WO2000009162A1 - Medicaments preventifs/curatifs pour le glaucome - Google Patents
Medicaments preventifs/curatifs pour le glaucome Download PDFInfo
- Publication number
- WO2000009162A1 WO2000009162A1 PCT/JP1999/004403 JP9904403W WO0009162A1 WO 2000009162 A1 WO2000009162 A1 WO 2000009162A1 JP 9904403 W JP9904403 W JP 9904403W WO 0009162 A1 WO0009162 A1 WO 0009162A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- hydrogen
- aralkyl
- formula
- substituent
- Prior art date
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- 208000010412 Glaucoma Diseases 0.000 title claims abstract description 94
- 230000003449 preventive effect Effects 0.000 title claims abstract description 17
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- 108010041788 rho-Associated Kinases Proteins 0.000 claims abstract description 21
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
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- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 5
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- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- ZDGQAVFYXBCIKB-UHFFFAOYSA-N tetrazolo[1,5-a]pyrimidine Chemical compound C1=CC=NC2=NN=NN21 ZDGQAVFYXBCIKB-UHFFFAOYSA-N 0.000 description 1
- 150000008634 thiazolopyrimidines Chemical class 0.000 description 1
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to an agent for preventing and treating glaucoma. More specifically, the present invention relates to a preventive / therapeutic agent for glaucoma, comprising a compound having Rho kinase inhibitory activity as an active ingredient.
- Glaucoma is a disease in which the eye pressure becomes abnormally high due to abnormally high internal pressure of the eyeballs, which gradually weakens vision and eventually leads to blindness.
- the aqueous humor which c which maintains a constant intraocular pressure (1 0 ⁇ 2 0 mm H g) the circulation of blood and lymphocytes, elasticity of the eyeball wall, dominated It is regulated by the action of the nerves, but if any of these are modulated, intraocular pressure will increase, leading to glaucoma.
- Various drugs are used to prevent or treat glaucoma, to prevent or reduce elevated intraocular pressure.
- sympathomimetics such as epinephrine and dipibefrin are known, but when used for narrow-angle glaucoma due to mydriasis, corner occlusion becomes severe.
- Acute intraocular pressure may occur, as well as blood pressure and pigmentation.
- parasympathomimetics such as pilocarpine have strong side effects such as iris cyst, iris adhesion, cataract, and retinal detachment due to long-term use, as well as blackness of the visual field due to miosis and ocular hyperemia.
- thi-adrenergic blockers such as timolol and pindolol have the advantage of lowering intraocular pressure by suppressing aqueous humor production and having no effect on the pupil, they are widely used.
- side effects such as dryness, allergic blepharitis and superficial keratitis
- i3-adrenergic blockers have been reported as systemic side effects such as bradycardia, heart failure, and asthma attack. It cannot be used for patients who have.
- ⁇ -adrenergic blockers have the effect of promoting aqueous humor outflow, suggesting that bunazosin hydrochloride and the like may be new therapeutic agents for glaucoma (Ikuro Higashi, Japan Bulletin of Ophthalmology, 42, 710-714, 1991).
- bunazosin hydrochloride and the like may be new therapeutic agents for glaucoma (Ikuro Higashi, Japan Bulletin of Ophthalmology, 42, 710-714, 1991).
- ⁇ 1-adrenergic blockers cannot prevent conjunctival hyperemia and miosis due to their vasodilatory effects.
- Rho quinase inhibitory activity has a blood pressure lowering effect in various hypertension model animals (Masayoshi Uehata, et al., Nature 389, 990-994, 1997). . Rho kinase has been confirmed to be present in corneal epithelial cells (Nirmala SundarRaj. Et al., IOVS, 39 (7) 1266-1272, 1998). However, it is not known whether Rh kinase is present in other ocular tissues.
- WO 98Z06433 The pharmaceutical use of a compound having a Rh kinase inhibitory activity is disclosed in WO 98Z06433, and is described as useful in ophthalmology for retinopathy.
- WO98 / 064333 does not mention that it is useful for glaucoma, nor does it mention that it is useful for glaucoma.
- a compound represented by the following general formula (I) As a compound having Rh kinase inhibitory activity, a compound represented by the following general formula (I) has been reported (WO98Z064333).
- Compounds represented by the general formula (I) include potent and persistent drugs for treating hypertension, angina pectoris, renal and peripheral circulatory disorders, cerebral vasospasm, etc. It is already known to be useful as a prophylactic / therapeutic agent for cardiovascular diseases such as peripheral arteries and as a therapeutic agent for asthma (Japanese Patent Application Laid-Open Nos. 62-89679 and 3-221 No. 8356, JP-A-4-273781, JP-A-5-194041, JP-A-6-41080 and WO95 / 28387.
- An object of the present invention is to solve the above problems, and an object of the present invention is to provide a novel glaucoma prevention / treatment agent having excellent glaucoma prevention / treatment effects.
- a compound having an Rho kinase inhibitory activity has an ocular hypotensive effect, an optic nerve head blood flow improving effect, and an aqueous humor outflow promoting effect.
- Complete the present invention by finding it useful for prevention or treatment I came to.
- the present invention is as follows.
- Rh kinase inhibition activity is represented by the following general formula (I)
- R represents hydrogen, alkyl or a cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring, or
- R 6 is hydrogen, alkyl or a formula: NR 8 R 9 (where R 8 and R 9 are the same or different and represent hydrogen, alkyl, aralkyl or phenyl); and R 7 is hydrogen.
- Alkyl, aralkyl, phenyl, nitro or cyano, or R 6 and R 7 are bonded to each other to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. And a group forming a heterocyclic ring which may be substituted.
- R 1 represents hydrogen, alkyl or cycloalkyl optionally having a substituent on the ring, cycloalkyl / reazolequinole, feninole, or aralkyl.
