TW200526205A - Nitrogen-containing heterocyclic compound, and medicine containing such compound as effective ingredient - Google Patents

Abstract

The present invention is related to a compound represented by the general formula (I), salts thereof, solvates thereof, prodrugs thereof or cyclodextrin inclusion compound of the same, (wherein all the symbols are as defined in the description). Because the compounds of the present invention have strong agonistic action to EP2, strong effect of reducing intraocular pressure and small irritation to eyes, they are useful in treating eye diseases such as glaucoma, ocular hypertension, macular edema, macular degeneration, the decrease in blood flow of retina and optic papilla, the rise in tension of retina and optic nerve, myopia, hyperopia, astigmatism, xerophthalmia, retinal detachment, cataract and so on.

Description

200526205 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to: (1) a compound represented by the general formula ⑴, a salt thereof, a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof ( cyclodextrin inclusion compound)

(All symbols in the formula have the same meanings as those described later), (2) a therapeutic and / or preventive agent for eye diseases containing a compound represented by the general formula ⑴, and (3) 2-[(2-{(2R)- Crystallization of 2-[(3,5-Digasphenoxy) methylketopyrrolidinyl} ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester. [Prior technology] Glaucoma is characterized by the circulatory disturbance of the aqueous humor leading to the suffering of the aqueous humor, which continuously raises the intraocular pressure and oppresses the optic nerve, causing temporary or permanent eye loss, vision loss and other visual dysfunction. . The onset of the disease is originally an increase in intraocular pressure, but even if the intraocular pressure is normal, ^ product may continue to cause an increase in intraocular pressure, visual field defects, and decreased vision. Although it is an increase in intraocular pressure, there are cases where the intraocular pressure is normal. This is called normal or low tonic pressure in ancient clothes. Even if the intraocular pressure is high, there will be no obstacles. Calendar. The above glaucoma is effective. Glaucoma and high eye treatment, surgical treatment. Eye treatment is the mainstream for the first treatment. . The cause of the disease, but there are also optic nerves that are legitimate or you even if the intraocular pressure is normal. Eye disgust I. Reed or low intraocular pressure sound ancient BP. ~ .Ilm.,

In order to avoid the J effect, the initial treatment was administered locally. 316616 5 200526205 is a single addition for reducing intraocular pressure. The mechanism of action of 丨 y is to inhibit the eyes and households and promote the outflow of aqueous humor. The former is, for example, an anti-production agent, and the latter is, for example, parasympathetic nerve overflow / dehydration prostaglandin drugs. Among them, there are two combinations: two: two: drug, pre-glaucoma drug therapy needs long-term. " Because of this, it is possible to suppress the side effects of the two magnets. It is true that the reduction effect and side effects of the Ninja system use less medicine, starting from low concentrations. 】 Jian Zhi Zuo added 1 dose of high-concentration medicament or the action of the medicament is different: Lifting agent = such as sympathetic nerve action, parasympathetic nerve action, prostaglandin-based agent, carbonic acid dehydratase hindrance: branch π adduction ^ sensory nerve depression Yaozhiwan blocking medicine side effects ^ support ^ And, reports of inter-state status, fatigue, insanity, sexual dysfunction, insufficiency, Xu Mai, blood loss, shaking, etc. Facial selective adrenaline, which is used as a copious drug, is used locally as a drug, and its chance of causing an allergic or toxic reaction is quite high. Cardiac agonists can effectively reduce dust. But cause allergic reactions or drug properties (rapid response 孀

发生 _ylaxia)) 's occurrence_high. @ Sympathetic nerve action of the bile test action The drug has symptoms of cataract and conjunctival congestion. Carbonic dehydratase inhibitors have side effects such as fatigue or loss of appetite, depression, paresthesia, abnormal serum electrolytes, gallstones, and blood diseases. Some patients also complained that there was a bad taste in their mouths. The prostaglandin-based agents currently used are isoproterone (dipropyrono]] rostone and latanoprost as agonists. FP agonists promote aqueous humor outflow. The aqueous humoral outflow pathway is the fiber column belt outflow pathway and the uveal sclera outflow pathway. There are FP 316616 6 200526205 agonists to promote the allergy of the aqueous humor from grape m FP agonists: a report.廿 >% I do not see systemic side effects in one hundred and ten, "The main side effect is to increase the vocabulary in the rainbow / especially 疋> canine brown iridescence, etc. > children, reports of worsening glucoperitonitis. Hand color The EP2 agonist not only promotes the release of aqueous humor from the eye, but also promotes the development of P. lucidum. There is no outflow pathway in the epidermis, and the pathway “outflows”, which decreases _. It also has neuroprotection for the retina and optic nerve: ‘so you can go back to ... as seen by the activator. Therefore, ΕΙ > 2 stimulates 1 & ~ Yueyouyan For the manufacture of pharmaceuticals, especially pharmaceuticals in the ophthalmology field are high-purity original drugs. Due to the fact that EP is stunned at this time, and EIW ’s glandular organisms are "active shellfish, even if only a small amount of impurities are mixed, it needs to be avoided. As a result, :::: scribe: it is an oily substance that is difficult to crystallize. The compound is also difficult to be distilled. It is purified by two-column chromatography. In order to be used in the manufacture of pharmaceuticals: substance: Γ: Yuanle's purity to a sufficient level, it is necessary to use crude = column chromatography, for example. After refining or making the compound into any salt, the multi-step process is repeated. However, the re-column layer is related to the increase in the number of steps. It is time-consuming and time-consuming to remove the solvent. The compound is made into a salt and recrystallized. In this case, the structure of the compound needs to have an acidic group or a test group, and it is not suitable for neutral compounds. As long as it can be obtained, a crystalline EP2 agonist can be used as a simple product for simple recrystallization operation. 'Especially the high-purity tritium agonist II WO2003 / 74483, which is expected in the ophthalmology field, is disclosed. The compound disclosed in the specification is known to have 316616 7 200526205 agonism, and can be used for the prevention and / or treatment of immune diseases and allergic diseases. , Dysmenorrhea, early 1, miscarriage, alopecia, "membrane neurological disorder, erectile insufficiency, arthritis, lung injury, pulmonary fibrosis, pneumonia, bronchitis, chronic obstructive respiratory disease, liver injury treasure, " Hepatitis, cirrhosis, shock 1 inflammation, renal insufficiency, circulatory system diseases, systemic inflammatory syndrome, sepsis, Hemophagocytlc syndrome, macrophage activation syndrome, SUirs dlsease , Kawasaki disease, heat injury, systemic granulomatosis, ulcerative colitis, Crohn's disease (CrGhn, howling, Cytocamemia during dialysis, multiple organ insufficiency, bone disease, However, there is no record of the crystal of the disclosed EP2 agonist. [Summary of the Invention] The subject of the present invention is to provide a safe and useful EP2 agonist for glaucoma treatment, especially a high-purity protopamine with EI > 2 agonism. As a result of intensive research by the characters of the present invention, it is found that the novel lysate σ represented by the general formula (1) has a strong Ep2 agonizing effect. It is further found that the compound of the present invention represented by the general formula 具 has It has a strong effect on reducing the eye, and has a stinging effect on the eyes. Therefore, the compounds of the present invention have reduced blood flow to eye diseases, such as glaucoma, eye disease I, papilloma, macular degeneration, and retina and optic nerve papillae. The treatment of retinal and optic nerve tension, myopia, hyperopia, vision, dry eye, retinal detachment, cataract, etc. is effective. It is found that in the manufacture of pharmaceuticals, especially the eye drops with strict specifications, it will be 2 degrees higher. Manufactured by a simple method, which is very advantageous in the industrial manufacture of pharmaceuticals. Even in prostaglandin derivatives, it is known to be particularly difficult to crystallize. 316616 8 200526205 Vinegar derivatives that can be crystallized by simple methods (recrystallization) can also be crystallized. , Its crystal manufacturing. More surprisingly, the researchers found that in the chemical compound b shown in the material, the new compound 2 which is very useful as a pharmaceutical raw material [(2-{(2R) -2-[(3 , 5-Dichlorophenoxy) methyl] _5_Branyl, each group is small, "Ethyl) thio] -1,3. this invention. That is, the present invention relates to 1 · 2-[(2-{(2R) -2 _ [(3,5_ 二) characterized by having any one or more of the following physicochemical values represented by A, B, and C Benzyloxy) methyl] -5_ketopyrrolidine-1 -yl} ethyl) thio; crystallization of isopropyl 3, thiazole_4_carboxylic acid: A · Powder X shown in Figure 1 X-ray diffraction spectrum diagram; B · Infrared absorption spectrum diagram shown in Fig. 2 measured by the total reflection method; c · Differential scanning calorimetry diagram shown in Fig. 3, 2 · It has the following A, B1 and C1 2-[(2-{(2R) -2-[(3,5-digas phenoxy) fluorenyl ketone group than each 17-l-yl group} Ethyl) thio] -1,3-thiazole-4-isopropyl carboxylate crystal: A1 · In the powder X-ray diffraction spectrum pattern, 20 is 12 · 8 2, 1 3.3 0, 15.15, 16.71 , 16.95, 18.85, 21.06, 21.54, 22.55, 24.25, 25.50, 26.26, 27.06, 28.30, and 29.92; B 1: In the infrared absorption spectrum measured by total reflection method, at 1 71 7, 1687, 1675, 1661, 1 586, 1567, 1443, 1423, 1382, 1257, 1211, 1202, 1107, 1020, 949, 924 829,798,781,746, 667,654,616,569,506,427, and 411cm-1 absorption peak; 9 316616 200526205 C1: in differential scanning calorimetry at 60.6. (: There is an endothermic peak, 3. The crystals disclosed in the above 1 A 2 have a chemical purity of more than 99.0%, and the crystals that cannot be exposed in the household have 99. Zheng Shang's chemical pure sound 5. The one in the above 1 or 2 is disclosed. , Electricity producer, crystallizer, ..., r, organic solvents that can contain water for the junction 6. The above 5 is disclosed in Ganshan ^ # 1 > ii ^ # 1 τ; ^ fi; ^ Vk ^ #J ^ ^ ^ ^ ^ ^ f Lower alcohol-based solvents and organic solvent solvents, mixed solvents on the above, kinds of grains or two kinds of 7. 7. The crystal system disclosed in 1 and 2 above can be used to contain water directly. Paraffin-based solvents, 7'-chain ether-based solvents, and 8. The above! Or 2 revealed "A; Γρ complex solvent to recrystallize the producer, < ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, H-p, ep2, 9 in the above 1 Or 2 revealed the place said 3 users, "have the prevention and / or treatment of eye diseases 10. The crystals disclosed in 9 above, wherein the disease, yao disease is glaucoma or high intraocular pressure 11. Use 1 or 2 above The crystallized therapeutic agent disclosed, the prevention and / or treatment of people's diseases. 12. The prevention and / or treatment disclosed in the above 11 is glaucoma or ocular hypertension, among which Mugen disease is The crystals revealed by the above 2]%, Le, Parasympathetic Nerve Acting, Sympathetic Nerve-Spontaneous Sympathetic Nerve Acting Agent, Carbonic Acid Dehydration Mother-Barrier Drug, and T ~~ Wood-making, Prostaglandin-based Gasoline Medicines, 10 200526205 14. Combination of the medicinal composition disclosed in the above 1 or 2 15. Mammalian glaucoma characterized by administering an effective amount of the above-mentioned process or the crystal disclosed in 2 above in mammals Or a method for preventing and / or treating ocular hypertension, 16. Use of the crystals disclosed in 1 or 2 above for the manufacture of a preventive and / or therapeutic agent for glaucoma or ocular hypertension, Π. Formula (I) Compound 'its salt, its solvate, its prodrug or: its cyclodextrin inclusion compound--COOR1

