WO2005061492A1 - Nitrogen-containing heterocyclic compounds and drugs comprising the same as the active ingredient - Google Patents

Abstract

Compounds represented by the following general formula (I): (I) wherein each symbol is as defined in the description; salts thereof, solvates thereof, prodrugs thereof or cyclodextrin clathrates thereof. Because of having a potent agonism to EP2 and a potent effect of lowering ocular tension while little irritating the eye, these compounds are useful in treating eye diseases such as glaucoma, ocular hypertension, macular edema, macular degeneration, blood flow loss in retinal and optic nerve papillae, retinal and optic nerve hypertension, myopia, hyperopia, astigma, dry eye, retinal detachment, cataract and so on.

Description

 Description Nitrogen-containing heterocyclic compounds and pharmaceuticals containing them as active ingredients

 The present invention relates to (1) a compound represented by the general formula (I):

 (Wherein all symbols have the same meanings as described below), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof, and (2) a compound represented by the general formula ( (I) a therapeutic and / or prophylactic agent for eye diseases comprising a compound represented by (I), and (3) isopropyl 2-([2-((2R) 1-2-[(3,5-dichlorophenoxy) ) Methyl] -5-oxopyrrolidine-1-thiophene) thio] — 1,3-thiazole-4-carboxylate.

 Background art

Glaucoma is characterized by visual dysfunction that causes the accumulation of aqueous humor due to the disorder of circulation of the aqueous humor, the continuous increase in intraocular pressure, the compression of the optic nerve, temporary or permanent visual loss, and loss of vision. Eye disease. It is said that the cause of the onset is increased intraocular pressure. However, even if the intraocular pressure is normal, damage to the optic nerve may occur. This is called normal or low-tension glaucoma. Conversely, high intraocular pressure may not cause optic nerve damage. This is called ocular hypertension. In the treatment of glaucoma and ocular hypertension described above, it is effective to lower intraocular pressure. For the treatment of glaucoma and ocular hypertension, Examples include drug treatment, laser treatment, and surgical treatment. In drug treatment, eye drops, which are topically administered to avoid side effects, are the mainstream.

The mechanism of action of drugs for reducing intraocular pressure is to suppress aqueous humor production and promote aqueous outflow. The former include, for example, blockers and carbonic anhydrase inhibitors, and the latter include, for example, parasympathomimetics, a-blockers, and prostaglandins. Some drugs have both effects. Because glaucoma pharmacotherapy is long-lasting, side effects must be minimized. Therefore, confirm the intraocular pressure lowering effect and side effects of the drug, select a drug with few side effects, and administer the drug at a low concentration. If one drug is not effective enough, add high-concentration drugs or drugs with different mechanisms of action one by one. Currently used drugs include, for example, sympathomimetics, parasympathomimetics, sympathomimetics, prostaglandins, carbonic anhydrase inhibitors, and hypertonic osmotic agents. Side effects associated with blockers, which are sympathomimetic drugs, include bronchoconstriction, breathing, depression, fatigue, confusion, impotence, hair loss, heart failure, bradycardia, decreased blood pressure, dizziness, etc. . Topical use of non-selective adrenergic agonists, which are sympathomimetics, has a much higher probability of causing allergic and toxic reactions. Shed ₂ Agoni strike, effectively lowering the Meushitora圧. However, the rate of allergic reactions and drug resistance (Takif Iraqi I) is high. Cholinergic drugs, which are parasympathetic agonists, rarely show symptoms of cataract and conjunctival congestion. Carbonic anhydrase inhibitors may have side effects such as fatigue, anorexia, depression, paresthesias, abnormalities in serum electrolytes, gallstones, and blood disorders. Some patients complain that they have a bad taste in the mouth after instillation. The drug currently used as a prostaglandin, FP agonist, promotes aqueous outflow. The aqueous humor outflow pathway includes the trabecular meshwork outflow pathway and the pseudo-scleral outflow pathway, and FP agonists have been reported to promote aqueous outflow from the uveoscleral outflow pathway. FP agonists are allergic Although there is little birth and few systemic side effects are observed, the main side effects are reported to be increased pigmentation in the iris, especially the light brown iris, and exacerbation of uveitis.

 The EP 2 agonist not only promotes aqueous humor outflow from the uveoscleral outflow pathway, but also promotes aqueous humor outflow from the trabecular meshwork outflow pathway and reduces intraocular pressure. In addition, it has a protective effect on the retina and optic nerve. In addition, since EP2agon does not act on melanin-producing cells, it can avoid the side effects of iris coloring seen in FPagoest. Thus, EP 2 agonist is useful as a glaucoma treatment drug.

 In addition, high-purity drug substances are indispensable for the manufacture of pharmaceuticals, especially for ophthalmics. Furthermore, since prostaglandin derivatives such as EP2agonist are very active substances, contamination of trace impurities must be avoided. However, EP 2 agonist is generally a hardly crystalline oily compound, and is difficult to evaporate. Therefore, it is usually purified industrially by column chromatography. To improve the purity of the drug substance to a satisfactory degree for use in pharmaceutical manufacturing, e.g., purify the crude product multiple times with column chromatography or recrystallize the compound after converting it to some salt In addition, multiple steps are required. However, re-purification by column chromatography leads to an increase in the number of steps, and it takes a lot of time to evaporate the solvent. In order to recrystallize a compound as a salt, the compound must have an acidic group or a basic group in the structure of the compound, and cannot be applied to neutral compounds. Therefore, if the EP2agonist can be obtained as crystals, it is possible to provide a high-purity EP2agonist that is useful as a medicine only by a simple recrystallization operation and that is particularly desired in the ophthalmic field.

Compounds described in WO2003 / 74483 Noflet are known to have an EP2 agonistic action, and include immune diseases, allergic diseases, nerve cell death, menstruation Difficulty, premature birth, miscarriage, baldness, retinal neuropathy, erectile dysfunction, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive respiratory disease, liver injury, acute hepatitis, cirrhosis, shock, nephritis, Renal failure, circulatory disease, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulation fl fl, ulcerative colitis, Crohn's disease, dialysis It has been shown to be useful in the prevention or treatment of hypercytokinemia, multiple organ failure, and bone disease. However, there is no description or suggestion of the EP 2 agonist crystal described therein. Disclosure of the invention

 An object of the present invention is to provide an EP 2 agonist that is safe and useful as a therapeutic agent for glaucoma, in particular, a high-purity drug substance having an EP 2 agoest action. Means for Solving the Problems As a result of intensive studies, the present inventors have found that a novel compound represented by the general formula (I) has a strong EP 2 agonist activity. Further, the compound of the present invention represented by the general formula (I) has a strong intraocular pressure-lowering effect and is less irritating to the eyes. It was found to be effective in the treatment of degeneration, decreased blood flow in the retinal optic nerve head, increased retinal and optic nerve tension, myopia, hyperopia, astigmatism, dry eye, retinal detachment, cataract and the like.

 In the manufacture of pharmaceuticals, especially eye drops with strict specifications, manufacturing a high-purity drug substance by a simple method is very advantageous for industrial manufacturing of pharmaceuticals, but it is particularly difficult to produce crystalline prostaglandin derivatives. Despite being an ester derivative known to have a property, it was found that crystallization is possible and that the crystal can be produced by a simple method (recrystallization).

More surprisingly, the present inventors have found that among the compounds represented by the general formula (I), isopropyl 2 -— ((2-{(2R) -2) is a novel compound that is very useful as a drug substance. -[(3,5-dichlorophenoxy) methyl] -5 —Oxopyrrolidine-1-yl} ethyl) thio] —1,3-thiazole-4-carboxylate was successfully crystallized, and the present invention was completed.

 That is, the present invention

 1. Isopropyl 2 -— ((2 -— ((2R) —2) characterized by having at least one of the physicochemical data represented by A, B, and C below.

— [(3,5-Dichlorophenoxy) methyl] — 5-oxopyrrolidine-1 1-yl} ethyl) thio] —1, 3-thiazole-14 crystal of propyloxylate:

 A: powder X-ray diffraction spectrum chart shown in FIG. 1;

B: infrared absorption spectrum chart shown in FIG. 2 measured using the total reflection method;

 C: differential scanning calorimetry chart shown in FIG.

