JP2011524912A - Ophthalmic formulation of RHO kinase inhibitor compound - Google Patents

Abstract

The present invention relates to an aqueous pharmaceutical formulation comprising at least one inhibitor of Rho-related protein kinase (ROCK). The aqueous pharmaceutical formulation of the present invention has an osmotic pressure at a ROCK inhibitor of 0.01 to 0.4% w / v, a nonionic surfactant of 0.01 to 2% w / v, and a pH of 6.3 to 7.8. Isotonic agent capable of maintaining a 220-360 mOsm / kG, ROCK inhibitor, surfactant and isotonic agent are compatible in the formulation. The aqueous ophthalmic formulation of the present invention exhibits increased aqueous humor concentration without increased ocular bioavailability and / or increased systemic concentration. Furthermore, the present invention provides a method for reducing intraocular pressure, particularly a method for treating glaucoma by administering an aqueous pharmaceutical formulation to a subject.
[Selection] Figure 1

Description

  The present invention relates to pharmaceutical formulations, particularly ophthalmic aqueous formulations, of Rho kinase (ROCK) inhibitor compounds and related analogs. The invention also provides for treating diseases or disorders by altering cytoskeletal integrity and remodeling, particularly for diseases with elevated intraocular pressure (IOP), such as primary open angle glaucoma. It relates to the use of the above formulations for treatment.

Rho family low molecular weight GTP-binding proteins are activated by several extracellular stimuli such as growth factors, hormones and mechanical stress, and circulate between inactive and active GTP-bound forms Can act as a molecular signal switch and trigger a cellular response. Rho kinase (ROCK) functions as an important downstream mediator of Rho and exists as two ubiquitously expressed isoforms (ROCK1 and ROCK2). ROCK is a cytoskeletal protein such as moesin, Na ⁺ -H ⁺ exchange transporter 1 (NHE1), LIM kinase and vimentin, contractile proteins such as myosin light chain phosphatase binding subunit (MYPT-1), CPI-17, Numerous substrates including myosin light chain and calponin, microtubule binding proteins such as Tau and MAP-2, nerve cell growth cone related proteins such as CRMP-2, signaling proteins such as PTEN, and transcription factors such as serum response factors Is a serine / threonine kinase that regulates the function of lysine (Loirand et al., Circ Res 98: 322-334 (2006)). ROCK is also required for cell transformation induced by RhoA. As an important vehicle for multiple signaling pathways, ROCK is a cytoskeleton remodeling, actin stress fiber formation, proliferation, chemotaxis, cytokinesis, cytokine and chemokine secretion, endothelial and epithelial cell junction integrity. ), Control a variety of cellular phenomena including apoptosis, transcriptional activation and smooth muscle contraction. As a result of these cellular effects, ROCK controls physiological processes such as vasoconstriction, bronchoconstriction, tissue remodeling, inflammation, edema, platelet aggregation and proliferative diseases.

An example of well-proven ROCK activity is smooth muscle contraction. In smooth muscle cells, ROCK mediates increased calcium sensitivity and smooth muscle contraction. Agonists that bind to G protein-coupled receptors (noradrenaline, acetylcholine, endothelin, etc.) cause contraction by increasing both cytosolic Ca ²⁺ concentration and contractile apparatus Ca ²⁺ sensitivity. The effect of increasing Ca ²⁺ sensitivity by smooth muscle contractors is due to ROCK-mediated phosphorylation of the regulatory subunit of MYPT-1, ie, myosin light chain phosphatase (MLCP), resulting in inhibition of MLCP activity resulting in myosin lightness. Promotion of chain phosphorylation and smooth muscle contraction occur (WO 2005 / 003101A2, WO 2005 / 034866A2).

  Glaucoma is an eye disease that causes irreversible visual impairment. It is the fourth most common cause of blindness in the United States, the second most common cause of visual impairment, and the most common cause of irreversible visual impairment in African Americans. In general, the disease is characterized by progressive optic neuropathy caused at least in part by adverse effects resulting from increased intraocular pressure. In normal individuals, intraocular pressure ranges from 12 to 20 mmHg, with an average of about 16 mmHg. However, in individuals suffering from primary open-angle glaucoma, intraocular pressure is generally elevated and exceeds 22-30 mmHg. In closed angle or acute glaucoma, intraocular pressure can reach up to 70 mmHg and can lead to blindness within a few days. Interestingly, visual impairment can usually result from statistically normal intraocular pressure in individuals with pressure sensitive eyes. That is, it is a disease known as normal tension glaucoma [for example, PL Kaufman and TW Mittag, "Medical Therapy Of Glaucoma," Ch. 9, Sec. II (pp. 9.7-9.30) In PL Kaufman and TW Mittag (eds .): Glaucoma (Vol. 7 of SM Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); AC Guyton, Textbook of Medical Physiology (WB Saunders Co. , Sixth Ed.), Pp. 386-89 (1981)].

  Open-angle glaucoma accounts for about 90% of all primary glaucoma and is characterized by an unusually high resistance to fluid (aqueous humor) outflow from the eye. Normal tolerance is necessary to maintain sufficient intraocular pressure to maintain the eye shape required for eye integrity. This resistance is brought about by a trabecular meshwork that is a complex of a multi-layered tissue consisting of specialized cells and a dense actomyosin cytoskeletal network, collagenous beams and extracellular matrix. The trabecular meshwork resistance typically has an intraocular pressure of ˜16 mmHg, at which the aqueous humor flows at the same rate as its production rate (2.5 μL / min). In glaucomatous eyes, aqueous humor production rates are constant, but resistance to outflow, which is associated with increased intraocular pressure, is increased.

  Typical treatments for glaucoma include approaches with various intraocular pressure (IOP) lowering drugs, each with its drawbacks. β-blockers and carbonic anhydrase inhibitors reduce aqueous humor production required for the growth of avascular lens and corneal endothelial cells, and prostaglandins account for only about 10% of total efflux function. Acts on the uvealscleral outflow pathway. The trabecular meshwork is a site of aqueous humor outflow, and increased resistance to aqueous humor outflow contributes to an increase in IOP, but currently there are no approved commercial therapies that act directly on the trabecular meshwork. Thus, there remains a medical need for improved IOP-lowering drugs that target this structure. Agents that target the trabecular meshwork will provide comfort for many patients who do not respond well to current IOP-lowering drugs and / or cannot tolerate the side effects associated with these agents. In addition, these molecules would be useful as adjuvant therapy in combination with other classes of IOP-lowering drugs.

  US Pat. Nos. 6,586,425, 6,110,912 and 5,798,380 describe glaucoma using compounds that affect ocular actin filament integrity and promote aqueous outflow. A method of treatment is disclosed. These patents specifically disclose latrunculin A, latrunculin B, swinholide A and jasplakinolide, which are the trabecular meshwork Causes perturbation of the actin cytoskeleton and tight junction complex in or changes in interaction with the underlying membrane.

  US Pat. Nos. 6,649,625 and 6,673,812 disclose the pharmaceutical use of certain compounds having Rho kinase inhibitory activity for the treatment of glaucoma.

  It has been recognized for many years that systemic absorption of glaucoma drugs applied topically in ophthalmic medications through the conjunctiva and nasal mucosa can cause significant side effects [eg, Nelson, WL, Fraundfelder, FT, Sills, JM , Arrowsmith JB, Kuritsky, JN, "Adverse respiratory cardiac events attributed to timolol ophthalmic solution," Am. J. Ophthalmol. 1986, 102, pp606-11; Saxena, R.; Prakash, J., Mathur, P., Gupta , SK "Pharmacotherapy of Glaucoma," Ind. J. Pharmacol, 2002, 34, pp71-85].

  There is a need for improved IOP-lowering drugs that exhibit increased drug bioavailability without increasing drug concentration in the systemic circulation, thereby reducing or eliminating undesirable drug-related side effects.

  The present invention relates to at least one ROCK inhibitor of formula II 0.01-0.4% w / v, nonionic surfactant 0.01-2% w / v, and pH 6.3. 7.8 An aqueous pharmaceutical preparation comprising an isotonic agent capable of maintaining an osmotic pressure at 220-360 mOsm / kG, wherein the ROCK inhibitor, the surfactant and the isotonic agent are compatible in the preparation. To the aqueous pharmaceutical formulation.

  Preferred surfactants in the formulation are polysorbates, polaxamers or combinations thereof. The preferred pH in the formulation is 6.3-7.5. A more preferable pH in the preparation is 6.3 to 7.3. The preparation may further contain a chelating agent and / or a preservative as necessary. The tonicity agent can be a non-ionic tonicity agent such as glycerol, mannitol or dextrose. The tonicity agent can also be an ionic tonicity agent such as sodium chloride.

  The aqueous ophthalmic formulation of the present invention exhibits increased ocular bioavailability and / or aqueous humor concentration without increasing systemic concentration.

  The present invention further provides a method for reducing intraocular pressure by identifying a subject in need of treatment and administering the aqueous pharmaceutical preparation to the subject, particularly a method for treating glaucoma.

FIG. 1 shows the stability of Compound A at a temperature of 60 ° C., pH 5.3, 6.3 and 7.3. After the preparation was stored at 60 ° C. for a certain period, the residual ratio of Compound A was measured and shown in FIG. FIG. 2A shows the aqueous humor (AH) Cmax after administration of 0.12% Compound A at pH 5.3, 6.3 and 7.3. FIG. 2B shows aqueous humor AUC after administration of 0.12% Compound A at pH 5.3, 6.3 and 7.3. Data are mean ± SEM, N = 4 eyes. FIG. 3A shows plasma Cmax after administration of 0.12% Compound A at pH 5.3, 6.3, and 7.3. FIG. 3B shows plasma AUC after administration of 0.12% Compound A at pH 5.3, 6.3, and 7.3. Data are mean ± SEM, N = 2 animals. FIG. 4 shows the ocular surface concentration over time after administration of 0.12% (3 mM) Compound A at pH 5.3, 6.3 and 7.3. Data are mean ± SEM, N = 4 eyes. FIG. 5 shows the eye comfort score for various formulations. FIG. 6 shows the eye comfort score for various concentrations of Compound 2.039 compared to other drugs.

Definitions Unless otherwise stated, the following terms are generally defined as follows, but are not limited thereto.
The halo substituent is selected from fluorine, chlorine, bromine and iodine.

  “Alkyl” is a linear or branched group containing 1 to 12, more preferably 1 to 8, most preferably 1 to 6 carbon atoms.

  “Alkenyl” is a straight or branched group containing 2 to 12 carbon atoms and contains at least one double bond, but may contain two or more double bonds.

