JP2000273082A - Prostaglandin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject novel prostaglandin derivative that has excellent PGD2-like agonist activity and is useful for the renal diseases and the cardiovascular diseases, for example, ischemic diseases, cardiac insufficiency, hypertension and the like. SOLUTION: This prostaglandin derivative is represented by formula I (X is a halogen; n is 1 or 2; R1 is a 3-10 cycloalkyl, a 1-4C alkyl-substituted 3-10C cycloalkyl, a 4-13C cycloalkylalkyl or the like; R2 is H, a 1-10C alkyl or the like), typically 3-thia-9-deoxy-9β-chloro-16,17,18,19,20-pentanol-15-cyclohexyl-13,14- didehydro-PGF1α, methyl ester 3-oxide. The compound of formula I is prepared by allowing a compound of formula II to react with an organoaluminum of formula III and subjecting the resultant stereospecific compound of formula IV to hydrolysis, reduction, halogenation, deprotection, oxidation and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0002]

2. Description of the Related Art Since prostaglandin (hereinafter referred to as PG) exerts various important physiological actions in a very small amount, the synthesis and biological synthesis of natural PG and a large number of its derivatives are intended for pharmaceutical applications. The activity has been studied and reported in a large number of documents, Japanese Patent Application Laid-Open No. Sho 52-100446, Japanese Patent Application Laid-Open No. 2-502009, and the like. Japanese Patent Application Laid-Open No. 502009/1990 discloses a group of PG derivatives in which the 9-position is substituted with halogen. [KH Thierauch et al., Drug of the
Future (Drug of the Future), Volume 17, Volume 8
09 pages (1992)], PG derivatives having an agonist activity of PGD ₂ like have been reported.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel PG derivative having excellent PGD ₂ -like agonist activity.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a novel PG derivative represented by the following formula (I) having a triple bond at the 13th and 14th positions can achieve the above object. Heading, the present invention has been completed.

That is, the present invention provides a compound represented by the formula (I)

[0006]

Embedded image

Wherein X represents a halogen atom, and n represents 1
Or 2 and R ¹ is a C _3-10 cycloalkyl group, C _1-4
A C _3-10 cycloalkyl group substituted with an alkyl group of
A C _4-13 cycloalkylalkyl group, a C _5-10 linear or branched alkyl group, a C _5-10 linear or branched alkenyl group, a C _5-10 linear or A branched alkynyl group or a bridged cyclic hydrocarbon group, wherein R ² is a hydrogen atom,
_{It represents a 1-10} straight-chain or branched alkyl group or a C _3-10 cycloalkyl group. ), A pharmaceutically acceptable salt thereof or a hydrate thereof.

[0008] The present invention is also a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

In the present invention, the halogen atom is a fluorine, chlorine, bromine or iodine atom.

The C _3-10 cycloalkyl group includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,
And cyclohexyl and cycloheptyl.

The C _3-10 cycloalkyl group substituted by a C _4-13 alkyl group is, for example, a methylcyclopropyl group, a methylcyclohexyl group, an ethylcyclohexyl group or the like.

The C _4-13 cycloalkylalkyl group is
Examples include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a cycloheptylmethyl group, and the like.

The C _5-10 linear or branched alkyl group for R ¹ includes, for example, pentyl, hexyl, heptyl, octyl, 1-methylpentyl, 2-methylpentyl, -Methylhexyl group, 2-methylhexyl group, 2,4-dimethylpentyl group, 2-ethylpentyl group, 2-methylheptyl group, 2-ethylhexyl group, 2
-Propylpentyl group, 2-propylhexyl group, 2,
And a 6-dimethylheptyl group.

The C _5-10 linear or branched alkenyl group includes, for example, 3-pentenyl, 4-hexynyl, 5
-Heptenyl group, 4-methyl-3-pentenyl group, 2,
4-dimethylpentenyl group, 6-methyl-5-heptenyl group, 2,6-dimethyl-5-heptenyl group and the like.

The C _5-10 linear or branched alkynyl group includes, for example, 3-pentynyl group, 3-hexynyl group,
-Hexynyl group, 1-methylpent-3-ynyl group, 2
-Methylpent-3-ynyl group, 1-methylhexa-3
-Inyl group, 2-methylhex-3-ynyl group and the like.