A (I) (wherein A represents a hydrocarbon group which may have a substituent, and R1 represents a C1 to 6 hydrocarbon group which may be substituted by a halogen atom, one is α_configuration, cold-configuration, or a mixture thereof), 18 · 17 The disclosed compound is selected from 2-[(2-{(2R) _2 _ [(3,5_dichlorophenoxy) methyl] -5-ketopyrrolidine- 丨 _yl} ethyl) thio group丨, isothiazole, thiazolium acid, 2-[(2-{(2 porphyrin 2 _ [(3,5_digas phenoxy) methyl] dongone pyrrolidine small group} ethyl) thio] -; 1,3-thiazole-4-carboxylic acid ethyl ester, 2-[(2-{(2R) -2-[(lE, 4S) -4- (l-ethylcyclobutylylbutylene) Yl] -5-ketopyrrolidine-i-yl} ethyl) thio] q, 3-thiwalic acid isopropyl acetate and 2-[(2-{(2R) -2-[(lE, 4S ) l (1-ethylcyclobutyl) _cardiacyl small butenyl] -5-ketopyrrolidine-i-yl} ethyl) thiothiazole_cardiobutyl carboxylate group, 19 .The above 18 unresolved compounds are 2 _ [(2 _ {(2 is called 2 _ [(3,5_digas styloxy 316616 11 200526205 group) methyl] -5-keto □ slightly burned-丨 _ group} iso Propyl ester, ethyl) thio] -1,3- thiawa_4-gallic acid 20. The compounds disclosed in the above 17 to 19 are thallium agonists, 21. containing the above 17 The pharmaceutical composition of the compound disclosed in the above: The pharmaceutical composition of the above 21 is prevention and / or treatment of the eye disease wherein glaucoma or 23. The pharmaceutical composition of the above 22 in ocular hypertension, 24. Taking mammals with glaucoma isolated from an effective amount of the compound disclosed in the above-mentioned mouth, its salt, its solvate, drug-injection, or dextrin-encapsulated compound A method for preventing and / or treating ocular tension, and 25. A compound represented by the general formula (1) disclosed in the above 17 for the manufacture of a preventive and / or therapeutic agent for glaucoma or ocular hypertension, ^ * 1 ^ The use of Liuxing salt, its solvate, its hydrazone or its cyclodextrin inclusion compound. In the general formula ⑴, the "nicotinyl group" in the "hydrocarbyl group which may have a substituent" shown by A may be exemplified by a straight chain Or branched aliphatic hydrocarbon group, cyclic hydrocarbon group or cyclic hydrocarbon group-aliphatic hydrocarbon group, cyclic hydrocarbon group-cyclic hydrocarbon group, etc. Examples of the "linear or branched aliphatic hydrocarbon group" include " q to 8 aliphatic hydrocarbon groups ", etc.," C1 to 8 lipids `` Group hydrocarbon '' may be exemplified by fluorenyl, ethyl, propyl, isopropyl, butyl, second-butyl, p-butyl, pentyl, hexyl, heptyl, octyl, etc. Example 2 ^ Alkenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octyl Diene 3] 6616 200526205, hexadienyl, heptadienyl, heptadienyl and the like. 2 to 8 alkyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl, hexadiynyl, heptyl C2 to 8 alkynyl bad hydrocarbon groups such as dialkynyl, octyl-alkynyl, hexatriynyl, heptadiynyl, octatriynyl, and the like can be listed as "11 quaternary / working; ^^-like hydrocarbon group". Examples of the "saturated cyclic hydrocarbon group" include cyclopropane, cyclobutane, cyclopentane, ring M, cyclofluorene, cyclobranch, cyclononane, cyclodecane, malundeane, bad dodecane, and cyclodeca Cyclocarbons such as tricarbonane, cyclotetradecane, cyclodeca, and carbon, such as perhydropentadiene, perhydrokappa, perhydrogenation, perhydronaphthalene, perhydroheptene, spiro [4.4] non Burn, snail [4 5] sesame burn, snail [5 A ten: burn people —% [2.2_1] Geng Yuan, Second Ring [3.1 .; 1] Geng Yuan, Second Ring [2 2 2], Wu, Zhigang Alkanes, normantanes (noradaman tan and cyclic hydrocarbons), etc. "Unsaturated Yan Canguang's saturated saturated clothes-like hydrocarbons" can be exemplified by cyclopentene, cyclohexane, nuclear heptane, cyclooctane , Cyclopentamidine-Lithium-π Clothing 戍 — ^ ¥ Cycloalkenyl pings such as hexadiene, cycloheptadiene, nuclear octadiene, etc. ^ 丄 For example, aromatic compounds such as Ben, Austria, Nai, phenanthrene, anthracene, etc. Groups, such as pendene, indene, indane, dihydronaphthalene, Wang Ruben, as · benzodi = bicyclo, irbefil, t 2 diisocyanate. 1,1] hept-2-ene , Bicyclic [2.2.2] octylene-2, "3 to 15-membered unsaturated cyclic hydrocarbons", etc. "Cycloalkyl-aliphatic hydrocarbons Base "aliphatic hydrocarbyl group", a bad-looking hydrocarbyl group of a beautiful man ", and naphthyl-1-naphthylmethanyl C7 5 > Benzyl ethyl, propyl iryl, C7 to 16 aralkyl earth , 2- (2-naphthylvinyl), 4 1 acryl coat 1-lane-1-butane:% groups such as C8 to 16-3166] 6 13 200526205 Dilute groups, such as cyclopropylmethyl, cyclohexylmethyl, Cyclohexylethyl, cyclohexyl, propyl, 1-methyl small cyclohexylfluorenyl, etc. (C3 to 8 cycloalkyl) _ (ci to 4 alkyl), such as 3-cyclohexylmethyl, etc. (C3 to 8-ring dilute group) _ (ci to 4-carbyl), etc. ^ "Cyclic hydrocarbon group-cyclic hydrocarbon group" can be exemplified by the above-mentioned "cyclic hydrocarbon group" and "cyclic fe group" in combination, for example, phenylbenzene Group, anthylphenylphenyl group, etc. The "substituent group" in the "hydrocarbon group which may have a substituent group" shown in A can be listed. For example, (1) may have a substituent group (for example (: to 4 alkyl group, amine (Sulfo, sulfo, halide, atom, carboxyl, cyano, nitro, keto, thioketo, hydroxyl, methoxy ', rudifluorofluorenyl, trifluoromethoxy, etc.) ", The" hydrocarbyl group "has the same meaning as the above-mentioned" hydrocarbyl group ", (2) may Has a substituent (such as a hydrocarbyl group, an amino group, a stone kappa group, a halogen atom, a carboxyl group, a cyano group, a nitro group, a keto group, a thioketo group, a hydroxyl group, a fluorenyl group, a trifluorofluorenyl group, a trifluoromethoxy group, (Ethyl fluorenyl, etc.) heterocyclic groups, '(3) amine, (4) C1 to 6 amines such as acetamino, propylamino, etc., (5) e.g. Propyl, propylamino, isopropylamine, butylamino, heptylamine, octylamino, difamino, diethylamino, cyclohexylamino, 丨 aminomethylmethyl-2-cyclohexylethylamine Alkyl group substituted with a hydrocarbon group such as N-butyl-cyclohexylamidoamino group, stilbeneamino group, 6,6-dimethylbicyclo [3.1 · 1] heptylamidoamino group ( Here, the "hydrocarbon group" has the same meaning as the above-mentioned "hydrocarbon group", and may be substituted with a halogen atom, a keto group, an amine group, a carbamoyl group and the like), (6) such as a methylsulfonylamino group, C1 to 4 alkylsulfonamido groups such as sulfosulfenylamino, sulfonylsulfenylamino groups, (8) C1 to 4-membered sulphenyl groups such as methylpermethoxanthenyl, ethylpermethoxamine, etc., (9) Basal stilbene, (10) halogen atom (such as fluorine atom, chlorine atom Bromine atom, iodine atom), (11) carboxyl group, (12) fluorenyl group, 316616 14 200526205 () shawyl (14) keto group, (1 5) thioketo group, (16) warpyl group, (17) such as fluorene Oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, first butoxy, third-butoxy, cyclohexylfluorenyloxy, benzyloxy, etc. C1 to丨 〇 Benzyloxy, (18) C3 to 8 cycloalkoxy, such as cyclohexyloxy, Π9) Example: phenoxy, which can be substituted with ci ... group, halogen atom, trisamino group, etc., (20) 5,6,7,8-tetrahydro-1-naphthyloxy, (2 丨) mercapto, (22) such as methylthio, ethylthio, propylthio, isopropylthio, butylthio C1 to 4 alkylthio groups such as methyl, tris-butylthio, etc., (23) benzylthio, (24) aminofluorenyl, (25) N-butylaminocarbonyl, cyclohexylmethylaminocarbonyl, N _Butylsulphonylaminocarbonyl, N-cyclohexylaminocarbonyl, anilinecarbonyl and other aminocarbonyl groups substituted with 8fe groups (here, the "hydrocarbon group" has the same meaning as the "hydrocarbon group" above), ( 26) Aminosulfonyl groups, (27) Hydrocarbyl-substituted aminesulfonyl groups such as methylaminosulfonyl groups (this The "hydrocarbyl group" has the same meaning as the above-mentioned "hydrocarbyl group", (28) such as dimethylaminoethylaminosulfonyl, dimethylaminopropylamino stone κ S & Aminosulfonyl (here, the "L" group has the same meaning as the "rfe group" above), (29) C1 to 6 alkanes such as methoxyweilyl, ethoxycarbonyl, and third-butoxycarbonyl Oxycarbonyl, (30) sulfonic acid (-SO3H), (31) sulfinyl, (32) phosphonic acid, (33) fluorenyl, (34) imino, (3 5) -8 (011) 2, (3 6) such as sulfenylsulfenyl, ethylsulfinylsulfenyl, C 1 to 4 alkylsulfinite, and (3 7) such as sulfonyl, ethyl, and propyl C1 to 6-fluorenyl, such as alkyl, butylfluorenyl, (38) phenylfluorenyl, (39) hydroxyimino, (40) alkyloxyimino Private base and so on. The "hydrocarbon group which may have a substituent" may also have 1 to 5 substituents selected from the above (1) to (40). When the number of the substituents is 2 or more, each of them is 316616 15 200526205 and the substituents may be the same or different. Seven of the substituents of the "nicotinyl group" shown in A may be selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and may contain two-type heterocyclic rings. Examples of the "heterocyclic ring" include M, two-percent bad, bicyclic or tricyclic heterocyclic ring "," 3 to...-Unsaturated monocyclic heterocyclic ring ", and the like. Saturated early ring, second ring, or three to 15 members, and single ring, second ring, two cases, each other, saliva, three saliva, four. Sit and roar: two: hee, triazine, 咲 RAN, 嚷 phen々, sit, two: Qin, 咲 咲,. Dioxin, oxadithia ring, thiadiwa ring, etc., isopyrene, isopyrex, noise, benzopyran, isobenzyl, and dumb _ Γ ′ such as _, spray. Sit, oxoline, iso, phthalazine K, isobenzothiophene, quinoxaline, quinazoline,-^ (naphthyndme) ^ benzofurazine, benzothiadiwa, stupid-enterprise ^ Kailuan Benzotriazole, phenanthrene, dibenzopyran, diphenyl di-heptane, :: :: heptane (nitrogen), 20 g of heptane, ran,: indion :: D volume ... oxazine . Oxadiazine, Yagenin ,. ㈣ Benzene " /, D vertiazine, thiazine, thiadiazine, indoxazine, fluorene color, open noise, benzo. Bad mouth yamphenin, benzo-azepine, benzothiapine, benzothiazepine: Γίyin, benzo, yin ... two; Peroxoline, tetrazoline, pyrazoline, 疋 A 疋, tetrahydropyridine, dihydropyrazine, E9 hydropyrazine, trihydropyrimidine, hydrofluorene, monohydropyridazine, tetrahydropyridazine, tetrahydrotriazine , Dihydroazepine, 316616 16 200526205 Tetrahydroazepine, Dihydrodiazepine, Tetrahydrodiazepine, Dihydropyran, Dihydro D thiopyran, Dihydrooxazine, Tetrahydrooxine Heptane, dihydrothiophene, dihydrothioan, dihydrothiopine, tetrahydrothiopine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydroxanthazine, dihydroxan Diazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxazepine, tetrahydrooxazepine, dihydrothiadiazole, Dihydrothiazine, dihydrothiadiazine, dihydrothiazine, tetrahydrothiazine, dihydrothiazine, tetrahydrothiazine, indolin, isoindolin, Dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydro Benzothiophene, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydropyridine, tetrahydropyridine , Dihydroquinoxaline, Tetrahydroquinoxaline, Dihydroquinoxaline, Tetrahydroquina succinoline, Dihydroxoline, Tetrahydroxoline, Benzoxathiane, Dihydrobenzoxazine, Di Hydrobenzothiazine, pyrazinylmorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzoazepine, tetrahydrobenzoazepine, dihydrobenzene Benzodiazepine, Tetrahydrobenzodi-Daheptene, Benzodi. Benzodioxazepan, Dihydrobenzodiazepine, Tetrahydrobenzodiazepine, Dihydrocarbazole , Tetrahydrocarbazole, dihydro- / 3-carboline, tetrahydro- / 5-carboline, dihydroacridine, tetrahydroacridine, dihydrodibenzopyran, dihydrodibenzothiophene, tetrahydro Hydrodibenzopyran, tetrahydrodibenzothiophene, dioxindane, benzodioxane, chroman, benzodithiane, benzodithiane, 6,7,8,9-tetrahydro -5H-pyridine [4 ', 3, · 4,5] pyrrolo [2,3-b] pyridine, 2,3,4,5-tetrahydro-1H-pyridine [4,3-b] D Citation , 6,7,8,9-tetrahydro-5H-pyridine [3 ', 4': 4,5] Homopyrrolo [2 > b] Hydridine ring and other non-aromatic unsaturated heterocycles, etc. Also, " 3- to 15-membered saturated monocyclic, bicyclic, or tricyclic heterocycles "17 316616 200526205 For example, azacyclopropane, azetidine, D-bile, acetone, and trisial :) : End, four-degree sitting burn, roar degree sitting:!: End, hexahydro D than bite, hexahydro D than hydrazine, total hydrogen. Melidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazine, ethylene oxide, oxetane, tetrahydro1: 1 furan, tetrahydro 1: 1 Biran, perhydro sigmaoxane, ethylene sulfide, thietane, tetrahydrothiophene, tetrahydrothioan, perhydro thiohexane, tetrahydro ° salary (σsalary), tetrahydroisosigma Oxadiazine (iso ° oxacin), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydroxanthazine, tetrahydrooxadiazole (oxadiazolium), tetrahydrooxazine, Tetrahydrooxadiazine, perhydrodioxaine, perhydrodiazepine, tetrahydrothiadiazepine (thiadiazepine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine , Perhydrothiadiazepine, morpholine, thiomorpholine, oxothane, perhydrobenzofuran, perhydroisobenzofuran, perhydrobenzothiophene, perhydroisobenzothiophene, perhydro Indazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydropyridine, perhydroquinoxaline, perhydroquinazoline, perhydroxazoline, perhydrobenzoxazole, perhydro Benzothiazole, perhydrobenzimidazole, all hydrogen sits yesterday, all hydrogen--yesterday, all Π bite Ah, perhydro-dibenzo furans Kou, perhydro dibenzothiophene, dioxolane, dioxane, dithiolane, dithiane ring. Examples of the "C1 to 6 hydrocarbon group" of the "C1 to 6 hydrocarbon group which may be substituted with a halogen atom" represented by R1 include C1 to 6 aliphatic hydrocarbon group and C1 to 6 cyclic hydrocarbon group. Here, "aliphatic hydrocarbon group" and "cyclic hydrocarbon group" have the same meaning as the above. Examples of R1 include fluorenyl, ethyl, propyl, isopropyl, butyl, trifluoroethyl, cyclohexyl, and phenyl. Examples of the compound represented by the general formula (I) include the compounds disclosed in Examples. 18 316616 200526205 More preferably 2-[(2-{(2RV7_ “u < >-[(3,5 -Monophenoxy) methyl] -5 -ketopyridine-1 -yl} Ethyl) Shi Mengqi Ί 刀 [土] -1,3-嚷 〇 4-isopropyl acetic acid, 2-[(2-{(211) -2-[(3,5-Diphenyl / = · #, Milk, milk-based) methyl] _5_ketopyrrolidine-butyl) ethyl) thio] -1,3-thiotamine bismuth field ~ Jin Shuangxing ethyl ester, 2- [ (2-{(2R) -2-[(1 £, 43) -4- (1-ethylcyclobutyryl) ~ yl) -4-yl- ^ butenylketopyrrolidine-1 -yl } Ethyl) You Qi Ί t earth, M, 3- πoxazole-4-carboxylic acid isopropyl ester, 2-[(2-{(2R) -2-[(lE, 4S) -4- (1 Glutinyl butyrate, U ethyl% butyl) -4-hydroxy-1-butenyl] -5-ketosulfonyl} ethyl) thio] m collar, etc. In the present invention, if Without special instructions, the symbols that are clear to the operator .. ,,,,, indicate ^ on the opposite side of the paper (that is, α-configuration), 〆 means that it is combined with the paper ^ 2.) Indicates α • Configuration, / 5-configuration, or the And other mixtures. / Represents a mixture of α-configuration and 10,000-configuration. Packing text, without special instructions in the middle of the month, includes all isomers. Examples, Yuantu Group, alkynyl group, alkoxy group, alkylthio group, alkylene group, weld group, and fast f group include linear and branched isomers. Also, the double bond, ring, condensed ring isomers (E , Z, cis, g J2UA,, trans)), isomers (R, S, α, A configuration, enantiomers, diastereomers) ^ due to the presence of asymmetric carbon, etc. ), Optically active substances with optical rotation (D, L, d, ytterbium, polar bodies (high polar bodies, low polar bodies) via chromatography knife #, balanced compounds ::: isomers, etc. Mixtures and racemic compounds in any proportion are included in the present invention. In the present invention, the optically active compound is not only 100% pure, but also contains 50% other optical isomers. 316616 19 200526205 通The compound represented by formula ⑴ can be converted into a salt by a known method. The salt is preferably a pharmacologically acceptable salt. Examples of the salt include alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, acid addition salts, and the like. Water-soluble ones are preferred. Suitable salts include alkali metal (potassium, sodium, etc.) salts, soil test metals (ma, magnesium, etc.) salts, Salts, pharmaceutically acceptable organic amines (tetramethylene ammonium, triethylamine, amidine, diammonium, cyclopentylamine, amidine, phenethylamine, hexahydropyridine, monoethanolamine, diethanolamine, tri (hydroxyamidine) Group) salts of aminoamidoxane, lysine, arginine, N-fluorenyl reduced glucosamine, etc. The acid addition salt is preferably water-soluble. Suitable acid addition salts include, for example, hydrochloric acid Salt, hydrobromide, hydroiodate, sulfate, phosphate, nitrate and other inorganic acid salts or acetates, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate Organic acid salts such as acid salts, benzenesulfonate, toluenesulfonate, isethionate, glucuronide, and gluconate. The compound represented by the general formula (I) and the salts thereof can be converted into a solvate. The solvate is preferably non-toxic and water-soluble. Examples of suitable solvates include solvates of water and alcohol-based solvents (for example, ethanol). The compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is preferred. Specific examples include the compounds disclosed in the examples or their pharmacologically acceptable salts. In addition, salt also includes four grades of money salt. The quaternary salt is a compound in which the nitrogen atom of the compound of the present invention is quaternized with an RQ group. Here, the RQ group represents a C1 to 8 alkyl group, and a C1 to 8 alkyl group substituted with a phenyl group. The compound of the present invention can be made into an N-oxide by any method. N-20 316616 200526205 An oxidant means an oxidized nitrogen atom of a compound of the present invention. The compounds of the present invention can be converted into dextrin-producing medicaments by using the methods disclosed in Japanese Patent Publication No. 5 · 62, No. Sho No. 61 or No. 61.52146 f. Inclusion compounds. After being converted into a cyclodextrin inclusion compound, it is suitable for use as a medicament because of increased safety or increased water solubility. The prodrug of the compound of the present invention is a compound that is converted into a compound of the present invention through a reaction of enzymes or gastric acid in the living body. The compounds of the present invention are pre-drug-prevented. When the compounds of the present invention have amine groups, there can be listed compounds in which the amine group is fluorinated, alkylated, and phosphorylated (for example, the amine group of the compound of the present invention is icosated, Alanine carbonylation, pentylamino carbonylation, (5-fluorenyl-2-keto-1,3-dioxane-4_yl) methoxycarbonylation, tetrahydrofuranation, pyrrolidinyl methylation, Trimethyl ethoxylated methylation, ethoxylated fluorenated, second-butylated compounds, etc.); when the compound of the present invention has a hydroxy group, hydroxy groups are fluorinated and alkylated , Phosphorylated, borated compounds (for example, the hydroxyl groups of the compounds of the present invention are acetylated, palmitized, propylated S & acetylated, disulfide ethylated, humic acid, fumarized, propylamine donated, Diamidoamino carbonyl compounds, etc.); and when the compound of the present invention has a tertiary group, can be listed compounds whose target group is g-denatured and donkey-aminated (for example, the compound of the present invention is esterified by the sulfonyl group) , Ethyl ester, ethyl ester, isopropyl ester, butyl esterification, isobutyl esterification, second-butyl esterification, Tri-butyl esterification, amyl esterification, pentamyl esterification, neopentyl esterification, cyclopentyl esterification, hexane esterification, cyclohexane esterification, trifluoroethylation, phenyl esterification, carboxymethyl ester Esterification, diamidinoaminofluorene esterification, trimethylaminoacetoxyoxymethylesterification, ethoxycarbonyloxyethylation, ketoesterification, 316616 200526205 (5-amido-2-g isopropyl (1,3-dioxocyano_4_yl) hydrazone, cyclohexyloxyethyl acetoacetate, hydrazone-based amination compounds, etc.). These compounds can be produced by methods known per se. The prodrug of the compound of the present invention may be either a solvate or an unsolvate. 2-[(2-{(211) -2-[(3,5-Digasphenoxy) fluorenyl] -5-5-ketopyrrolidin-l-yl} ethyl) thio] -1,3- The crystal of isothiazole thiazolate (hereinafter referred to as compound 1) has a powder X-ray diffraction spectrum shown in Fig. 1 obtained using a Cu-Kα line or a diffraction angle (2 0) and relative Characteristics of intensity values. Table 1 Diffraction angle (2Θ) Relative intensity 12.82 19 13.30 22 15.15 23 16.71 78 16.95 73 18.85 93 21.06 60 21.54 61 22.55 100 24.25 75 25.50 51 26.26 38 27.06 53 28.30 45 29.92 30 The crystal of compound 1 has been measured using the total reflection method Figure 2 shows the infrared absorption spectrum (IR) or 1717, 1687, 1675, 166, 1 5 86, 1567, 1443, 1423, 1 382, 1257, 1211, 1202, 1107, 1020, 22 316616 200526205 State , 924, δ29, top, 7δ1, 746,, 654, 6i6, 569, 506, 427, and 411cm]. The crystal of Huakou 1 has a characteristic of a differential scanning calorimetry (DSC) chart shown in Fig. 3 or an endothermic peak of about 6 rc. Therefore, the crystal of Wu1 is a physicochemical property disclosed in this specification. 4 inches, but because each spectral value may be slightly changed in nature, it cannot be explained very closely.