- R and R 1 are bonded together with an adjacent nitrogen atom to form a group forming a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent.
- R 2 represents hydrogen or alkyl.
- R 3 and R 4 may be the same or different, and include hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acryl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, Indicate rubamoyl, alkyl rubamoyl or azide.
- A is the formula
- R 1 C and R 11 are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl.
- R 10 and R ] 1 represent a group which forms a cycloalkyl by bonding. 1, m, and n each represent 0 or an integer of 1 to 3. ).
- L represents hydrogen, alkyl, aminoalkyl, mono'dialkylaminoalkyl, tetrahydrofurfuryl, dirubamoylalkyl, phthalimidalkyl, amidino, or O
- B is hydrogen, alkyl, alkoxy, aralkyl, oxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, ⁇ -aminobenzyl, furyl, pyridyl, phenyl, phenylamino) , Styryl or imidazopyridyl.
- Q 1 is hydrogen, halogen, hydroxyl, aralkyloxy or
- Q 2 is hydrogen, halogen, hydroxyl group:
- Q 3 represents hydrogen, halogen, hydroxyl, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-1,2,3,4,5-tetrahydropyridazine-161-yl.
- ⁇ represents a single bond, alkylene or alkenylene.
- a broken line indicates a single bond or a double bond.
- R 5 represents hydrogen, hydroxyl, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy.
- R b is hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkyla
- R c represents a nitrogen-containing heterocyclic ring which may have a substituent.
- the preventive or therapeutic agent for glaucoma which is an amide compound represented by the formula: or an isomer thereof and Z or a pharmaceutically acceptable acid addition salt thereof.
- Rh kinase inhibitory activity is represented by the following general formula (1 ′)
- R ′ represents hydrogen, alkyl or cycloalkyl, cycloalkylalkynole, phenyl or aralkyl which may have a substituent on a ring.
- R 1 represents hydrogen, alkyl, or cycloalkyl optionally having a substituent on the ring, cycloanolealkylalkynole, phenyl or aralkynole.
- R 'and R 1 are bonded together with an adjacent nitrogen atom to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent. Is shown.
- R 2 represents hydrogen or alkyl.
- R 3 and R 4 may be the same or different, and include hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acryl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, Indicate rubamoyl, alkyl rubamoyl or azide.
- R 1 Q and R 11 are the same or different and represent hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl.
- R 10 and R 11 are bonded to form a cycloalkyl
- m and n each represent 0 or an integer of 1 to 3.
- Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono'dialkylaminoalkyl.
- R c represents a nitrogen-containing heterocyclic ring which may have a substituent.
- Rh kinase inhibitory activity is (+)-trans-4- (1-aminocetyl) -111 (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1 H-Pyro mouth [2,3-b] Pyridine-1-yl) 1-4- (1-Aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-Pyridyl) -1- 4- (1-Aminoethyl) benzamide, (R)-(+)-N- (1H-Pyro mouth [2,3-b] pyridine_4 ⁇ ) 1-41- (1-aminoethyl) )
- the glaucoma preventive and therapeutic agent according to the above (1) which is benzamide and / or a pharmaceutically acceptable acid addition salt thereof.
- the preventive or therapeutic agent for glaucoma according to the above (5) which is in the form of eye drops.
- a pharmaceutical composition for preventing and treating glaucoma comprising a compound having Rh kinase inhibition activity and a pharmaceutically acceptable carrier.
- composition for prevention and treatment of glaucoma which is an amide compound represented by the formula: or an isomer thereof and Z or a pharmaceutically acceptable acid addition salt thereof.
- the pharmaceutical composition for preventing or treating glaucoma which is an amide compound represented by the formula: or an isomer thereof and Z or a pharmaceutically acceptable acid addition salt thereof.
- Rh kinase inhibitory activity examples include (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H-Pyro mouth [2,3-b] Pyridine-1-4 ⁇ f) 1-4- (1-Aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl ) —4— (1-Aminoethyl) benzamide, (R) — (+) — N— (1 H—pyromouth
- a method for preventing and treating glaucoma which comprises administering to a patient an effective amount of a compound having Rh kinase inhibition activity.
- An amide compound represented by the following formula, its isomer and / or its pharmaceutically acceptable The method for preventing and treating glaucoma according to the above (13), which is a W 00/1 acid addition salt.
- the compound having Rh kinase inhibition activity is (+)-trans-41- (1-aminoethyl) -1-1- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1H-Pyro mouth [2,3-b] pyridine-141-f) 4-141 (1-aminoethyl) cyclohexanecarboxamide, (R) — (+) — N— (4-— Pyridyl) -4--(1-aminoethyl) benzamide, (R)-(+)-N- (1H-pyro mouth [2,3-b] pyridine-14-yl) (Aminoethyl)
- the method for preventing and treating glaucoma according to the above (13), which is benzamide or a pharmaceutically acceptable acid addition salt thereof.
- the compound having Rh kinase inhibition activity is (+)-trans-4- (1-aminoethyl) -11- (4-pyridylcarbamoyl) cyclohexane, (+)-trans-N- (1 H-Pyro mouth [2,3-b] pyridine-4-yl) 1-4- (1-aminoethyl) cyclohexanecarboxamide, (R)-(+)-N- (4-pyridyl) — 4- (1-aminoethyl) benzamide, (R)-(+)-N- (1H-pyro mouth [2,3-b] pyridine-14-yl) 1-4- (1-aminoethyl)
- Prevention of glaucoma The use according to (19) above, wherein the therapeutic agent is for topical administration to the eye.
- FIG. 1 is a graph showing the effect of the eye drops of Example 1 on normal intraocular pressure.
- the vertical axis indicates intraocular pressure, and the horizontal axis indicates time after instillation. Indicates an eye instilled with the eye drop of Example 1, and ⁇ indicates a control eye.