  “Alkynyl” is a linear or branched group containing 2 to 12 carbon atoms and contains at least one triple bond, but may contain two or more triple bonds, One or more double bond moieties may be included.

  “Alkoxy” is a group called alkyl-O—, the alkyl group is as defined above, and also includes those in which the alkyl group defined above is optionally substituted.

  “Alkenoxy” is a group called alkenyl-O—, where the alkenyl group is as defined above, and includes those in which the alkenyl group defined above is optionally substituted.

  “Alkynoxy” is a group called alkynyl-O—, the alkynyl group has the same meaning as described above, and includes those in which the alkynyl group defined above is optionally substituted.

  “Aryl” is an unsaturated aromatic carbocyclic group containing 6-14 carbon atoms having one ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl). Preferable aryl includes, for example, phenyl, naphthyl and the like.

  “Arylalkyl” is an aryl-alkyl- group, preferably containing 1 to 6 carbon atoms in the alkyl portion and 6 to 10 carbon atoms in the aryl portion. Examples of such arylalkyl groups include benzyl and phenethyl.

  “Arylalkenyl” is an aryl-alkenyl- group, preferably containing 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 carbon atoms in the aryl moiety.

  “Arylalkynyl” is an aryl-alkynyl- group, preferably containing 2 to 6 carbon atoms in the alkynyl moiety and 6 to 10 carbon atoms in the aryl moiety.

  “Cycloalkyl” is a cyclic alkyl group containing 3 to 12 carbon atoms having one ring or multiple condensed rings optionally substituted with 1 to 3 alkyl groups. Examples of such cycloalkyl include a monocyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and a multi-ring structure such as adamantyl. Can be mentioned.

  “Cycloalkenyl” has one ring or a plurality of fused rings optionally substituted with 1 to 3 alkyl groups and has at least one unsaturation in the molecule. A cyclic alkenyl group containing carbon atoms. Suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

  “Cycloalkylalkyl” is a radical of cycloalkyl-alkyl-, preferably containing 1 to 6 carbon atoms in the alkyl portion and 6 to 10 carbon atoms in the cycloalkyl portion. Examples of such cycloalkylalkyl groups include cyclopropylmethyl, cyclohexylethyl and the like.

  “Cycloalkylalkenyl” is a radical of cycloalkyl-alkenyl-, preferably containing 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 carbon atoms in the cycloalkyl moiety. Examples of such cycloalkylalkenyl groups include cyclohexylethenyl and the like.

  “Cycloalkylalkynyl” is a radical of cycloalkyl-alkynyl-, preferably containing 2 to 6 carbon atoms in the alkynyl moiety and 6 to 10 carbon atoms in the cycloalkyl moiety. Examples of such a cycloalkylalkynyl group include cyclopropylethynyl and the like.

  “Heteroaryl” is a monovalent aromatic heterocyclic group containing 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups can have one ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolizinyl or benzothienyl).

  “Heteroarylalkyl” is a heteroaryl-alkyl- group, preferably containing 1 to 6 carbon atoms in the alkyl portion and 6 to 10 atoms in the heteroaryl portion. Examples of such heteroarylalkyl groups include pyridylmethyl and the like.

  “Heteroarylalkenyl” is a heteroaryl-alkenyl- group preferably containing 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 atoms in the heteroaryl moiety.

  “Heteroarylalkynyl” is a group called heteroaryl-alkynyl-, preferably containing 2 to 6 carbon atoms in the alkynyl moiety and 6 to 10 atoms in the heteroaryl moiety.

  “Heterocycle” includes one ring or a plurality of fused rings containing 1 to 8 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring. It has a saturated or unsaturated group. Such heterocyclic groups may have one ring (eg piperidinyl or tetrahydrofuryl) or multiple condensed rings (eg indolinyl, dihydrobenzofuran or quinuclidinyl). Preferred heterocycles include, for example, piperidinyl, pyrrolidinyl and tetrahydrofuryl.

  “Heterocycle-alkyl” is a group called heterocycle-alkyl-, preferably containing 1 to 6 carbon atoms in the alkyl portion and 6 to 10 atoms in the heterocyclic portion. Examples of such a heterocyclic-alkyl group include morpholino-ethyl, pyrrolidinylmethyl and the like.

  “Heterocycle-alkenyl” is a group called heterocycle-alkenyl-, preferably containing 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 atoms in the heterocyclic moiety.

  “Heterocycle-alkynyl” is a group called heterocycle-alkynyl, preferably containing 2 to 6 carbon atoms in the alkynyl moiety and 6 to 10 atoms in the heterocyclic moiety.

  Specific examples of the heterocycle and heteroaryl include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, Indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine Imidazoline, piperidine, piperazine, pyrrolidine, indoline and the like.

  Unless otherwise specified, the position occupied by hydrogen in the above group may be further substituted with a substituent. Examples of the substituent include, but are not limited to, hydroxy, oxo, nitro, methoxy, ethoxy , Alkoxy, substituted alkoxy, trifluoromethoxy, haloalkoxy, fluoro, chloro, bromo, iodo, halo, methyl, ethyl, propyl, butyl, alkyl, alkenyl, alkynyl, substituted alkyl, trifluoromethyl, haloalkyl, hydroxyalkyl , Alkoxyalkyl, thio, alkylthio, acyl, carboxy, alkoxycarbonyl, carboxyamide, substituted carboxyamide, alkylsulfonyl, alkylsulfinyl, alkylsulfonylamino, sulfonamide, substituted sulfone Amide, cyano, amino, substituted amino, alkylamino, dialkylamino, aminoalkyl, acylamino, amidino, amidoximo, hydroxamoyl, phenyl, aryl, substituted aryl, aryloxy, arylalkyl, arylalkenyl, Arylalkynyl, pyridyl, imidazolyl, heteroaryl, substituted heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, Substituted cycloalkyl, cycloalkyloxy, pyrrolidinyl, piperidinyl, morpholino, heterocycle, (heterocycle) oxy, And (heterocycle) alkyl, with preferred heteroatoms being oxygen, nitrogen and sulfur. If there is a vacancy in these substituents, they may be further substituted with alkyl, cycloalkyl, aryl, heteroaryl and / or heterocyclic groups. Where there is a vacancy in the carbon valence, it may be further substituted with halogen and with oxygen, nitrogen or sulfur bond substituents. If there are multiple such valence vacancies, these groups may be combined to form a ring by direct formation of a bond or by formation of a bond to a new heteroatom, preferably oxygen, nitrogen or sulfur. Good. The above substitutions are made when hydrogen substitution with substituents does not introduce unacceptable instabilities in the molecules of the invention, and when substitution of hydrogen with substituents is otherwise chemically reasonable. be able to.

  A “heteroatom-containing substituent” is a substituent that contains at least one non-halogen heteroatom. Specific examples of such substituents are not particularly limited. For example, hydroxy, oxo, nitro, methoxy, ethoxy, alkoxy, substituted alkoxy, trifluoromethoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl , Thio, alkylthio, acyl, carboxy, alkoxycarbonyl, carboxyamide, substituted carboxyamide, alkylsulfonyl, alkylsulfinyl, alkylsulfonylamino, sulfonamido, substituted sulfonamido, cyano, amino, substituted amino, alkylamino, dialkyl Amino, aminoalkyl, acylamino, amidino, amidoximo, hydroxamoyl, aryloxy, pyridyl, imidazolyl, heteroaryl, substituted hetero Preferred heteroatoms include reel, heteroaryloxy, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyloxy, pyrrolidinyl, piperidinyl, morpholino, heterocycle, (heterocycle) oxy, and (heterocycle) alkyl. Are oxygen, nitrogen and sulfur. If there is a vacancy in these substituents, they may be further substituted with alkyl, cycloalkyl, aryl, heteroaryl and / or heterocyclic groups. Where there is a vacancy in the carbon valence, it may be further substituted with halogen and with oxygen, nitrogen or sulfur bond substituents. If there are multiple such valence vacancies, these groups may be combined to form a ring by direct formation of a bond or by formation of a bond to a new heteroatom, preferably oxygen, nitrogen or sulfur. Good. The above substitutions are made when hydrogen substitution with substituents does not introduce unacceptable instabilities in the molecules of the invention, and when substitution of hydrogen with substituents is otherwise chemically reasonable. be able to.

A “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound but does not have undesired toxic effects. Pharmaceutically acceptable salt forms include, for example, various salts derived from acid or base adducts in polymorphic and amorphous forms. Acid addition salts can be formed using inorganic or organic acids. Specific examples of such acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, propionic acid, benzoic acid, naphthoic acid, oxalic acid, succinic acid Gentisic acid, maleic acid, fumaric acid, malic acid, adipic acid, lactic acid, tartaric acid, salicylic acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and ethanesulfonic acid It is done. Pharmaceutically acceptable base addition salts include metal or organic counterions such as, but not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium _{Alternatively} , it can be formed using a tetraalkylammonium salt, that is, NX ₄ ⁺ (X is C _1-4 ).

  A “tautomer” is a compound that can exist in one or more forms, referred to as tautomeric forms, one or more of the compounds resulting from the rearrangement of adjacent double bond configurations or Interconversion can be achieved by movement of two or more hydrogen atoms. These tautomeric forms are in equilibrium with each other, and the equilibrium point depends on the exact properties of the physical state of the compound. As long as tautomeric forms are possible, the present invention should be understood to relate to all possible tautomeric forms.

  A “solvate” is an addition complex compound in which a compound of Formula I or Formula II is bound to a pharmaceutically acceptable cosolvent in a certain ratio. The co-solvent is not particularly limited. For example, water, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol, tert-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, Examples include toluene, xylene, ethylene glycol, dichloromethane, 1,2-dichloroethane, N-methylformamide, N, N-dimethylformamide, N-methylacetamide, pyridine, dioxane and diethyl ether. Hydrates are solvates where the co-solvent is water. It should be understood that the definition of compounds of formula I and formula II includes all possible hydrates and solvates in any possible proportions so long as they have a given activity.

The present invention relates to pharmaceutical formulations comprising ROCK inhibitor compounds and related analogs.
To successfully develop a topical formulation for treating glaucoma, there are five important constraints: solubility, formulation stability, ocular surface tolerance, systemic exposure and aqueous humor exposure. The ocular surface is related to the corneal surface and the conjunctival surface. The ocular surface residence time is the average time that the drug stays on the ocular surface. Aqueous humor is a liquid in the anterior chamber and has a close correlation with the concentration in the trabecular meshwork, which is the site of action. Drugs with physicochemical properties that can simultaneously optimize all five constraints under certain conditions are rare. The ideal ophthalmic formulation for treating glaucoma is (1) sufficiently soluble to deliver a therapeutic amount of drug, and (2) sufficient to be stored for a long time as a commercial product as a glaucoma treatment. (3) good ocular surface tolerance at therapeutic doses, and (4) achievement of drug concentrations in the aqueous humor (site of action) in the treatment area with minimal systemic exposure and This makes it possible to minimize systemic side effects.