The crosslinked cyclic hydrocarbon group includes, for example, a norbornyl group, an adamantyl group, a pinanyl group, a tuyoyl group, a caryl group, a bornyl group, a camphanyl group and the like.

The C _1-10 linear or branched alkyl group of R ² includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group , Isopentyl, 2-ethylpropyl, hexyl, isohexyl, 1-ethylbutyl, heptyl, isoheptyl, octyl, nonyl, decyl and the like.

S (O) _n in the α chain is as follows when n = 1

[0019]

Embedded image

Where n = 2

[0021]

Embedded image

Represents the following.

The pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine Benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane and the like.

[0024]

The compounds of formula (I) can be prepared, for example, by the methods summarized in the following schemes.

[0025]

Embedded image Reaction formula 1

[0026]

Embedded image Continuation of Reaction Formula 1

(In the reaction formula, TBS represents a tert-butyldimethylsilyl group, R ³ represents a C _1-10 linear or branched alkyl group or a C _3-10 cycloalkyl group,
X, R ¹ and n are as defined above. (1) First, a well-known formula by the method of Sato et al. [Journal of Organic Chemistry (J. Org. Chem.), Vol. 53, p. 5590 (1988)]. The compound of (II) is added with 0.8 to 2.0 equivalents of the organoaluminum compound represented by the formula (III) for -10 to 30.
Reaction in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) at 0 DEG C., preferably 0 DEG-10 DEG C., to give the compound of formula (IV) stereospecifically. .

(2) A compound of the formula (IV) is mixed with 0.5 to 4 equivalents of the organic copper compound represented by the formula (V) and 0.5 to 4.0 equivalents of trimethylchlorosilane in an inert solvent (for example, benzene, Toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, n-pentane, etc.)
In the medium, the reaction is carried out at −78 to 40 ° C., and an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) or an organic acid (eg, acetic acid, p-
0 to 40 ° C. in an organic solvent (for example, acetone, methanol, ethanol, isopropanol, diethyl ether or a mixed solvent thereof) using toluenesulfonic acid or an amine salt thereof (for example, pyridine salt of p-toluenesulfonic acid). To give the compound of formula (VI) stereoselectively.

(3) A compound of formula (VI) is treated with 0.5 to 5 equivalents of a reducing agent such as potassium borohydride, sodium borohydride, lithium tricyanoborohydride, lithium trisec-butylborohydride in an inert solvent. (Eg, tetrahydrofuran, diethyl ether, ethyl alcohol, methyl alcohol, etc.)
C. to give compounds of formula (VII) and formula (VII '). These formulas (VII) and (VI)
The compound of I ') can be purified by a commonly used separation method such as column chromatography.

(4) Formula (VII) (or Formula (VI)
The compound of I ′)) is converted, for example, from 1 to 6 equivalents of methanesulfonyl chloride or p-toluenesulfonyl chloride in a suitable solvent such as pyridine to 0.8 to 6
-20 to 4 in the presence of an equivalent amount of 4-dimethylaminopyridine
After mesylation or tosylation at 0 ° C, tetra-n-
Chlorination with 1 to 16 equivalents of butylammonium chloride gives a compound of the formula (VIII) (or (VIII ′)) (X is a chlorine atom). Here, bromination and fluorination can also be performed by a usual method. For example, bromination is
It is obtained by reacting in acetonitrile using 1 to 10 equivalents of carbon tetrabromide in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of pyridine.
The fluorination is obtained, for example, by reacting 5 to 20 equivalents of diethylaminosulfur trifluoride (DAST) in methylene chloride.

(5) Formula (VIII) (or formula (VII)
I ′)) The compound is treated with methanol, ethanol, acetonitrile, a mixed solvent thereof, or a mixed solvent thereof with water under a condition usually used using hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid and the like. In the reaction, the tert-butyldimethylsilyl group which is a protecting group for a hydroxyl group was removed, and the compound represented by the formula (IX) (or the compound represented by the formula (I
X ')) is obtained.

(6) Formula (IX) (or Formula (IX '))
The compound of the formula (X) is hydrolyzed using 1 to 6 equivalents of a base in a solvent usually used for hydrolysis.
(Or formula (X ′)). Examples of the base include lithium hydroxide and potassium carbonate.
Acetonitrile, acetone, methanol, ethanol,
Examples thereof include water and a mixed solvent thereof.