- N 6, * p * 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001)
- FIG. 2 is a graph showing the effect of the ophthalmic preparation of Example 1 on optic nerve head blood flow dynamics.
- the vertical axis shows the relative optic disc blood flow, and the horizontal axis shows the time after instillation.
- ⁇ Indicates an eye instilled with the ophthalmic solution of Example 1, and ⁇ indicates a control eye.
- N 6, * p ⁇ 0.05, ** p ⁇ 0.01,
- Figure 3 is a Draf showing the effect of Compound A on carbachol contraction in ciliary muscle.
- the vertical axis shows the contraction rate of ciliary muscle, and the horizontal axis shows the concentration of carbachol.
- ⁇ is a control
- Qin 1 X 1 0- 5 iM of Compound A, garden is a Compound A 3 X 1 0- 6 M
- ⁇ is
- Compound A 1 X 1 0- 6 M shows the case of administration.
- FIG 4 shows Example 2 [0.1% compound A] (a) and Example 5 [0.1% compound C].
- FIG. 4 is a graph showing the effect of the eye drops of (b) on normal intraocular pressure.
- the vertical axis indicates intraocular pressure, and the horizontal axis indicates time after instillation. Hata indicates an eye instilled with eye drops, and ⁇ indicates a control eye.
- (N 6,
- FIG. 5 is a graph showing the effects of Example 3 [0.03% compound A] (a) and Example 4 [0.03% compound B] (b) on normal intraocular pressure.
- the vertical axis indicates intraocular pressure, and the horizontal axis indicates time after instillation.
- Ginseng is an eye instilled with eye drops, and ⁇ is a control eye.
- N 6,
- FIG. 6 is a graph showing the effect of eye drops of Example 6 [0.03% compound C] (c) and Example 7 [0.03% compound D] (d) on normal intraocular pressure. .
- the vertical axis indicates intraocular pressure, and the horizontal axis indicates time after instillation.
- FIG. 7 shows Example 2 [0.1% Compound A] (a) and Example 5 [0.1% Compound C]
- FIG. 4 is a graph showing the effect of the eye drop of (b) on optic nerve head blood flow dynamics.
- the vertical axis indicates the relative optic disc blood flow, and the horizontal axis indicates the time after instillation.
- ⁇ Indicates an eye instilled with eye drops, and ⁇ indicates a control eye.
- glaucoma for example, primary open-angle glaucoma, normotensive glaucoma, excess aqueous glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma
- Specific examples include steroid glaucoma, capsular glaucoma of the lens, pigmented glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.
- Rho kinase means a serine / threonine kinase that is activated with the activation of Rho.
- ROKa ROCKII: Leung, T. et al., J. Biol. Chem., 270, 29051-29054, 1995
- ⁇ 160 ROCK ROCK
- ROCK-I Ishizaki, T. et al., The EMB0 J., 15 (8), 1885-1893, 1996)
- other proteins with serine / threonine kinase activity ROKa (ROCKII: Leung, T. et al., J. Biol. Chem., 270, 29051-29054, 1995)
- ROCK-I ROCK-I: Ishizaki, T. et al., The EMB0 J., 15 (8), 1885-1893, 1996)
- other proteins with serine / threonine kinase activity ROKa (ROCKII: Leung, T. et al., J. Biol. Chem., 270, 29051-29054, 1995)
- ROCK-I ROCK
- the compound having a Rho kinase inhibitory activity used as an active ingredient in the present invention may be any compound having a Rho kinase inhibitory activity.
- the compound represented by the general formula (I) may be mentioned.
- the compound represented by the general formula (1 ′) is more preferably used.
- one kind of compound having a Rh kinase inhibitory activity may be contained alone, or if necessary, several kinds thereof may be used in combination.
- R, R ', the alkyl group in R 1 an alkyl having 1 to 1 0 straight-chain or branched carbon atoms, methyl, Echiru, propyl, isopropyl, butyl, Isopuchi Le, secondary butyl And tertiary butyl, pentyl, hexyl, heptyl, octyl, nol, decyl and the like, and alkyl having 1 to 4 carbon atoms is preferable.
- R, R ' denotes cyclopropyl Cycloalkyl in R 1, cyclobutyl, consequent opening pentyl, cyclohexyl, carbon number 3-7 amino cycloalkyl Le of heptyl and the like cyclohexylene.
- R, R ', and cycloalkylalkyl in R 1 is cycloalkyl portion is the cycloalkyl of 3-7 carbons, alkyl portion is of one to six carbon atoms straight-chain or branched alkyl (Methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), which is cycloalkylalkyl, cyclopropylmethyl, cyclobutynolemethinole, cyclopentylmethyl, cyclohexynolemethinole, cycloheptizolemethyl, cyclopropyl Chinole, cyclo, ethylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropizole, cyclohexylpropyl, cycloheptylpropy
- the aralkyl in R, R 'and R 1 has 1 to 4 carbon atoms as the alkyl portion, and is selected from the group consisting of benzyl / le, 1-phenyl / 2-ethyl, 2-phenyl-2-ethyl, It represents phenyl / realkyl such as 3-phenylpropyl and 4-phenylbutyl.
- R, R ', and R] may have a substituent on the ring, such as cycloalkyl, cycloalkylalkyl, phenyl, and aralkyl, which may be halogen (chlorine, bromine, fluorine, iodine), alkyl (R , R, and R 1 ), alkoxy (linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 2-butoxy, showing a Kishiruokishi and tertiary butoxy, Penchiruokishi to,.), Ararukiru (R, R ', Ararukiru synonymous) in R 1, haloalkyl (R, R',.
- halogens such as fluoromethyl, difluoromethinole, triflightolemethinole, 2,2,2 Roechiru, 2 shows a 2, 3, 3, 3-pentamethylene full O b propyl.), Nitro, Amino, Shiano, azides, and the like.