  Regarding the ROCK-inhibiting compounds of the present invention, the inventors have found that the pH of the formulation can affect three of the above five constraints. Lowering the pH improves the solubility and stability of the ROCK inhibitor compound in the aqueous formulation. On the other hand, the inventors have shown that increasing the pH of the formulation increases the drug penetrating into the anterior chamber by increasing the ocular surface residence time of the compound, resulting in an increase in the concentration of the compound in the aqueous humor. I found. The inventors have found that the pH of the formulation (pH 5.3-7.3) has no effect on systemic exposure. We have not found any evidence that the eye comfort is affected when the pH of the formulation is below pH 7.3. However, the ocular surface is generally more tolerant to acidic formulations than basic formulations.

  We have set pH 6.3-7.8 as a range of pH that allows acceptable sacrifice or exchange between solubility, stability, eye tolerance, systemic exposure and aqueous humor exposure. Specific and selected (eg, insufficient solubility is acceptable if tolerability or increased exposure is achieved at a certain pH).

  The concentration of the ROCK inhibitory compound affects eye comfort. That is, comfort decreases as the concentration decreases. The inventors have identified and selected 0.01 to 0.4% (w / v) as the concentration range of the ROCK inhibitor compound in the preparation. At such concentrations, the therapeutic effect is effectively realized and no eye inconvenience occurs.

  In the pharmaceutically acceptable pH range (pH 4.5 to pH 7.8) as a topical ophthalmic preparation, the present inventors adjust the pH of the preparation from an acidic pH to a physiological pH, and the water solubility becomes pH. It was unexpectedly found that certain ROCK inhibitor compounds that decrease with increase exhibit significantly increased anterior chamber bioavailability. The present inventors have also unexpectedly found that when the pH of the ophthalmic preparation increases, the ocular surface residence time of the ROCK inhibitor compound of the present invention increases and the concentration of aqueous humor increases. Increased ocular surface residence time and anterior chamber bioavailability allow for lower drug concentrations to be used in the treatment of diseases and disorders associated with cytoskeletal disruption, such as primary open angle glaucoma.

  We have found that systemic exposure, for example systemic exposure as measured by plasma concentration, is only related to the concentration and amount of ROCK inhibitor in the ophthalmic formulation and not to the pH or composition of the formulation. . Accordingly, by providing an ophthalmic formulation having a pH of 6.3-7.8 that is close to neutral pH but higher than the pH of commonly used ophthalmic formulations, the anterior eye of the formulation through increased membrane penetration. Increasing tuft bioavailability, but not accompanied by increased systemic exposure, can increase the eye treatment limit to the systemic treatment limit.

  Thus, even if the pH is limited to 6.3-7.8 due to solubility and stability, aqueous humor exposure is increased enough to make up for this limitation. According to the present invention, it is not necessary to expose a high concentration drug to the ocular surface, and the risk-to-effect of treatment can be optimized.

Rho Kinase Inhibiting Compounds Rho kinase inhibiting compounds useful in the present invention include compounds of general formula I and general formula II, and / or tautomers thereof, and / or pharmaceutically acceptable salts thereof, and / or The solvates and / or hydrates thereof are included.

  Compounds of formula I or formula II may exist as several forms of diastereomers. The general structures of Formula I and Formula II include all forms of diastereomers of the material, unless otherwise specified. Formula I and Formula II include mixtures of compounds of these formulas, for example, mixtures containing enantiomers, diastereomers, and / or other isomers in any ratio.

［式中、
Ｒ₁はアリールまたはヘテロアリールであり、任意に置換されていてもよく；
ＱはＣ＝Ｏ、ＳＯ₂または(ＣＲ₄Ｒ₅)_n3であり；
ｎ₁は１、２または３であり；
ｎ₂は１または２であり；
ｎ₃は０、１、２または３であり；

で表される環は、アルキル、ハロ、オキソ、ＯＲ₆、ＮＲ₆Ｒ₇またはＳＲ₆で任意に置換されていてもよく；
Ｒ₂は任意に置換されていてもよい次のヘテロアリール系から選択され；

Ｒ₃−Ｒ₇は独立してＨ、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルケニルまたはシクロアルキルアルキニルであり、任意に置換されていてもよい。］ A. Formula I
The compounds of formula I are as follows:

[Where:
R ₁ is aryl or heteroaryl and may be optionally substituted;
Q is C═O, SO ₂ or (CR ₄ R ₅ ) _n3 ;
n ₁ is 1, 2 or 3;
n ₂ is 1 or 2;
n ₃ is 0, 1, 2 or 3;

The ring represented by may be optionally substituted with alkyl, halo, oxo, OR ₆ , NR ₆ R ₇ or SR ₆ ;
R ₂ is selected from the following optionally substituted heteroaryl systems;

R ₃ -R ₇ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, which may be optionally substituted. ]

In formula I, preferred R ₁ is substituted aryl, more preferred R ₁ is substituted phenyl, preferred Q is (CR ₄ R ₅ ) _n3 , more preferred Q is CH ₂ , preferred n ₁ is 1 Or 2, preferred n ₂ is 1, preferred n ₃ is 1 or 2, and preferred R ₃ —R ₇ is H.

[1] One embodiment of the present invention is represented by Formula I, wherein R ₂ is optionally substituted 5-indazolyl or 6-indazolyl (R ₂ -1).
[1a] In embodiment 1, R ₂ -1 is substituted with one or more alkyl or halo substituents.
[1b] In embodiment 1, R ₂ -1 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[1c] In embodiment 1, R ₂ -1 is unsubstituted.

[2] In another embodiment, the present invention is represented by Formula I, wherein R ₂ is optionally substituted 5-isoquinolinyl or 6-isoquinolinyl (R ₂ -2).
[2a] In embodiment 2, R ₂ -2 is substituted with one or more alkyl or halo substituents.
[2b] In embodiment 2, R ₂ -2 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[2c] In embodiment 2, R ₂ -2 is unsubstituted.

[3] In another embodiment, the present invention is represented by Formula I, wherein R ₂ is optionally substituted 4-pyridyl or 3-pyridyl (R ₂ -3).
In [3a] embodiment 3, R ₂ -3 is substituted by one or more alkyl or halo substituents.
[3b] In embodiment 3, R ₂ -3 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[3c] In embodiment 3, R ₂ -3 is unsubstituted.

[4] In another embodiment, the present invention is represented by formula I, wherein R ₂ is optionally substituted 7-azaindol-4-yl or 7-azaindol-5-yl ( R ₂ -4).
[4a] In embodiment 4, R ₂ -4 is substituted with one or more alkyl or halo substituents.
[4b] In embodiment 4, R ₂ -4 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[4c] In embodiment 4, R ₂ -4 is unsubstituted.

[5] In another embodiment, the present invention is represented by formula I, wherein R ₂ is optionally substituted 4- (3-amino-1,2,5-oxadiazole-4 - yl) phenyl or 3- (3-amino-1,2,5-oxadiazol-4-yl) phenyl (R ₂ -5).
In [5a] embodiment 5, R ₂ -5 is unsubstituted.

[6] In another embodiment, the present invention is represented by formula I, wherein R ₂ is substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents; one of the group consisting of R ₂ -1~R ₂ -5 is.
[6a] In embodiment 6, R ₂ is substituted with one or more alkyl or halo substituents.
[6b] In embodiment 6, R ₂ is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.

[7] In another embodiment, the invention is represented by formula I, wherein R ₂ is one of the group consisting of R ₂ -1 to R ₂ -5 and is unsubstituted.

[8] In another embodiment, the present invention is represented by Formula I, wherein R ₃ is H.

[9] In another embodiment, the present invention is represented by Formula I, wherein Q is (CR ₄ R ₅ ) _n3 and n ₃ is 1 or 2.

[10] In another embodiment, the present invention is represented by formula I, wherein Q is (CH ₂ ) _n3 and n ₃ is 1.

[11] In another embodiment, the invention is represented by Formula I, wherein R ₁ is one or more alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl substitution Aryl or heteroaryl substituted with a group, and the above substituents may be optionally substituted.

  Specific examples of the embodiment 11 include, for example, the compounds shown in Table I below 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011 , 2.019, 2.020, 2.022, 2.023 and 2.031.

[12] In another embodiment, the invention is represented by formula I, wherein R ₁ is aryl or heteroaryl substituted with one or more heteroatom-containing substituents provided that First, when the substituent of R ₁ is acyclic and is bonded to R ₁ by a carbon atom, the substituent contains at least one nitrogen or sulfur atom, and secondly, R ₁ When the substituent is acyclic and attached to R ₁ by an oxygen or nitrogen atom, the substituent contains at least one additional oxygen, nitrogen or sulfur atom, and third, the substituents R ₁ are sulfone linkage "-SO ₂ -" when attached to R ₁ by, R ₂ is not R ₂ -2 substituted with nitrogen or oxygen.
[12a] In embodiment 12, the heteroatom-containing substituent is bonded to R ₁ by an oxygen atom or a nitrogen atom.
[12b] In embodiment 12, the heteroatom-containing substituent is bonded to R ₁ by a sulfide bond “—S—”.

  Specific examples of the embodiment 12 include, for example, the compounds shown in Table I below 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, 2.007, 1.003, 1.006, 1.007, 1.018. 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044 , 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029.

[13] In another embodiment, the invention is represented by formula I, wherein R ₁ is one or more alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl , Heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) Aryl or heteroaryl substituted with an alkynyl substituent, wherein the substituent is further substituted with one or more heteroatom-containing substituents provided that the substituent of R ₁ is acyclic. Te, carbon to bond the substituents R ₁ When the hetero-containing substituent of the substituent is located in the child, the hetero-containing substituent contains at least one nitrogen atom or sulfur atom.

  Specific compounds of the embodiment 13 include, for example, compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106 shown in Table I below. , 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122.