(7) Formula (IX) (or Formula (IX '))
Compound of sodium metaperiodate, aqueous hydrogen peroxide,
Using an oxidizing agent such as peracetic acid, m-chloroperbenzoic acid, or tert-butyl hydroperoxide, the reaction is carried out at -20 to 50 ° C in diethyl ether, methanol, ethanol, methylene chloride, water or a mixed solvent thereof. The PG derivative of the formula (Ia) (or the formula (Ia ′)), which is an inventive compound, is obtained.

(8) Formula (Ia) (or Formula (Ia '))
Is hydrolyzed using a base in the same manner as in (6) to obtain a PG derivative of the formula (Ib) (or the formula (Ib ′)) of the present invention. Further, the compound of the formula (Ib) (or the formula (Ib ′)) of the present invention is oxidized using the compound of the formula (X) (or the formula (X ′)) in the same manner as in (7). A PG derivative is obtained.

The compounds of the present invention can be administered systemically or locally orally or parenterally in conventional dosage forms. These are, for example, tablets, powders, granules, powders, capsules, which can be produced by ordinary methods.
It can be administered orally in the form of a solution, emulsion, suspension or the like. As preparations for intravenous administration, aqueous or non-aqueous solutions, emulsions, suspensions, solid preparations used by dissolving in an injection solvent immediately before use, and the like can be used. The compound of the present invention can also be formulated by forming an inclusion compound with α, β or γ-cyclodextrin or methylated cyclodextrin. Further, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. The dose varies depending on the age, body weight, etc., but is 1 ng to 1 mg / day for an adult, and is administered once or several times a day.

Typical compounds of the formula (I) according to the present invention include the compounds shown in Table 1.

[0037]

[Table 1] Table 1

[0038]

[Table 2] Continued from Table 1 (1)

[0039]

[Table 3] Continued from Table 1 (2)

[0040]

The present invention is useful for good PGD ₂ like indicates agonist activity, renal disease and ischemic heart disease, heart failure, cardiovascular disease such as hypertension.

[0041]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. In the compound naming, “16, 17, 1
“Nor” in “8,19,20-pentanor” means that there is no carbon chain at that position.

Example 1 3-Thia-9-deoxy-9β-chloro-16,17,
18,19,20- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ alpha production of methyl ester 3-oxide (1) (3S) -3- ( tert- butyldimethylsiloxy) -3-cyclohexyl-prop - 1-in (3.6
1g) was dissolved in 28.8 ml of toluene, and n-butyllithium (1.95M, hexane solution, 6.4m) was dissolved at 0 ° C.
l) was added and the mixture was stirred at the same temperature for 30 minutes. 0
At 0 ° C., diethyl aluminum chloride (0.97 M, hexane solution, 14.8 ml) was added, and the mixture was stirred for 30 minutes to room temperature. At room temperature, (4R) -2- (N, N-diethylamino) methyl-4- (tert-butyldimethylsiloxy) cyclopent-2-en-1-one (0.
25M, toluene solution, 14.8 ml) was added and stirred for 15 minutes. The reaction solution was treated with hexane (100 ml) -saturated aqueous ammonium chloride solution (100 ml) -hydrochloric acid aqueous solution (3
M, 30 ml) with stirring, and then the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate (50 ml).
The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the obtained residue was purified by silica column chromatography (eluent: hexane: ether = 10: 1) to give (3R, 4R) -2-methylene. -3-[(3S) -3
-(Tert-butyldimethylsiloxy) -3-cyclohexylprop-1-ynyl] -4- (tert-butyldimethylsiloxy) cyclopentan-1-one (3.
69 g) were obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.07, 0.08 and 0.12 (3s, 1
2H), 0.88 (s, 18H), 0.92-1.92.
(M, 11H), 2.32 (dd, J = 17.8, 7.
4 Hz, 1 H), 2.71 (dd, J = 17.8, 6.
5Hz, 1H), 3.48-3.58 (m, 1H),
4.11 (dd, J = 6.2, 1.4 Hz, 1H),
4.20-4.32 (m, 1H), 5.55 (d, J =
2.6 Hz, 1 H), 6.13 (d, J = 3.0 Hz,
1H) IR (neat); 2930, 2850, 13
75, 1640, 1470, 1380, 1255, 83
0.770 cm ^-1 .