- a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring together with an adjacent nitrogen atom in which R and R 1 or R ′ and R 1 are bonded to each other;
- a 5- to 6-membered ring or a bond thereof is preferable.
- alkyl, Ararukiru, Haroaru Kill R, R ' the same meaning as in the R 1.
- the alkyl in R 2 has the same meaning as the alkyl in R, R ′ and R 1 .
- R 3 , R 4 halogen, alkyl, alkoxy, aralkyl is R, R ′, R 1 Is the same as that shown in.
- the acyl in R 3 and R 4 is an alkanol having 2 to 6 carbon atoms (such as acetyl, propionyl, butyryl, valeryl, and pivaloyl), a benzoyl, or a alkanol portion in which the alkanol portion has 2 to 4 carbon atoms.
- alkanol having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, and pivaloyl
- a benzoyl or a alkanol portion in which the alkanol portion has 2 to 4 carbon atoms.
- Lacetyl, phenylpropionyl, phenylbutyryl, etc. etc.
- the alkylamino in R 3 and R 4 is an alkylamino having a straight-chain or branched alkyl having 1 to 6 carbon atoms in the alkyl portion, such as methylamino, ethylamino, propylamino, isopropylamino, Shows butylamino, isobutylamino, secondary butylamino, tertiary butylamino, pentylamino, hexylamino and the like.
- the acylamino in R 3 and R 4 is an acylamino having 2 to 6 carbon atoms such as alkanol, benzyl, or alkenyl having an alkanol portion of 2 to 4 carbon atoms, such as acetylamino or propionylamino.
- acylamino having 2 to 6 carbon atoms such as alkanol, benzyl, or alkenyl having an alkanol portion of 2 to 4 carbon atoms, such as acetylamino or propionylamino.
- the alkylthio represented by R 3 and R 4 is an alkylthio having a linear or branched alkyl having 1 to 6 carbon atoms in the alkyl portion, and is methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl Shows thio, secondary butylthio, tertiary butylthio, pentylthio, hexylthio and the like.
- the aralkyloxy in R 3 and R 4 has an aralkyl having an alkyl group having 1 to 4 carbon atoms in the alkyl portion thereof, and includes benzyloxy, 1-phenylethyl / reoxy, and 2-phenylethyloxy. Xy, 3-phenylpropynoleoxy, 4-phenylbutyloxy and the like.
- the aralkylthio in R 3 and R 4 has an aralkyl having an alkyl group having 1 to 4 carbon atoms in the alkyl portion thereof, and includes benzylthio, 1-phenylethylthio, 2-phenylethylthio, and 3-alkylthio. It represents fuynylpropylthio, 4-funylbutylthio and the like.
- the alkoxycarbel in R 3 R 4 has a straight-chain or branched-chain alkoxy having 16 carbon atoms in the alkoxy moiety, and is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl. Butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
- the alkyl rubamoyl in R 3 R 4 is a carbamoyl mono- or di-substituted by an alkyl having 14 carbon atoms, and is methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, propylcarbamoyl, Dipropyl carbamoyl, butylcarbamoyl, dibutylcarbamoyl, etc.
- alkoxy for R 5 has the same meaning as the alkoxy for RR′R 1 .
- the alkoxycarbonyl O alkoxy in R 5 is those having 1 6 straight-chain or branched alkoxy carbon alkoxy part, main butoxycarbonyl Okishi, ethoxycarbonyl O alkoxy, propoxy carbonylation Ruo 'Xy, isopropoxycarbonyl / reoxy, butoxycarbonyloxy, isobutoxycarboninoleoxy, secondary butoxycarbonyloxy, tertiary butoxycarbonyloxy, pentyloxycarbonyloxy, xyloxycarbonyloxy, etc. Show.
- the Al force Noiruokishi in R 5 be one having a number 2 6 Al force Noiru carbon Arukanoiru section shows Asechiruokishi, propionyl Ruo alkoxy, Buchiriruo alkoxy, Bareriruokishi, the Bibaroiruokishi like.
- the aralkyloxycarbonyloxy in R 5 has an aralkyl having an alkyl having 14 carbon atoms in the alkyl portion of the aralkyl portion, and includes benzyloxycarbonyloxy and 1-phenylethyl. Examples thereof include oxycarbonyloxy, 2-phenylethyloxycarbonyloxy, 3-phenylpropyloxycarbonyloxy, 4-phenylbutyloxy / reoxycarbonyloxy, and the like.
- the alkyl in R 6 has the same meaning as the alkyl in RR′R 1 .
- the alkyl at R 8 R 9 is 'has the same meaning as alkyl at R 1, Ararukiru of definitive to R 8 R 9 is RR' RR is synonymous with Ararukiru in R 1.
- R 6 and R 7 combine to form a heterocyclic ring, which may have an oxygen atom, a sulfur atom or a substituent in the ring, or may have a nitrogen atom
- substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, and noroalkyl.
- alkyl, Ararukiru, the Nono Roarukiru R, R ' the same meaning as in the R 1.
- the hydroxyalkyl represented by R 10 and R 11 is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms which is substituted with 1 to 3 hydroxy, such as hydroxymethyl, 2-hydroxyl, 1-hydroxyl, 3-hydroxypropyl, 4-hydroxybutyl and the like.
- the alkyl in R 10 and R 11 has the same meaning as the alkyl in R, R 'and R 1 , and the haloalkyl and alkoxycarbonyl in R 10 and R 11 have the same meanings as those shown in R, R' and R 1 Aralkyl in R, R 10 and R 11 is synonymous with aralkyl in R, R ⁇ R 1 .
- the cycloalkyl formed by the combination of R 10 and R 11 has the same meaning as the cycloalkyl in R, R ′ and R 1 .