 2. Among the physicochemical data represented by Al, B1, and C1 below, isopropyl 2 -— ((2 -— ((2R) 1-2 — [( 3,5-Dichlorophenoxy) methyl] 1-5-oxopyrrolidine-1-ethyl) thio] —1,3-thiazono 1-14

 A 1: In the powder X-ray diffraction spectrum pattern, 20 is 12.82, 13.30, 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;

B1: In the infrared absorption spectrum measured using the total reflection method, 1717, 1687, 1675, 1661, 1586, 1567, 1443, 1423, 1382, 1257, 1211, 1202, 1107, 1020, 949, Having absorption peaks at 924, 829, 798, 781, 746, 667, 654, 616, 569, 506, 427 and 411 cm- ¹ ;

C 1: has an endothermic peak at 60.6 ° C in differential scanning calorimetry,

3. The crystal according to the above 1 or 2, which has a chemical purity of 99.0% or more,

4. 99.5 ° /. The crystal according to the above 1 or 2, which has the above chemical purity, 5. The crystal according to the above 1 or 2, which is produced by crystallizing with an organic solvent which may contain water,

 6. The organic solvent is selected from aromatic carbocyclic solvents, ester solvents, chain ether solvents, ketone solvents, nitrile / lean solvents, lower alcohol solvents and organic linear alkane solvents One type of solvent or a mixture of two or more types

 7. The above item 1 or 2 produced by recrystallization with a mixed solvent of a chain ether solvent which may contain water and a linear alcohol solvent which may contain water. Crystal,

8. The crystal according to the above 1 or 2, which is an EP 2 agonist,

 9.The crystal according to 1 or 2, which has an eye disease preventive and / or therapeutic effect,

10. The crystal according to the above 9, wherein the dizziness is glaucoma or ocular hypertension,

 11. A prophylactic or therapeutic agent for an ophthalmic disease using the crystal according to 1 or 2 above,

 12. The prophylactic and / or Z or therapeutic agent according to 11 above, wherein the eye disease is glaucoma or ocular hypertension,

 13. The crystal according to the above 1 or 2, and one or more selected from a sympathomimetic, a parasympathomimetic, a sympathomimetic, a prostaglandin, a carbonic anhydrase inhibitor, and a hypertonic osmotic agent. A medicine comprising a combination of

14. A pharmaceutical composition comprising the crystal according to the above 1 or 2,

 15. A method for preventing and treating glaucoma or ocular hypertension in a mammal, which comprises administering an effective amount of the crystal according to the above 1 or 2 to the mammal,

 16. Use of the crystal according to the above 1 or 2, for producing a glaucoma or ocular hypertension prophylaxis Z or therapeutic agent,

17. General formula (I)

(In the formula, A represents a hydrocarbon group which may have a substituent, R ¹ represents a C 1-6 hydrocarbon group which may be substituted with halogen, and is _α -configuration, β-configuration. Or a mixture thereof), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof;

 18. Isopropyl 2-[(2-{(2R) -1-2-[(3,5-dichlorophenoxy) methyl] -5-oxopyrrolidine-1-yl} ethyl) thio] -1-1,3-thiazole-4 Monocarboxylate, ethyl 2 -— [(2-{(2R) —2 -— [(3,5-dichlorophenoxy) methyl] -15-oxopyrrolidine-1-yl} ethyl) thio] —1,3— Thiazole-4—Ripoxylate, isopropyl 2 -— ((2-{(2R) 1-2 — [(1Ε, 4S) -14— (1-Echinolecyclobutynole) 1-4—Hydroxy-1-buteninole ] —5—oxopyrrolidine-1 1-inole) echinole) 才] 1,1,3-thiazonole-4—force Rupoxylate and butyl 2_ [(2- {(2R) — 2— [(1 Ε, 4 S) —4— (1-Echinolecyclobutyl) -1-4-hydroxy-1--1-buteninole] -1-5-oxopyrrolidine-1-yl} ethynole) thio] — 1, 17. The compound according to the above 17, wherein the compound is returned from the group consisting of 3-thiazolone 1-4-carboxylate,

19. Isopropyl 2-[(2-{(2R) -1-2-[(3,5-dichlorophenoxy) methyl] _- 5-oxopyrrolidine-1-1-^^ ethylino) thio] 1-1,3-thiazole-14 The compound according to the above 18, which is a monocarboxylate, 20. The compound according to the above 177b to 19, which is a agonist,

21. A pharmaceutical composition comprising the compound according to 17 above,

22. The pharmaceutical composition according to 21 above, which is an agent for preventing and treating ocular diseases or Z or a therapeutic agent, 23. The pharmaceutical composition according to 22 above, wherein the ophthalmic disease is glaucoma or ocular hypertension. 24. An effective amount of the compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof according to the above item 17, is administered to a mammal. Glaucoma or ocular hypertension prevention and Z or treatment method in mammals, and

 25. The compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof, or a prodrug thereof for producing a preventive and / or therapeutic agent for glaucoma or ocular hypertension. It concerns the use of cyclodextrin inclusion compounds.

 In the general formula (I), the “hydrocarbon group” in the “optionally substituted hydrocarbon group j” represented by A includes, for example, a linear or branched aliphatic hydrocarbon group and a cyclic Examples include a hydrocarbon group, a cyclic hydrocarbon group-aliphatic hydrocarbon group, a cyclic hydrocarbon group-a cyclic hydrocarbon group, and the like.

 Examples of the “linear or branched aliphatic hydrocarbon group” include “C 1-8 aliphatic hydrocarbon group” and the like. As the “C 1-8 aliphatic hydrocarbon group”, Is a Cl-8 alkyl group such as methyl, ethyl, propyl / butyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexinole, heptyl, octyl, etc. C2 to C8, such as, butyr, penteel, hexeneol, hepteninole, octeninole, butadjenole, pentagennole, hexagenil, heptagenil, genius ctageninole, hexatenlinele, heptatrile, octatrile, etc. Mouth piernole, puchnore, pentinole, hekisnore, heptunore, occiniole, bu Jiiniru, Pentajiiniru to, Kisajiiniru, Heputajii two Norre, Okuta Jiiniru to, Kisatoriiyuru, hepta Toryiniru, such as Okutatoriiyuru based on

And C 2-8 alkynyl groups.

 The “cyclic hydrocarbon” includes “unsaturated cyclic hydrocarbon” or “saturated 瀵 -hydrocarbon”. Examples of “saturated cyclic carbon dioxide” include, for example, cyclopropyl

S Cyclononane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, etc .; Perhydroazulene, perhydroindene, perhydronaphthalene, perhydroheptalene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] pentane, bicyclo [2.2.1] ] "3- to 5-membered saturated cyclic hydrocarbons" such as heptane, bicyclo [3.1.1] heptane, bicyclo [2.2.2] octane, adamantane, noradamantane and the like. Examples of the “unsaturated cyclic hydrocarbon” include cyclopentene, cyclopentene, cyclopentene, cyclopentene, cyclopentene, cyclohexagene, cycloheptagen, cyclooctagene, etc. Aromatic hydrocarbons such as benzene, azulene, naphthalene, phenanthrene, and anthracene; and further, for example, pentalene, indene, indane, dihydronaphthalene, tetrahydronaphthalene, heptalene, biphenylene, as-indacene, s-indacene, isenaphthene, Acenaphthylene, phenolenolen, phenalene, bicyclo [2.2.1] heptane 2-ene, bicyclo [3.1.1] hepter 2-ene, bicyclo [2.2.2] octa-2-ene, etc. "3- to 15-membered unsaturated cyclic hydrocarbon" and the like.

Examples of the "cyclic hydrocarbon group-aliphatic hydrocarbon group" include those in which the above-mentioned "cyclic hydrocarbon group" and "aliphatic hydrocarbon group" are bonded, and examples thereof include benzyl, pheninoletinol, phenylpropyl, and naphthalene. C 7-16 aralkyl group such as 1-inolemethinole, for example, C 8-16 aralkyl group such as 3_phenyl-2-propyl, 2- (2-naphthylvinyl), 4-cyclobutyl-1-butyr , For example, propylmethyl, cyclohexylmethyl, hexinoletinol, hexinolepropinole, 1-meth / l- (C 3-8 cycloalkyl) 1 (C 1-4 alkyl) groups such as silmethyl, for example, (C 3-8 cycloalkyl) 1 (C 1-4 alkyl) such as 3-cyclohexylmethyl Can be

 Examples of the “cyclic hydrocarbon group-cyclic hydrocarbon group” include those in which the above “cyclic hydrocarbon group” and “cyclic hydrocarbon group” are bonded, and examples thereof include 3-fuylphenyl and 4-fuylphenyl. No.

As the “substituent” in the “hydrocarbon group which may have a substituent” represented by A, (1) a substituent (for example, a Cl-4 alkyl group, an amino group, a sulfo group, a halogen atom, A hydrocarbon group which may have a canolepoxinole group, a cyano group, a nitro group, an oxo group, a thioxo group, a hydroxyl group, a methoxy group, a trifluoromethylinole group, a trifluoromethoxy group, etc. This “hydrocarbon group” has the same meaning as the above “hydrocarbon group”.), (2) Substituents (for example, hydrocarbon group, amino group, snoreho group, halogen atom, force / repoxy group, A heterocyclic group which may have a cyano group, a nitro group, an oxo group, a thioxo group, a hydroxyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, an acetyl group, etc .; Groups, (4) C1-6 acylamino such as acetylamino, propio-amino, etc., (5) methylamino, ethylamino, aminopinoleamino, isopropinoleamino, aminobutylamino, heptylamino, octamino, dimethylamino, aminohexamino, etc. Xylamino, 1-lumbamoinole 2-cyclohexylethylamino, N-butynole N-cyclohexylmethinoleamino, phenyl ^ / amino, 6,6-dimethinolevisic mouth [3.1.1] Heptylmethylamino A primary or secondary amino group substituted with a hydrocarbon group (here, this “hydrocarbon group” has the same meaning as the above “hydrocarbon group”, and includes a halogen atom, oxo, amino, It may be substituted with rubamoyl, etc.), (6) For example, methinolesulfonylami , E Ji Le sulfonyl § amino etc. C 1 to 4 alkyl sulfonylamino Nino les amino group, (7) Hue -Sulfonylamino group, (8) C 1-4 alkylsulfonyl group such as methylsulfonyl and ethylsulfol, (9) phenylenosulfonyl group, (10) halogen atom (eg, fluorine, chlorine, bromine , Iodine), (1 1) carboxyl group, (12) cyano group, (13) nitro group, (14) oxo group, (15) thioxo group, (16) hydroxyl group, (17) for example, methoxy, ethoxy, C 1-10 alkoxy groups such as propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclohexinolemethyloxy, pendinoleoxy, etc. (18) C 3-8 cycloalkoxy such as cyclohexyloxy (19) a phenoxy group which may be substituted by, for example, a C 1-4 alkyl group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, etc .; 6,7,8-tetrahydro 1-naphthyloxy group, (21) mercapto group, (22) Cl-4 alkylthio group such as methylthio, ethylthio, propinorethio, isopropylthio, ptinolethio, tert-butylthio, etc., (23 ) Pheninolethio group, (24) carpamoyl group, (25) N-butylaminocarbyl, N-cyclohexylmethylaminocarbonyl, N-butyl-N-cyclohexylmethylaminocarbinole, N-cyclohexino Aminocarbonyl groups substituted with 1 to 8 hydrocarbon groups such as reaminocanolepouzole and pheninoleaminocanolepoenole (where the “hydrocarbon group” is the aforementioned “hydrocarbon group” And (26) a sulfamoyl group, and (27) an aminosulfonyl group substituted with a hydrocarbon group such as methylaminosulfonyl. Groups (here, the “hydrocarbon group” has the same meaning as the above “hydrocarbon group”), (28) such as dimethylaminoethylaminosulfuryl, dimethylaminopropylaminosulfonyl, etc. An aminosulfonyl group substituted by a hydrocarbon group substituted by an amino group (here, this “hydrocarbon group” has the same meaning as the above “hydrocarbon group”), (29) Shikanoleponyl, ethoxycarbonyl, C. 1 to 6 Arukokishikaru Interview le groups such as tert- butoxycarbonyl, (3 0) sulfo group (an S 0 ₃ H), (3 1) sulfino group, (3 2) a phosphono group, (3 3) amidino Group, (34) imino group, (35) — B (OH) ₂ group, (36) C1-4 anolequinolenorefinyl such as methylsulfinole and etinoresnorefuenole (37) For example, Cl to 6 acyl groups such as formyl, acetyl, propioyl, butyryl, (38) benzoyl, (39) hydroxyimino group,