(2) 4-Thia-5-carbomethoxypentyl zinc (II) iodide (0.75 M, tetrahydrofuran solution, 18.0) at -70 ° C. under an argon stream.
(13.5 ml), copper (I) cyanide · lithium dichloride (1.0 M, tetrahydrofuran solution, 16.
9 ml, 16.9 mmol) and stirred at the same temperature for 20 minutes. A solution of the compound (3.21 g, 6.74 mmol) obtained in the above (1) in diethyl ether (23.6 ml) and chlorotrimethylsilane (1.
54 ml, 12.1 mmol) and the temperature was raised to 0 ° C. over about 1 hour with stirring. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction solution, and the mixture was extracted with hexane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was dissolved in diethyl ether (6.8 ml) -isopropyl alcohol (27 ml), and p-toluene was dissolved. Sulfonic acid pyridine salt (85 mg, 0.34 mmol) was added,
Stirred at room temperature for 12 hours. Hexane (200m
l), and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue obtained was subjected to silica gel column chromatography (developing solvent;
Hexane: ethyl acetate = 15: 1) to give 3-thia-16,17,18,19,20-pentanol-15-.
Cyclohexyl-13,14-didehydro-PGE ₁
The methyl ester 11,15-bis (tert-butyldimethylsilyl) ether (2.51 g) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.08 (s, 3H), 0.09 (s, 3
H), 0.10 (s, 3H), 0.12 (s, 3H),
0.84-1.92 (m, 17H), 0.89 (s, 9
H), 0.90 (s, 9H), 2.03-2.27.
(M, 1H), 2.17 (dd, J = 18.2, 7.0)
Hz, 1H), 2.56-2.76 (m, 4H), 3.
22 (s, 2H), 3.74 (s, 3H), 4.09
(Dd, J = 6.2, 1.5 Hz, 1H), 4.23-
4.35 (m, 1H) IR (neat); 2929, 2856, 2235, 1
746,1463,1436,1362,1280,1
257, 1133, 1103, 1008, 899, 83
8,779,670 cm ^-1 .

(3) The compound obtained in (2) (1.55 g,
2.47 mmol) of methyl alcohol (24.7 m)
l) Cool the solution to 0 ° C and add potassium borohydride (0.1
267 g, 4.94 mmol) and stirred for 15 minutes. Water was added and ether: n-hexane (2: 1, 21
0 ml), washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane: AcOEt = 7: 1 to 4: 1) to give 3-thia-16,17,18,19. , 20-Pentanoru 15-cyclohexyl-13,14-didehydro-PGF ₁ alpha methyl ester 11,15- bis (tert- butyldimethylsilyl) ether (608
mg), and 3-thia-16,17,18,19,20
- Pentanoru -15- cyclohexyl-13,14 Jidehidoro PGF ₁ beta methyl ester 11,15-
Bis (tert-butyldimethylsilyl) ether (6
42 mg).

3-thia-16,17,18,19,20
- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ alpha methyl ester 11,15-
Bis (tert-butyldimethylsilyl) ether ¹ H-NMR (CDCl ₃ , 200 MHz) δ ppm;
0.08 (s, 3H), 0.09 (s, 3H), 0.1
0 (s, 3H), 0.11 (s, 3H), 0.84-
1.92 (m, 19H), 0.88 (s, 9H), 0.
90 (s, 9H), 1.93-2.07 (m, 1H),
2.40-2.50 (m, 1H), 2.53 (br
s, 1H), 2.65 (t, J = 7.0 Hz, 2H),
3.23 (s, 2H), 3.74 (s, 3H), 4.0
1-4.19 (m, 1H), 4.07 (dd, J = 6.
3,1.8 Hz, 1H), 4.23-4.32 (m, 1
H) IR (neat); 3523,2929,2856,2
231, 1740, 1472, 1463, 1437, 1
408, 1389, 1362, 1338, 1279, 1
256, 1217, 1133, 1103, 1071, 1
007,964,939,899,838,778,6
69 cm ^-1 .