[14] In another embodiment, the invention is represented by Formula I, wherein R ₁ is one or more alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl substitution An aryl or heteroaryl substituted with a group, wherein the substituent may be optionally substituted and R ₂ may be optionally substituted 5-indazolyl (R ₂ -1) or 5 - is isoquinolinyl (R ₂ -2) .
[14a] In embodiment 14, R ₂ is 5-indazolyl (R ₂ -1) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl, or alkoxy substituents. is there.
[14b] In embodiment 14, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[14c] In embodiment 14, R ₂ is unsubstituted.

  Specific examples of the embodiment 14 include, for example, compounds 1.09, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011 shown in Table I below. , 2.019, 2.020, 2.022, 2.023 and 2.031.

[15] In another embodiment, the invention is represented by formula I, wherein R ₁ is aryl or heteroaryl substituted with one or more heteroatom-containing substituents, and R ₂ is Optionally substituted 5-indazolyl (R ₂ -1) or 5-isoquinolinyl (R ₂ -2), provided that the substituent of R ₁ is acyclic and contains a carbon atom When bound to R ₁ by a hydrogen atom, the substituent contains at least one nitrogen atom or sulfur atom, and secondly, the substituent of R ₁ is acyclic and R is bound by an oxygen atom or nitrogen atom. _When bound to ₁ , the substituent contains at least one additional oxygen, nitrogen or sulfur atom, and third, the substituent of R ₁ is a sulfone bond “—SO ₂ —. when attached to R ₁ by ", R ₂ is nitrogen or Not R ₂ -2 substituted by oxygen.
[15a] In embodiment 15, R ₂ is 5-indazolyl (R ₂ -1) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[15b] In embodiment 15, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[15c] In embodiment 15, R ₂ is unsubstituted.
[15d] In embodiment 15, the heteroatom-containing substituent is bonded to R ₁ by an oxygen atom or a nitrogen atom.
[15e] In embodiment 15, the heteroatom-containing substituent is bonded to R ₁ by a sulfide bond “—S—”.

  Specific examples of the embodiment 15 include, for example, the compounds shown in Table I below 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, 2.007, 1.003, 1.006, 1.007, 1.018. 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044 , 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029.

[16] In another embodiment, the invention is represented by Formula I, wherein R ₁ is one or more alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, hetero Aryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) ) Aryl or heteroaryl substituted with an alkynyl substituent, wherein at least one of the substituents is further substituted with one or more heteroatom-containing substituents, and R ₂ is optional May be substituted with 5 -Indazolyl (R ₂ -1) or 5-isoquinolinyl (R ₂ -2) provided that, firstly, the substituent of R ₁ is acyclic and the substituent is attached to R ₁ When a hetero-containing substituent of the substituent is attached to an atom, the hetero-containing substituent contains at least one nitrogen atom or sulfur atom.
In [16a] embodiment 16, R ₂ is one or more alkyl, halo, amino, alkylamino, with a hydroxyl or alkoxy substituents may be optionally substituted 5- indazolyl (R ₂ -1) is there.
[16b] In embodiment 16, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
In [16c] embodiment 16, R ₂ is unsubstituted.

  Specific examples of the embodiment 16 include, for example, compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106 shown in Table I below. , 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122.

［式中、
Ａｒは単環式または二環式のアリールまたはヘテロアリール環、例えばフェニルであり；
ＸはＡｒにおける１〜３個の置換基であり、それぞれが独立してＺがＡｒに結合しているＹ−Ｚの形態であり；
ＹはＺにおける１個または２個以上の置換基であり、それぞれが独立してＨ、ハロゲンまたはヘテロ原子含有置換基、例えば、特に限定されるわけではないが、ＯＲ₈、ＮＲ₈Ｒ₉、ＮＯ₂、ＳＲ₈、ＳＯＲ₈、ＳＯ₂Ｒ₈、ＳＯ₂ＮＲ₈Ｒ₉、ＮＲ₈ＳＯ₂Ｒ₉、ＯＣＦ₃、ＣＯＮＲ₈Ｒ₉、ＮＲ₈Ｃ(＝Ｏ)Ｒ₉、ＮＲ₈Ｃ(＝Ｏ)ＯＲ₉、ＯＣ(＝Ｏ)ＮＲ₈Ｒ₉またはＮＲ₈Ｃ(＝Ｏ)ＮＲ₉Ｒ₁₀、から選択され；
Ｚは、例えば、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、シクロアルキル、シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルケニル、シクロアルキルアルキニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、複素環、（複素環）アルキル、（複素環）アルケニル、（複素環）アルキニルまたは不存在から独立して選択され；
Ｒ₈はＨ、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、シクロアルキル、シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルケニル、シクロアルキルアルキニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、（複素環）アルキル、（複素環）アルケニル、（複素環）アルキニルまたは複素環であり；１個または２個以上のハロゲンまたはヘテロ原子含有置換基、例えば、特に限定されるわけではないが、ＯＲ₁₁、ＮＲ₁₁Ｒ₁₂、ＮＯ₂、ＳＲ₁₁、ＳＯＲ₁₁、ＳＯ₂Ｒ₁₁、ＳＯ₂ＮＲ₁₁Ｒ₁₂、ＮＲ₁₁ＳＯ₂Ｒ₁₂、ＯＣＦ₃、ＣＯＮＲ₁₁Ｒ₁₂、ＮＲ₁₁Ｃ(＝Ｏ)Ｒ₁₂、ＮＲ₁₁Ｃ(＝Ｏ)ＯＲ₁₂、ＯＣ(＝Ｏ)ＮＲ₁₁Ｒ₁₂またはＮＲ₁₁Ｃ(＝Ｏ)ＮＲ₁₂Ｒ₁₃、で任意に置換されていてもよく；
Ｒ₉およびＲ₁₀は独立してＨ、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、シクロアルキル、シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルケニル、シクロアルキルアルキニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、（複素環）アルキル、（複素環）アルケニル、（複素環）アルキニルまたは複素環であり；１個または２個以上のハロゲンまたはヘテロ原子含有置換基、例えば、特に限定されるわけではないが、ＯＲ₁₄、ＮＲ₁₄Ｒ₁₅、ＮＯ₂、ＳＲ₁₄、ＳＯＲ₁₄、ＳＯ₂Ｒ₁₄、ＳＯ₂ＮＲ₁₄Ｒ₁₅、ＮＲ₁₄ＳＯ₂Ｒ₁₅、ＯＣＦ₃、ＣＯＮＲ₁₄Ｒ₁₅、ＮＲ₁₄Ｃ(＝Ｏ)Ｒ₁₅、ＮＲ₁₄Ｃ(＝Ｏ)ＯＲ₁₅、ＯＣ(＝Ｏ)ＮＲ₁₄Ｒ₁₅またはＮＲ₁₄Ｃ(＝Ｏ)ＮＲ₁₅Ｒ₁₆、で任意に置換されていてもよく；
Ｒ₈、Ｒ₉およびＲ₁₀のいずれか２個は、直接結合、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ₂−および−ＮＲ₁₇−からなる群より選択された結合で任意に連結されて環を形成していてもよく；
Ｒ₁₁−Ｒ₁₇は独立してＨ、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、シクロアルキル、シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルケニル、シクロアルキルアルキニル、ヘテロアリール、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、（複素環）アルキル、（複素環）アルケニル、（複素環）アルキニルまたは複素環である。］ B. Formula II
In preferred compounds of formula I, R ₁ = Ar—X, as shown in formula II below.

[Where:
Ar is a monocyclic or bicyclic aryl or heteroaryl ring such as phenyl;
X is 1 to 3 substituents in Ar, each independently in the form of YZ where Z is bonded to Ar;
Y is one or more substituents in Z, each independently H, a halogen or a heteroatom-containing substituent such as, but not limited to, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , OCF ₃ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C ( ═O) OR ₉ , OC (═O) NR ₈ R ₉ or NR ₈ C (═O) NR ₉ R ₁₀ ;
Z is, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl Independently selected from: heteroarylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or absent;
R ₈ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; one or more halogen or heteroatom containing substituents, eg but _{not, OR 11, NR 11 R 12} , nO 2, SR 11, SOR 11, SO 2 R 11, SO 2 NR 11 R 12, NR 11 SO 2 R 12, OCF 3, CONR 11 R 12, NR 11 _{C (= O) R 12,} NR 11 C (= O) OR 12, OC ( O) NR ₁₁ R ₁₂ or _{NR 11 C (= O) NR} 12 R 13, in may be optionally substituted;
R ₉ and R ₁₀ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; one or more halogen or heteroatom-containing substituents, such as Although not specifically limited, OR ₁₄ , NR ₁₄ R ₁₅ , NO ₂ , SR ₁₄ , SOR ₁₄ , SO ₂ R ₁₄ , SO ₂ NR ₁₄ R ₁₅ , NR ₁₄ SO ₂ R ₁₅ , OCF ₃ , CONR _{14 R 15, NR 14 C (} = O) R 15, NR 14 C ( _{O) OR 15, OC (=} O) NR 14 R 15 or _{NR 14 C (= O) NR} 15 R 16, in may be optionally substituted;
Any two of R ₈ , R ₉ and R ₁₀ are optionally a direct bond, a bond selected from the group consisting of —O—, —S—, —SO—, —SO ₂ — and —NR ₁₇ —. They may be linked to form a ring;
R _{11 to} R ₁₇ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle. ]

In Formula II, preferred Y is H, halogen, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , OCF ₃ CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (═O) OR ₉ , OC (═O) NR ₈ R ₉ or NR ₈ C (═O) NR ₉ R ₁₀ More preferable Y is H, halogen, OR ₈ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , CONR ₈ R ₉ or NR ₈ C (═O) NR. ₉ R ₁₀ , preferred Z is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or absent, more preferred Z is alkyl, alkenyl, alkynyl, cycloalkyl or absent, Preferred Q is (CR ₄ R ₅ ) _n3 , Further preferred Q is CH ₂ , preferred n ₁ is 1 or 2, preferred n ₂ is 1, preferred n ₃ is 1 or 2, preferred R ₃ -R ₇ is H, preferred R ₈ is H, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl or heterocyclic ring, and preferred substituents of R ₈ are H, halogen, OR ₁₁ , NR ₁₁ R ₁₂ , SR ₁₁ , SOR ₁₁ , SO ₂ R ₁₁ , SO ₂ NR ₁₁ R ₁₂ , NR ₁₁ SO ₂ R ₁₂ , CONR ₁₁ R ₁₂ , NR ₁₁ C (═O) R ₁₂ , and preferred R ₉ -R ₁₇ is H or alkyl.