- Alkyl in L is R, R ', the same meaning as alkyl at R 1.
- the aminoalkyl in L is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms substituted by amino, such as aminomethyl, 2-aminoethyl, Examples include 1-aminoethyl, 3-aminobutyryl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like.
- the mono'dialkylaminoalkyl in L is an aminoalkyl mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, such as methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, acetylaminomethyl, propylamino Methylene, dipropylaminomethyl, butylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 2-ethylaminoaminoethyl, etc.
- L-bulbamoylalkyl in L is a straight- or branched-chain alkyl having 1 to 6 carbon atoms substituted with l-rubamoyl, for example, l-rubamoyl methyl, 2--l-rubamoyl ethyl, 1-l-rubamoyl ethyl, Examples include 3-force rubamoyl propyl, 4-force rubamoyl butyl, 5-force rubamoyl pentyl, 6-force rubamoyl hexyl, and the like.
- the phthalimidalkyl in L is a straight-chain or branched alkyl having 1 to 6 carbon atoms substituted by phthalimid.
- phthalimidomethyl 2-phthalimidoethyl, 1-phthalimidoethyl, 3- Examples include phthalimidpropyl, 4-phthalimidbutyl, 5-phthalimidopentyl, 6-phthalimidhexyl and the like.
- Alkyl in B is R, R ', the same meaning as alkyl at R 1.
- Alkoxy at B is R, R ', the same meaning as alkoxy at R 1.
- Ararukiru in B is R, R ', the same meaning as Ararukiru in R 1.
- the aralkyloxy in B is the same as the aralkyloxy in R 3 and R 4 .
- Aminoalkyl in B has the same meaning as aminoalkyl in L.
- the hydroxyalkyl in B is the same as the hydroxyalkyl in R 10 and R 11 .
- the alkanoyloxyalkyl in B is a straight-chain or branched-chain alkyl having 1 to 6 carbons which is substituted by an alkynooxy having an alkynoyl moiety having 2 to 6 carbons.
- the alkoxycarbonylalkyl in B is a straight-chain or branched alkyl having 1 to 6 carbons substituted by an alkoxycarbonyl having an alkoxy moiety having 1 to 6 carbons, For example, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, secondary butoxycarbonylmethyl, tertiary butoxycarbonylmethyl, pentyloxycarbonylmethyl, Xyloxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonyl / reethyl, isopropoxycarbonyl / reethyl, butoxycarbonylethyl, isobutoxycarbonylethyl, secondary butyl Kishikarubo two Ruechiru, tertiary butoxycarbonyl E chill, pentylene Ruo alk
- the halogen in Q ⁇ Q 2 and Q 3 has the same meaning as the halogen in R, R ′ and R 1 .
- Ararukiruokishi in Q ⁇ Q 2 have the same meanings as Ararukiruokishi in R 3, R 4.
- the alkoxy in Q 3 has the same meaning as the alkoxy in R, R ′ and R 1 .
- the alkylene in W, X, and Y is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, etc. .
- the alkenylene in Y is a linear or branched alkenylene having 2 to 6 carbon atoms, such as vinylene, propenylene, butenylene, pentenylene and the like.
- the alkyl in R b has the same meaning as the alkyl in R, R ′ and R 1 .
- Aralkyl in R b is synonymous with aralkyl in R, R ', R ] .
- the aminoalkyl for R b has the same meaning as the aminoalkyl for L.
- the nitrogen-containing heterocyclic ring represented by R c represents a monocyclic pyridine, pyrimidine, pyridazine, triazine, pyrazole or triazole, and a condensed ring represents a pyrrole pyridin (1H-pyrrolate [2, 3 — B] Pyridine, 1 H-pyrro [3,2-b] Pyridine, 1 H-pyrro [3,4-b] pyridine, etc., Pyrazo pyridine (1H-pyrazo [3,4-1b] Pyridine, 1 H-pyrazo port [4,3-b] pyridine, etc.), imidazo pyridine (1 H-I ⁇ f midazo [4,5-b] pyridine, etc.), pyro-pyrimidine (1 H-pyro-port [ 2,3-d] pyrimidine, 1 H-pyro mouth [3,2-d] pyrimidine, 1 H-pyro mouth [3,4-1d] pyrimidine, etc.), pyrazo-
- pyridine and pyro-mouth pyridine Preference is given to pyridine and pyro-mouth pyridine. These rings may be halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, alkylamino, cyano, formyl, acyl, aminoalkynole, mono- or dialkylaminoalkyl, azide, carboxy, alkoxycarbonyl, alkavamoyl, alkyl May be substituted with a substituent such as carbamoyl, alkoxyalkyl (eg, methoxymethyl, methoxethyl, methoxypropyl, ethoxymethyl, ethoxymethyl, ethoxypropyl), and hydrazino which may have a substituent. Les ,.
- examples of the substituent of the hydrazino which may have a substituent include alkyl, aralkyl, nitro, cyano and the like.
- alkyl and aralkyl have R, R ′,
- Alkyl in R 1 have the same meanings as Ararukiru, e.g. Mechiruhi Dorajino, E Ji Ruhi Dorajino, Benjiruhi Dorajino the like.
- Specific examples of the compound represented by the general formula (I) include the following compounds.
- the compound having Rho kinase inhibitory activity may be a pharmaceutically acceptable acid addition salt, which includes inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, methanesulfo, acid, fumaric acid, maleic acid, and mandel.
- Organic acids such as acid, citric acid, tartaric acid, salicylic acid and the like can be mentioned.
- the compound having a carboxyl group may be a salt with a metal such as sodium, potassium, calcium, magnesium, aluminum or the like, or a salt with an amino acid such as lysine.
- the compounds represented by the general formula (I) are described, for example, in JP-A-62-89679, JP-A-3-2183556, JP-A-5-194401,
- the compound can be synthesized by the method described in, for example, No. 6-41080, WO95 / 28387, WO98 / 64433.