3-thia-16,17,18,19,20
- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ beta methyl ester 11,15-
Bis (tert-butyldimethylsilyl) ether ¹ H-NMR (CDCl ₃ , 200 MHz) δ ppm;
0.07 (s, 3H), 0.08 (s, 6H), 0.1
1 (s, 3H), 0.83-1.94 (m, 20H),
0.88 (s, 9H), 0.90 (s, 9H), 2.2
3 (ddd, J = 9.0, 6.2, 1.6 Hz, 1
H), 2.65 (t, J = 7.0 Hz, 2H), 3.2
2 (s, 2H), 3.74 (s, 3H), 3.90-
4.06 (m, 1H), 4.08 (dd, J = 6.2,
1.6 Hz, 1H), 4.16-4.30 (m, 1H) IR (neat); 3458, 2928, 2856, 2
232, 1739, 1472, 1463, 1451, 1
388,1361,1338,1281,12555,1
132, 1104, 1068, 1007, 898, 83
8,778,670 cm ^-1 .

(4) 3 obtained in (3) under a stream of argon
-Thia-16,17,18,19,20-pentanor-
15-cyclohexyl-13,14-didehydro-PG
F ₁ α-methyl ester 11,15-bis (tert-
Butyldimethylsilyl) ether (839 mg, 1.3
4 mmol) in pyridine (6.70 ml) at 0 ° C. methanesulfonyl chloride (0.31 ml, 4.0 mmol).
l) was added and the mixture was stirred at room temperature for 2 hours. To this solution was added tetra n-butylammonium chloride (7.45 g, 2
(6.8 mmol) in toluene (6.70 ml) was added and the mixture was stirred at 45 ° C. for 4 hours. To this was added water, extracted with ether, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (developing solvent; n-hexane: AcOEt = 10: 1) to give 3-thia-9.
-Deoxy-9β-chloro-16,17,18,19,
20-Pentanol-15-cyclohexyl-13,14
-Didehydro-PGF ₁ α methyl ester 11,15
-Bis (tert-butyldimethylsilyl) ether
(764 mg) was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.07 (s, 3H), 0.08 (s, 6
H), 0.11 (s, 3H), 0.74-1.92
(M, 17H), 0.88 (s, 9H), 0.90
(S, 9H), 1.98-2.20 (m, 2H), 2.
14 (dd, J = 7.7, 5.7 Hz, 1H), 2.2
8 (ddd, J = 8.9, 5.1, 1.6 Hz, 1
H), 2.58-2.72 (m, 2H), 3.23.
(S, 2H), 3.74 (s, 3H), 3.95 (d
d, J = 15.5, 7.7 Hz, 1H), 4.08 (d
d, J = 6.1, 1.6 Hz, 1H), 4.25 (q,
J = 5.1 Hz, 1H) IR (neat); 2929,2856,2233,1
741,1472,1463,1451,1408,1
389, 1362, 1339, 1279, 1256, 1
189, 1133, 1101, 1073, 1007, 9
62,939,899,838,815,778,67
0,588 cm ^-1 .

Similarly, 3-thia-16,1 obtained in (3)
7,18,19,20- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ with β methyl ester 11,15- bis (tert- butyldimethylsilyl) ether 3-thia-9-deoxy -9α-
Chloro-16,17,18,19,20-pentanor-
15-cyclohexyl-13,14-didehydro-PG
F ₁ α methyl ester 11,15-bis (tert
-Butyldimethylsilyl) ether was obtained.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.06 (s, 3H), 0.08 (s, 3
H), 0.09 (s, 3H), 0.11 (s, 3H),
0.71-2.18 (m, 17H), 0.89 (s, 9
H), 0.90 (s, 9H), 2.02 (ddd, J =
15.3, 3.6, 1.7 Hz, 1H), 2.46-
2.76 (m, 4H), 3.23 (s, 2H), 3.7
4 (s, 3H), 4.04-4.27 (m, 2H),
4.27-4.36 (m, 1H) IR (neat); 2929, 2856, 2237, 1
741,1472,1463,1451,1387,1
361,1279,1256,1102,1073,1
007,888,838,778,670,626cm
^-1 .