[1] One embodiment of the present invention is represented by Formula II, in which R ₂ is optionally substituted 5-indazolyl or 6-indazolyl (R ₂ -1).
[1a] In embodiment 1, R ₂ -1 is substituted with one or more alkyl or halo substituents.
[1b] In embodiment 1, R ₂ -1 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[1c] In embodiment 1, R ₂ -1 is unsubstituted.

[2] In another embodiment, the present invention is represented by Formula II, wherein R ₂ is optionally substituted 5-isoquinolinyl or 6-isoquinolinyl (R ₂ -2).
[2a] In embodiment 2, R ₂ -2 is substituted with one or more alkyl or halo substituents.
[2b] In embodiment 2, R ₂ -2 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[2c] In embodiment 2, R ₂ -2 is unsubstituted.

[3] In another embodiment, the present invention is represented by Formula II, wherein R ₂ is optionally substituted 4-pyridyl or 3-pyridyl (R ₂ -3).
In [3a] embodiment 3, R ₂ -3 is substituted by one or more alkyl or halo substituents.
[3b] In embodiment 3, R ₂ -3 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[3c] In embodiment 3, R ₂ -3 is unsubstituted.

[4] In another embodiment, the present invention is represented by formula II, wherein R ₂ is optionally substituted 7-azaindol-4-yl or 7-azaindol-5-yl ( R ₂ -4).
[4a] In embodiment 4, R ₂ -4 is substituted with one or more alkyl or halo substituents.
[4b] In embodiment 4, R ₂ -4 is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.
[4c] In embodiment 4, R ₂ -4 is unsubstituted.

[5] In another embodiment, the present invention is represented by Formula II, wherein R ₂ is optionally substituted 4- (3-amino-1,2,5-oxadiazole-4 - yl) phenyl or 3- (3-amino-1,2,5-oxadiazol-4-yl) phenyl (R ₂ -5).
In [5a] embodiment 5, R ₂ -5 is unsubstituted.

[6] In another embodiment, the invention is represented by Formula II, wherein R ₂ is substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents; one of the group consisting of R ₂ -1~R ₂ -5 is.
[6a] In embodiment 6, R ₂ is substituted with one or more alkyl or halo substituents.
[6b] In embodiment 6, R ₂ is substituted with one or more amino, alkylamino, hydroxyl or alkoxy substituents.

In [7] In another aspect, the present invention is represented by Formula II, in Formula II, R ₂ is a one of a group consisting of R ₂ -1~R ₂ -5, is unsubstituted.

[8] In another embodiment, the invention is represented by Formula II, wherein R ₃ is H.

[9] In another embodiment, the present invention is represented by Formula II, wherein Q is (CR ₄ R ₅ ) _n3 and n ₃ is 1 or 2.

[10] In another embodiment, the present invention is represented by Formula II, wherein Q is (CH ₂ ) _n3 and n ₃ is 1.

[11] In another embodiment, the present invention is represented by formula II, wherein Z is alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, hetero Arylalkynyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkylalkyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl.

  Specific examples of the embodiment 11 include, for example, the compounds shown in Table I below 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011 , 2.019, 2.020, 2.022, 2.023 and 2.031.

[12] In another embodiment, the invention is represented by Formula II, wherein Z is absent and Y is a heteroatom-containing substituent, such as, but not limited to, OR ₈ , NR ₈ R ₉ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (= O) OR ₉ , OC (═O) NR ₈ R ₉ or NR ₈ C (═O) NR ₉ R ₁₀ , provided that, firstly, the substituent Y is acyclic and Ar is substituted by a carbon atom. In the case where the substituent contains at least one nitrogen or sulfur atom, and secondly, the substituent Y is acyclic and is bonded to Ar by an oxygen or nitrogen atom. The substituent contains at least one additional oxygen, nitrogen or sulfur atom, and thirdly, When substituent Y is attached to Ar by a sulfone bond “—SO ₂ —”, R ₂ is not R ₂ -2 substituted with nitrogen or oxygen.
[12a] In embodiment 12, the heteroatom-containing substituent is bonded to R ₁ by an oxygen atom or a nitrogen atom.
[12b] In embodiment 12, the heteroatom-containing substituent is bonded to R ₁ by a sulfide bond “—S—”.

  Specific examples of the embodiment 12 include, for example, the compounds shown in Table I below 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, 2.007, 1.003, 1.006, 1.007, 1.018. 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044 , 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029.

[13] In another embodiment, the present invention is represented by formula II, wherein Z is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl, Y is a heteroatom Containing substituents such as, but not limited to, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R _{9 , OCF 3, CONR 8 R 9} , NR 8 C (= O) R 9, R ₈ C (= O) is _{OR 9, OC (= O)} NR 8 R 9 or _{NR 8 C (= O) NR} 9 R 10, provided that a Z acyclic, conjugating Z to Ar When Y is located on the carbon atom to be produced, Y contains at least one nitrogen atom or sulfur atom.

  Specific compounds of the embodiment 13 include, for example, compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106 shown in Table I below. , 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122.

[14] In another embodiment, the invention is represented by formula II, wherein Z is alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, hetero Arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl, R ₂ is optionally substituted 5-indazolyl (R ₂ -1) or 5-isoquinolinyl (R ₂ -2).
[14a] In embodiment 14, R ₂ is 5-indazolyl (R ₂ -1) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl, or alkoxy substituents. is there.
[14b] In embodiment 14, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[14c] In embodiment 14, R ₂ is unsubstituted.

  Specific examples of the embodiment 14 include, for example, compounds 1.09, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011 shown in Table I below. , 2.019, 2.020, 2.022, 2.023 and 2.031.

[15] In another embodiment, the invention is represented by Formula II, wherein Z is absent and Y is a heteroatom-containing substituent, such as, but not limited to, OR ₈ , NR ₈ R ₉ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (= O) OR ₉ , OC (═O) NR ₈ R ₉ or NR ₈ C (═O) NR ₉ R ₁₀ , wherein R ₂ is optionally substituted 5-indazolyl (R ₂ -1) or 5-isoquinolinyl (R ₂ -2), provided that, first, when substituent Y is acyclic and is bonded to Ar by a carbon atom, the substituent is at least one nitrogen atom Or a sulfur atom, and secondly, the substituent Y is acyclic and bonded to Ar by an oxygen or nitrogen atom If that is the substituent comprises at least one additional oxygen atom, a nitrogen atom or a sulfur atom, and, thirdly, the substituent Y is sulfone linkage - bound to Ar by "-SO _2" In some cases, R ₂ is not R ₂ -2 substituted with nitrogen or oxygen.
[15a] In embodiment 15, R ₂ is 5-indazolyl (R ₂ -1) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[15b] In embodiment 15, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
[15c] In embodiment 15, R ₂ is unsubstituted.
[15d] In embodiment 15, the heteroatom-containing substituent is bonded to R ₁ by an oxygen atom or a nitrogen atom.
[15e] In embodiment 15, the heteroatom-containing substituent is bonded to R ₁ by a sulfide bond “—S—”.

  Specific examples of the embodiment 15 include, for example, the compounds shown in Table I below 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, 2.007, 1.003, 1.006, 1.007, 1.018. 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044 , 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029.

[16] In another embodiment, the invention is represented by formula II, wherein Z is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl, Y is a heteroatom Containing substituents such as, but not limited to, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R _{9 , OCF 3, CONR 8 R 9} , NR 8 C (= O) R 9, _{R 8 C (= O) OR} 9, OC (= O) NR 8 R 9 or NR ₈ C (= O) a NR ₉ R _10, R ₂ is optionally optionally substituted 5- indazolyl (R ₂ -1) or 5- isoquinolinyl (R ₂ -2), however, the first, a Z is acyclic, when located Y is a carbon to couple Z to Ar, Y is Contains at least one nitrogen or sulfur atom.
In [16a] embodiment 16, R ₂ is one or more alkyl, halo, amino, alkylamino, with a hydroxyl or alkoxy substituents may be optionally substituted 5- indazolyl (R ₂ -1) is there.
[16b] In embodiment 16, R ₂ is 5-isoquinolinyl (R ₂ -2) optionally substituted with one or more alkyl, halo, amino, alkylamino, hydroxyl or alkoxy substituents. is there.
In [16c] embodiment 16, R ₂ is unsubstituted.

  Specific examples of the embodiment 16 include, for example, compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106 shown in Table I below. , 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122.

In embodiments 11 to 16 of formula II, preferred Q is (CR ₄ R ₅ ) _n3 , more preferred Q is CH ₂ , preferred n ₁ is 1 or 2, and preferred n ₂ is 1 and preferred n ₃ is 1 or 2, and preferred R ₃ is H.

  The compounds of the present invention are useful for ophthalmic applications, particularly for reducing intraocular pressure or treating glaucoma. In order to exert a therapeutic effect in ophthalmic applications, the compound must have sufficient efficacy and proper pharmacokinetic properties, such as good permeability to the ocular surface. In general, compounds having polar functional groups have favorable absorption properties and are particularly suitable for topical ophthalmic applications. In general, compounds having small lipophilic functional groups have good ROCK inhibitory potency.

The substitution of R ₁ in Formula I and X in Formula II are important factors for pharmacokinetic properties and ROCK inhibitory efficacy. Specifically, a compound having a polar functional group, in particular, a compound defined by the above aspects 11, 12, 13, 14, 15, and 16 of formulas I and II has sufficient ROCK inhibitory activity, Particularly suitable for topical ophthalmic use. Compounds with small lipophilic functional groups as defined in the above aspects 11, 12, 13, 14, 15 and 16 of formulas I and II have sufficient ocular permeability and show ROCK inhibition.

Specific compounds of Formula I and Formula II are shown in Table I below. In the compound examples, the number 1.nnn indicates a compound in which R ₂ is R ₂ -1, the number 2.nnn indicates a compound in which R ₂ is R ₂ -2, and the remaining compound numbers And the group R ₂ are numbered in a similar manner. In the following structures, hydrogen is omitted from the structural formula for convenience. The tautomers described indicate all possible tautomers. Structures are described to show preferred stereochemistry, but where stereoisomers can occur in these compounds, each one of the possible stereoisomers or a mixture of stereoisomers in any ratio is meant.

(R)-2-(3-((3-(イソキノリン-5-イルアミノ)ピロリジン-1-イル)メチル)フェノキシ)エタノール（化合物2.039）

(R)-N-(3-((3-(1H-インダゾール-5-イルアミノ)ピペリジン-1-イル)メチル)フェニル)エタンスルホンアミド（化合物1.123） Preferred ROCK inhibitor compounds of the present invention are not particularly limited. For example, the ROCK inhibitor compounds according to the above-mentioned aspects 5, 14, 15 and 16 and their related salts, tautomers, solvates or Hydrates are mentioned. Compound 2.039 and compound 1.123 are particularly preferred.