For example, in the nature of the X-ray diffraction spectrum value of gray powder, the 'diffraction angle (2Θ) or the overall figure is very important in the identification of crystal identity, but the relative intensity basis,' σ a refers to the direction of growth, the size of the particles The measurement conditions may vary slightly. For the identification of the crystal identity of the infrared absorption (IR) spectrum, the overall pattern is not important, but may vary slightly depending on the measurement conditions. The overall pattern is very important when the DSC value is used to determine the identity of the crystal. However, it may vary slightly depending on the measurement conditions. Therefore, the crystalline powder x-ray diffraction spectrum, infrared absorption (IR) spectrum, or differential scanning calorimetry (DSC) value and pattern of the compound of the present invention are all included in the crystal of the compound. The chemical purity of the crystal is preferably above 97.0%, more preferably above 99.0%, and most preferably above 99.5%. [Manufacturing method of the compound of the present invention] The compound of the present invention represented by the general formula (I) can be prepared by a known method, for example, by Comprehensive Organic Transformation: A Guide to

Functional Group Preparations, 2nd Edition (Richard C. 23 316616 200526205

Laococ, John Wlley & Sons Inc, 1 999) or WO2003 / 74483 5 tiger. The method can be produced by a method known in the following months, a method based on this method, or a method in which the methods described in the examples are appropriately modified and combined. The compound represented by the general formula (I) of right-hand clothing can make a carboxylic acid derivative represented by the general formula (η)

COOH (all symbols in the formula have the same meaning as above) and alcohols represented by φ HO-R1 (III) (wherein R has the same meaning as the above) are subjected to the following esterification reaction, and if necessary, produced by recrystallization . The acetation reaction is well known, and examples thereof include (丨) a dehydration condensation reaction in the presence of an acid catalyst, (2) a transesterification reaction, and the like. · (1) Dehydration-condensation reaction in the presence of an acid catalyst To produce a compound represented by the general formula (I), for example, a metabotropic acid derivative represented by the general formula (11) can be used in an organic solvent (alcohol represented by the general formula (melon) or A mixed solvent of the alcohol and other organic solvents), in an acid (inorganic acid (such as sulfuric acid, hydrochloric acid, etc.), an organic acid (such as p-toluenesulfonic acid, trifluoroacetic acid, etc.) or a Lewis acid (such as boron trifluoride) Ether complex compounds, etc.)) in the presence of 0. It is produced by reacting from 0 to 100 ° C. (2) Transesterification reaction To produce a compound represented by the general formula (I), for example, a simple ester such as a methyl ester of a carboxylic acid derivative represented by the general formula (II) can be used in an alcohol solvent represented by the general formula (melon) 24 316616 In 200526205, in acids (inorganic acids (such as sulfuric acid, hydrochloric acid, etc.), organic acids (such as p-toluene xanthate tritridonic acid, etc.) or Lewis acids (such as ethyl trifluoride complex compounds, etc.), alkali (Such as potassium carbonate, sodium carbonate, carbonic acid shavings, potassium tert-butoxide, sodium methoxide, sodium ethoxide, etc.) or titanium alkoxide (such as titanium tetraisopropoxide, etc.) in the presence of 0 ° C to 100 ° c. Manufacturing. In addition to the above-mentioned esterification reaction, the following esterification reaction can be used, for example, (3) a method using a g! -Based halide, a method using a mixed acid liver, and (5) a method using a condensing agent. These methods are specifically described below. You (3) The method of making hydrazone functional compounds, for example, can make hydrazone in organic solvents (aerosol, difluoromethane, ether, tetrahydrofuran, etc.) or without solvents with fluorene-based toothing agent (grass chloride) Thiochlorine, etc.) K_2 (rc to reflux temperature to carry out the reaction, the fluorenyl compound obtained is then base (anhydropyridine, triethylamine, diamidanilide, dimethylamino). Ding, diisopropylethyl Amine, etc.) in the presence of an alcohol and an organic solvent (aerobic, dichloromethane, ether, tetrahydrofuran, etc.) at a temperature of 0 to ° C = temperature. X 'can also be in an organic solvent (two. Tetrachloroamidine = etc.), the test aqueous solution (sodium bicarbonate water or sodium hydroxide solution, etc.) and the halogenated halide are reacted at 0 to 40 ° C. 〃⑷ 〃⑷ using a method of mixed acid anhydride 'for example, Carboxylic acids in organic solvents: (aerobic, dichloromethane, ether, tetrahydrofuran, etc.) or in the absence of solvents: in bases (pyridine, triethylamine, difluorenylbenzylamine, diamidopyridine, Isopropylethylamine, etc.) Derived from fluorenyl compounds (trimethylacetamide, methylbenzyl, sulfonium, etc.) or acids (Ethyl pivalate, pivalate acid; ^, etc.) The reaction is performed at 0 to thief, and the resulting mixed acid is then mixed with organic ^ 316616 25 200526205 tetrahydrofuran, etc.) with alcohol at 0 to 400c (gasform (Dioxane, dioxane, ether). (The method of whip = agent can make the slow acid and alcohol in the organic solvent lice-lice, -methyl methylamine, ether, tetrahydrofuran, etc.) or in a solvent-free Under the base (Hou. Ding, triethylamine, dimethylaniline

Ji roar. (Conditions, etc.) Condensing agents are used in the presence or absence (U • dicyclohexamethylene diimide (⑽), 1-ethyl Example: methylamine fine group] carbonized diresidue fire (EDC), U,-carbon group Two mouth saliva (cm), methylpyridine bump, bupropionate ring liver (1_propanephOsphomc acid c'yciic anhydnde, PPA, etc.) 'with or without using HOBt), between 0 and 40. . Perform the reaction. The compound represented by the general formula (I) may be a carboxylic acid derivative represented by the general formula (11) and a compound represented by the general formula (IV) X-Ri (IV) (wherein X represents a halogen atom, R1 has the same meaning as the above) is produced by performing the following esterification reaction. This esterification reaction is well-known. For example, a compound represented by the general formula (I) is a carboxylic acid derivative represented by the general formula (II) and a compound represented by the general formula (JV) in an organic bath agent (eg, difluorenylamine). , Dimethylacetamidamine, dimethylimidazoledione, tetrahydrofuran, diethyl ether, methylene chloride, aerosol, etc.), in a base (such as potassium invertate, sodium carbonate, cesium carbonate, sodium hydride, In the presence of potassium butoxide, sodium ethoxide, sodium ethoxide, etc.), it can be produced by reacting at 0 ° C to 100 ° C. The above esterification reaction can be carried out in the presence or absence of an inert gas such as argon or nitrogen. 26 316616 200526205 In the above production method, the compound represented by the general formula (π) can be produced according to the method disclosed in the specification of WO2003 / 74483 or a part of the method. The compounds used as other reagents are known or will be known methods, such as Comprehensive Organic Transformation: A Guide to Functional Group Preparations, 2nd Edition (Richard 'C. Larock, John Wiley & Sons Inc? 1999) or Elmer e J Rauckman et al., J. Org. Chem., V. 1.41, No. 3, 1976, p564_565, etc. can be easily manufactured by combining the methods disclosed. Each of the reactions described in this specification, and the reaction accompanied by heating, can be carried out using a water bath, oil bath, sand bath, or microwave oven as the industry knows. For each reaction in this specification, a solid-phase supporting reagent supported on a high-molecular polymer (for example, polystyrene, polypropylene ammonium, polypropylene, polyethylene glycol, etc.) may be appropriately used. · For each reaction in this specification, the reaction product can be purified by ordinary methods, such as distillation under normal pressure or reduced pressure, high-speed (high-performance) liquid chromatography (HPLC, High using silica gel or magnesium silicate) Performance Liquid