- an optical isomer a racemate or a cis-trans isomer thereof is present in the above-mentioned compound having the Rho kinase inhibitory activity, all of them can be used in the present invention.
- the isomer can be isolated by a conventional method or can be produced by using each isomer raw material.
- Rho kinase inhibitory activity especially compounds represented by the general formula (I), isomers thereof and / or pharmaceutically acceptable acid addition salts thereof include human and human. Since it has an intraocular pressure-lowering effect, optic nerve head blood flow improving effect and aqueous humor outflow promoting effect on mammals such as mice, rats, dogs, mice, and rats, various glaucoma, such as primary open angle Glaucoma, normotensive glaucoma, excessive aqueous glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, scleroid glaucoma, lens capsule glaucoma, pigment It is used as a prophylactic and therapeutic agent for glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, etc.
- various glaucoma such as primary open angle Glaucoma, normoten
- the glaucoma preventive / therapeutic agent of the present invention is administered orally or parenterally.
- the dosage form include oral forms such as tablets, capsules and syrups, liquid injections such as solutions, emulsions and suspensions, ointments (especially ophthalmic ointments), and external preparations such as eye drops
- oral forms such as tablets, capsules and syrups
- liquid injections such as solutions, emulsions and suspensions, ointments (especially ophthalmic ointments), and external preparations
- parenteral administration forms are exemplified, but considering the effects on other circulatory systems and their effects, it is preferable to use them in the form for topical administration to the eye, and they are preferably in the form of eye drops or ointments. Especially preferred ,.
- the preparation of the above-mentioned administration form can be produced by compounding the present compound with usual additives required for preparation such as carriers, excipients, binders, stabilizers and the like, and formulating by conventional means.
- a compound having Rho kinase inhibitory activity is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.).
- compositions or tablets, pills, powders, granules, capsules, troches, syrups, solutions, emulsions, suspensions, injections (solutions, suspensions, etc.), suppositories, inhalants It is formulated in a form suitable for oral or parenteral use as a preparation, such as a transdermal absorption agent, eye drops, and eye ointment.
- excipients such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tragacanth gum , Gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl / resel mouth, hydroxypropylmethylcellulose / glycerin, Polyethylene glycol, sodium hydrogen carbonate, magnesium stearate, talc and the like are used.
- tablets should be tablets coated with normal skin as required, such as sugar-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets. Can be.
- animal and vegetable oils in the case of semi-solid preparations, animal and vegetable oils (olive oil, corn oil, castor oil, etc.), mineral oils (vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, carnapa wax, beeswax, etc.), A partially or totally synthesized glycerin fatty acid ester (such as lauric acid, myristic acid, or palmitic acid) is used.
- these marketed products include Witebsol (Dynamiz Donovan), Pharmasol (Nippon Oil & Fats), and the like.
- examples of the additives include sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, and ethyl alcohol.
- liquid preparation examples include injections, eye drops and the like.
- a sterile aqueous solution such as a physiological saline solution, isotonic solution, oily solution, for example, sesame oil or soybean oil is used.
- a suitable suspending agent such as sodium carboxymethylcellulose, a nonionic surfactant, a solubilizer, for example, benzyl benzoate, benzyl alcohol and the like may be used in combination.
- aqueous solutions or aqueous solutions are used, and particularly, sterile aqueous solutions for injection are mentioned.
- Various additives such as buffers, stabilizers, wetting agents, emulsifiers, suspending agents, surfactants, isotonic agents, preservatives, and thickeners may be appropriately added to eye drops.
- a buffer for example, a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, a tallowate buffer, an amino acid and the like are used.
- the stabilizer for example, sodium edetate, citric acid and the like are used.
- the humectant include glycerin.
- emulsifier examples include polyvinylpyrrolidone.
- suspending agent examples include hydroxypropyl methylcellulose, methylcellulose and the like.
- surfactant examples include polysorbate 80, polyoxyethylene hydrogenated castor oil, and the like.
- tonicity agent for example, sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; and salts such as sodium chloride are used.
- quaternary ammonium salts such as benzalcoum chloride and benzenitonium chloride, paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and the like Salt, thimerosal, chlorobutanol, etc. are used.
- hydroxyxethyl cellulose for example, hydroxyxethyl cellulose, hydroxypropyl phenolylose, methinoresolelolose, hydroxypropizolemethy / resenolose, strength / repoxymethylcellulose, and salts thereof are used.
- hydroxyxethyl cellulose hydroxypropyl phenolylose, methinoresolelolose, hydroxypropizolemethy / resenolose, strength / repoxymethylcellulose, and salts thereof are used.
- the pH is usually adjusted to about 4 to 9, preferably about 6 to 8.5.
- the preparation is an ophthalmic ointment
- it can be produced by appropriately selecting an ointment base (such as vaseline, lanolin, plastibase), a preservative (such as benzalkonium chloride, paraoxybenzoic acid esters, and chlorobutanol).
- an ointment base such as vaseline, lanolin, plastibase
- a preservative such as benzalkonium chloride, paraoxybenzoic acid esters, and chlorobutanol.
- the amount of the active ingredient in the glaucoma preventive / therapeutic agent of the present invention is from 0.0001 to 100% by weight of the preparation, suitably from 0.001 to 50% by weight.
- the dose and frequency of administration vary depending on the symptoms, age, body weight, and dosage form.
- a compound having Rho kinase inhibitory activity is 0.001 for adults.
- the formulation containing I wZ v% is administered several times per day, preferably 1 to 6 times, 1 drop, preferably 1 to 3 drops.
- the compound can be used in the amount of 0.0001 to 10 wZw. /.
- the formulation containing, preferably 0.001 to 1 w / w% can be applied several times a day, preferably 1 to 6 times.