(R) -2- (3-((3- (Isoquinolin-5-ylamino) pyrrolidin-1-yl) methyl) phenoxy) ethanol (compound 2.039)

(R) -N- (3-((3- (1H-indazol-5-ylamino) piperidin-1-yl) methyl) phenyl) ethanesulfonamide (Compound 1.123)

Formulation Formulation The present invention relates to a ROCK inhibitor compound formulated in an aqueous solvent that is pH adjusted to increase ocular surface residence time and bioavailability in aqueous humor of the anterior chamber and to reduce systemic exposure. Formulations containing one or more drugs that improve ophthalmic properties are provided.

  The present invention provides an aqueous formulation of a ROCK inhibitor compound that is suitable for therapeutic use and is stable for long periods of time under storage conditions during normal use. The formulation is useful for reducing intraocular pressure in mammals. For topical administration, 1-2 drops of the formulation are administered to the ocular surface 1 to 4 times per day.

  The aqueous ophthalmic formulation of the present invention exhibits increased residence time and / or increased aqueous humor concentration on the ocular surface without increasing systemic concentrations.

  The present invention relates to a 0.001-2% ROCK inhibitor compound, a 1-100 mM buffer suitable for maintaining a pH of about 6.3-7.8, 0.01-2% surfactant, and osmotic pressure. Relates to an aqueous pharmaceutical formulation containing an isotonic agent capable of maintaining a pH of about 220-360 mOsm / kG. As used herein, “about” means ± 15%. A preferred pH is about 6.3 to 7.5, and a more preferred pH is about 6.3 to 7.3.

  The concentration of the ROCK inhibitor compound in the aqueous preparation is usually 0.001 to 2%, preferably 0.01 to 0.5%, more preferably 0.01 to 0.4%, more preferably 0.03 to 0. 0.2%, more preferably 0.03-0.15 or 0.03-0.1% (w / v).

  Suitable buffers for maintaining the pH between 6.3 and 7.8 include, for example, citrate buffer, phosphate buffer, maleate buffer, or combinations thereof. A suitable concentration of the buffer is 1-100 mM, preferably 5-50 mM, more preferably 5-25 mM, most preferably 10-20 mM.

  Surfactants or solubilizers suitable in the present invention are those that are acceptable for use in ophthalmic formulations. Surfactants can be ionic or nonionic. Preferably, the surfactant is nonionic. Useful surfactants include, but are not limited to, polysorbate 80, tyloxapol, polyoxyl stearate, polyethoxylated castor oil, poloxamer, poloxamine, medium and long chain fatty acids and phospholipids. The concentration of the surfactant in the preparation is about 0.01 to 3%, preferably 0.01 to 2%, more preferably 0.1 to 1% w / v.

  The isotonic agent is present in an amount that results in a final osmotic pressure of the formulation of 220-360 mOsm / kG, preferably 250-340 mOsm / kG, most preferably 260-320 mOsm / kG. The tonicity agent can be nonionic or ionic. Examples of the nonionic tonicity agent include diols such as glycerol, mannitol, and erythritol; and sugars such as dextrose. As other nonionic tonicity agents, polyethylene glycol, propylene glycol and the like that also function as a cosolvent can be used. The amount of nonionic tonicity agent is usually 0-20%, preferably 0-10%, more preferably 0-5%. Preferred nonionic tonicity agents are 2-6% glycerol, mannitol and dextrose.

  The tonicity agent may be an ionic tonicity agent such as sodium chloride, potassium chloride, balanced salt solution, sodium phosphate or sodium citrate. The ionic tonicity agent may be present in an amount of 0.3-1.5%, preferably 0.6-0.9%.

  Surfactants, tonicity agents, buffers and other components introduced into the formulation should have good water solubility and compatibility with other components in the formulation. Various national health regulations require that repeatedly administered ophthalmic formulations contain preservatives. Many of the known preservatives used in some other ophthalmic formulations cannot be used in the present invention. These preservatives are not considered safe for repeated use in the eye and also interact with the surfactants used in the present invention to form a complex that reduces the bactericidal activity of the preservatives. Because. In some embodiments, benzalkonium chloride is used as a safe preservative. Benzalkonium chloride may be used with disodium edetate (EDTA), a chelating agent that enhances antimicrobial activity. Other suitable preservatives include, for example, benzyl alcohol, methyl paraben, propyl paraben, chlorobutanol, chlorinated borate and benzethonium chloride. Typically, these preservatives are used at a level of 0.001-1%, preferably 0.001-0.25%, most preferably 0.001-0.2%.

  If desired, the formulation can contain a thickening agent that increases the residence time of the formulation on the ocular surface. Thickeners should not cause eye discomfort. For example, hydroxypropyl methylcellulose is acceptable as a thickener of the present invention.

  In some embodiments, the pharmaceutical formulation contains 0.5-0.9% ionic osmotic pressure regulator (eg, sodium chloride). The formulation further comprises 5-100 mM buffer (eg, sodium phosphate), 0.01-3% surfactant, 0.001-0.1% preservative, 0.01-0 chelating agent. Contains 5% w / v and pH adjuster. Such an aqueous composition has an osmotic pressure of 220-360 mOsm / kG and is formulated to pH 6.3-7.8.

  In another aspect, the pharmaceutical formulation contains 1-3% non-ionic tonicity agent (eg, glycerol). The formulation comprises 5-50 mM buffer (eg sodium phosphate and / or sodium citrate and citric acid), 0.01-2% surfactant, 0.005-0.5% chelating agent w / Contains v and pH regulators. Such an aqueous composition has an osmotic pressure of 220-360 mOsm / kG and is formulated to pH 6.3-7.8. The formulation contains 0.001-0.1% w / v preservative as needed.

  The present invention also relates to an aqueous pharmaceutical formulation comprising 0.001-2% ROCK inhibitor compound, 0.02-0.25% poloxamer, and an isotonic agent that maintains osmotic pressure at 220-360 mOsm / kG. The formulation optionally contains 1-100 mM buffer that maintains the pH at 6.3-7.8. Suitable buffers include, for example, phosphate buffer, citrate buffer, maleate buffer, or combinations thereof. A phosphate buffer is preferred.

  In certain embodiments, the pharmaceutical formulations of the invention are administered topically to the eye in the form of eye drops. The pharmaceutical preparation of the present invention is produced by an aseptic method or is finally sterilized. The liquid preparation of the present invention comprises a ROCK inhibitor compound, a buffer solution, an osmotic pressure regulator, a surfactant, a chelating agent; a nonionic polymer, a complexing agent, a solubilizer, a preservative and an antioxidant as necessary. Prepared by thorough mixing.

  The findings leading to the present invention relate to water solubility and formulation stability associated with pH. The inventors have unexpectedly found that the solubility and formulation stability of the formulation are increased in the low pH range (pH 4.5) acceptable for topical ophthalmic formulations, rather than in the high pH range. . The stability and solubility of the formulation decreases with increasing pH. However, at pH 6.3-7.8, the stability and solubility of the pharmaceutical formulations of the present invention are acceptable. Thus, the formulations of the present invention have acceptable water solubility and long-term stability, as well as improved therapeutic properties. At pH higher than 7.8, the stability of the compound is not acceptable and ocular tolerability is reduced.

  The pharmaceutical formulation can be sterilized by filtering the formulation with a sterile grade filter, preferably with a nominal pore size of 0.22 microns. The pharmaceutical formulation can also be sterilized by terminal sterilization using one or more sterilization methods. Although it does not necessarily limit as a sterilization method, For example, heat processing, such as an autoclave method, is mentioned.

  The pharmaceutical preparation of the present invention is useful as a drug for regulating wound healing after trabeculectomy. The pharmaceutical formulations of the present invention are generally less toxic to corneal endothelial cells than antimetabolites such as 5-fluorouracil or mitomycin C. The pharmaceutical formulations of the present invention inhibit actomyosin-induced contractions that cause deterioration of the actin microfilament system and perturbation of its membrane anchoring and weaken cell-extracellular matrix adhesion. These properties inhibit wound healing, thereby reducing post-surgery bleb failure.

  The pharmaceutical preparation of the present invention is useful as a drug for reducing intraocular pressure, and is useful for the treatment or prevention of glaucoma or glaucoma-related eye diseases.

  The pharmaceutical formulations of the present invention are useful for the treatment or prevention of neurodegenerative diseases resulting from increased intraocular pressure and damage to ocular neurons.

  The present invention provides methods for reducing intraocular pressure, methods for treating glaucoma, and methods for inhibiting wound healing after trabeculectomy. The method of the invention comprises administering the pharmaceutical formulation of the invention to a subject in need of treatment in an amount effective to alter the actin cytoskeleton, eg, to alter the actin cytoskeleton by inhibiting actin polymerization. including.

  The pharmaceutical formulations of the present invention can be administered to the patient's eye by any suitable means, but are preferably administered in the form of eye drops, sprays or gel-forming aqueous solutions. The pharmaceutical preparation of the present invention can also be applied to the eye using an aqueous preparation of liposomes, micelles, emulsions and / or microemulsions. Furthermore, the pharmaceutical preparation of the present invention can be injected into the tear film using a pump catheter system. In another aspect, the pharmaceutical formulation of the present invention can be applied to a continuous or selective release device such as a membrane, such as, but not limited to, Ocusert® (Alza Corp., Palo Alto, CA) or It is contained in the membrane used in Retisert (Bausch & Lomb, Rochester, NY). In yet another aspect, the pharmaceutical formulation of the present invention may be contained in, or carried on or bound to, a contact lens worn on the eye. Another aspect of the present invention includes pharmaceutical formulations contained within swabs or sponges that can be applied to the ocular surface. Another aspect of the invention includes a pharmaceutical formulation contained within a liquid spray that can be applied to the ocular surface. Another aspect of the invention includes direct injection of the pharmaceutical formulation into the lacrimal tissue or ocular surface.

  The present invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention to the specific embodiments described in the examples. Those skilled in the art will be able to fully practice the invention based on the above description. Accordingly, the following preferred specific embodiments are merely exemplary and are not to be construed as limiting the disclosure in any way.

  The present invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention to the specific embodiments described in the examples.

Example 1: Effect of pH on Compound Solubility Solubility was measured within a targeted pH range of 4.0-9.0 using a buffered co-solvent system (plON pSOL Evolution). The results in Table 1 show that compound 2.039 (A) had a solubility of> 20 mg / mL from pH 4 to 5.8 and that compound 1.123 (B) had a maximum solubility of 5 mg / mL at pH 5.6. Indicates that he was doing. These results indicate that the solubility of the compound decreases with increasing pH.