Chromatography), thin layer chromatography, ion exchange resin, deslagging. (SCanrenger) resin or column chromatography, or washing, recrystallization and other methods. The known system can be carried out in each reaction or after several reactions are completed. Among the compounds represented by the general formula (I), the crystals of Compound 1 can be produced by examples or by the methods disclosed below. That is, the crystallization of compound 1 is based on the use of at least one of compound i. 316616 27 200526205 can be selected from aromatic carbocyclic solvents, ester solvents, chain ether solvents, ketone solvents, nitrile solvents, and lower alcohols that can contain water. Solvent-based solvents, or one or more of the above solvents may be mixed with a linear alkane-based solvent that may contain water, and then it may be produced by recrystallization treatment. During recrystallization, a good solvent (good solvent) that can be easily dissolved can be used, that is, an aromatic carbocyclic solvent containing water (such as toluene), an ester solvent (such as ethyl acetate, isopropyl acetate, etc.) Vinegar, etc.), chain ether solvents (such as tertiary butyl fluorenyl ether, diisopropyl ether, diethyl ether, dimethoxy ethane, etc.), ketone solvents (such as acetone, etc.), nitrile solvents (such as Acetonitrile) or lower alcohol solvents (such as methanol, ethanol, isopropanol, etc.) as a single solvent, multiple solvents can also be used, such as a mixed solvent of multiple good solvents (good solvents) or good solvents (good solvents) and solutes are not easy The dissolved weak solvent can also be a mixed solvent of a linear-fired solvent (such as hexane, heptane, etc.) containing water. The order of operations can be a solution in which a solute is dissolved in a good solvent (good solvent) is added to a weak solvent, or a weak solvent is also added to a solution in which a solute is dissolved in a good solvent (good solvent). Examples of the preferable recrystallization solvent include a mixed solvent of a linear ether-based solvent which may contain water and a linear alkane-based solvent which may contain water. Specific examples include a mixed solvent of diisopropyl ether and heptane, a mixed solvent of tertiary-butylfluorenyl ether and heptane, and the like. [Toxicity] The compound represented by the general formula ⑴ has very low toxicity and is very safe to use as a pharmaceutical. [Application of pharmaceuticals] 28 316616 200526205 The compound of the present invention having the general formula ⑴ Table 717 has the effect of P2 agonizing effect. It has the effect of I1 bovine low eye I, the effect of protecting the retina and the optic nerve, and the effect of changing to the optic nerve papilla. For eye diseases, such as glaucoma; ocular tension, macular edema, tone mκ, bisexuality, retina and optic nerve papillary blood-salt), increased retinal and optic nerve tension, myopia, hyperopia dry eye disease, retinal detachment, Cataract is effective in preventing and / or treating cataracts. The compound represented by the general formula ⑴ is used to supplement the therapeutic effect of drugs, 2) improve the amount of the compound, and / or 3) reduce the compound, and reduce the administration of the compound as a concomitant agent. The combination of compound J and other drugs of Group d in Bada City with other agents. It can be administered in the form of a mixture of 20% / knife in the solidified preparation. It can also be prepared separately. Giving and administering, what is the basis of the other medicaments of the present invention, other medicaments may be administered first, and then each administration method may be the same or different. Red to the agent of the present invention, other agents may be low-molecular compounds, polypeptides, polynucleotides (DNA, RNA, Maine ,, ‘,,., S. spp. Attractor Cdecoy;), antibodies or vaccines #. Soil ▲ (antlSenSe), the amount used on the bed as a basis for the appropriate choice; the amount of Le Jian's administration is based on the ratio of other medicines can be based on the target of the administration of the drug and the time of the invention Choose it. For example, two parts by mass of I U, and other medicines are used in the range of 0.001 to 100. For example, the 1 agent of the invention can also be the same from the following: the amount can be. Other medicines are randomly selected from different populations]. 316616 29 200526205 or two or more, and administered in an appropriate ratio. Other agents that supplement or enhance the therapeutic effect of the compounds of the present invention are based on the above-mentioned mechanisms, ^ only those who have been discovered so far, and those who discover later. Other agents include, for example, sympathetic nerve agonists (such as α 2 agonists, such as apralonidin Ηα, etc., and stone 2 agonists such as dipivefrine HC), and parasympathetic nerves. Action drugs (such as pilocarpine Ηα, carbachol, or distigmine bromide, etc.), sympathetic inhibitors (α! Blockers: such as cloth hydrochloride Benzazine (bunaz〇sin), etc., 10,000 blocking drugs ·· Examples such as maleic acid timoi maleate (tim〇i〇i maleate), befolol hydrochloride (befn〇i〇i HC1), card hydrochloride 1 tcirolol (carte〇] 〇; 1 hci) or betataxolol hydrochloride (Betaxolol HC1), etc., α] 10,000 blocking drugs · such as levobimol hydrochloride (levobimolol HC1), niprodilol ( nipradil〇i), etc.), a prostaglandin 5 = lJ (for example, isopropyl unoprost g with (dipr〇)] ylun〇pr〇st〇n), latanoprost, FP agonist, Ep2 agonist or Dp agonist) Shifanfan dehydrated maternal resistance domain music (such as Acetazolaniide, glutamine) diclophenamide), metazamide (metaz〇iamide), dozozine hydrochloride (d〇rZ〇] amide HC1) or brinzolamide (brinz〇lamid), etc., hypertonic osmotic drugs (such as glycerol, glycerol and fructose Compound preparations, isosorbide, Eu mannitol, etc.) The compounds of the present invention have therapeutic and inhibitory effects on ocular diseases occurring in humans and animals, and are more preferably used as glaucoma therapeutic agents. The compound may be added with pharmaceutical-allowable additives, if necessary, and formulated using techniques widely used alone or in combination. 30 316616 200526205 The compound of the present invention represented by the general formula ⑴ or a combination of the compound represented by the general formula 与 and other agents For the above purposes, it is usually administered systemically or locally, orally or parenterally. Oral administration agents include liquids for internal administration (such as syrups, liquids allowed by the drug, suspensions) Preparations, emulsions), solid preparations for internal use (such as lozenges (She U dagger, under tongue, disintegrating tablets in the mouth), pills, capsules (including hard capsules, Xixili riders Capsules, gelatin capsules, microcapsules), powders, granules, oral preparations), etc. Examples of parenteral administration include liquids (such as injections (subcutaneous injections, intravenous injections, muscle injections, intraperitoneal injections) , Drops, etc.), eye drops (such as aqueous eye drops (water-based eye drops, water-based counties, heart U eye drops, viscous eye drops, can be used eye drops), non-water eye Mlj (non- Qiandian eye drops, etc.)), etc.), external preparations (such as ointments (eye ointment can be quick-release preparations, Xufang sexual preparation, clothing 7 \ A clothing d) release control agent. These preparations are manufactured according to a well-known method, such as the method disclosed in Japan. Take the liquid preparation M, ^, y within the oral administration agent. For example, by dissolving, turbidizing, or emulsifying the active ingredient in the commonly used 矣 4 ^ heart thinner (for example, purified water, ethanol 31 M 'YM can also contain wetting agents, heart turbidity agents, emulsifiers, sweeteners, buffering agents, etc. L Wod, fragrances, preservatives, orally administered solid preparations, ^ n % \ L ^ j If you can combine the active ingredients with d (such as gift sugar, mannitol, grapes, door line, crystalline cellulose, starch, etc.) binders (such as hydroxypropyl cellulose, aluminum锃 堃, 山 ”I, ethyl alkanone, magnesium stearate (silicone stearate); Calcium ethyl acetate, etc.), lubricants (such as Wenyue Temple), stabilizers, dissolution subsidies U Conjugic acid, aspartic acid, etc.) 316616 31 200526205, etc., formulated according to conventional methods. In addition, if necessary, coating agents (such as sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose) Aqueous adipic acid ester, etc.), or two or more layers can also be coated. Non-oral administration agents can be prepared by known methods or Manufactured according to the usual use. For example, ointments can be produced by grinding and melting the active ingredients in a base. Ointment bases are well-known or selected from commonly used bases. For example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid vinegar, palmitic acid vinegar, stearic acid vinegar, oleic acid, etc.), wax Class (such as series, etc.), surfactants (such as polyoxyethylene ethyl alcohol; purpose), southern alcohols (such as cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, etc.), polysiloxane Paraffin oil (such as dimethyl polysiloxane, etc.), hydrocarbons (such as hydrophilic vaseline, white vaseline, refined lanolin, liquid rock, etc.), glycols (such as ethylene glycol, diol, polyethylene glycol, etc.) Additives of alcohol, called macroglycol, etc.), vegetable oils (such as ramie oil, olive oil, sesame oil, turpentine, etc.), animal oils (such as Shao oil, Indian butter, carrageenan, etc.), Water, absorption enhancer, and domain inhibitor can be used alone or in combination of two or more. It can also contain moisturizers. Agents, preservatives, oxidants, perfumes, etc. ^ Injections for parenteral administration include solutions ^ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ SY _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 液 ； ； ； 5; Dissolve or suspend in the solvent with T. Use 闳 俨Injectables for mm are used, for example, to suspend or emulsify in a solvent with a bath angle. As the solvent, for example, paste-distilled water, physiological saline, vegetable oils, such as propylene glycol, alcohols such as ethanol, and the like are used in combination. This injection also has: 316616 32 200526205 with stabilizers, dissolution aids (such as glutamic acid, aspartic acid vinegar _ main trademark), etc.) 'suspending agent, emulsifier, painless agent, palliative, Preservatives, etc. These are taken at the grave, step by step into the lamp, or go through the aseptic method, and clothing k. In addition, for the manufacture of sterile solid preparations, such as freeze-dried products, sterilize or dissolve in sterile distilled water or other solvents before use, and use the compound of this compound as a therapeutic agent for eye diseases. Agents, eye ointments, lozenges, etc., are better for the eyes. These can be formulated using widely used techniques. For example, for 2 eyes, Yang can be appropriately blended with isotonicity agents, buffers, regulators, solubilizers, thickeners, stabilizers, preservatives, etc. as additives. In addition,: Power: pH »Zhou instant preparations, thickeners, dispersants, etc. can suspend the drug to obtain stable eye drops. Examples of the isotonicity agent include glycerin, propylene glycol, sodium gasification, potassium chloride, sorbitol, mannitol, and the like. Examples of the buffering agent include wall acid, tartaric acid, clavulanic acid, and aminoacetic acid acetate. Examples of κ PH adjusting agents include hydrochloric acid, citric acid, phosphoric acid, acetic acid, and sodium hydroxide: Hydroxide, Wei, Zeyi, sodium carbonate, sodium bicarbonate, etc. ^ Soluble agents include polysorbate 80 , Polyoxyethylene hardened vitexum oil 60, macroethylene glycol 4000 and so on. Examples of the agents and dispersants include hydroxypropyl methylcellulose, hydroxypropyl cellulose cellulose-based polymer compounds such as polyethylene glycol and polyethylene pyridoxine. Examples of stabilizers include eddy Acid, sodium edetate, etc. 316616 33 200526205 Preservatives (preservatives) include, for example, widely used sorbic acid, potassium behenate, chlorhexidine, paraben, ammonium paraben, acetic acid propyl acetate, gas butanol, etc. ' These preservatives may be used in combination. … Eye drops containing a compound of the invention The value of 11 is preferably set to 40 to 8.5, and the osmotic pressure ratio is preferably set to about i q. When the compound of the invention is used as a therapeutic agent for ocular diseases, it can be placed in an appropriate oral administration according to symptoms, age, dosage form, etc. It is preferably 1 to 1 milligram, more preferably milligram, ^ to several milligrams. (For example, 1 to 3 and 2 owed). For eye drops, it is better to use _01 to 1% (w / v), more preferably 0.001 to 001%. «Concentration of force concentration of 1 to 1 to several drops per day, 1 per day Just click a few times (for example, 1 to 8 times). In the case of an eye ointment, it is preferable to apply medicament having a concentration of 0 to ⑼ (w / w), more preferably 0.00001 to 001% (w / w), in one day to several times (for example, 1 to 4 times). can. Tian Ran, as mentioned above, the dosage will change due to various conditions, so it is sufficient to give a smaller amount than the above, and sometimes it is necessary to give an amount exceeding the above range. _ [Effect of the invention]. The compound of the present invention has a strong EP2 agonizing effect. In addition, the compound of the present invention 2 has a strong effect of reducing intraocular pressure and is irritating to the eyes. Therefore, it is effective for eye diseases such as glaucoma, ocular hypertension, macular edema, 'reduced blood flow to the retina and optic nerve papilla, retina and The prevention and / or treatment of asthenia light 2 rise, myopia, hyperopia, I vision, dry eye disease, retinal detachment, and early internal bleeding are effective. In addition, 2-[(2-{(2R) -2-[(3,5_ 316616 34 200526205 dichlorophenoxy) fluorenyl] -5 -S is based on pyrimidine-1 -yl} ethyl) The crystal of thio] -1,3-sialazol-4-carboxylic acid isopropyl ester can be used as a high-purity original drug for pharmaceuticals. [Embodiment] [Best Mode for Carrying Out the Invention] Hereinafter, the present invention will be described in detail with examples, but the present invention is not limited to these examples. The solvent at the separation point of the chromatography method and in parentheses shown by TLC is the dissolution solvent or developing solvent used, and the ratio is volume ratio. Unless otherwise disclosed, the NMR value is a 1H-NMR value. The brackets shown at NMR indicate the solvents used in the measurement. The compound names used in this manual are computer programs, ACD / Name (trademark registration, Advanced Chemistry Development Inc., manufactured by the company) or ACD / Name program group (trademark registration, Advanced Chemistry Development Inc.) based on the general IUPAC rules. ·, Manufactured by the company) or based on the IUPAC nomenclature. E.g

The compound represented is named 2-[(2-{(2R) -2-[(lE, 4S) -4- (l-ethylcyclobutyl) -4-hydroxy-1-butenyl] -5 -Ketopyrrolidin-1-yl} ethyl) thio] -1,3-thiwa-4-isopropyl isopropyl. 35 316616 200526205 Examples The carboxylic acid derivatives used as raw materials are disclosed in WO2003 / 74483. For example 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) fluorenyl] -5-ketopyrrolidin-l-yl} ethyl) thio]-] " -Thiazepam acid is a compound prepared in Example 6 (32) of No. 0203/74483. Example 1 24 (2-((211) -24 (3,5-Digasphenoxy) methyl > 5-ketopyrrolo-l-yl} ethyl) thio) -1,3- Thiazole-4-carboxylic acid isopropyl g (Compound OX Ai 3