- Example 3 Eye drops 3
- (+)-trans-N- (1H-pyro-port [2,3-b] pyridine-14-yl) 14- which is a compound having a Rh kinase inhibition activity, 1-amino aminoethyl) cyclohexane carboxamide Mi de 2HC 1 ⁇ 6/5 H 2 0 (hereinafter compound and B) were prepared eye drops containing a concentration of 0.03%.
- Example 1 (+) —N— (4-pyridyl) -14- (1-aminoethyl) benzamide 2HC 1 (hereinafter referred to as Compound C) ) was prepared at a concentration of 0.1%.
- Example 7 Eye drops 7
- Compound A lactose, corn starch and crystalline cellulose were mixed, kneaded using polyvinylpyrrolidone K30 size liquid, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and a tablet with a diameter of 12 mm was produced using a 7 mm diameter punch.
- Compound A 1 0. Omg lactose, 50. Omg corn starch 20. Omg microcrystalline cellulose 29.7 mg polyvinylpyrrolidone K 30 5. Omg talc 5. Omg magnesium stearate 0.3 mg
- Compound A lactose and corn starch were mixed, kneaded using polyvinylpyrrolidone 30 size liquid, and granulated through a 20 mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and the mixture was filled in hard capsules (No. 4) to produce 12 Omg capsules.
- a male male colored eagle weighing about 2 kg was used.
- the rabbits were placed in a fixed can for 3 to 5 hours a day to acclimatize them, and then the rabbits with stable intraocular pressure were selected and used by a tonometer [Pneumatograph (Alcon)].
- a tonometer Pneumatograph (Alcon)
- one eye was treated with one eye of the eye drop of Example 1 at 50 ⁇ l, and the other eye was treated with the base obtained by removing Compound ⁇ ⁇ from the eye drop of Example 1 in the same manner as the control eye.
- Intraocular pressure was measured at 30, 60, 90, and 120 minutes after instillation, and then at 60-minute intervals thereafter, and the intraocular pressure was measured over time until the intraocular pressure returned to the initial value, and the duration of the effect was examined. .
- FIG. 1 shows the effect of the eye drops of Example 1 on normal intraocular pressure.
- a significant maximum intraocular pressure lowering effect of 5 mmHg was observed as compared with the control eyes.
- a significant intraocular pressure lowering effect was observed up to 180 minutes after instillation as compared with the control eyes.
- it showed almost the same intraocular pressure value as the control eye, and returned to the initial value.
- a male male colored eagle weighing about 2 kg was used.
- One eye was given 50 ⁇ m of the ophthalmic solution of Example 1, and the other eye was similarly applied with a base obtained by removing the compound ⁇ ⁇ from the ophthalmic solution of Example 1 to obtain a control eye.
- the blood flow of the optic disc was measured using a laser speckle peripheral circulation analyzer at 30, 60, 90, and 120 minutes after instillation, and thereafter at intervals of 60 minutes until 300 minutes after instillation.
- FIG. 2 shows the effect of the ophthalmic solution of Example 1 on the optic nerve head blood flow dynamics.
- Glucose 11.5 mM
- the ciliary body separated from the eyeball was suspended in a Magnus tube filled with Krebs solution and equilibrated under resting tension of 20-3 Omg. The change in tension was recorded on the pen recorder via the transducer and amplifier.
- Carbachol was used as a constrictor, and the inhibitory effect on the dose-response of phasic contraction was examined.
- Study drug (+) -. Trans one 4- (1-aminoethyl) Single 1 (4-pyridyl carbamoylthiophenol Le) hexane 2HC 1 cyclohexane 1 H 2 0 (Compound A) with carbachol added 5 min before Was added to the Magnus tube.
- Ciliary muscle contraction and relaxation also play an important role in aqueous outflow.
- Relaxation of the ciliary muscle suppresses aqueous humor outflow through the trabecular meshwork, but promotes aqueous humor outflow through the uveosclera (Kenshi Yoshitomi, Neuro-Ophthalmology, 15 (1) , 76-81, 1998). It is thought that the ciliary muscle relaxes in this way and the outflow of aqueous humor is promoted, resulting in a decrease in intraocular pressure.
- Japanese white egrets weighing about 2 kg and purchased from the Japan Institute of Medical Science and Animal Resources were used. These animals were bred in a breeding room set at a temperature of 23 ⁇ 3 ° C and a humidity of 55 soils and 10%, and fed a 100 g daily limit of solid feed (Lab R Stock, Nippon Agricultural Industries). Water was supplied by tap water freely. Rabbits with stable intraocular pressure were selected and used by a tonometer [Pneumatograph (Alcon)] from 2 days before the test, after acclimatizing the rabbits in a fixed can for 5 hours a day.
- tonometer Pneumatograph (Alcon)
- one eye was instilled with 20 ⁇ m of each eye drop, and the other eye was similarly instilled with a base obtained by removing the test drug from each eye drop to serve as a control eye.
- the measurement of intraocular pressure is performed at 30, 60, 90, 120, 150, and 180 minutes after instillation, and then at 1-hour intervals, and the intraocular pressure is measured over time until the intraocular pressure returns to the initial value. The duration of the study was examined.
- FIG. 4 The effect of eye drops containing each test drug at a concentration of 0.1% on normotensive pressure is shown in Fig. 4 (Examples 2 and 5). The results are shown in FIG. 5 (Examples 3 and 4) and FIG. 6 (Examples 6 and 7). In all cases, a significant intraocular pressure lowering effect was observed. In particular, Compound I (Examples 2 and 3) showed an intraocular hypotensive effect early after instillation, and Compound D (Example 7) showed a remarkable and sustained intraocular pressure-lowering effect. Was.