  Another experiment was conducted in which Compound A was formulated in a medium containing an isotonic agent (NaCl) and a nonionic surfactant and the solubility of the compound at the targeted pH 7.3 was measured. The surfactant concentration used was the maximum allowable concentration for excipients generally accepted as safe (GRAS). A compound at a concentration of 20 mM was formulated in 0.85% NaCl, then filtered and the concentration of Compound A was determined by UV analysis. As a result, Compound A had the highest solubility in the formulation containing polysorbate 80 and poloxamer 407. Thus, polysorbate 80 and poloxamer 407 can correct to some extent the decrease in solubility at a neutral pH of about 7.3.

Example 2: Stability of Compound A (improved stability)
Compound A was added to 0.9% saline containing 0.1% EDTA, 0.01% benzalkonium chloride and 0.8% polysorbate 80 at three pH levels: 5.3, 6.3. And 7.3. In order to determine the effect of pH on compound solubility, solutions were stored at 60 ° C. and analyzed by HPLC with UV detection. As shown in FIG. 1, an increase in pH from pH 5.3 to pH 6.3 and 7.3 caused a decrease in stability of Compound A due to chemical degradation.

Example 3: Effect of pH on ocular surface, aqueous humor and systemic bioavailability Dose formulation and administration. Compound A in 0.1 mM w / v (equivalent millimolar concentration is 3 mM) in 10 mM phosphoric acid, 0.8% polysorbate 80, 0.85% NaCl, 0.01% BAC, 0.1% EDTA Were formulated at three different pH levels: 5.3, 6.3 and 7.3. Compound A was administered as a drop (30 μL) to both eyes of each animal in the dosing group to examine the effect of pH on eye and systemic exposure.

  sampling. Plasma, aqueous humor and eye samples were collected from 2 animals (4 eyes) in each dosing group at 0.25, 0.5, 1 and 2 hours after dosing.

  FIG. 2A shows aqueous humor Cmax versus pH. FIG. 2B shows aqueous humor AUC vs. pH. Aqueous humor is a liquid in the anterior chamber of the eye that has a close correlation with the concentration at the site of action, ie the trabecular meshwork. Cmax indicates the peak concentration of the drug observed in the aqueous humor. AUC indicates the total concentration of drug in the aqueous humor over time. The results in FIGS. 2A and 2B show that increasing the pH of the formulation promotes exposure in aqueous humor.

  FIG. 3A shows plasma Cmax versus pH. FIG. 2B shows plasma AUC versus pH. Plasma concentration analysis indicates systemic exposure. Systemic exposure is exposure of the drug to the whole body. Cmax and AUC are the peak drug concentration for Compound A in plasma and the total drug concentration over time, respectively. The results in FIGS. 3A and 3B show that increasing the pH of the formulation has no effect on the plasma concentration of the compound.

  FIG. 4 shows the ocular surface concentration of Compound A over time. At 0.25 hours, 0.5 hours, 1 hour, and 2 hours after administration of Compound A, 40 μL of saline was applied to the eye, and the washing solution was collected as a sample. The ocular surface is related to the surface of the cornea and conjunctiva. The ocular surface residence time is the average time that Compound A stays on the ocular surface. FIG. 4 shows the increase in residence time as the pH of the Compound A formulation is increased from 5.3, 6.3 to 7.3. At 0.25 hours, the eye concentration of Compound A increased slightly between pH 5.3 and 6.3, but did not change from pH 6.3 to 7.3. At the point where time passed, the difference in the eye concentration of Compound A between pH 5.3 and 7.3 was large. The eye concentration of Compound A was constant between 1 and 2 hours at pH 7.3. This data shows that higher pH can increase the residence time over 2 hours, thereby increasing the drug that penetrates the anterior chamber.

  These experiments show that as the pH of the formulation increases, ROCK-inhibiting compounds exhibit increased ocular surface residence time and increased aqueous concentration in the anterior chamber, while having no effect on systemic exposure. Indicates not to.

Example 4: Effect of concentration and formulation on eye comfort Dose formulation and administration. Compound 2.039 was formulated into the following four types of formulations A to D so as to be 0.16% w / v.

  Formulation A: 10 mM phosphoric acid, 1% polysorbate 80, 0.85% NaCl, 0.02% BAC, 0.2% EDTA, pH 7.0

  Formulation B: 10 mM phosphoric acid, 1% polysorbate 80, 2.36% glycerol, 0.02% BAC, 0.2% EDTA, pH 7.1

  Formulation C: 10 mM phosphoric acid, 1% polysorbate 80, 2.36% glycerol, 0.02% BAC, 0.2% EDTA, 0.5% hydroxypropyl methylcellulose, pH 7.1

  Formulation D: 10 mM phosphoric acid, 1% polysorbate 80, 2.36% glycerol, 0.02% BAC, 0.2% EDTA, 1% 1,2 dimyristoyl-sn-glycero-3-phosphocholine, pH 7.1

  Pharmacodynamic analysis. Formulation AD was administered as 2 drops (1 drop 30 μL) to the right eye of each rabbit in the dosing group. Rabbits were evaluated for 15 minutes after instillation and behavioral changes were recorded. The composite score for each rabbit in each treatment group was calculated based on the number of times the rabbit blinks one eye, blinks both eyes, rubs the face (front pay wipe of the face), scratches and shakes the head. As the score increases, animal incomfort increases. Mean ± SE was calculated for each group.

  FIG. 5 shows the eye comfort score vs. prescription. As shown in FIG. 5, the addition of certain adjuvants such as 1,2 dimyristoyl-sn-glycero-3-phosphocholine, which is a thickener and increases ocular surface retention, increases eye comfort. did.

  Compound 2.039 is then formulated with Formula A above to 0.03%, 0.1% and 0.32% w / v, and compared to other approved glaucoma medications, The effect of concentration on comfort was investigated. The results are shown in FIG.

  FIG. 6 shows the eye comfort score versus the concentration of Compound A. As shown in FIG. 6, the eye comfort increased with increasing concentration of the ROCK inhibitor compound. However, eye comfort at low concentrations (0.03 and 0.1% w / v) has been observed in approved glaucoma medications such as ALPHAGAN (R), RESTASIS (R), pilocarpine and LUMIGAN (R). Comparable to that of

Claims (18)

At least one ROCK inhibitor of formula II 0.01-0.4% w / v, nonionic surfactant 0.01-2% w / v, and pH 6.3-7.8 An aqueous pharmaceutical formulation comprising an isotonic agent capable of maintaining an osmotic pressure between 220 and 360 mOsm / kG,
The aqueous pharmaceutical preparation, wherein the ROCK inhibitor, the surfactant and the isotonic agent are compatible in the preparation.

[Where:
Q is C═O, SO ₂ or (CR ₄ R ₅ ) _n3 ;
n ₁ is 1, 2 or 3;
n ₂ is 1 or 2;
n ₃ is 0, 1, 2 or 3;

The ring represented by may be optionally substituted with alkyl, halo, oxo, OR ₆ , NR ₆ R ₇ or SR ₆ ;
R ₂ is R ₂ -1 or R ₂ -2 and may be optionally substituted;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring;
X is 1 to 3 substituents in Ar, OR ₈ each _{independently, NR 8 R 9, SR 8} , SOR 8, SO 2 R 8, SO 2 NR 8 R 9, NR 8 SO 2 R ₉ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (═O) OR ₉ , OC (═O) NR ₈ R ₉ and NR ₈ C (═O) NR ₉ R ₁₀ Selected from the group;
R ₃ -R ₇ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, which may be optionally substituted;
R ₈ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₁ , NR ₁₁ R ₁₂ , NO ₂ , SR ₁₁ , SOR ₁₁ , SO ₂ R ₁₁ , SO ₂ NR ₁₁ R ₁₂ , NR ₁₁ SO ₂ R ₁₂ , OCF ₃ , CONR ₁₁ R ₁₂ , NR ₁₁ C (═O) R ₁₂ , NR ₁₁ C (═O _{) oR 12, OC (= O} ) NR 11 R 12 and _{NR 11 C (= O) NR} 12 R 13 Tona It may be optionally substituted with one or more heteroatom-containing substituents selected from the group;
R ₉ and R ₁₀ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₄ , NR ₁₄ R ₁₅ , NO ₂ , SR ₁₄ , SOR ₁₄ , SO ₂ R ₁₄ , SO ₂ NR ₁₄ R ₁₅ , NR ₁₄ SO ₂ R ₁₅ , OCF ₃ , CONR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , NR ₁₄ C (═O) OR ₁₅ , OC (═O) NR ₁₄ R ₁₅ and NR ₁₄ C (═O) Optionally substituted with one or more heteroatom-containing substituents selected from the group consisting of NR ₁₅ R ₁₆ ;
Any two of the substituents R ₈ , R ₉ and R ₁₀ are a direct bond, a bond selected from the group consisting of —O—, —S—, —SO—, —SO ₂ — and —NR ₁₇ —. Optionally linked to form a ring;
R _{11 to} R ₁₇ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle;
However,
First, when X is acyclic and is bonded to Ar by a carbon atom, X contains at least one nitrogen or sulfur atom,
Second, when X is acyclic and is bonded to Ar by an oxygen or nitrogen atom, X contains at least one additional oxygen, nitrogen or sulfur atom, and
Third, when X is bonded to Ar by a —SO ₂ — bond, R ₂ is not R ₂ -2 substituted with nitrogen or oxygen. ] At least one ROCK inhibitor of formula II 0.01-0.4% w / v, nonionic surfactant 0.01-2% w / v, and pH 6.3-7.8 An aqueous pharmaceutical formulation comprising an isotonic agent capable of maintaining an osmotic pressure between 220 and 360 mOsm / kG,
The aqueous pharmaceutical preparation, wherein the ROCK inhibitor, the surfactant and the isotonic agent are compatible in the preparation.