〇 sJY ^ o called

Cl in the atmosphere '2-[(2-{(2R) _2 _ [(3,5_dichlorophenoxy) methyl] -5-ketopyrrolidin-1-yl} ethyl) thio ] _153_Thiazole_4_carboxylic acid (mg) and isopropyl moth (29 mg) in dimethylmethoxamine (1 ml) solution. Anhydrous potassium carbonate (31 mg) was added to the hair, and the mixture was stirred at room temperature for 10 hours. , Stir for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the layers were washed with water and saturated brine, and the residue was purified with anhydrous sulfuric acid, and the obtained residue was subjected to gel column chromatography (n-hexane: ethyl acetate, ethyl acetate) Refined 'to obtain the title compound with the following physical properties: Compound (50 mg). TIX: Rf 0.32 (n-hexane: ethyl acetate = 1: ι); 316616 36 200526205 NMR (CDCI3): δ 1.37 (d, J = 6.30 Hz, 6 H) 2.06 (m, 1 H) 2.23 ( mf 1 H) 2.39 (ddd, J = 17.00, 9.90, 5.30 Hz, 1H) 2.58 (ddd, J = 17.00, 10.20, 7.20 Hz, 1 H) 3.26 (ddd, J = 13.60, 9.60, 5.60 Hz, 1 H ) 3.47 (ddd, J = 13.60, 9.80, 5.20 Hz, 1 H) 3.61 (ddd, J = 13.70, 9.60, 5.40 Hz, 1 H) 3.85 (ddd, J = 13.70, 9.80, 5.70 Hz, 1 H) 4.01 (dd, J = 10.40, 3.10 Hz, 1 H) 4.14 (m, 1 H) 4.70 (dd, J = 10.40, 2.90 Hz, 1 H) 5.28 (sept, J = 6.30, Hz, 1 H) 6.88 (d, J = 1.80 Hz, 2 H) 6.93 (t, J = 1.80 Hz, 1 Η) 7.96 (s, 1 H). Examples 1Π) to (24) Substituting 2-[(2-{(2R) -2-[(3,5-digasphenoxy) fluorenyl] -5-ketopyrrole) with corresponding carboxylic acid derivatives Alkyl-l-yl} ethyl) thio] -i, 3-thiazole-4-carboxylic acid was treated in the same manner as in Example 1 using 'isopropyl moth' or using the corresponding molybdenum compound to obtain the following compounds of the present invention . Example 1 (1): 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5-ketopyrrolidin-1-yl} ethyl) Thio] -1,3-thiazole-4-carboxylic acid ethyl ester (Compound 1-1) TLC: Rf 0.47 (toluene: ethyl acetate = i: 1); NMR (CDCla): δ 1.40 (t, J = 7.10 Hz, 3 H) 2.05 Gn, 1 H) 2.24 (m, 1 H) 2.39 (ddd, J = 16.80, 10.00, 5.40 Hz, 1 H) 2.58 (ddd, J = 16.80, 10.00, 6.90 Hz, 1 H ) 3.27 (ddd, J = 13.80, 9.60, 5.40 Hz, 1 H) 3.47 (ddd, J = 13.80, 9.60, 5.40 Hz, 1 H) 3.61 (ddd, J = 13.80, 9.60, 5.40 Hz, 1 H) 3.85 (ddd, J = 13.80, 9.60, 5.40 Hz, 1 H) 4.01 (dd, J = 10.20, 3.30 Hz, 1 H) 4.13 (m, 1 H) 4.40 (m, 2 H) 4.67 (dd, J = 10.20 , 3.00 Hz, 1 H) 6.87 (d, J = 1.80 Hz, 2 H) 6.93 (t, J = 1.80 Hz, 1 H) 7.99 (s, 1 H). Example 1 (2): 2-[(2-{(2R) -2-[(lE, 4S) -4- (l-ethylcyclobutylyl-1-butenyl] -5-one Pyrrolidine- 丨 _yl} ethyl) thio] _ 丨, isothiazol-4-carboxylic acid isopropyl ester (Compound 1-2) TLC ·· Rf 0.56 (ethyl acetate); 316616 37 200526205 NMR ( CDCI3): δ 0.90 (t, J = 7.50 Hz, 3 H) 1.37 (d, J = 6.30 Hz, 6 H) 1.41 · (m, 1 H) 1.81 (m, 10 H) 2.31 (m, 4 H) 3.46 (m, 4 H) 3.81 (m, 1 H) 4.20 (m, 1 H) 5.24 (sept, J = 6.30 Hz, 1 H) 5.39 (dd, J = 15.00, 8.90 Hz, 1 H) 5.83 (dt , J = 15.00, 7.30 Hz, 1 H) 7.98 (s, 1 H). Example 1 (3): 2-[(2-{(2R) -2-[(lE, 4S) -4- (l -Ethylcyclobutylhydroxy-1-butenyl] -5-ketopyrrolidin-l-yl} ethyl) thio, hydrazone, 3__sigma · -4-carboxylic acid butyl ester (Compound 1-3) \ TLC: Rf 0.60 (ethyl acetate); 'NMR (CDCla)-δ 0.90 (t, J = 7.50 Hz, 3 H) 0.97 (t, J = 7.30 Hz, 3 H) 1.43% (m, 3 H) 1.81 (m, 13 H) 2.31 (m, 4 H) 3.45 (m, 4 H) 4.19 (m, 1 H) 4.33 (t, J = 6.80 Hz, 2 H) 5.39 (dd, J = 1 5.20, 8.80 Hz , 1 H) 5.82 (dt, J = 15.20, 7.20 Hz, 1 H) 7.99 (s, 1 H). Example 1 (4): 2-{[2-((2R) -2-{(2- Chloro-3- ( Fluorofluorenyl) phenoxy] methyl] -methyl} -5-1 isopropyl 17 each alkyl-1-yl) ethyl] thio} -1,3-pentasyl-4-metanoic acid isopropyl ester (Compound 1-4) TLC ·· Rf 0.42 (ethyl acetate); NMR (CDCl3): δ 1.36 (d, J = 6.22 Hz, 6 H) 2.10 (m, 1 H) 2.32 (m, 2 H) 2.75 (m, 1 H) 3.33 (m, 1 H) 3.49 (m, 1 H) 3.67 (m, 1 H) 3.85 (m, 1 H) 4.10 (dd, J = 10.16, 3.57 Hzr 1 H) 4.2 0 ( m, 1 H) 4.71 (dd, J = 10.16, 2.84 Hzt 1 H) 5.22 (m, 1 H) 7.26 (m, 3 H) 7.94 (s, 1 H). Example 1 (5): 2-[(2-{(5R) -2-keto-5-[(2,3,4-trichlorophenoxy) fluorenyl] cyclohexan-l-yl} Ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-5) TLC: Rf 0.42 (ethyl acetate); 38 316616 200526205 a NMR (CDCla) · δ 1.36 (d, J = 6.30 Hz, 3 H) 1.37 (d, J 2 6.30 Hz, 3 H) 2.10 (m, 1 H) 2.34 (m, 2 H) 2.73 (m, 1 H) 3.29 (m, 1 H) 3.47 ( m, 1 H) 3.66 (m, 1 H) 3.81 Gn, 1 H) 4.07 (dd, J = 10.07, 3.39 Hz, 1 H) 4.17 (m, 1 H) 4.72 (dd, J = 10.07, 2.56 Hz, 1 H) 5.22 (m, 1 H) 7.01 (d, J = 8.97 Hz, 1 H) 7.24 (d, J = 8.97 Hz, 1 H) 7.94 (s, 1 H). Example 1 (6): 2-[(2-{(2R) -2-[(4-Ga-3,5-dimethylphenoxy) methyl · yl] -5-ketopyrrolidine-l- Group} ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (compounds 1-6) TLC: Rf 0.45 (ethyl acetate); see NMR (CDCla)-δ 1.36 (d , J = 6.22 Hz, 6 H) 2.02 (m, 1 H) 2.29 (m, 2 H) 2.29 (s, 6 H) 2.57 (m, 1 H) 3.45 (m, 3 H) 3.86 (m, 1 H ) 3.94 (dd, J = 10.34, 3.84 Hz, 1 H) 4.12 (m, 1 H) 4.44 (dd, J = 10.34, 3.20 Hz, 1 H) 5.24 (m, 1 H) 6.64 (s, 2 H) 7.95 (s, 1 H). · Example 1 (7): 2-[(2-{(5R) -2-keto-5-[(2,3,5-three-gas phenoxy) fluorenyl'yl] cyclohexan-l- Group} ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-7) TLC: Rf 0.46 (ethyl acetate); ® NMR (CDCla)-δ 1.37 (d; J = 6.22 Hz, 6 H) 2.25 (m, 3 H) 2.76 (m, 1 H) 3.22 (m, 1 H) 3.47 (m, 1 H) 3.68 (m, 1 H) 3.79 (m, 1 H) 4.07 (dd, J = 10.34, 3.11 Hz, 1 H) 4.15 (m, 1 H) 4.90 (dd, J = 10.34, 2.47 Hz, 1 H) 5.27 (m, 1 H) 7.05 (d, J = 2.20 Hz, 1 H) 7.13 (d, J = 2.20 Hz, 1 H) 7.95 (s, 1 H). Example 1 (8): 2-[(2-{(2R) -2-[(4-Gas-2,6-diamidinophenoxy) methyl] -5-ketopyrrolidine-l- Group} ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl Sa 39 316616 200526205 TLC: Rf 0.45 (ethyl acetate); NMR (CDCl3): δ 1.3l (d, J = 6.22Hz , 6H) 2.08 (m, lH) 2.16 (s, 6Η) 2.31 (m, 2 H) 2.56 (m, 1 H) 3.51 (m, 3 H) 3.81 (d, J = 4.03 Hz, 2 H) 4.15 ( m, 2 H) 5.18 (m, 1 H) 6.95 (s, 2 H) 7.95 (s, 1 H). Example 1 (9) ·· 2-{[2-((2R) -2-{[4H (trifluoromethyl) phenoxy] methyl} -5-ketopyrrolidin-1-yl) ethyl [Iso] thiopropyl, 3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-9) · TLC: Rf 0.43 (ethyl acetate);, NMR (CDCk): δ 1.35 (d, J = 6.41 Hz, 6 H) 2.08 (m, 1 H) 2.30 (m, 2 H) 2.59 (m, 1 H) 3.27 (m, 1 H) 3.45 (m, 1 H) 3.61 (m, 1 H) 3.83 ( m, 1 H) 4.05 (dd, J = 10.34, 3.02 Hz, 1 H) 4.15 (m, 1 H) 4.72 (dd, J = 10.34, 3.02 Hz, 1 H) 5.22 (m, 1 H) 7.05 (dd , J = 8.79, 2.93 Hz, 1 H) 7.26 (m, 1 H) 7.33 (d, J = 8.79