(40) Examples include an alkyloxyimino group such as methyloxyimino and ethyloxyimino. The “optionally substituted hydrocarbon group” may have 1 to 5 substituents selected from the above (1) to (40), and the number of substituents is 2 In the above case, each substituent may be the same or different.

 The `` heterocycle '' as a substituent of the `` hydrocarbon group '' represented by A is a monocyclic ring which may contain 1 to 7 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, Represents a bicyclic or tricyclic heterocyclic ring. As the "heterocycle", for example, "3- to 5-membered unsaturated monocyclic, bicyclic or tricyclic heterocyclic ring", "3- to 5-membered saturated monocyclic, bicyclic or tricyclic heterocyclic ring" and the like Is mentioned.

Examples of the "3- to 5-membered unsaturated monocyclic, bicyclic or tricyclic heterocyclic ring" include, for example, pyrrole, imidazo / re, torizozole, tetrazo ^ "nore, pyrazonole, pyridine, pyrazine, Pyrimidines, pyridazines, triazines, furans, thiophenes, oxazones, isoxazones, thiazoles, isothiazones, furans, aromatic monocyclic heterocycles such as oxadiazoles, thiadiazoles, etc., for example, indolines, isoindofranes, etc. , Isobenzofuran, Benzothiophene, Isobenzothiophene, Indazo ゾ ^, Quinoline, Isoquinoline, Purine, Phthalazine, Pteridine, Naphthyridine, Quinoxaline, Quinazoline, Cinnoline, Benzoxazonole, Benzothiazozol, Benzomidazo Honoré, Benzoburazan, benzothiadiazole, benzotriazole § zone Honoré, Kalesubazonore, β-strength norevoline, atarizine, phenazine, dibenzofuran, dibenzothiophene, phenanthridine, phenanthone phosphorus, perimidine ring, and other fused aromatic heterocycles such as azepine, diazepine, pyran, oxepin, thiopyran, chepin, Oxazine, oxazineazine, oxazepine, oxazineazepine, thiazine, thiadiazine, thiazepine, thiadiazepine, indolizine, dithianaphthalene, quinolidine, chromene, benzoxepin, benzoxazepine, benzoxazezepine, benzochepine, benzozoazepine Thiadiazepine, benzazepine, benzodiazepine, xanthene, phenothiazine, phenoxazine, phenoxatiin, thianthrene, pylori , Imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydrovirazine, tetrahydrovirazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, tetrahydrotriazine, dihydrohydrodazepine, dihydrohydrodazepine Pin, Tetrahydridosezepine, Dihydrofuran, Dihydropyran, Dihydrodoloxepin, Tetrahydroxepin, Dihidrochifen, Dihydrothipipyran, Dihydrochepin, Tetrahydrochepin, Dihydrooxazoi / le, Dihydroisoisoxazole, Dihydrothiazotizole Nore, dihydrofurazan, dihydrooxadiazole, dihi Drooxazine, dihydrooxazine diazine, dihydrooxazepine, tetrahydrooxazepine, dihydroxoxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, tetrahydrothia Zepin, dihydrothiadiazepine, tetrahydrothiadazepine, indolin, isoindoline, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothienephen, dihydroindazole, dihydroquinoline, tetrahydro Quinoline, dihydroisoquinori , Tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, benzoxazotane, dibenzoxanthione Dihydrobenzozothiazine, pyrazinomonoleforin, dihydrobenzozoxazole, dihydrobenzozothiazole, dihydro benzozoimidazole, dihydrobenzozepine, tetrahydrobenzozepine, dihydrobenzozoazepine, tetrahydrobenzozoazepine, benzodioxepane, dihydrobenzoza Tetrahydrobenzoxazepine, dihydrolurazole , Tetrahydroforce rubazo / re, dihydroβ-carboline, tetrahydro-] 3-canoleporin, dihydroacridine, tetrahydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzozofuran, tetrahydrodibenzothifenphen, dioxa Indane, benzodioxane, chroman, benzodithiene orchid, benzodithiane, 6,7,8,9-tetrahydro 5 5-pyrido [4,, 3 ': 4,5] Pyro [2,3-b] pyridine, 2,3,4,5-tetrahydro 1H-pyrid [4,3-b] indole, 6,7,8,9-tetrahydro-5H-pyrid [3,, 4 ': [4, 5] Pyro mouth [2, 3-b] Non-aromatic unsaturated heterocycle such as pyridine ring. Examples of the "3- to 15-membered saturated monocyclic, bicyclic or tricyclic heterocyclic ring" include, for example, aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, Perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazosin, oxolane, oxetane, tetrahydrofuran, tetrahydridopyran, /, ° -hydrodroxepine, thiirane, chetan, tetrahydrothione Phen, tetrahydrothiovirane, perhydrochepin, tetrahydrooxazole (oxazolidine), Tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazonole (isothiazolidine), tetrahydrofurazan, tetrahydrooxaziazol (oxaziazolidine), tetrahydrooxazine, Tetrahydrooxazine diazine, norhydroxoxazepine, perhydroxoxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine, perhydrothiazine Azepine, monoreforin, thiomonoleforin, oxaxian, perhydrobenzozofuran, perhydroisobenzofuran, perhydrobenzobenzothiophene, perhydroisobenzothiophene,,. Perhydroquinoline, Perhydroquinoline, Perhydroisoquinoline, Perhydrophthalazine, Perhydronaphthyridine, Perhydroquinoxaline, Perhydroquinazoline, Perhydrocinnoline, Perhydrobenzoquinone, Perhydrobenzoquinone, Perhydrobenzoquinone And perhydrobenzoimidazolone, perhydrocarbazole, perhydro-l-carboline, perhydroacridine, perhydrodibenzofuran, perhydrodibenzothiophene, disolan, dioxane, dithiolane, dithiane ring and the like.

The “C 1-6 hydrocarbon group” in the “C 1-6 hydrocarbon group optionally substituted with halogen” represented by R ¹ includes, for example, a C 1-6 aliphatic hydrocarbon group or C And 1-6 cyclic hydrocarbon groups. Here, “aliphatic hydrocarbon group” and “cyclic hydrocarbon group” have the same meaning as described above. Preferable examples of R ¹ include, for example, methyl, ethyl, propyl, isopropyl, butyl, trifluoroethyl, cyclohexyl and phenyl.

 The compound represented by the general formula (I) preferably includes, for example, the compounds described in the examples.

More preferably, isopropyl 2-[(2-{(2R) -2 — [(3,5-dichlorophenoxy) methinole]] — 5-oxopyrrolidine-1-1-inole} Ethyl) thio] —1,3-thiazole-14-carboxylate, ethyl 2-[(2 — {(2R) —2 — [(3,5-dichlorophenoxy) methyl] -1-5-oxopyrrolidine-1 Thiol) thio] —1,3-thiazole-14-carboxylate, isopropyl 2-— ((2 — {(2R) 1-2 — [(IE, 4S) -4- (1-ethynolecyclo) (Ptinole) 1-4-Hydroxy 1-butyl) 15-oxopyrrolidine 1-1-inole) ethyl) Thio] — 1,3-thiazol-4-carboxylate, butyl 2-— ((2- {(2R)-2 -[(1E, 4S) -4- (1-Ethylcyclobutyl) -1-hydroxy-1butyr] —5-oxopyrrolidine-1-yl} ethyl) thio] — 1,3-Triazole_4 And the like.

In the present invention, unless otherwise specified, the symbols...,..., ^X indicate that they are connected to the other side of the paper surface (that is, α-configuration), and that結合 indicates a single configuration, a configuration or a mixture thereof, and Ζ indicates a mixture of a single configuration and a single configuration. Indicates that.

 In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkellen group and the alkulene group include those having a straight chain and those having a branched chain. In addition, isomers (Ε, Ζ, cis, trans) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbons (R, S, α, configuration, enantiomers, diastereomers), optical rotation Optically active form (D, L, d, 1 form), polar form (high polar form, low polar form) by chromatographic separation, equilibrium compound, rotamer, mixture of any ratio of these, racemic All mixtures are included in the present invention.