[Where:
Q is C═O, SO ₂ or (CR ₄ R ₅ ) _n3 ;
n ₁ is 1, 2 or 3;
n ₂ is 1 or 2;
n ₃ is 0, 1, 2 or 3;

The ring represented by may be optionally substituted with alkyl, halo, oxo, OR ₆ , NR ₆ R ₇ or SR ₆ ;
R ₂ is R ₂ -1 or R ₂ -2 and may be optionally substituted;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring;
X is 1 to 3 substituents in Ar, each independently in the form of YZ where Z is bonded to Ar;
Y is one or more substituents in Z, and each independently represents H, halogen, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , OCF ₃ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (═O) OR ₉ , OC (═O) NR ₈ R ₉ and NR Selected from the group consisting of ₈ C (═O) NR ₉ R ₁₀ ;
Z is alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, Heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl;
R ₃ -R ₇ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, which may be optionally substituted;
R ₈ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₁ , NR ₁₁ R ₁₂ , NO ₂ , SR ₁₁ , SOR ₁₁ , SO ₂ R ₁₁ , SO ₂ NR ₁₁ R ₁₂ , NR ₁₁ SO ₂ R ₁₂ , OCF ₃ , CONR ₁₁ R ₁₂ , NR ₁₁ C (═O) R ₁₂ , NR ₁₁ C (═O _{) oR 12, OC (= O} ) NR 11 R 12 and _{NR 11 C (= O) NR} 12 R 13 Tona It may be optionally substituted with one or more heteroatom-containing substituents selected from the group;
R ₉ and R ₁₀ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₄ , NR ₁₄ R ₁₅ , NO ₂ , SR ₁₄ , SOR ₁₄ , SO ₂ R ₁₄ , SO ₂ NR ₁₄ R ₁₅ , NR ₁₄ SO ₂ R ₁₅ , OCF ₃ , CONR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , NR ₁₄ C (═O) OR ₁₅ , OC (═O) NR ₁₄ R ₁₅ and NR ₁₄ C (═O) Optionally substituted with one or more heteroatom-containing substituents selected from the group consisting of NR ₁₅ R ₁₆ ;
Any two of the substituents R ₈ , R ₉ and R ₁₀ are a direct bond, a bond selected from the group consisting of —O—, —S—, —SO—, —SO ₂ — and —NR ₁₇ —. Optionally linked to form a ring;
R _{11 to} R ₁₇ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle. ] At least one ROCK inhibitor of formula II 0.01-0.4% w / v, nonionic surfactant 0.01-2% w / v, and pH 6.3-7.8 An aqueous pharmaceutical formulation comprising an isotonic agent capable of maintaining an osmotic pressure between 220 and 360 mOsm / kG,
The aqueous pharmaceutical preparation, wherein the ROCK inhibitor, the surfactant and the isotonic agent are compatible in the preparation.

[Where:
Q is C═O, SO ₂ or (CR ₄ R ₅ ) _n3 ;
n ₁ is 1, 2 or 3;
n ₂ is 1 or 2;
n ₃ is 0, 1, 2 or 3;

The ring represented by may be optionally substituted with alkyl, halo, oxo, OR ₆ , NR ₆ R ₇ or SR ₆ ;
R ₂ is R ₂ -1 or R ₂ -2 and may be optionally substituted;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring;
X is 1 to 3 substituents in Ar, each independently in the form of YZ where Z is bonded to Ar;
Y is one or more substituents in Z, each independently OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , OCF ₃ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (═O) OR ₉ , OC (═O) NR ₈ R ₉ or NR ₈ C (= O) NR ₉ R ₁₀ ;
Z is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkyl Alkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl or (heterocycle) alkynyl;
R ₃ -R ₇ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, which may be optionally substituted;
R ₈ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₁ , NR ₁₁ R ₁₂ , NO ₂ , SR ₁₁ , SOR ₁₁ , SO ₂ R ₁₁ , SO ₂ NR ₁₁ R ₁₂ , NR ₁₁ SO ₂ R ₁₂ , OCF ₃ , CONR ₁₁ R ₁₂ , NR ₁₁ C (═O) R ₁₂ , NR ₁₁ C (═O _{) oR 12, OC (= O} ) NR 11 R 12 and _{NR 11 C (= O) NR} 12 R 13 Tona It may be optionally substituted with one or more heteroatom-containing substituents selected from the group;
R ₉ and R ₁₀ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₄ , NR ₁₄ R ₁₅ , NO ₂ , SR ₁₄ , SOR ₁₄ , SO ₂ R ₁₄ , SO ₂ NR ₁₄ R ₁₅ , NR ₁₄ SO ₂ R ₁₅ , OCF ₃ , CONR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , NR ₁₄ C (═O) OR ₁₅ , OC (═O) NR ₁₄ R ₁₅ and NR ₁₄ C (═O) Optionally substituted with one or more heteroatom-containing substituents selected from the group consisting of NR ₁₅ R ₁₆ ;
Any two of the substituents R ₈ , R ₉ and R ₁₀ are a direct bond, a bond selected from the group consisting of —O—, —S—, —SO—, —SO ₂ — and —NR ₁₇ —. Optionally linked to form a ring;
R _{11 to} R ₁₇ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle;
Provided that when Z is selected from the group consisting of alkyl, alkenyl and alkynyl, and Y is located on the carbon that bonds Z to Ar, then Y contains at least one nitrogen or sulfur atom. ] At least one ROCK inhibitor of formula II 0.01-0.4% w / v, nonionic surfactant 0.01-2% w / v, and pH 6.3-7.8 An aqueous pharmaceutical formulation comprising an isotonic agent capable of maintaining an osmotic pressure between 220 and 360 mOsm / kG,
The aqueous pharmaceutical preparation, wherein the ROCK inhibitor, the surfactant and the isotonic agent are compatible in the preparation.

[Where:
Q is C═O, SO ₂ or (CR ₄ R ₅ ) _n3 ;
n ₁ is 1, 2 or 3;
n ₂ is 1 or 2;
n ₃ is 0, 1, 2 or 3;

The ring represented by may be optionally substituted with alkyl, halo, oxo, OR ₆ , NR ₆ R ₇ or SR ₆ ;
R ₂ -5 are

And may be optionally substituted;
Ar is a monocyclic or bicyclic aryl or heteroaryl ring;
X is 1 to 3 substituents in Ar, each independently in the form of YZ where Z is bonded to Ar;
Y is one or more substituents in Z, and each independently represents H, halogen, OR ₈ , NR ₈ R ₉ , NO ₂ , SR ₈ , SOR ₈ , SO ₂ R ₈ , SO ₂ NR ₈ R ₉ , NR ₈ SO ₂ R ₉ , OCF ₃ , CONR ₈ R ₉ , NR ₈ C (═O) R ₉ , NR ₈ C (═O) OR ₉ , OC (═O) NR ₈ R ₉ and NR Selected from the group consisting of ₈ C (═O) NR ₉ R ₁₀ ;
Z is independently absent, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, Selected from the group consisting of heteroarylalkenyl, heteroarylalkynyl, heterocycle, (heterocycle) alkyl, (heterocycle) alkenyl and (heterocycle) alkynyl;
R ₃ -R ₇ are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, which may be optionally substituted;
R ₈ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl , Heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₁ , NR ₁₁ R ₁₂ , NO ₂ , SR ₁₁ , SOR ₁₁ , SO ₂ R ₁₁ , SO ₂ NR ₁₁ R ₁₂ , NR ₁₁ SO ₂ R ₁₂ , OCF ₃ , CONR ₁₁ R ₁₂ , NR ₁₁ C (═O) R ₁₂ , NR ₁₁ C (═O _{) oR 12, OC (= O} ) NR 11 R 12 and _{NR 11 C (= O) NR} 12 R 13 Tona It may be optionally substituted with one or more heteroatom-containing substituents selected from the group;
R ₉ and R ₁₀ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle; with one or more halogens, OR ₁₄ , NR ₁₄ R ₁₅ , NO ₂ , SR ₁₄ , SOR ₁₄ , SO ₂ R ₁₄ , SO ₂ NR ₁₄ R ₁₅ , NR ₁₄ SO ₂ R ₁₅ , OCF ₃ , CONR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , NR ₁₄ C (═O) OR ₁₅ , OC (═O) NR ₁₄ R ₁₅ and NR ₁₄ C (═O) Optionally substituted with one or more heteroatom-containing substituents selected from the group consisting of NR ₁₅ R ₁₆ ;
Any two of the substituents R ₈ , R ₉ and R ₁₀ are a direct bond, a bond selected from the group consisting of —O—, —S—, —SO—, —SO ₂ — and —NR ₁₇ —. Optionally linked to form a ring;
R _{11 to} R ₁₇ are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, hetero Arylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle) alkyl, (heterocycle) alkenyl, (heterocycle) alkynyl or heterocycle. ]   The nonionic surfactant is selected from the group consisting of polysorbate, tyloxapol, polyoxyl castor oil, poloxamer, polyethylene glycol, caprylic acid triglyceride, polyoxyl stearate, glyceryl monostearate and combinations thereof. The aqueous pharmaceutical formulation in any one of -4.   6. The aqueous pharmaceutical formulation of claim 5, wherein the nonionic surfactant is polysorbate, poloxamer or a combination thereof.   The aqueous pharmaceutical formulation according to any one of claims 1 to 4, further comprising a 1 to 100 mM buffer capable of maintaining a pH of 6.3 to 7.8.   The aqueous pharmaceutical formulation of claim 7, wherein the buffer is a citrate buffer, a phosphate buffer, a maleate buffer, or a combination thereof.   The aqueous pharmaceutical formulation according to any one of claims 1 to 4, further comprising a chelating agent and / or a preservative.   The aqueous pharmaceutical formulation according to any one of claims 1 to 4, wherein the tonicity agent is a nonionic tonicity agent.   11. An aqueous pharmaceutical formulation according to claim 10, wherein the nonionic tonicity agent is glycerol, mannitol or dextrose.   The aqueous pharmaceutical formulation according to any one of claims 1 to 4, wherein the tonicity agent is an ionic tonicity agent.   The aqueous pharmaceutical formulation according to claim 1, wherein the ROCK inhibitor is (R) -2- (3-((3- (isoquinolin-5-ylamino) pyrrolidin-1-yl) methyl) phenoxy) ethanol.   The aqueous pharmaceutical according to claim 1, wherein the ROCK inhibitor is (R) -N- (3-((3- (1H-indazol-5-ylamino) piperidin-1-yl) methyl) phenyl) ethanesulfonamide. Formulation.   The aqueous pharmaceutical formulation according to any one of claims 1 to 4, wherein the ROCK inhibitor is 0.03 to 0.2% (w / v).   The aqueous pharmaceutical preparation according to any one of claims 1 to 4, wherein the pH is 6.3 to 7.3. A method for reducing intraocular pressure in a subject in need thereof,
Identifying a subject in need thereof, and administering to the subject the aqueous pharmaceutical formulation of any of claims 1 to 4 in an amount effective to inhibit actomyosin interaction, Method.   The method of claim 17, wherein glaucoma is treated by the method.

Images