JPH07242623A - Prostaglandin derivative and its use - Google Patents

Abstract

PURPOSE:To obtain a new prostaglandin derivative having strongly improving action on renal diseases, ischemic cardiac disease, cardiac incompetence or lowering action on intraocular tension. CONSTITUTION:A compound is expressed by formula I (R<1> is a 1-6C alkyl; R<2> is a 5-7C cycloalkyl-substituted methyl or a cross-linked hydrocarbon) or its salt such as 3-oxa-9-deoxy-9beta-chloro-13,14-dihydro-17,18,19,20-tetranor-16- cyclopentyl-PGF2alpha. The compound is obtained by successively introducing an co-side chain and an alpha-side chain of PG to a compound of formula II to give a compound of formula III, reducing stereoselectively the compound by using lithium tri-see-butylborohydride to give a compound of formula IV, deprotecting ethoxyethyl group to give a compound of formula V, reacting the compound with a compound of the formula, Br-CH2-COOR3 (R3 is a 1-6C alkyl) by using sodium hydroxide, converting the prepared compound of formula VI into a chlorine-substituted substance and deprotecting the protecting group of a hydroxyl group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel prostaglandin (hereinafter abbreviated as PG) derivative and its use. More specifically, it relates to the use of the novel PG derivative as a renal disease improving agent, ischemic heart disease improving agent or heart failure improving agent.

[0002]

2. Description of the Related Art Since PG and its derivatives exert various important physiological effects even in a trace amount, the synthesis and biological activity of natural PG and a large number of its derivatives are intended for pharmaceutical applications. Has been done. The results of these examinations are reported in a large number of documents, for example, in Japanese Patent Laid-Open No.
This is reported in Japanese Patent Publication No. 100446 and Japanese Patent Publication No. 2-502009 (WO89 / 00559). P
The physiological actions of G and its derivatives include vasodilatory action, inflammation action, platelet aggregation action, uterine muscle contraction action, intestinal tract contraction action, intraocular pressure lowering action and the like. However, since PG derivatives have various actions, there is a problem in using them as medicines. For example, when a PG derivative is administered with one effect as a medicinal effect, it also has other effects at the same time, so these other effects often appear as side effects. Therefore,
It is necessary to enhance the expression of the action expected as the main drug effect.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel PG derivative having a potent renal disease improving action, ischemic heart disease improving action, heart failure improving action or intraocular pressure lowering action.

[0004]

The present invention provides a compound of formula (I)

[0005]

[Chemical 4]

[Wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms, R ² represents a cycloalkyl-substituted methyl group having 5 to 7 carbon atoms, or a bridged cyclic hydrocarbon, preferably a norbornyl group or Indicates an adamantyl group. ] The PG derivative or its salt represented by these are provided. The present invention further provides a renal disease improving agent, an ischemic heart disease improving agent or a heart failure improving agent, which contains the above-mentioned PG derivative or a salt thereof as an active ingredient.

The compound of the present invention is disclosed in Table 2-50
It is included in the general formula (I) described in the claims of Japanese Patent No. 009. However, there is no specific description of the compound of the present invention in the above publication. Formula (I) of the present invention
The compound can be produced, for example, by the method described below. The reaction formula in this production method is shown below.

[0008]

[Chemical 5]

[0009]

[Chemical 6]

[0010] (In the reaction formula, TBS represents a t- butyl dimethylsiloxy group, Et represents an ethyl group, R ² represents the same meaning as R ² of formula (I), R ³ is the formula (I) It has the same meaning as R ¹ without hydrogen atom, and EE represents an ethoxyethyl group.).

That is, the compound of formula (II) is added to the compound of formula (III)
Of the formula (IV) by introducing the ω-side chain of PG by reacting the compound of
The compound of On the other hand, a compound obtained by reacting (Z) -iodo-3- (1-ethoxyethyloxy) -1-propene with t-butyllithium and lithium 2-thienylcyanocuprate is reacted with a compound of the above formula (IV). Then, the α-side chain of PG is introduced to obtain a compound of formula (V). Next, this is stereoselectively reduced with lithium tri-sec-butylborohydride to obtain a compound of formula (VI), and then the ethoxyethyl group is deprotected to obtain a compound of formula (VII). With sodium hydroxide This formula Br-CH ₂ -
A compound of COOR ³ (R ³ has the same meaning as R ¹ of the formula (I) from which a hydrogen atom has been removed), for example, a compound of (VIII) when reacted with t-butyl ester of 2-bromoacetic acid can get. Then, the hydroxyl group of the compound of the formula (VIII) is mesylated with methanesulfonic acid chloride and then reacted with tetra-n-butylammonium chloride to give a chloro substitution product, and the hydroxyl group-protecting group is removed with hydrogen fluoride pyridine. ) Compound. Finally, the formula (I
Hydrolysis of the compound of a) with lithium hydroxide gives the compound of formula (Ib).