The optically active compound in the present invention may contain not only 100% pure but also other optical isomers of less than 50 ° / ₀ . The compound represented by the general formula (I) is converted into a salt by a known method. As the salt, a pharmacologically acceptable salt is preferable.

 Examples of the salt include an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amine salt and an acid addition salt.

 The salt is preferably water-soluble. Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethinole ammonium, triethylamine, methylamine). Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amino methane, lysine, arginine, N-methyl-1-D-glucamine, and the like.

 The acid addition salt is preferably water-soluble. Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, Organic salts such as benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and dalconate.

 The compound represented by the general formula (I) and a salt thereof can also be converted to a solvate.

 Preferably, the solvate is non-toxic and water-soluble. Suitable solvates include, for example, water and solvates such as alcoholic solvents (eg, ethanol and the like).

All of the compounds represented by the general formula (I) or pharmacologically acceptable salts thereof are preferred. Specific examples include the compounds described in the Examples or pharmacologically acceptable salts thereof. Salts also include quaternary ammonium salts. The quaternary ammonium salt means that the nitrogen atom of the compound of the present invention is R. Represents those quaternized by a group. Here, the R ⁰ group represents a C 1-8 alkyl group or a C 1-8 alkyl group substituted by a phenyl group.

 The compound of the present invention can be converted to N-oxide by any method. N-oxo refers to an oxidized nitrogen atom of the compound of the present invention.

 The compound of the present invention can be prepared by the method described in JP-B-50-3362, JP-B-52-31404 or JP-B-61-52146 using 1, 3) or "y-cyclodextrin, or a mixture thereof. When used as a drug, it can be converted into a cyclodextrin clathrate compound because it increases stability and increases water solubility by converting into a cyclodextrin clathrate compound. It is.

Further, a prodrug of the compound of the present invention refers to a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid, or the like in a living body. As a prodrug of the compound of the present invention, when the compound of the present invention has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, the amino group of the compound of the present invention is eicosaylated, valylated) , Pentylaminocarbonylation, (5-methyl-1-oxo-1,3-dioxolen-4-yl) methoxyl / repotination, tetrahydrofuranylation, pyrrolidylmethylation, viva-methyloxymethylation When the compound of the present invention has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, phosphorylated (for example, the compound of the present invention) The hydroxyl group of acetylation, palmitoylation, propanoylation, bivaloylation, succinylation, fumarinole, aranylation, A compound in which the carboxy group is esterified or amidated (for example, the carboxy group of the compound of the present invention is methyl esterified; Ethyl esterification, propyl esterification, isopropyl esterification, butyl esterification, isobutyl esterification, sec-butyl esterification, tert-butyl esterification, pentyl esterification, isopentyl esterification, neopentinole esterification, cyclopentyl esterification, hexino Reesterification, cyclohexyl esterification, trifluoroethyl esterification, phenylesterification, ethoxypropyl esterification, dimethylaminomethyl esterification, vivaloyloxymethyl esterification, ethoxycarponyloxy ester Thioesterolation, phthalidyl esterification, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidation Conversion Things, etc.), and the like. These compounds can be produced by a method known per se. The prodrug of the compound of the present invention may be any of a solvate and a non-solvate. Isopropyl 2-[(2-{(2R) —2 -— [(3,5-dichlorophenoxy) methyl] _- 5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3-thiazol-4-carboxylate ( Hereinafter, the compound is abbreviated as compound 1.) is obtained by using a powder X-ray diffraction spectrum shown in FIG. 1 obtained by using a Cu—Ka ray or a diffraction angle (shown in Table 1 below). 20) and relative intensity data.

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 was measured using the infrared absorption spectrum (IR) shown in Figure 2 measured by the total reflection method, or 1717, 1687, 1675, 1661, 1586, 1567, 1443, 1423, 1382, 1257 , 1211, 1202, 1107, 1020, 949, 924, 829, 798, 781, 746, 667, 654, 616, 569, 506, even cowpea the absorption peak of 427 and 411 cm one ¹ characterized.

 The crystal of Compound 1 is characterized by the differential scanning calorimetry (DSC) chart shown in FIG. 3 or by an endothermic peak at about 60 ° C.

 The crystal of Compound 1 is specified by the physicochemical properties described in this specification, but it should not be interpreted strictly because each spectrum data may vary slightly in its properties. .

For example, due to the nature of powder X-ray diffraction spectrum data, In this case, the diffraction angle (20) and the overall pattern are important, and the relative intensity can vary slightly depending on the direction of crystal growth, particle size, and measurement conditions.

 Also in the infrared absorption (IR) spectrum, the overall pattern is important in determining the identity of a crystal, and may vary slightly depending on the measurement conditions. Furthermore, in the differential scanning calorimetry (DSC) data, the overall pattern is important in certifying the identity of the crystal, and may vary slightly depending on the measurement conditions.

 Therefore, those having an overall pattern similar to the powder X-ray diffraction spectrum, infrared absorption (IR) spectrum or differential scanning calorimetry (DSC) data of the compound 1 crystal of the present invention are those of the compound 1 crystal. It is included in.

 The chemical purity of the crystal is preferably 97.0% or more, more preferably 99.0% or more, and particularly preferably 99.5% or more.

 [Method for producing compound of the present invention]

 The compound of the present invention represented by the general formula (I) can be produced by a known method, for example, Comprehensive Organic Transformations' ■ A Guiae to Functional Group Preparations, 2na Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) or WO2003 / 74483 The method can be manufactured by appropriately improving the method described in the pamphlet, the method according to the method, or the method described in the examples, and using them in combination.

 The compound represented by the general formula (I) is represented by the general formula (II)

(Wherein all symbols have the same meanings as described above.) HO-R ¹ (Ml)

(In the formula, R ¹ has the same meaning as described above.) The compound can be produced by subjecting the alcohol represented by the following formula to the following esterification reaction and, if necessary, recrystallization.

 The esterification reaction is known, and examples thereof include (1) a dehydration-condensation reaction in the presence of an acid catalyst, and (2) a transesterification reaction.

 (1) Dehydration condensation reaction in the presence of an acid catalyst

 The compound represented by the general formula (I) can be obtained, for example, by converting a carboxylic acid derivative represented by the general formula (Π) into an organic solvent (an alcohol or the alcohol represented by the general formula (III) or another organic solvent). In a mixed solvent, an acid (an inorganic acid (eg, sulfuric acid, hydrochloric acid, etc.), an organic acid (eg, paratoluenesulfonic acid, trifluoroacetic acid, etc.), or a Lewis acid (eg, boron trifluoride getyl ether complex, etc.) It can be produced by reacting at 0 ° C to 10 ° C in the presence.

 (2) Transesterification

 —The compound represented by the general formula (I) is obtained by converting a simple ester such as a methyl ester of a carboxylic acid derivative represented by the general formula (Π) into an alcohol solvent represented by the general formula (III), (An inorganic acid (eg, sulfuric acid, hydrochloric acid, etc.), an organic acid (eg, paratoluenesulfonic acid, trifluoroacetic acid, etc.), or a Lewis acid (eg, boron trifluoride getyl ether complex, etc.)), a base (eg, In the presence of potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium methoxide, sodium ethoxide, or titanium alkoxide (eg, titanium tetraisopropoxide) at 0 ° C to 100 ° C. It can be manufactured by reacting at ° C.

In addition to the above esterification reaction, the esterification reactions described below, for example, (3) a method using an acid halide, (4) a method using a mixed acid anhydride, and (5) a method using a condensing agent Etc. can also be used. These methods will be specifically described below.

 (3) A method using an acid halide includes, for example, a method in which a carboxylic acid is converted into an acid halide agent (oxalyl chloride, thioyl chloride) in an organic solvent (eg, chloroformate, dichloromethane, methyl alcohol, tetrahydrofuran, etc.) or in the absence of a solvent. ) At 120 ° C to reflux temperature, and the resulting acid halide is reacted with an alcohol in the presence of a base (eg, pyridine, triethylamine, dimethylinoureulin, dimethylaminopyridine, diisopropylethylamine). And an organic solvent (eg, form, dichloromethane, dimethyl ether, tetrahydrofuran, etc.) at a temperature of 0 to 40 ° C. Alternatively, the reaction can be carried out by reacting with an acid halide in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (aqueous sodium bicarbonate or sodium hydroxide solution) at 0 to 40 ° C.

 (4) A method using a mixed acid anhydride includes, for example, a method in which a carboxylic acid is dissolved in an organic solvent (chlorophoronem, dichloromethane, dimethyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine, dimethylaniline, dimethyl Acid halides (such as pivaloyl chloride, tosyl or mesyl chloride) or acid derivatives (such as ethyl ethyl formate and isobutyl chloroformate) in the presence of aminopyridine or diisopropylethylamine. By reacting the resulting mixed acid anhydride with an organic solvent in an organic solvent (e.g., chloroform, dichloromethane, dimethyl ether, tetrahydrofuran, etc.) at 0 to 40 ° C. Done.

(5) The method using a condensing agent is, for example, a method in which a carboxylic acid and an alcohol are mixed with an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, dimethyl ether, tetrahydrofuran, etc.) or in a solvent-free base ( In the presence or absence of pyridine, triethylamine, dimethyla- phosphorus, dimethylaminopyridine, etc., a condensing agent (1,3-dicyclohexylcarposimide (DC C), 1-Ethyl-1- [3- (dimethylamino) propyl] carbodiimide (EDC), 1,1, 1-l-poerdiimidazo-mono (CDI), 2-chloro 1-methylpyridinyl Using iodine, 1-propanephosphonic acid cyclic anhydride (PPA), etc., with or without 1-hydroxybenztriazole (HOBt) The reaction is carried out at 0 ° C.