[0053] (5) (4) was obtained in 3-thia-9-deoxy -9β- chloro -16,17,18,19,20- Pentanoru -15- cyclohexyl over 13,14-didehydro-PGF ₁ alpha methyl Ester 11,15-bis (tert-butyldimethylsilyl) ether (738
mg, 1.14 mmol) of tetrahydrofuran (20
aqueous solution of hydrofluoric acid (6.0 m) at 0 ° C.
l) was added, and the mixture was stirred for 6 hours while heating to room temperature. The reaction solution was poured into ethyl acetate (60 ml) -saturated aqueous sodium hydrogen carbonate solution (170 ml) with stirring, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (developing solvent; n-hexane: AcOEt).
= 2: 1) to give 3-thia-9-deoxy-9β-
Chloro-16,17,18,19,20-pentanor-
15-cyclohexyl-13,14-didehydro-PG
F ₁ alpha-methyl ester (474 mg).

¹ H-NMR (CDCl ₃ , 300 MHz)
δ ppm; 0.96-1.33 (m, 6H), 1.46
-1.90 (m, 11H), 2.09-2.34 (m,
2H), 2.20 (ddd, J = 13.8, 7.7,
6.1 Hz, 1 H), 2.31 (ddd, J = 9.9,
6.3, 1.8 Hz, 1H), 2.66 (t, J = 7.
0 Hz, 2H), 3.23 (s, 2H), 3.75
(S, 3H), 3.90-4.01 (m, 1H), 4.
16 (dd, J = 6.1, 1.8 Hz, 1H), 4.3
3-4.42 (m, 1H) IR (KBr); 3392, 2926, 2854, 22
36, 1736, 1457, 1439, 1410, 13
70, 1341, 1278, 1228, 1140, 11
28, 1140, 1126, 1097, 1016, 89
2,730,706,546 cm ^-1 .

(6) The compound obtained in (5) (150 mg,
0.36 mmol) in methanol (9 ml).
Sodium metaperiodate (292 mg, 1.37
mmol) in water (2 ml), and the mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution, washed with saturated saline, dried using anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The crude product obtained by concentration was purified by silica gel column chromatography (developing solvent: AcOEt) to obtain the title compound (70 mg).

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.96 to 2.40 (m, 21H), 2.7
8-3.05 (m, 4H), 3.71 and 3.7
2 (2s, 2H), 3.80 (s, 3H), 3.85-
4.00 (m, 1H), 4.05-4.20 (m, 1
H), 4.27-4.43 (m, 1H) IR (KBr); 3418, 2935, 2854, 22
34, 1736, 1437, 1286, 1134, 10
65, 1028, 890, 696, 576 cm ^-1 .

Example 2 3-Thia-9-deoxy-9β-chloro-16,17,
18,19,20- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ alpha 3-oxide (1) Preparation of Example 1 (4) obtained in 3-thia-9-deoxy -
9β- chloro -16,17,18,19,20- Pentanoru-15-cyclohexyl-13,14-didehydro-PGF ₁ alpha methyl ester (222 mg, 0.5
32 mmol) in methanol (17.7 ml) -water (1.8 ml) was added to lithium hydroxide monohydrate (1
22 mg, 2.9 mmol) and stirred at room temperature for 2 hours. After neutralization by adding a 1N aqueous hydrochloric acid solution, the mixture was concentrated. After 0.1N hydrochloric acid (4 ml), ether (40 ml) and ethyl acetate (8 ml) were added to the residue, the mixture was salted out with ammonium sulfate and the organic layer was separated. The organic layer was purified by silica gel column chromatography (developing solvent; AcOEt) to give colorless crystals of 3-thia-9-deoxy-9β-chloro-13,14-didehydro-16,17,18,1.
9,20-Pentanol-15-cyclohexyl-PGF
Was obtained _{1 α} a (171mg).

¹ H-NMR (CDCl ₃ , 300 MHz)
δ ppm; 0.94-1.37 (m, 6H), 1.45
-1.90 (m, 11H), 2.10-2.33 (m,
2H), 2.20 (ddd, J = 14.1, 7.8,
6.1 Hz, 1 H), 2.33 (dddd, J = 9.
9, 6.5, 1.8 Hz, 1H), 2.70 (t, J =
6.6 Hz, 2H), 2.78 (brs, 3H),
3.24 (s, 2H), 3.90-4.05 (m, 1
H), 4.21 (dd, J = 6.1, 1.8 Hz, 1
H), 4.32-4.41 (m, 1H) IR (KBr); 3576, 3393, 3209, 29
42,2927,2855,2230,1716,16
80, 1448, 1414, 1393, 1338, 12
58,1232,1213,1143,1093,99
8,890,865,729,576 cm ^-1 .

