0015g
Sodium dihydrogen phosphate 0.15g
Glycerin appropriate amount Polyoxyl 35 castor oil 1.7g
Sodium edetate 0.05g
Benzalkonium chloride 0.005g
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount
［製剤例２］
眼軟膏（１００ｇ中）
本化合物 ０．０１ｇ
タフルプロスト ０．００１５ｇ
流動パラフィン １０．０ｇ
白色ワセリン 適量
[Formulation Example 2]
Eye ointment (in 100g)
0.01 g of this compound
Tafluprost 0.0015g
Liquid paraffin 10.0g
White petrolatum
上記処方において、本化合物の量を０．００１ｇ、０．００３ｇ、０．０３ｇ、０．１ｇなどに変えて、また、タフルプロストの量や添加剤の種類および量を変えて、所望の組み合わせおよび所望の濃度の点眼剤および眼軟膏を調製することができる。 In the above formulation, the amount of this compound is changed to 0.001 g, 0.003 g, 0.03 g, 0.1 g, etc., and the amount of tafluprost and the type and amount of additives are changed to achieve the desired combination and desired Eye drops and eye ointments at different concentrations can be prepared.
［薬理試験］
［実施例１］
本化合物とタフルプロストとの組み合わせの有用性を調べるため、実験動物（正常眼圧サル）に本化合物とタフルプロストを併用投与したときの眼圧下降効果を検討した。
[Pharmacological test]
[Example 1]
In order to investigate the usefulness of the combination of this compound and tafluprost, the intraocular pressure lowering effect when this compound and tafluprost were administered in combination to experimental animals (normal intraocular pressure monkeys) was examined.
（被験化合物溶液の調製）
（１）基剤の調製
ポリオキシル３５ヒマシ油１．７ ｇに０．５％ エデト酸ナトリウム／１０％グリセリン溶液１０ ｍＬ、１％塩化ベンザルコニウム溶液１ｍＬ、精製水３０ｍＬ、２％ホウ酸／０．２％ソルビン酸溶液５０ｍＬを加え溶解した。溶解を確認後、これに水酸化ナトリウム溶液もしくは希塩酸を適量加え、製剤のｐＨを６．５前後とした後、精製水を適量加えて全量を１００ｍＬとした。
(Preparation of test compound solution)
(1) Preparation of base 0.5 g of sodium edetate / 10% glycerin solution 10 mL, 1 mL of 1% benzalkonium chloride solution, 30 mL of purified water, 2% boric acid / 0 to 1.7 g of polyoxyl 35 castor oil .50 mL of 2% sorbic acid solution was added and dissolved. After confirming dissolution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto to adjust the pH of the preparation to around 6.5, and then an appropriate amount of purified water was added to make up a total volume of 100 mL.
（２）本化合物溶液の調製
ポリオキシル３５ヒマシ油０．８ｇに本化合物 ０．０００６ｇを加え、０．５％ エデト酸ナトリウム／１０％グリセリン溶液１０ ｍＬ、１％塩化ベンザルコニウム溶液１ｍＬ、精製水３０ｍＬ、２％ホウ酸／０．２％ソルビン酸溶液５０ｍＬを加え溶解した。溶解を確認後、これに水酸化ナトリウム溶液もしくは希塩酸を適量加え、製剤のｐＨを６．５前後とした後、精製水を適量加えて全量を１００ｍＬとした。
(2) Preparation of this compound solution 0.0006 g of this compound is added to 0.8 g of polyoxyl 35 castor oil, 10 mL of 0.5% sodium edetate / 10% glycerol solution, 1 mL of 1% benzalkonium chloride solution, purified water 30 mL of 2 mL of 2% boric acid / 0.2% sorbic acid solution was added and dissolved. After confirming dissolution, an appropriate amount of sodium hydroxide solution or dilute hydrochloric acid was added thereto to adjust the pH of the preparation to around 6.5, and then an appropriate amount of purified water was added to make up a total volume of 100 mL.
（３）生理食塩液の調製
市販の生理食塩液（商品名：大塚生食注、株式会社大塚製薬工場より入手）をそのまま使用した。
(3) Preparation of physiological saline Commercially available physiological saline (trade name: Otsuka raw food injection, obtained from Otsuka Pharmaceutical Factory Co., Ltd.) was used as it was.
（４）タフルプロスト溶液の調製
市販のタフルプロスト点眼液をそのまま使用した。
(4) Preparation of tafluprost solution Commercial tafluprost ophthalmic solution was used as it was.
（試験方法）
本化合物とタフルプロストとを併用投与した時の眼圧下降効果を検討した。比較対照として、本化合物を単独投与またはタフルプロストを単独投与した時の眼圧下降効果についても検討した。コントロールには基剤および生理食塩水を投与した。
(Test method)
The effect of lowering intraocular pressure when this compound and tafluprost were administered in combination was examined. As a comparative control, the intraocular pressure lowering effect when this compound was administered alone or tafluprost was administered alone was also examined. For the control, a base and physiological saline were administered.