 Further, the compound represented by the general formula (I) is a compound represented by the general formula (IV) and a carboxylic acid derivative represented by the general formula (II).

XR ¹ (IV) (wherein, X represents a halogen atom and R ¹ has the same meaning as described above). The compound may be produced by subjecting the compound to the following esterification reaction. it can.

 This esterification reaction is known. For example, the compound represented by the general formula (I) is obtained by converting the compound represented by the general formula (II) and the compound represented by the general formula (IV) into an organic solvent ( For example, in dimethylformamide, dimethylacetamide, dimethylimidazolidinone, tetrahydrofuran, getyl ether, dichloromethane, chloroform, etc.) in a base (eg, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, t) The reaction can be carried out at 0 ° C to 100 ° C in the presence of potassium butoxide, sodium methoxide, sodium ethoxide and the like.

 The above esterification reaction can be performed in the presence or absence of an inert gas such as argon or nitrogen.

 In the above production method, the compound represented by the general formula (II) can be produced by the method described in WO2003 / 74483 or a partially modified method.

Compounds used as other reagents may be any known or publicly known compounds. Methods of knowledge, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) or Elmer J. Rauckman et. Al., J. Org. Chem., vol.41, No.3, 1976, p564-565, etc., and can be easily manufactured by using them in combination.

 In each reaction in the present specification, a reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.

 In each reaction in the present specification, a solid-phase-supported reagent supported on a high-molecular polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like) may be used as appropriate.

 In each reaction in the present specification, the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by a method such as scavenger resin or column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after several reactions are completed.

 Among the compounds represented by the general formula (I), the crystal of the compound 1 can be produced by the methods described in Examples or below.

 That is, the crystal of Compound 1 is obtained by converting Compound 1 into an aromatic carbocyclic solvent, an ester solvent, a chain ether solvent, a ketone solvent, a nitrile solvent, and a lower alcohol solvent which may contain water. Or a mixture of one or more of the above-mentioned solvents and a linear alginate-based solvent which may contain water, followed by recrystallization. Can be

The recrystallization involves water, which is a good solvent (good solvent) in which the solute is easily dissolved. Aromatic carbocyclic solvents (eg, toluene, etc.), ester solvents (eg, ethyl acetate, isopropyl acetate, etc.), chain ether solvents (eg, t-peptinolemethinole ether, diisopropynole) Ethanol, getyl ether, dimethoxyethane, etc.), ketone solvents (eg, acetone, etc.), turile solvents (eg, acetonitrile) or lower alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, etc.) It may be used as a single solvent, or it may contain a mixture of multiple solvents, for example, multiple good solvents (good solvents), or a good solvent (good solvents), and a poor solvent in which solutes are difficult to dissolve. A mixed solvent with an optionally used linear alkane-based solvent (eg, hexane, heptane, etc.) may be used. The order of operation may be such that a solution in which the solute is dissolved in a good solvent (good solvent) may be added to the poor solvent, or a poor solvent may be added to a solution in which the solute is dissolved in the good solvent (good solvent).

 Preferred recrystallization solvents used to obtain the crystals of Compound 1 include a mixed solvent of a linear ether solvent that may contain water and a linear alkane solvent that may contain water. . Specifically, for example, a mixed solvent of diisopropyl pyrether and heptane, a mixed solvent of t-butyl methyl ether and heptane and the like can be mentioned. '

 [Toxic]

 The compound represented by the general formula (I) has a very low toxicity and is sufficiently safe for use as a medicament.

 [Application to pharmaceutical products]

Since the compound of the present invention represented by the general formula (I) has an EP 2 agonist effect, has an intraocular pressure lowering effect, a protective effect on the retina and the optic nerve, and a ameliorating effect on the optic nerve head circulation, it has an ocular disease such as glaucoma and ocular hypertension. Effective in preventing and / or treating pressure, macular edema, macular degeneration, decreased blood flow in the retina and optic disc, increased retinal and optic nerve tension, myopia, hyperopia, astigmatism, dry eye, retinal detachment, cataract, etc. The

 The compound represented by the general formula (I) includes 1) supplementation and enhancement of the therapeutic effect of the compound, ぴ Z or enhancement, 2) improvement of kinetics and absorption of the compound, reduction of the dose, and Z or 3) It may be administered in combination with other drugs to reduce side effects.

The concomitant drug of the present compound and another drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or may be in the form of separate preparations for administration. When administered in the form of separate preparations, simultaneous administration and administration at different times are included. In addition, administration by the time difference may be performed by administering the agent of the present invention first and then administering another agent, or administering another agent first and then administering the agent of the present invention. Regardless, the respective administration methods may be the same or different. The other drug may be a low molecular weight compound, a high molecular weight protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. And so on. The dose of the other drug can be appropriately selected based on the clinically used dose. The mixing ratio of the agent of the present invention and other agents can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, and the like. For example, 0.01 to 100 parts by mass of another agent may be used for 1 part by mass of the agent of the present invention. Other drugs may be administered, for example, in combination of any one or more of the following homologous groups and heterogeneous groups in appropriate proportions. Further, other drugs that complement and / or enhance the therapeutic effect of the compound of the present invention include those that have been found up to now and those that will be found in the future based on the mechanism described above. Other agents, e.g., sympathomimetics _{(alpha 2} Agonisuto: For example, Apurakuroejin hydrochloric acid or the like, / 3 ₂ § GORE - be sampled: for example, hydrochloric acid di pin base Flynn etc.), parasympathomimetics (e.g. , Pilocarpine hydrochloride, carbachol, or distigmine bromide, etc.), sympatholytics (blockers: eg, bunazosin hydrochloride) // 3 blockers: for example, timolol maleate, befnolol hydrochloride, hydrochloric acid salt, or betaxolol hydrochloride, etc. a / 3 blockers: for example, lepopnolol hydrochloride, nipradilol, etc., prostaglandin drugs ( For example, isopropyl unoprostone, latanoprost, FP agonist, EP 2 agonist, or DP agust), a carbonic anhydrase inhibitor (for example, acetazolamide, diclofenamide, metazolamide, dorzolamide hydrochloride, or brinzolamide), Hypertonic drugs (eg, glycerin, a combination preparation of glycerin and fructose, isosorbide, D-mantol, etc.).

 The compound of the present invention has a therapeutic and inhibitory effect on eye diseases occurring in humans and animals. More preferably, it is used as a therapeutic agent for glaucoma.

 The compound of the present invention can be formulated as a single preparation or a compound preparation using a technique widely used, if necessary, by adding a pharmaceutically acceptable additive.

In order to use the compound of the present invention represented by the general formula (I) or the combination of the compound represented by the general formula (I) and another drug for the above-mentioned purpose, usually, systemically or locally, It is administered orally or parenterally. Oral preparations include, for example, liquids for internal use (eg, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), and solid preparations for internal use (eg, tablets (sublingual tablets, oral cavity) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, troches and the like. Parenteral preparations include, for example, liquid preparations (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (eg, aqueous eye drops (aqueous Ophthalmic solution, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous ophthalmic solution (non-aqueous ophthalmic solution, non-aqueous suspension ophthalmic solution, etc.)), etc.), external preparations (for example, ointment ( Ophthalmic ointment, etc.) These preparations include immediate release preparations and sustained release preparations. Release controlling agents such as lipophilic preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.

 Liquid preparations for oral administration are manufactured, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). You. Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

 Solid preparations for internal use as oral preparations include, for example, excipients such as lactose, mannitol, grape / recose, microcrystalline cellulose, starch, etc., binders (eg, hydroxypropylcellulose, polybutylpyrroli). Don, magnesium metasilicate aluminate, etc.), disintegrant (eg, calcium cellulose glycolate, etc.), lubricant (eg, magnesium stearate, etc.), stabilizer, dissolution aid (glutamic acid, aspartic acid) Etc.) and formulated according to standard methods. Also, if necessary, a coating agent (eg, sucrose,

1155 Larathintin, baboon dodroxyxysipropropirpircecenonorrelorose, baboon dodrolo

 May be covered with) or may be covered with a layer of 22 or more. It may be good. .

 External preparations as non-parenteral oral preparations can be prepared by using a method known in the art or a formulation that is usually used regularly. It is manufactured and manufactured by . For example, an ointment ointment is prepared by adding an active ingredient to a base material, or by melting and melting.

It is manufactured and manufactured in 2200. . The base of the ointment is selected from publicly known or commonly used ones. .

 For example, higher-grade fatty fatty acids, or higher-grade fatty acid es-estere (for example, aazidipicinic acid, mimyrististinic acid, paparulimi, Titinic acid, stearearalinic acid, oleireic acid, aesidipipinic acid estesterate, mimilyrististinic acid estesterate, nono, Esstelluric acid, esstereol oleate, etc.),), Loours (for example, Lobster, Beetle, Loose, Seserelesicin etc.)) ,,

2255 interfacial surfactant (eg, for example, polyalkyloxyoxyethylethylene aralkyl killer ether teresteryl phosphoric acid ester ester, etc.), high-grade aralcochol ((For example, for example, seseta nonoruru, suteteaaririru ruarukokoruru, Stearyl alcohol, silicone oil (eg, dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, ethylene glycol glycol, propylene glycol / , Polyethylene glycol ^ /, macrogol, etc.), vegetable oils (for example, castor oil, olive oil, sesame oil, turpentine, etc.), animal oils (for example, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, Those selected from rash preventive agents may be used alone or in combination of two or more. Further, it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.