The PG derivative of the present invention may be a salt or an ester of a carboxyl group. A salt or ester is a physiologically acceptable salt or ester. Examples of the salt include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, and monomethylmonoethanolamine. , Ammonium salts of tromethaline, lysine and the like are exemplified. Examples of the ester include alkyl esters having 1 to 6 carbon atoms which may have a straight chain or a side chain such as methyl, ethyl, butyl and t-butyl.

The compounds of the present invention are administered orally or parenterally, such as intravenously or rectally. As a dosage form for oral administration, for example, solid preparations such as tablets, granules and capsules, liquid preparations such as solutions, fat emulsions and liposome suspensions can be used. As a preparation for intravenous administration, an aqueous or non-aqueous solution, an emulsifier, a suspension, a solid preparation to be dissolved in a solvent for injection immediately before use, and the like can be used. Further, a suppository can be used as a preparation for rectal administration and a dosage form such as pessary can be used as a preparation for vaginal administration. The compounds of the present invention are α, β, or γ
It is also possible to form a clathrate compound with cyclodextrin or methylated cyclodextrin to form a formulation. The daily dose is 0.05 to 60 μg for intravenous administration or rectal administration, and 1 to 600 μg for oral administration.
It is g and is administered once to 5 times a day as needed.

[0014]

The present invention compounds according to the present invention, as is apparent from below test examples, strong platelet aggregation inhibitory action, also, PGE ₁
It shows a selective and strong dilating effect on renal and coronary blood vessels and has a long duration of action. Compared with the control drug A (compound described in Example 9 of Japanese Patent Publication No. 2-502009), the effect of dilating action on renal blood vessels was strong and the action was also persistent. Therefore, the compound of the present invention has various renal diseases such as nephritis, nephropathy and renal failure due to its renal vasodilatory action, and peripheral circulatory disorder, ischemic heart disease (angina) and heart failure due to its platelet aggregation inhibitory action and antihypertensive action. , It is useful for cardiovascular diseases such as hypertension.

The effects of the present invention will be specifically described below with reference to test examples. Compounds 1 and 2 were produced in Examples 1 and 5 described below, respectively, and contrast agent A was the compound described in Example 9 of Tokuhyo No. 2-502009 having the following structure.

[0016]

[Chemical 7]

Test Example 1 [Human Platelet Aggregation Inhibition Test] Blood was collected from human and immediately after the blood collection, it was mixed with 1 volume of 3.8% sodium citrate aqueous solution to 9 volumes of blood. After centrifugation at 180 xg for 15 minutes at room temperature, platelet-rich plasma (PRP) was obtained from the upper layer. The measurement of platelet aggregation is Born
Method (Nature, Volume 194, Page 927,
1962). To 100 μl of PRP was added 5 μl of a test drug solution having various concentrations dissolved in ethanol, and the mixture was incubated at 37 ° C. under stirring at 1000 rpm for 1 minute. To this, 5 μl of an aggregation inducer [ADP (final concentration 4.5 to 12.5 μM)] was added to induce platelet aggregation, and the maximum agglutination rate (induced platelet aggregation by an aggregometer). The maximum change in light transmittance within 5 minutes after the start was determined. The agglutination inhibition rate of the test drug was calculated from the maximum agglutination rate of the test drug with respect to the maximum agglutination rate when ethanol was used instead of the test drug solution, and the IC ₅₀ value was calculated from the dose-response curve, and simultaneously measured. Obtained P
The relative value of GE _{1 to} the IC ₅₀ value was defined as the aggregation inhibitory activity. The results are shown in Table 1.