（試験に使用した薬剤および動物）
本化合物溶液：０．０００６ｗ／ｖ％ 本化合物溶液（点眼量：２０μＬ）
タフルプロスト溶液：タフルプロスト点眼液（商品名：Ｔａｆｌｏｔａｎ（登録商標） Ｏｐｈｔｈａｌｍｉｃ Ｓｏｌｕｔｉｏｎ ０．００１５％、点眼量：２０μＬ）
実験動物：カニクイザル（性別：雄性、一群６頭）
(Drugs and animals used in the study)
The present compound solution: 0.0006 w / v% The present compound solution (eye drop amount: 20 μL)
Tafluprost solution: Tafluprost ophthalmic solution (trade name: Taflotan (registered trademark) Ophthalmic Solution 0.0015%, eye drop amount: 20 μL)
Experimental animal: cynomolgus monkey (sex: male, 6 animals per group)
（投与方法および測定方法）
〔１〕本化合物とタフルプロストとの併用投与
（１）０．４％塩酸オキシブプロカイン点眼液（商品名：ベノキシール（登録商標）点眼液０．４％）を実験動物の両眼に一滴点眼し局所麻酔をした。
(Administration method and measurement method)
[1] Combined administration of this compound and tafluprost (1) One drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution (trade name: Benokiseal (registered trademark) ophthalmic solution 0.4%) Local anesthesia was performed.
（２）被験化合物溶液投与直前に眼圧を測定し、初期眼圧とした。 (2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
（３）本化合物溶液を実験動物の片眼に点眼した（対側眼は無処置）。少し時間をおいてタフルプロスト溶液を同一眼に点眼した。 (3) This compound solution was instilled into one eye of an experimental animal (the contralateral eye was untreated). After a while, the tafluprost solution was instilled into the same eye.
（４）本化合物溶液点眼後２時間、４時間、６時間および８時間に０．４％塩酸オキシブプロカイン点眼液を一滴ずつ眼圧測定眼に点眼し局所麻酔後、眼圧を測定した。また、眼圧は各３回測定し、その平均値を結果に示す。 (4) At 2 hours, 4 hours, 6 hours and 8 hours after the instillation of this compound solution, 0.4% oxybuprocaine hydrochloride ophthalmic solution was dropped into the intraocular pressure measurement eye drop, and the intraocular pressure was measured after local anesthesia. The intraocular pressure was measured three times, and the average value is shown in the result.
〔２〕本化合物の単独投与
タフルプロスト溶液を生理食塩水に代え、他は上記併用投与試験と同じ方法で試験をした。
[2] Single administration of this compound The tafluprost solution was replaced with physiological saline, and the others were tested in the same manner as the above combined administration test.
〔３〕タフルプロストの単独投与
本化合物溶液を基剤に代え、他は上記併用投与試験と同じ方法で試験をした。
[3] Single administration of tafluprost The compound solution was replaced with a base, and the others were tested in the same manner as the above combined administration test.
〔４〕コントロール
本化合物溶液を基剤に、タフルプロスト溶液を生理食塩水に代え、他は上記併用投与試験と同じ方法で試験をした。
[4] Control The present compound solution was used as a base, the tafluprost solution was replaced with physiological saline, and the others were tested in the same manner as the above combination administration test.
（結果および考察）
各投与群の点眼後６時間の眼圧下降幅（対コントロール群平均値）を表１に示す。眼圧下降幅（対コントロール群平均値）は、コントロール群の初期眼圧値からの眼圧値変動幅（ΔＩＯＰ）の平均値と各個体のΔＩＯＰの差を各群６頭の平均値で示す。
(Results and Discussion)
Table 1 shows the decrease in intraocular pressure (vs. control group average value) 6 hours after instillation in each administration group. The decrease in intraocular pressure (vs. control group average value) represents the difference between the average value of intraocular pressure fluctuation (ΔIOP) from the initial intraocular pressure value of the control group and ΔIOP of each individual as the average value of 6 animals in each group.
表１から明らかなように、本化合物とタフルプロストの併用投与群は、薬剤単独投与群、すなわち、本化合物投与群およびタフルプロスト投与群よりも大きかった。 As is clear from Table 1, the combination administration group of the present compound and tafluprost was larger than the drug alone administration group, that is, the present compound administration group and the tafluprost administration group.
以上から、本化合物とタフルプロストを組み合わせることにより、強力な眼圧下降効果が得られることがわかった。 From the above, it was found that a powerful intraocular pressure lowering effect can be obtained by combining this compound with tafluprost.
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