(2) Using the compound obtained in the above (1), the title compound was obtained in substantially the same manner as in Example 1 (5).

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.86-2.44 (m, 21H), 2.8
0-3.44 (m, 5H), 3.64 (d, J = 14.
5Hz, 1H), 3.82 and 3.84 (d, J
= 14.5 Hz, 1H), 3.84-4.02 (m, 1
H), 4.06-4.24 (m, 1H), 4.30-
4.42 (m, 1H) IR (neat); 3368, 2927, 2853, 2
233, 1719, 1450, 1407, 1281, 1
009,893,854,756 cm ^-1 .

Example 3 3-Thia-9-deoxy-9β-chloro-16,17,
18,19,20- Pentanoru -15- cyclohexyl-13,14-didehydro-PGF ₁ alpha methyl ester 3,3-dioxide of Example 1 (4) the compound obtained (100 mg, 0.24 m
mol) in chloroform (8 ml) at 0 ° C.
Chloroperbenzoic acid (190 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate-n-hexane to give the title compound as colorless crystals (90 mg).

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.87-2.38 (m, 23H), 3.3
0 (t, J = 7.8 Hz, 2H), 3.80-4.04
(M, 1H), 3.84 (s, 3H), 3.98 (s,
2H), 4.09-4.22 (m, 1H), 4.29-
4.44 (m, 1H) IR (KBr); 3375, 3002, 2941, 28
56,2237,1740,1456,1322,13
03,1229,1157,1125,1104,10
12,928,819,730,634,511,47
1 cm ^-1 .

Example 4 3-Thia-9-deoxy-9β-chloro-16,17,
18,19,20- Pentanoru -15- cyclohexyl-13,14-didehydro -PGF using ₁ alpha 3,3-dioxide compound obtained in Production Example 3, Example 2 (1) substantially in the same manner To give the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz)
δ ppm; 0.84-2.40 (m, 21H), 3.1
2-3.50 (m, 5H), 3.87-4.44 (m, 5H)
2H), 4.00 and 4.02 (2s, 2H),
4.23 (dd, J = 5.9, 1.5 Hz, 1H) IR (neat); 3400, 2928, 2853, 2
235,1729,1450,1384,1305,1
141, 1119, 1008, 894, 846, 82
2,594,512 cm ^-1 .

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hideo Tanaka 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Naoya Ono 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Shin Yagi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C086 AA03 DA04 MA01 MA04 NA14 ZC12 4H006 AA01 AC22 AC30 AC62 AC80 AD17 UE14 UE16 UE31 UE32 UE58

Claims (3)

[Claims] (1) Formula (1) (Wherein, X represents a halogen atom, n represents 1 or 2, R ¹ represents a C _3-10 cycloalkyl group, a C _3-10 cycloalkyl group substituted with a C _1-4 alkyl group. A C _4-13 cycloalkylalkyl group, a C _5-10 linear or branched alkyl group, a C _5-10 linear or branched alkenyl group, a C _5-10 linear group Or a branched alkynyl group or a bridged cyclic hydrocarbon group, and R ² represents a hydrogen atom, a C _1-10 linear or branched alkyl group or a C _3-10 cycloalkyl group ), A pharmaceutically acceptable salt thereof or a hydrate thereof. 2. In the formula (I), R ¹ is a C _3-10 cycloalkyl group, a C _3-10 cycloalkyl group substituted by a C _1-4 alkyl group, or a C _4-13 cycloalkyl group. An alkyl group, a C _5-10 branched alkyl group, a C _5-10 branched alkenyl group, a C _5-10 branched alkynyl group or a bridged cyclic hydrocarbon group. 3. The prostaglandin derivative, a pharmaceutically acceptable salt or a hydrate thereof according to item 1. 3. In the formula (I), X is a chlorine atom or a bromine atom, and R ¹ is a C _3-10 cycloalkyl group or
The prostaglandin derivative according to claim 1, which is a cycloalkylalkyl group of _4-13 , wherein R ² is a hydrogen atom or a C _1-10 linear or branched alkyl group. An acceptable salt or a hydrate thereof.