Hz, 1 H) 7.94 (s, 1 H). -Example 1 (10): 2-[(2-{(2R) -2-[(4-chloro-3-ethylphenoxy) fluorenyl] -5- 'ketopyrrolidine-l-yl } Ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (compound 1-10) TLC · Rf 0.44 (ethyl acetate); NMR (CDCIa): δ 1.17 (t, J = 7.60 Hz, 3 H) 1.36 (d, J = 6.22 Hz, 6 H) 2.06 (m, 1 H) 2.21 (m, 1 H) 2.37 (m, 1 H) 2.56 (m, 1 H) 2.66 (q, J = 7.63 Hz, 2 H) 3.46 (m, 3 H) 3.87 (m, 1 H) 3.97 (dd, J = 10.44, 3.48 Hz, 1 H) 4.12 (m, 1 H) 4.47 (dd, J = 10.44, 3.11 Hz, 1 H) 5.23 (m, 1 H) 6.68 (dd, J = 8.42, 3.02 Hz, 1 Η) 6.78 (d, J = 3.02 Hz, 1 H) 7.16 (d, J = 8.42 Hz, 1 H) 7.95 (s, 1 H). Example 1 (11): 2-[(2-{(2R) -2-[(3,4-Diphenylphenoxy) fluorenyl] -5-ketopyrrolidine-l-yl} ethyl) Thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (Chem. 40 316616 200526205 Compound 1-11) TLC: Rf 0.43 (ethyl acetate); NMR (CDCla): δ 1.36 (d, J = 6.00 Hz, 3 H) 1.37 (d, J = 6.00 Hz, 3 H) 2.05 (m, 1 H) 2.23 (m, 1 H) 2.38 (m, 1 H) 2.58 (m, 1 H) 3.28 (m, 1 H) 3.45 (m, 1 H) 3.59 (m, 1 H) 3.84 (m, 1 H) 3.99 (dd, J = 10.34, 3.20 Hz, 1 H) 4.13 (m, 1 H) 4.63 (dd, J = 10.34, 3.02 Hz, 1 H) 5.25 (m, 1Ή) 6.78 (dd, J = 8.97, 2.93 Hz, 1 H) 7 09 (d, J = 2.93 Hz, 1 H) 7.24 On, 1 H) 7.95 (s , 1 H). Example 1 (12): 2-[(2-{(5R) -2-keto-5-[(5,6,7,8-tetrahydronaphthalen-1-yl'oxy) fluorenyl] D Pyrrolidine-l-yl} ethyl) thio> 1,3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-12) TLC: Rf 0.47 (ethyl acetate); NMR (CDCla)- δ 1.36 (d, J = 6.30 Hz, 3 H) 1.37 (d, J = 6.30 Hz, 3 H) 1.73 (m, 4 H) 2.05 (m, 1 H) 2.30 (m, 2 H) 2.62 (m, 5 H) 3.34 (xnf 1 H) 3.51 (m, 2 H) 3.90 (m, 1 H) 3.97 (dd, J = 10.44, 3.39 Hz, 1 H) 4.17 (m, 1 H) 4.40 (dd, J = 10.44, 2.93 Hz, 1 H) 5.25 (m, 1 H) 6.67 (t, J = 7.87 Hz, 2 H) 6.99 (t, J: 7.87 Hz, 1 Η) 7.94 (s, 1 H). Example 1 (13): 2-{[2-((511) -2-keto-5--5-[[3- (trifluorofluorenyloxy) benzyloxy] fluorenyl} pyrrolidine-1-yl ) Ethyl] thiol 1,3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-13) TLC ·· Rf 0.45 (ethyl acetate); NMR (CDCla) · δ 1.36 (d, J = 6.22 Hz, 6 H) 2.07 (m, 1 H) 2.23 (m, 1 H) 2.39 (m, 1 H) 2.59 (m, 1 H) 3.31 (m, 1 H) 3.54 (m, 2 H) 3.89 (m , 1 H) 4.01 (dd, J = 10.44, 3.30 Hz, 1 H) 4.16 (m, 1 H) 4.59 (dd, J = 10.44, 3.11 Hz, 1 H) 5.23 (m, 1 Η) 6.81 ( m, 3 Η) 7.22 (m, 1 H) 7.94 (s, 1 H). 41 316616 200526205 Example 1 (14): 2-[(2-{(2R) _2-[({[(is, 2R, 5S) -6,6-difluorenylbicyclo [3 · 1 · 1] Hept-2-yl] fluorenyl} amino) fluorenyl] -5 -keto D Billowan-1 -yl} ethyl) thio] -1,3-fluorene 17 Vinegar (compound U4) TLC: Rf 0.31 (ethyl acetate: acetol = 9: 1); NMR (CDCls) · δ 0.94 (s, 3 Η) 1.15 (s, 3 Η) 1.36 (d, J = 6.41 Hz, 6 Η) 1.89 (m, 9 H) 2.13 (m, 2 H) 2.30 (m, 2 H) 2.44 (m, 1 H) 2.61 (d, J = 7.32 Hz, 2 H) 2.79 ( m, 2 H) 3.47 (m, 3 H) 3.88 (m, 2 H) 5.22 (m, 1 H) 7.97 (s, 1 H). Example 1 (15): 2-[(2-{(2R) -2-[(heptylamino) fluorenyl] -5_ketopyrrolidin-1-yl} ethyl) thio] -1,3 -Isopropyl-4-isopropanoate (Compound 1-15) TLC: Rf 0.23 (ethyl acetate: methanol = 9: 1); NMR (CDCle): 5 0.86 (m, 3 Η) 1.26 (m, 4 Η) 1.36 (d, J = 6.41 Hz, 6 H) 1.48 (s, 2 H) 1.96 (m, 1 H) 2.30 (m, 8 H) 2.64 (m, 2 H) 2.80 (dd, J = 12.27 , 6.41 Hz, 1 H) 2.94 (m, 1 H) 3.46 (m, 3 H) 3.88 (m, 2 H) 5.22 (m, 1 H) 7.97 (s, 1 H) 0 Example 1 (16): 2-{[2-((5R) -2-keto-5-{[((3,4,5-trichlorophenyl) amino] fluorenyl} hizolin-1-yl) ethyl] sulfur } -L, 3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-16) TLC: Rf 0.30 (n-hexane: ethyl acetate di 1: 2); NMR (CDCla) · δ 1.35 (m, 6 Η) 1.88 (m, 1 Η) 2.37 (m, 3 Η) 3.43 (m, 5 Η) 3.94 (mr 1 Η) 4.11 (m, 1 Η) 4.94 (br. S., 1 Η) 5.23 (m, 1 Η) 6.61 (s, 2 Η) 8.00 (s, 1 H) 0 Example 1 (17): 2-({2-[(2R) -2-(([4- 气 -3- (trifluoro Fluorenyl) benzyl] amino} fluorenyl) -5-ketopyrrolidin-1-yl] ethyl} thio) -1,3-thiazole-4-carboxylic acid isopropyl ester (compounds 1-17) 42 316616 200526205 TLC Rf 0.30 (n-hexane: ethyl acetate g 2: 1); · NMR (CDCle) * δ 1.32 (d, J = 6.20 Hz, 3 H) 1.35 (d, J = 6.20 Hz, 3 H) 1.89 ( m, 1 H) 2.38 (m, 3 H) 3.46 (m, 5 H) 3.95 (in, 1 H) 4.13 (m, 1 H) 4.92 (br. s., 1 H) 5.20 (m, 1 H) 6.64 (dd, J = 8.60, 2.80 Hz, 1 H) 6.86 (d, J = 2.80 Hz, 1 H) 7.21 (d, J = 8.60 Hz, 1 H) 7.99 (s, 1 H). Example 1 (18): 2-{[2-((2R) -2-{[(3,5-Diaminophenyl) amino] fluorenyl} _5_ketopyrrolidin-1-yl) ethyl [Iso] thiopropyl, 3-thiazole-4-carboxylic acid isopropyl ester (Compounds 1-18) 'TLC: Rf 0.35 (n-hexane · ethyl acetate = 1: 2); · NMR (CDCla): δ 1.35 (m, 6 Η) 1.88 (m, 1 Η) 2.36 (m, 3 Η) 3.32 (m, 3 Η) 3.55 (m, 2 Η) 3.95 (m, 1 Η) 4.12 (m, 1 Η) 4.87 (br. s., 1 Η) 5.24 (m, 1 Η) 6.44 (d, J = 1.80 Hz, 2 Η) 6.64 (t, J = 1.80 Hz, 1 Η) 8.00 (s, 1 Η). Example 1 (19): 2-({2-[(2R) -2-({[4-fluoro-3- (trifluoromethyl) phenyl] amino} fluorenyl) -5-ketopyrrole Benzene-1-yl] ethyl} thio) -i, 3-thiazole-4-carboxylic acid isopropyl ester (Compound 1-19) TLC: Rf 0.30 (n-hexane: ethyl acetate = 1: 2); NMR (CDCla): δ 1.32 (d, J = 6.20 Hz, 3 Η) 1.34 (d, J = 6.20 Hz, 3 H) 1.91 (m, ^ 1 H) 2.38 (m, 3 H) 3.34 ( m, 3 H) 3.57 (m, 2 H) 3.96 (m, 1 H) 4.13 (m, 1 H) 4.64 (br. s ”1 H) 5.21 (m, 1 Η) 6.71 (m, 2 H ) 6.96 (m, 1 H) 7.99 (s, 1 H). Example 1 (20): 2-[(2-{(2R) -2-[(octylamino) methyl] -5-one Pyrrolidine-l-yl} ethyl) thio] -1,3- 嚷 ° iso-4-isopropanoic acid (Compound U0) TLC: Rf 0.34 (ethyl acetate: methanol = 9: 1) 43 316616 200526205 NMR (CDCb): δ 0.88 (t, J = 6.60 Hz, 3 H) 1.26 (m, 9 H) 1.37 (d, J = 6.20 Hz, 6 H) 1.45 (m, 2 H) 1.91 ( m, 1 H) 2.15 (m, 1 H) 2.31 (ddd, J = 16.90, 9.90, 5.70 Hz, 1 H) 2.46 (ddd, J = 16.90, 9.80, 7.10 Hz, 1 H) 2.62 (m, 2 H ) 2.80 (dd, J = 12.30, 6.20 Hz, 1 H) 2.90 (dd, J = 12.30, 4.20 Hz, 1 H) 3.43 (m, 5 H) 3.39 (m, 2 H) 5.24 (m, 1 H) 7.98 (s, 1 H). Example 1 (21): 2-[(2-{(2R) -2-[(lE) -4- (l-ethylcyclobutyl) -1-butenyl] -5-ketopyrrolidine-l-yl} ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester (compound 1-21) TLC: Rf 0.71 (ethyl acetate); NMR (CDCla): δ 0.74 (t, J = 7.20 Hz, 3 H) 1.37 (d, J = 6.22 Hz, 6 H) 1.40 Ga, 4 H) 1.75 (m, 9 H) 2.29 (m, 3 H) 3.32 (m, 1 H) 3.45 (m, 2 H) 3.85 (m, 1 H) 4.16 (m, 1 H) 5.24 (m, 2 H) 5.69 (m, 1 H) 7.99 (s, 1 H). Example 1 (22) · 2-[(2- {(2R) -2-[(1E) -1-nonyl] -5-S isomer D is slightly more than 1-yl} ethyl) Thio] -1,3-fluorene. Iso-4-isopropanoic acid | Purpose (Compound 1-22) TLC: Rf 0.71 (ethyl acetate); NMR (CDCle): δ 0.88 (t, J = 6.90 Hz, 3 H) 1.26 (m, 10 H ) 1.37 (d, J = 6.22 Hz, 6 H) 1.71 (m, 1 H) 2.24 (m, 5 H) 3.29 (m, 1H) 3.45 (m, 2 H) 3.84 (m > 1 Η) 4 · 16 (m, 1 H) 5.22 (m, 2 H) 5.67 Gn, 1 H) 7.99 (s, 1 H). Example 1 (23) ··· 2-({2-[(2S) -2-heptyl-5-keto D-biroyl] ethyl} thio) -l, 3-thiazole-4-carboxyl Isopropyl ester (Compounds 1-23) TLC: Rf 0.71 (ethyl acetate); NMR (CDCle): δ 0.88 (t, J = 6.90 Hz, 3 H) 1.29 (m, 11 H) 1.37 (d, J = 6.22 Hz, 6 H) 1.71 (m, 2 H) 2.12 (m, 1 H) 2.34 (m, 2 H) 3.42 (m, 3 H) 3.72 (m, 1 H) 3.91 (m, 1 H) 5.25 (m, 1 H) 7.99 (s, 1 H). 316616 44 200526205 Example 1 (24): 2-[(2-{(2R) -2-[(3,5-Digasphenoxy) fluorenyl] -5-ketopyrrolidine-l-yl} Ethyl) thiothiazole-4-carboxylic acid 2,2,2-trifluoroethyl (Compound 1-24) TLC: Rf 0.51 (ethyl acetate); NMR (CDCla): δ 2.07 (m, 1 Η) 2.24 (m, 1 Η) 2.40 (m, 1 Η) 2.56 (m, 1 Η) 3.29 (m, 1 Η) 3.48 (m, 1 Η) 3.63 (m, 1 Η) 3.83 (m, 1 Η) 4.00 (dd, J = 10.34, 3.39 Hz, 1 H) 4.11 (m, 1 H) 4.60 (dd, J = 10.25, 2.93 Hz? 1 H) 4,72 (m, 2 H) 6.85 (d, J = 1.74 Hz, 2 H) 6.94 (t, J = 1.74 Hz, 1 H) 8.12 (s, 1 H). Example 2: 2-[(2-{(2R) -2-[(3,5-dichloro Phenoxy) methyl] -5-g isopropylpyridine sigma-l-yl} ethyl) thio] -1,3-exposure 17--4-isopropyl isopropyl crystalline A suspension of 5.0 g (g) of oil in diisopropyl ether (35 ml (mL)) was heated at 50 ° C. After the suspension has been dissolved, let it cool and add seed crystals (5 milligrams (mg)) at an internal temperature of about 30 ° C. Stir; After confirming the analysis of the crystal charge, n-heptane (150 ml) was added dropwise, and the solution was cooled in an ice bath. The precipitated crystals were filtered, and dried to obtain 2_ [〇 {(2R) _2 _ [(3,5-dichlorophenoxy) methyl] -5 -keto-pyrrolidine-1_yl} ethyl) Thio] -1,3-thiopyrene isopropyl crystalline powder (3.55 g). The chemical purity of this crystal was confirmed by HPLC using the following conditions. < HPLC measurement conditions > Official column · YMC-Pack C4 A-802 (inner diameter 4.6 mm (mm), length 150 mm), moving layer: acetonitrile / 20 millimolar (mm〇i) / liter of dihydrogen phosphate Potassium aqueous solution (pH adjusted to 3 with phosphoric acid) = 50/50, flow rate: 10 ml / mol, detected as a UV-visible detector (detection wavelength 210nm), analysis time: 35 minutes , Holding time: about 16 5 minutes. 316616 45 200526205 Take about 2 mg of sample and dissolve in about 4 ml of acetonitrile. Inject the solution about 2 // L. As a result, it was confirmed that the chemical purity of the crystal was 99.7%. Fig. 1 shows the powder X-ray diffraction spectrum of the crystal measured under the following conditions, Fig. 2 shows an infrared absorption (IR) spectrum, and Fig. 3 shows a differential scanning calorimetry (DSC). (1) Powder X-ray diffraction spectrum device: manufactured by BRUKERaxs DISCOVERwithGADDS, target: copper, filter: not used, voltage: 40kV, current: 40mA, scanning speed: 2.0 ° / minute. (2) Infrared absorption (IR) spectrum device: FT / IR-660Plus infrared spectrophotometer manufactured by Japan Spectroscopy Co., Ltd. Measurement method: total reflection method, decomposition energy: ^ ιτΤ1, number of scans: 16 times. (3) Differential scanning calorimetry (DSC) device: DSC822e differential scanning calorimetry device manufactured by Metra-Trade, sample volume: 1.8 1 mg, sample tank: Shao 40 // L, argon flow rate : 40 ml / min, heating rate: 5 ° C / min (25 to 100 ° C), 20 ° C / min (100 to 300 ° C). Experimental Example 1: Evaluation of intraocular pressure reducing effect and eye irritation at 10am to 11am in the male rabbit (NewZealandWhite, 2.0 to 3.0 kg) fully preliminarily single eyed at 50a L The base agent (PBS pH7.2, containing 0.5% Tween80) is prepared to a concentration of 0.00003% (w / v) (= 0.3ppm), 0.0001% (w / v) (= lppm), and 0.0003% (w / v) (Two 3 ppm) of compound 1 and compound 1-2. The other eye was not treated. The IOP and eye irritation were observed on the basis of the modified Draize method. 46 316 616 200526205 0.4% oxybuprocam hydrochloride (oxybuprocam) hydrochloride before an intraocular pressure measurement was performed. Local anesthesia was performed to measure the intraocular pressure and eye irritation before the test compound was spotted and after 1, 2, 4, 6, 8 and 24 hours. Sex. IOP was measured with a tonometer (Pneumatonometer Model30 Classic (Medtronic Solan)) and evaluated by "Iop (treated intraocular pressure-untreated intraocular pressure). The number of cases was 8 eyes. The results of the compound 丨 are as described in Section The results of compound 1-2 are shown in Figure 4 and Figure 5, and the results of Compound 1-2 are shown in Figure 6 and Figure 7. The compound of the present invention significantly reduces the intraocular pressure of rabbits compared with that before the compound treatment. It is not irritating to the eyes. From this, it can be seen that the Ep2 agonist of the present invention has a pressure-reducing effect and can be an excellent therapeutic agent for ocular diseases. Test Example 2: Stability when using a resin container 1 β g 5 mg 4 mg 0.1 Milligram proper flux 1ml compound 1 polysorbate 8 〇 sodium chloride T burning money dish acid gas ~~ _ full amount (for injection) —I about 5ml of the above prescription solution (pH7) is filled in the following place- The following month, the valley is "closed tightly" and the cap is closed and the uncertainty test sample HP W is taken as the stability of%, and the residual rate of compound 1 before storage at soft temperature and relative humidity is 316616. 47 200526205 Residual rate of compound 1 after storage for 1 month is 100% [Preparation Examples] The representative formulation examples used in the present invention are shown below. 1. Eye Drops The eye drops formulated below are prepared by a widely used method. Prescription Example 1: Glycerin and polysorbate are added to sterilized purified water. After the ester 80, compound 1 was added to dissolve, and the whole amount was 100 ml with sterilized purified water, filtered with a membrane filter, and then filled in a predetermined container to obtain 1 milligram of compound 1 in 100 ml. 2.5 g of glycerol, 500 mg of polysorbate, and a suitable amount of sterilized purified water eye drops. In the same manner as in Formula 1, eye drops containing 0.01 mg and 0.5 mg of the compound in 100 ml can be prepared. The other EP2 agonists of the present invention can be used instead of Compound 1. 2. Eye ointment is used to formulate the eye weakness of the following prescription in a widely used method. Prescription example 2: Liquid paraffin and white vaseline are pre-heated and sterilized. Compound is mixed with After the liquid paraffin has been thoroughly researched, add white petrolatum to the full amount of i⑼g, and fully knead to obtain 100 g of it! Mg compound of compound paragon liquid paraffin and an appropriate amount of white petrolatum Eye liquid. The same operation as in Formula Example 2 can be used to adjust the eye ointment by appropriately changing the amount of compound 丄. In addition, other Ep2 agonists of the present invention can be used instead of compound 1. 316616 48 200526205 [Industrial use Possibility] ^ The compound of the present invention represented by the general formula 具有 has an EP2 agonizing effect. In addition,-has an intraocular pressure reducing effect, a neuroprotective effect of the retina and the optic nerve, a protective effect of retinal nerve cell necrosis, and improvement of optic nerve papillary circulation =, So for eye diseases, such as glaucoma, ocular hypertension, macular edema, ridges, macular degeneration, decreased blood flow to the retina and optic nerve papilla, retina and vision, increased tension, myopia, hyperopia, disordered vision, dry eye , Retinal detachment, cataract, etc. are effective. Therefore, the EP2 agonist of the present invention can be used as a pharmaceutical. In addition, 2-[(2-{(211) -2-[(3,5-Digasphenoxy) methyl] -5_ketopyrrolidin 4-yl} ethyl) thio] 4,3_ The crystal of isopropyl thiazole carboxylate is very useful as a high-purity original drug for medical products. [Brief description of the figure] Figure 1 shows 2-[(2-{(2R) -2-[(3,5-Digasphenoxy) fluorenyl] _5_ keto D Billowan_yl} ethyl ) Sulfuryl] _ 丨, 3_thia. X-ray diffraction spectrum of crystalline powder of isopropyl isocyanate (compound 1). Figure 2 shows an infrared absorption (IR) spectrum of the crystal of Compound 1. Figure 3 shows a differential scanning calorimetry (Dsc) chart of the crystals of Compound 1. Fig. 4 is a graph showing the intraocular pressure difference between the treated eye and the control eye before and after the point 1 of Compound 1. Fig. 5 is a graph showing the eye irritation of Compound 1. Fig. 6 is a graph showing the intraocular pressure difference between the treated eye and the control eye of Compound 1-2 before and after the eye. Fig. 7 shows an eye irritation western diagram of Compound 1-2. 316616 49