 Parenteral injections include solutions, suspensions, emulsions, and solid injections which are dissolved or suspended in a solvent before use. The injection is used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcoholic compounds such as ethanol, etc., and combinations thereof are used. Further, this injection includes a stabilizer, a solubilizing agent (eg, daltamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. May be included. These can be sterilized or produced by aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be manufactured and then sterilized or dissolved in sterile distilled water for injection or other solvents before use.

When the compound of the present invention is used as a therapeutic agent for an ophthalmic disease, preferred administration forms include eye drops, eye ointments, tablets and the like, and more preferably eye drops or eye ointments. These can be formulated using commonly used techniques. For example, in the case of eye drops, additives such as a tonicity agent, a buffer, a pH regulator, a solubilizer, a thickener, a stabilizer, and a preservative can be appropriately added. Suspending drugs by adding pH regulators, thickeners, dispersants, etc. Thus, a stable eye drop can be obtained.

 Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

 Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid and the like.

 Examples of the p-regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

 Examples of the solubilizer include polysorbate 80, polyoxyethylene hardened castor oil 60, Macrogol 4000 and the like.

 Examples of the thickener and dispersant include, for example, cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polybutylpyrrolidone, and examples of the stabilizer include edetic acid. And sodium edetate.

 Examples of the preservative (preservative) include general-purpose sorbic acid, potassium sorbate, benzalcoium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, and the like. Preservatives can also be used in combination.

 In the eye drops containing the compound of the present invention, it is desirable to set ρΗ to 4.0 to 8.5, and it is desirable to set the osmotic pressure ratio to around 1.0.

When the compound of the present invention is used as a therapeutic agent for an ocular disease, the dose of the active ingredient can be appropriately selected depending on the condition, age, dosage form, etc., but if it is an oral preparation, it is preferably 1 to 100 mg, more preferably 5 to 3 O mg may be administered one to several times a day (for example, one to three times). If it is an ophthalmic solution, preferably a concentration of 0000001 to 1% (w / v), more preferably 0.00001 to 0.01% (w / v), one to several drops per dose 1 to several times a day (for example, 1 to 8 times) In addition, if it is an eye ointment, preferably 0.000001 to 1% (w / w), more preferably 000001 to 0.01% (w / w)

/ w) at a concentration of 1 to several times a day (for example, 1 to 4 times). Of course, as described above, the dose varies depending on various conditions, so a smaller dose than the above-mentioned dose may be sufficient, or may be required beyond the range.

 [The invention's effect]

 The compound of the present invention has a strong EP 2 agonist effect. Further, the compound of the present invention has a strong intraocular pressure-lowering effect and has little eye irritation. Therefore, ocular diseases such as glaucoma, ocular hypertension, macular edema, macular degeneration, decreased blood flow in the retinal optic disc, increased retinal optic nerve tension, myopia, hyperopia, astigmatism, dry eye, and retinal detachment It is effective in preventing and / or treating cataracts. Also, isopropyl 2-[(2-{(2R) -2-[(3,5-dichlorofunoxy) methyl] -5-oxopyrrolidine-1-yl} ethyl) thio] —1,3-thiazole— Crystals of 4-carboxylate are useful as high-purity drug substances for pharmaceuticals. Brief Description of Drawings

 Figure 1 shows isopropyl 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methinole] -15-oxopyrrolidine-1-1-inole} ethyl) thio] —1,3-thiazole- 4 shows a powder X-ray diffraction spectrum chart of a crystal of the lipoxylate (compound 1).

 FIG. 2 shows an infrared absorption (IR) spectrum chart of the compound 1 crystal. FIG. 3 shows a differential scanning calorimetry (DSC) chart of the compound 1 crystal. FIG. 4 is a graph showing the intraocular pressure difference between a treated eye and a control eye before and after instillation 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 before and after instillation of Compound 1-2.

 FIG. 7 is a graph showing the eye irritation of Compound 1-2. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

 The solvent in kakkoko indicated by the point of separation by chromatography and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

 NMR data is — NMR data unless otherwise noted.

 The parentheses shown in NMR indicate the solvent used for the measurement.

 The compound name used in this specification is generally a computer program for naming according to the rules of IUPAC, ACD / Name (registered trademark, manufactured by Advanced Chemistry Development Inc.) or ACD / Name patch (registered trademark). Trademarks,

Advanced Chemistry Development Inc.) or IUP

Named according to the AC nomenclature. For example,

The compound represented by is isopropyl 2-— [(2- {(2R) -2- [(1 E, 4 S) —4— (1-ethylethyl butyl) 1-4-hydroxy-1 1-butene Ί —5— Oxopyrrolidine (1-yl) ethyl) Named Zol-4-carboxylate.

 The carboxylic acid derivative used as a starting material in the examples is described in WO2003 / 74483. For example, 2-[(2-{(2R) -1-2-[(3,5-dichlorophenoxy) methyl] —5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3-thiazole-4 monorubonic acid Is a compound produced in Example 6 (32) of WO2003 / 74483.

 Example 1: Isopropyl 2-([2-((2R) -1-2-[(3,5-dichlorophenoxy) methinole]] — 5-oxopyrrolidine-1- (1-^^-ethynole) thio] —1,3- Thiazole 14-loxypropylate (Compound 1)

 Under an argon atmosphere, 2- [(2- {(2R) -2-[(3,5-dichlorophenoxy) methyl] methyl] —5-oxopyrrolidine-1-yl} ethynole) thio] 1-1,3-thiazole-4 To a solution of rubonic acid (50 mg) and isopropyl iodide (29 mg) in dimethylformamide (1 mL) was added anhydrous potassium carbonate (31 mg), and the mixture was stirred at room temperature for 10 hours and at 70 ° C for 2 hours. . Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → ethyl acetate) to give the title compound having the following physical data as an oil (50 mg).

 TLC: Rf0.32 (n-hexane: ethyl acetate, 1: 1);

NMR (CDCla): δ 1.37 (d, J = 6.30 Hz, 6 H) 2.06 (m, 1 H) 2.23 (m, 1 H) 2.39 (ddd, J = 17.00, 9.90, 5.30 Hz, 1 H) 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 H) 7.96 (s, 1 H).

Example 1 (1) to (24)

 2 — [(2 — {(2R) -2-[(3,5-dichlorophenoxy) methyl] -1-5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3_thiazol-lu-4 The same operation as in Example 1 was carried out using the corresponding carboxylic acid derivative instead of the corresponding carboxylic acid derivative, using isopropyl iodide, and using the corresponding iodide instead, to obtain the following compound of the present invention.

Example 1 (1): Ethyl 2 -— [(2-{(2R) —2 -— [(3,5-dichlorophenoxy) methyl] —5-oxopyrrolidine-1-yl} ethyl) thio] 1-1, 3-thiazole-4-carboxylate (compounds 1-1)

TLC: Ef 0.47 (toluene: ethyl acetate = 1: 1);

 N Fiber (CDCls): δ 1.40 (t, J = 7.10 Hz, 3 H) 2.05 (m, 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): isopropyl 2 -— ((2-{(2R) -1-2-((1E, 4S) —4- (1-ethylcyclobutyl) -4-hydroxy-1-1-buteninole) -15 —Oxopyrrolidine-1-ethyl} thiol) —1,3-thiazole Roux 4-carboxylate (Compound 1-2)

TLC: I ぱ 0.56 (Ethyl acetate);

_{NMR (CDC1 3): 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): Putinole 2-[(2-{(2R) —2 — [(IE, 4S) 1-41 (1-ethylethyl butyl) 1-4-hydroxy-1 1-butyr] —5—oxopyrrolidine-1 1-yl} ethyl) thio] 1-1,3-thiazole-4-carboxylate (compounds 1-3)

TLC: Rf 0.60 (ethyl acetate);

 NMR (CDCls): 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 = l 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): Isopropyl 2-{[2-((2R) -1-2-[[2-chloro-1- (trifluoromethyl) phenoxy] methyl} -1-5-pyroxy-lysine-1-yl 1) 1,3-thiazole-4-canolepoxylate (compounds 1-4)

TLC: RfO.42 (Ethyl acetate);

 NMR (CDCla): 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 Hz, 1 H) 4.20 (m, 1 H) 4.71 (dd, J = 10.16, 2.84 Hz, 1 H) 5.22 (m, 1 H) 7.26 m, 3 H) 7.94 (s, 1 H).

Example 1 (5): Isopropyl 2-[(2-{(5R) 1-2-oxo-1-5-1 [(2,3,4-trichlorophenoxy) methyl] pyrrolidine-1-yl] } Ethyl) thio] —1,3-thiazole-4-carboxylate (compounds 15)

 TLC: Rf 0.42 (ethyl ether);

 NMR (CDCla): δ 1.36 (d, J = 6.30 Hz, 3 H) 1.37 (d, J = 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 (m, 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): Isopropyl 2-[(2-{(2R) —2 -— [(4-chloro-1,3,5-dimethinolephenoxy) methyl] -1-5-pyrrolidine-1-1-yl } Ethyl) thio] _ 1,3-thiazole-4-carboxylate (Compound 1-6)

 TLC: Rf 0.45 (ethyl ether);

 NMR (CDCla): 8 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, 3H) 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, 2H) 7.95 (s, 1H).