- Test drugs Compound A and Compound C were dissolved in the following base materials at concentrations of 0.125, 0.25, 0.5, and 1.0%, respectively, and adjusted to pH 7 in this experiment. Used for (Base formulation)
- Japanese white egrets weighing about 2 kg and purchased from the Japan Institute of Medical Science and Animal Resources were used. These animals are bred in a breeding room set at a temperature of 23 ⁇ 3 ° C and a humidity of 55 to 10%, and are fed a 100 g daily limit of solid feed (Lab R Stock, Nippon Agricultural Industries). did. Water was supplied by tap water freely.
- each test drug was instilled in the right eye of each animal at a dose of 100 ⁇ l eight times at hourly intervals.
- the base was similarly instilled into the left eye.
- the anterior ocular segment was evaluated according to the eye damage criteria shown in Table 1 (Fukui Shigeyuki, Ike Fumihiko, Modern Clinical Practice 4, 277-289, 1970). A visual inspection was performed. In addition, corneal staining was observed using a slit lamp before the instillation and after the macroscopic observation after the eighth administration.
- Table 2 shows the results of the macroscopic observation of the anterior segment at the time of administration of Compound ⁇
- Table 3 shows the results of macroscopic observation of the anterior segment at the time of administration of Compound C.
- Eye damage score Before administration 2nd 4th 6th 8th corneal degree 0 0 0 0 0 0 area 0 0 0 0 0 0 0 conjunctiva eyelid congestion 0 0 0 0.17 0.33 eyelid edema 0 0 0 0.17 0.33 Eyeball Hyperemia 0 0 0.50 0.17 0.50 Tympanic membrane 0 0 0.33 0.33 0.50 Secretions 0 0 0.17 0.50 0 Total score 0 0 0 83 0.84 1.66 Cornea degree 0 0 0 0 0 0 0 Area 0 0 0 0 0 Iris hyperemia 0 0 0 0 0 0 0 Conjunctiva Eyelid hyperemia 0 0 0.33 0.33 0 Eyelid edema 0 0 0 0.17 0 Eyeball Hyperemia 0 0.33 0.33 0.50 0.67 Tympanic membrane 0 0.33 0.50 0.33 1.33 Secretions 0 0 0 0.
- the glaucoma preventive / therapeutic agent of the present invention can be used for various types of glaucoma, for example, primary open corners, since a compound having Rho kinase inhibitory activity exhibits an intraocular pressure lowering effect, an optic nerve head blood flow improving effect and an aqueous humor outflow promoting effect Angle glaucoma, normotensive glaucoma, excessive aqueous glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid glaucoma, lens capsule glaucoma, pigment It is useful as a prophylactic / therapeutic agent for glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.
- a compound having Rho kinase inhibitory activity suppresses ciliary muscle contraction, it is a prophylactic / therapeutic agent for eyestrain and pseudomyopia caused by persistent abnormal tension of the ciliary muscle. It is also useful.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002307285A CA2307285C (en) | 1998-08-17 | 1999-08-13 | Agent for prophylaxis and treatment of glaucoma |
KR1020007004051A KR100616466B1 (ko) | 1998-08-17 | 1999-08-13 | 녹내장 예방/치료제 |
JP2000564663A JP3720264B2 (ja) | 1998-08-17 | 1999-08-13 | 緑内障予防・治療剤 |
EP99937073A EP1034793B1 (en) | 1998-08-17 | 1999-08-13 | Preventives/remedies for glaucoma |
AU51981/99A AU5198199A (en) | 1998-08-17 | 1999-08-13 | Preventives/remedies for glaucoma |
DE69927936T DE69927936T2 (de) | 1998-08-17 | 1999-08-13 | Präventiva/mittel zur glaukombehandlung |
AT99937073T ATE307609T1 (de) | 1998-08-17 | 1999-08-13 | Präventiva/mittel zur glaukombehandlung |
US09/529,354 US6673812B1 (en) | 1998-08-17 | 1999-08-13 | Preventives/remedies for glaucoma |
HK01101779A HK1030883A1 (en) | 1998-08-17 | 2001-03-12 | Preventives/remedies for glaucoma |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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JP10/247762 | 1998-08-17 | ||
JP24776298 | 1998-08-17 | ||
JP11/122960 | 1999-04-28 | ||
JP12296099 | 1999-04-28 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US09/529,354 A-371-Of-International US6673812B1 (en) | 1998-08-17 | 1999-08-13 | Preventives/remedies for glaucoma |
US10/298,674 Division US6649625B2 (en) | 1998-08-17 | 2002-11-19 | Agent for prophylaxis and treatment of glaucoma |
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Publication Number | Publication Date |
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WO2000009162A1 true WO2000009162A1 (fr) | 2000-02-24 |
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PCT/JP1999/004403 WO2000009162A1 (fr) | 1998-08-17 | 1999-08-13 | Medicaments preventifs/curatifs pour le glaucome |
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US (2) | US6673812B1 (ja) |
EP (3) | EP1459742B9 (ja) |
JP (2) | JP3720264B2 (ja) |
KR (1) | KR100616466B1 (ja) |
CN (2) | CN1293878C (ja) |
AT (3) | ATE529102T1 (ja) |
AU (1) | AU5198199A (ja) |
CA (2) | CA2635412C (ja) |
DE (1) | DE69927936T2 (ja) |
ES (3) | ES2372572T3 (ja) |
HK (3) | HK1030883A1 (ja) |
WO (1) | WO2000009162A1 (ja) |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000057913A1 (fr) * | 1999-03-25 | 2000-10-05 | Welfide Corporation | Prophylaxies/remedes pour la pneumonie interstitielle et la fibrose pulmonaire |
WO2000057914A1 (fr) * | 1999-03-25 | 2000-10-05 | Santen Pharmaceutical Co., Ltd. | Agents permettant d'abaisser la tension oculaire |
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