Claims (1)

200526205 10. Scope of patent application: L A kind of 2-[(2-{(2R) -2-[(3,5-digasphenoxy) fluorenyl] ketopyrrolo-l-yl} ethyl) sulfur Base] _1,3, thiawa-4 isopropyl isopropyl ester crystal, characterized by having any one of the following physical and chemical values represented by A, B and C: A · powder shown in Figure 1 X-ray diffraction spectrum diagram; B · Infrared absorption spectrum diagram shown in Fig. 2 measured by total reflection method; c · · Differential scanning calorimetry diagram shown in Fig. 3. 2 · —Species 2-[(2-{(2R) -2 _ [(3,5-dichlorophenoxy) fluorenyl] ketopyrrolo-l-yl} ethyl) thio] -1,3 -A crystal of thiazole-4-carboxylic acid isopropyl ester, characterized by having any one of the following physicochemical values represented by Al, B1, and C1: A1 in the powder X-ray diffraction spectrum pattern, 2 Θ is 12.82, 13.30, 15.15, 16.7, 16.95, 18.85, 21.06, 21.54, 22.55, 24.25, 25.50, 26.26, 27.06, 28.30, and 29.92; Β1: In the infrared absorption spectrum measured using the total reflection method, in 1717, 1687, 1675, 1661, 1586, 1567, 1443, 1423, 13 82, 1257, 1211, 1202, 1107, 1020, 949, 924, 829, 798, 781, 746, 667, 654, 616, 569, 5 There are absorption peaks at 06, 427, and 411 cm-1. In the C1 ·· differential scanning calorimetry measurement, there is an absorption peak at 60.6 ° C. 3. If the crystal of item 1 or item 2 of the scope of patent application, it has a chemical purity of more than 99.0%. 50 316616 200526205 4 · If you apply for a chemical purity of item 1 or above in the scope of patents. The crystal of item 2 has 99.5 5. The crystal of the scope of patent application f 1IM or the item of item 2, wherein the crystal is produced by crystallizing with an organic solvent which may contain water. 6. Rushen—Please ask for the crystallization of item 5 in the scope, wherein the organic solvent is selected from the group consisting of a square stone anti-% solvent, an ester solvent, a chain ether solvent, a ketone solvent, a nitrile solvent, and a residual alcohol. One type of solvent or a mixture of two or more solvents among the organic solvent and the organic linear solvent. If the crystallization of item 丨 or item 2 of the scope of the patent application is applied, the bean name, | mouth, day, day, day: With water-containing chain ether solvents and water-containing linear alkanes / cereals The mixed solvent was recrystallized and manufactured. 8. Such as those applying for the patent scope. The crystal of item 2 or item 2 is an ep2 excitement. 9. If the crystal of item M or d of the patent application is applied, it is a person with a preventive and / or therapeutic effect on eye diseases. 10. The crystallization of item 9 of claim 22, wherein the pure disease is glaucoma or ocular hypertension. " .- A preventive and / or therapeutic agent for eye diseases, characterized by using the crystal of claim 1 or 2 of the main patent claim. 12. If the preventive and / or therapeutic agent according to item U of the patent application, the eye disease is glaucoma or ocular hypertension. 13-pharmaceutical products, characterized in that: 纟 Applicable to item i or item 2 of the scope of patent application, crystal and one or more selected from the group consisting of sympathetic nerve action drugs, parasympathetic nerve action drugs, sympathetic nerve inhibitors, and prostaglandin drugs , Carbonic acid removal 316616 200526205 Enzyme inhibitor and hypertonic osmotic drug combination. 14. A pharmaceutical composition characterized by using the crystals of the first or the second item of the patent application scope. 15. — A method of preventing and / or treating glaucoma or ocular hypertension in a mammal, which is characterized by administering to a mammal an effective amount of a crystalline substance in the scope of the first or second patent application. 16.-A crystalline application for which the scope of patent application item 丨 or 2 is applied, which is a preventive and / or therapeutic agent for the manufacture of glaucoma or ocular hypertension. -A compound represented by the general formula (I), a salt thereof, a solvate thereof, a precursor thereof, or a cyclodextrin inclusion compound thereof (In the formula, A represents a hydrocarbon group which may have a substituent, and R1 represents a C1 to 6 hydrocarbon group which may be substituted with a halogen atom. One is an α-configuration, a cold-configuration, or a mixture thereof). 18. The compound as claimed in claim 17 of the patent scope, wherein the compound is selected from 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5 _Ketopyrrole 1-yl} ethyl) thio] thiosigma-isocardial isocyanate, 2-[; (2] (2ΙΙ) _1 [(3,5-digas phenoxy) Fluorenyl] -5-ketopyrrolidinyl} ethyl) thio] -1,3-thiazole aspartate, 2 _ [(2] (2R) j [(lE, 4S) -4- (l —Ethylcyclobutyl) _4_Hydroxy- 丨 _butenyl] ketopyridine-Buyl 丨 ethyl) thio] -1,3-thiazole-4-carboxylic acid isopropyl ester and 52 316616 200526205 2-[(2-{(211) -2-[(1 £, 43) -4- (1-ethylcyclobutyl) _cardiacyl small butenyl] 1 ketoyl } Ethyl) thio sulfonyl I butyl ferulate group. 19. The compound according to item 18 of the scope of patent application, which is 2 _ [(^ {(Ice [(3,5-difluorobenzyloxy) fluorenyl] -5-ketopyrrolidine-butyl} ethyl) Thio] -1,3-thiazole-4-carboxylic acid isopropyl esters. 20. For example, the compounds in the 17th to the 19th of the scope of application for patents, which are Eh agonists. 2 21. A pharmaceutical composition It is characterized in that it contains the compound in the scope of application for item η. The pharmaceutical composition, which is generally covered by the scope of application for the scope of the patent, is 21, which is a preventive and / or therapeutic agent for eye diseases. A medicinal composition, wherein the eye disease is glaucoma or ocular hypertension. 24. A mammalian glaucoma or ocular hypertension prevention and / or treatment method 2, which is known as: effective for mammalian administration The scope of application for patents, 7 compounds of the general formula (I), their salts, their solvates, their prodrugs, or their cyclodextrin inclusion compounds. Μ: The general scope of patent application No. 17 The use of the compound represented by formula (I), its /, / mixture, its prodrug or its cyclodextrin inclusion compound is used for Making prevention of glaucoma or ocular hypertension and, or treatment 3] 661 653