Example 1 (7): Isopropyl 2 _ [(2-{(5R) -12-oxo-1-5-[(2,3,5-trichlorophenoxy) methyl] pyrrolidine-1-yl} thiol) thio] —1,3-thiazole-4-carboxylate (compounds 17)

 TLC: Rf 0.46 (ethyl ether);

_{NMK (CDC1 3): 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): isopropyl 2 -— ((2-{(2R) —2 -— ((4-chloro-1,2,6-dimethylphenoxy) methyl) -1-5-oxopyrrolidine-1-1-inole) etinole) Thio] —1, 3-thiazono-one 4-pot olepoxylate TLC: RfO.45 (ethyl ester);

NMR (CDCla): δ 1.31 (d, J = 6.22 Hz, 6 H) 2.08 (m, 1 H) 2.16 (s, 6 H) 2.31 (m, 2 H) 2.56 (m, 1 H) 3.51 (m, 3H) 3.81 (d, J = 4.03 Hz, 2H) 4.15 (m, 2H) 5.18 (m, 1H) 6.95 (s, 2H) 7.95 (s, 1H).

Example 1 (9): Isopropyl 2-{[2-((2R) —2 — {[4-chloro-1- (trifluoromethyl) phenoxy] methyl} —5-oxopyrrolidine-1-inole) ethyl ] 1,1,3-thiazole-41-carboxylate (compound 119)

TLC: Rf 0.43 (ethyl ether);

 NMR (CDCls): 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): Isopropyl 2-[(2-{(2R) -1-2-[(4-Chloro-3-ethylfurenoxy) methyl]-5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3 —Thiazole-4 lipoxylate (Compound 1-10)

 TLC: Rf 0.44 (ethyl acetate);

NMR (CDCls): 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 6 £

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° (HI 's) 96'L (HT ^<Z H' ⁸ = f 'Ρ) 91 ^ (HT ⁽ Z £ =' Ρ) 8A "9 (H

0996 contract OOZdf / e 3d NMR (CDCls): 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 Cm, 1 H) 6.81 (m, 3 H) 7.22 (m, 1 H) 7.94 (s, 1 H).

Example 1 (14): Isopropyl 2— [(2— {(2R) — 2_ [({[((1 S, 2 R, 5 S) -6, 6—dimethylbicyclo [3.1.1] heptau 2 —Yl] methinole} amino) methyl] 1-5-oxopyrrolidine-1 1-yl} ethynole) thio] —1,3-thiazol-4oneboxylate (compound 1-14)

TLC: Rf 0.31 (ethyl acetate: methanol = 9: 1);

 NMR (CDCls): δ 0.94 (s, 3 H) 1.15 (s, 3 H) 1.36 (d, J = 6.41 Hz, 6 H) 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): Isopropyl 2-[(2-{(2R) -2-[(heptylamino) methyl]-5-oxopyrrolidine-1-1-yl} ethyl) thio] -1,3-thiazole-14 —Carboxylate (Eye compound 1-15)

TLC: Rf 0.23 (ethyl acetate: methanol = 9: 1);

 NMR (CDCls): δ 0.86 (m, 3 H) 1.26 (m, 4 H) 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).

Example 1 (16): isopropyl 2 -— [[2-((5R) -12-oxo-1-5-{[(3,4,5-trichloromethyl) amino] methyl} pyrrolidine-11-yl ) Ethyl] thio} — 1,3-thiazole-14-carboxylate (compound 16)

TLC: Rf0.30 (n-hexane: ethyl acetate = 1: 2); NME (CDCls): δ 1.35 (m, 6 H) 1.88 (m, 1 H) 2.37 (m, 3 H) 3.43 (m, 5 H) 3.94 (m, 1 H) 4.11 (m, 1 H) 4.94 ( br. s., 1 H) 5.23 (m, 1 H) 6.61 (s, 2 H) 8.00 (s, 1 H).

Example 1 (17): isopropyl 2-({2-[(2R) -2-({[4-chloro-3- (trifluoromethyl) phenyl] amino} methyl) -1-5-oxopyrrolidine-1- 1,3-thiazole-14-carboxylate (compounds 11-17)

TLC: Rf0.30 (n-hexane: ethyl acetate = 1: 2);

 NMR (CDCls): 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 (m, 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): isopropyl 2-{[2-((2R) -2-{[(3,5-dichlorophenyl) amino] methyl} -15-oxopyrrolidine-1-yl) ethyl] thiol } One 1,3-thiazole-4 mono-loxylate (compounds 11-18)

 TLC: Rf 0.35 (n-hexane: ethyl acetate = 1: 2);

NMR (CDCls): δ 1.35 (m, 6 H) 1.88 (m, 1 H) 2.36 (m, 3 H) 3.32 (m, 3 H) 3.55 (m, 2 H) 3.95 (m, 1 H) 4.12 ( m, 1 H) 4.87 (br.s., 1 H) 5.24 (m, 1 H) 6.44 (d, J = 1.80 Hz, 2 H) 6.64 (t, J = 1.80 Hz, 1 H) 8.00 (s, 1 H) ₀

Example 1 (19): Isopropyl 2-({2-[(2R) -2-({[4-Fluoro-3- (trifluoromethyl) phenyl] amino} methyl) -5-oxopyrrolidine-1- 1-, 3-thiazole-4-carboxylate (compounds 1-19-1)

TLC: Rf0.30 (n-hexane: ethyl acetate = 1: 2);

NMR (CDCls): δ 1.32 (d, J = 6.20 Hz, 3 H) 1.34 (d, J = 6.20 Hz, 3 H) 1.91 (m, OMvu / & ld6ssa oi990

((JJ (J) () ((HHH sH S 9 τs S dimension S SH6S S Mrf H ΐ,, ...)

 ) ((() (J) () HHH9H 6H 99 τq I66 ΐ 9 9 inch ssa J J. *, ...

s 01

OJJ (() ((JJ (HHHH SH HS 9 S 9 ΐ S ΐ 6 ΖΈ τ3.- (J (() (() JHHHHH 9 τ 66 ΐΓ ΐ s- Example 1 (23): Isopropyl 2-({2-[(2S) -2-heptyl-l-5-oxopyrrolidine-l-yl] ethyl] thio) -l, 3-thiazole-l-carboxylate (Compound 1-23)

TLC: Rf 0.71 (ethyl acetate);

N accessories (CDCls): 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).

Example 1 (24): 2,2,2-Trifluoroethyl 2-[[2-((2R) -2-[(3,5-dichlorophenoxy) methyl] -5-oxopyrrolidinidine 1-inole} thiole] thio] -1,3 thiazolone 1-force zoleboxylate (compound 1-24)

TLC: Rf 0.51 (ethyl ether);

 NMR (CDCla): δ 2.07 (m, 1 H) 2.24 (m, 1 H) 2.40 (m, 1 H) 2.56 (m, 1 H) 3.29 (m, 1 H) 3.48 (m, 1 H) 3.63 ( m, 1 H) 3.83 (m, 1 H) 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 , 2H) 6.85 (d, J = 1.74 Hz, 2H) 6.94 (t, J = 1.74 Hz, 1H) 8.12 (s, 1H).

Example 2: Isopropyl 2-[(2-{(2R) -1-2-[(3,5-dichlorophenoxy) methyl]-5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3-thiazole-14 Crystal of one-strength ropoxylate

A suspension of compound 1 (5.0 g, oil) in diisopropyl ether (35 mL) was heated to 50 ° C. After confirming that the suspension was dissolved, the suspension was allowed to cool, and seed crystals (5 mg) were stirred at an internal temperature of about 30 ° C and stirred. After confirming sufficient precipitation of crystals, n-heptane (150 mL) was added dropwise, and the mixture was cooled in an ice bath. The precipitated crystals are collected by filtration and dried, and isopropyl 2-[(2-{(2R) -12-[(3,5-dichlorophenoxy) methyl] -15-oxopyrrolidine-1-yl} ethyl) thio] -1 1,3-Thiazole-4-carboxylate was obtained as a crystalline powder (3.55 g). The chemical purity of the crystals was confirmed by HP LC under the following conditions.

H PLC measurement conditions>

Column: YM Pack C4 A-802 (inner diameter 4.6mm, length 15 Omm), moving bed: acetate // 20mm o1 / L aqueous solution of dihydrogen phosphate dihydrogen (adjusted to pH3 with phosphoric acid) = 50 50 , Flow rate: l.OmLZ min, Detector: UV / Visible detector (detection wavelength 21 Onm), Analysis time: 35 minutes, Retention time: about 16.5 minutes

 A sample of about 2 mg was taken and dissolved in about 4 mL of acetonitrile. About 2 L of this solution was injected. As a result, it was confirmed that the chemical purity of the crystals was 99.7%.

 FIG. 1 shows an X-ray powder diffraction spectrum of the crystal measured under the following conditions, FIG. 2 shows an infrared absorption (IR) spectrum thereof, and FIG. 3 shows a chart of differential scanning calorimetry (DSC).

 (1) Powder X-ray diffraction spectrum

Equipment: BRUKER axs DISCOVER with GADDS, target: Cu, final letter: not used, voltage: 40 kV, current: 4 OmA, scan speed: 2.0 ° / min.

 (2) Infrared absorption (IR) spectrum

Apparatus: JASCO FTER-eeOPlis infrared spectrophotometer, Measurement method: Total reflection method, Resolution: 4 cm- ¹ , Number of scans: 16 times.

 (3) Differential scanning calorimetry (DSC)

Instrument: Mettler's Toledo DSC822e differential scanning calorimeter, sample amount: 1.81 mg, sample cell: aluminum pan 40 / XL, argon gas flow rate: 40 ml / min, heating rate: 5 ° C / min (25-100 °) C), 20 ° C / min (100-300.C).

Experimental Example 1: Evaluation of intraocular pressure lowering effect and eye irritation

Male ゥ egret (NewZealandWhite, 2.0-3.0 kg) that has been fully acclimated in advance In addition, 0.00003% (w / v) (= 0.3 m), 0.0001% (w / v) (= 1 pm) and 0.0003% (w / v) using a base (PBS pH 7.2, containing 0.5% Tween 80) 5) was instilled into one eye between 10 am and 11 am of the compound 1 and the conjugated product 1-2 prepared at a concentration of (= 3 ppm). The eyes were untreated. At the same time as intraocular pressure, eye irritation was observed based on the modified Draize method standard. Immediately prior to intraocular pressure measurement, local anesthesia was performed by instilling 0.4% oxybuproforcein, and intraocular pressure and eye irritation of the test compound were measured before and 1, 2, 4, 6, 8 and 24 hours after instillation. . Intraocular pressure was measured using a tonometer (Pneumatonometer Model30 Classic (Medtronic Solan)) and evaluated by lOP (treated intraocular pressure-untreated intraocular pressure). The number of cases was 8 eyes. The results for compound 1 are shown in FIGS. 4 and 5, and the results for compound 1-2 are shown in FIGS. 6 and 7. The compound of the present invention significantly reduced intraocular pressure in the egret compared to before the compound treatment. Almost no eye irritation was observed. This indicates that the EP 2 agonist of the present invention has an intraocular pressure lowering effect and can be an excellent therapeutic agent for eye diseases.

Experimental example 2: Stability when using a resin container

 Method

 Compound 1

 Polysorbate 80 5mg

 Sodium chloride 4mg

 Benzanorecoum chloride O.lmg

 Sodium hydrogen phosphate

 Cuenic anhydride ¾4

 Total volume (water for injection) lmL

About 5 mL of the above-mentioned formulation solution (PH7) was filled in a resin container shown below, the inside stopper was closed, and then the aluminum container was sealed and sealed in aluminum to obtain a stability test sample. Stable at 40 ° C and 25% relative humidity using this sample As a result, the residual ratio of Compound 1 after storage for one month was 100%, assuming that the residual ratio of Compound 1 before storage was 100%.

 [Formulation example]

 The typical preparation examples used in the present invention are shown below.

 1. Eye drops

 An eye drop having the following formulation was prepared using a commonly used method.

Prescription example 1:

 After adding glycerin and polysorbate 80 to sterilized purified water, add compound 1 and dissolve, make up to a total volume of 10 OmL with sterilized purified water, filter sterilize with a membrane filter, fill in a predetermined container, and add the compound in 10 OmL. An ophthalmic solution containing 1 mg of 1, 2.5 g of glycerin, 500 mg of polysorbate 80 and an appropriate amount of sterilized purified water was obtained.

 In the same manner as in Formulation Example 1, ophthalmic solutions containing 0.1 mg and 0.5 mg of Compound 1 in 10 OmL can be prepared. Further, in place of Compound 1, another EP2 exhaust of the present invention can be used.

2. Eye ointment

 An eye ointment having the following formulation was prepared using a commonly used method.

Formulation Example 2:

 Liquid paraffin and white petrolatum were heat-sterilized in advance. Compound 1 was thoroughly slurried with liquid paraffin, and white petrolatum was added to make a total amount of 100 g.The mixture was thoroughly kneaded to obtain an ophthalmic solution containing lmg of compound 1, 10 g of liquid paraffin, and an appropriate amount of white paraserine in 100 g. Was.

In the same manner as in Formulation Example 2, eye ointments of various concentrations can be prepared by appropriately changing the amount of Compound 1 added. Further, in place of compound 1, another EP2 agonist of the present invention can be used. Industrial applicability

 The compound of the present invention represented by the general formula (I) has an EP 2 agonist effect. In addition, it has an ocular hypotensive effect, a protective effect on retinal and optic nerve nerves, a protective effect on retinal nerve cell death, and an effect on improving optic nerve head circulation, so that ocular diseases such as glaucoma, ocular hypertension, macular edema, macular degeneration, and retinal depression. It is effective in reducing blood flow in the optic disc, increasing retinal and optic nerve tension, myopia, hyperopia, astigmatism, dry eye, retinal detachment, and cataract. Therefore, the EP 2 agonist of the present invention is useful as a medicine. Also, isopropyl 2-[(2-{(2R) —2 -— [(3,5-dichlorophenoxy) methyl] —5-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3-thiazole-4-carboxy Ret crystals are very useful as pure drug substances for pharmaceuticals.

Claims

The scope of the claims

1. Isopropyl 2 -— ((2 -— ((2R) —2 -— ((3,5) characterized by having at least one of the physicochemical data indicated by A, B, and C below. -Dichlorophenoxy) methyl] 1-5-oxopyrrolidine 1-inole etinole) thio] 1-1,3-thiazonole 4 1 crystal of propyloxylate:

 A: X-ray powder diffraction chart shown in FIG. 1;

 B: infrared absorption spectrum chart shown in FIG. 2 measured using the total reflection method;

 C: Differential scanning calorimetry chart shown in FIG.

2. Isopropyl 2 -— ((2 -— ((2R) -2—) characterized by having at least one of the physicochemical data indicated by Al, B1, and C1 below. [(3,5-Dichlorophenoxy) methyl] _ 5-oxopyrrolidine-1-ethyl-thio] — 1,3-thiazo-1 / le 4-canolepoxyl crystal:

 A1: In the powder X-ray diffraction spectrum pattern, 2 lines are 12.82, 13.30, 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;

B1: In the infrared absorption spectrum measured using the total reflection method, 1717, 1687, 1675, 1661, 1586, 1567, 1443, 1423, 1382, 1257, 1211, 1202, 1107, 1020, 949, Having absorption peaks at 924, 829, 798, 781, 746, 667, 654, 616, 569, 506, 427 and 411 cm- ¹ ;

C 1: has an endothermic peak at 60.6 ° C. in differential scanning calorimetry.

3. The crystal according to claim 1 or 2 having a chemical purity of 99.0% or more,

4. The crystal according to claim 1, having a chemical purity of 99.5% or more.

5. The crystal according to claim 1, which is produced by crystallization from an organic solvent which may contain water.

6. The organic solvent is selected from aromatic carbocyclic solvents, ester solvents, chain ether solvents, ketone solvents, nitrile solvents, lower alcohol solvents, and organic linear alcohol solvents. 6. The crystal according to claim 5, which is a kind of solvent or a mixed solvent of two or more kinds.

7. The process according to claim 1 or claim 1, wherein the product is recrystallized with a mixed solvent of a linear ether solvent that may contain water and a linear alicyclic solvent that may contain water. The crystal according to 2.

8. The crystal according to claim 1, which is an EP 2 agonist.

9. The crystal according to claim 1 or 2, which has an action for preventing and / or treating eye diseases.

10. The crystal according to claim 9, wherein the eye disease is glaucoma or ocular hypertension.

11. A prophylactic and / or therapeutic agent for ophthalmic diseases comprising the crystal according to claim 1 or 2.

12. The prophylactic and / or therapeutic agent according to claim 11, wherein the eye disease is glaucoma or ocular hypertension.

1 3. Crystals according to claims 1 or 2 and selected from sympathomimetics, parasympathomimetics, sympathomimetics, prostaglandins, carbonic anhydrase inhibitors, and hypertonic drugs Pharmaceuticals in combination with one or more.

14. A pharmaceutical composition comprising the crystal according to claim 1 or 2.

15. A method for preventing and / or treating glaucoma or ocular hypertension in a mammal, comprising administering an effective amount of the crystal according to claim 1 or 2 to the mammal.

16. Use of the crystal according to claim 1 or 2 for producing an agent for preventing and treating glaucoma or ocular hypertension.

1 7. General formula (I)

(In the formula, A represents a hydrocarbon group which may have a substituent, R ¹ represents a C 1-6 hydrocarbon group which may be substituted by halogen, and is _α -configuration, β-configuration Or a mixture thereof, or a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof.

18. Isopropyl 2-[(2-{(2R) -2-[[3,5-dichlorophenoxy) methinole] -1-5-oxopyrrolidine-1-yl} ethyl] thio]-1,3-Thiazol-4 , Etil 2— [(2— {(2 R) -1-[(3,5-Dichlorophenoxy) methyl] -5-oxopyrrolidin-1-one — [(2— {(2R) —2— [(1 E, 4 S) —4 1- (1-ethynolecyclobutynole) 1-4-hydroxy-1-pteninole] —5—oxopyrrolidine-1 1-innole} 1,3—thiazonole-one lipoxylate and butyl 2-[(2-{(2R) -2-[(1E, 4S) -4-1- (1-ethinolecyclobutinole) 18. The compound according to claim 17, wherein the compound is selected from the group consisting of 14-hydroxyl-l-butynole] -15-oxopyrrolidine-l-yl} ethyl) thio] -1, 3-thiazole-4l-loxyloxylate.

19. Isopropyl 2-[(2-{(2R) -1-2-[(3,5-dichlorophenoxy) methyl] -15-oxopyrrolidine-1-yl} ethyl) thio] 1-1,3-thiazole-4-carboxylate 19. The compound according to claim 18, which is:

20. The compound according to any one of claims 17 to 19, which is an EP 2 agonist.

21. A pharmaceutical composition comprising the compound according to claim 17.

22. The pharmaceutical composition according to claim 21, which is an agent for preventing and / or treating eye diseases.

23. The pharmaceutical composition according to claim 22, wherein the eye disease is glaucoma or ocular hypertension. The compound represented by the general formula (I) according to claim 17, a salt thereof, A method for preventing and treating glaucoma or ocular hypertension in a mammal, comprising administering to the mammal an effective amount of a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

2 5. A compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof, or a prodrug thereof for producing a glaucoma or ocular hypertension preventive and / or therapeutic agent according to claim 17. Use of its cyclodextrin inclusion compound.