[0018]

[Table 1] Test drug aggregation inhibitory activity PGE ₁ 1 Control drug A 9.7 Compound 1 15.5

Test Example 2 [Kidney vasodilatory action and antihypertensive action] Male and female Beagle dogs (7 to 11 kg, 4 animals per group) were anesthetized with pentobarbital sodium (30 mg / Kg iv), and blood pressure was obtained from the femoral artery. A retrogradely inserted cannula is introduced through a pressure transducer (TP-400T Nihon Kohden) to an amplifier for strain pressure (AP-630G Nihon Kohden) for measurement, and the heart rate is an instantaneous pulse using an arterial wave as a trigger pulse. Total (AT-600G Nihon Kohden)
It was measured by. The left posterior wall is incised, and a probe of an electromagnetic blood flow meter is attached to the left renal artery, which is then attached to the electromagnetic blood flow meter (MFV-
2100 Nihon Kohden) and measured the renal blood flow at the peak of the reaction caused by each drug administration (Tsuchida et al.,
Arzneim.-Forsch., 36, 1745, 19
1986). Each drug was dissolved in ethanol and PG
E ₁ is 300 to 3000 pmol / kg, control drug A is 1
0 to 3000 pmol / Kg, the compound of the present invention is 3 to 10
00 pmol / Kg was administered into the femoral vein. The dose volume was 1 μl / Kg each. The renal blood flow increasing action or antihypertensive action of each drug was shown as a dose ratio for increasing renal blood flow by 15% or lowering blood pressure by 5%, and indicated as an efficacy ratio with control drug A being 1. The results are shown in Table 2.

[0020]

Table 2 Efficacy ratio Test drug Renal blood flow increasing action Blood pressure lowering action PGE ₁ 2.0 2.0 Control drug A 1.0 1.0 Compound 1 11.9 10.3 Compound 2 4.0 3.1

[0021]

The present invention will be described in more detail with reference to Examples and Test Examples. Example 1 3-oxa-9-deoxy-9β-chloro-13,14
-Didehydro-17,18,19,20-tetranor-
Preparation of 16-cyclopentyl-PGF2α

[0022]

[Chemical 8] Note: In the nomenclature of compounds, "nor" of "17,18,19,20-tetranor" means that there is no carbon chain at that position (means that there is no carbon chain at 16 to 20 positions). .).

(1) (3S) -3- (t-butyldimethylsiloxy) -4-cyclopentylbut-1-yne (1.37 g) was dissolved in 13.48 ml of benzene, and
N-butyllithium (1.88N, hexane solution,
4.98 ml) was added and the mixture was stirred at room temperature for 30 minutes. Diethyl aluminum chloride (0.98
N, hexane solution, 5.93 ml) was added and the mixture was warmed to room temperature and stirred for 30 minutes. Add (4R) -2- to this solution at room temperature.
(N, N-diethylamino) methyl-4- (t-butylmethylsiloxy) cyclopent-2-en-1one (0.25N, benzene solution, 38.4 ml) was added,
Stir for 20 minutes. The reaction mixture was poured into a mixed solution of hexane (100 ml) -saturated ammonium chloride aqueous solution (100 ml) -hydrochloric acid aqueous solution (3N, 30 ml) with stirring, the organic layer was separated, and washed with saturated aqueous sodium hydrogen carbonate solution (50 ml). The obtained organic layer is dried and concentrated, and the resulting residue is subjected to silica gel column chromatography (developing solvent;
Purify with hexane: ether = 10: 1 (3R, 4
R) -2-Methylene-3-[(3S) -3- (t-butyldimethylsiloxy) -4-cyclopentylbut-1-ynyl] -4- (t-butyldimethylsiloxy) cyclopentan-1-one (1 .21 g) was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm; 0.07 to 0.17 (m, 12H), 0.8
9 (s, 18H), 1.03 to 1.80 (m, 13
H), 2.33 (dd, J = 17.9 Hz, 7.4H)
z, 1H), 2.71 (dd, J = 17.9 Hz, 6.
4Hz, 1H), 3.41 to 3.54 (m, 1H),
4.22 to 4.32 (m, 1H), 4.47 (t, J =
6.8 Hz, 1 H), 5.55 (d, J = 2.5 Hz,
1H), 6.14 (d, J = 2.7 Hz, 1H). IR (neat): 2930, 2850, 1735, 1
640, 1460, 1360, 1250, 1220, 1
100, 1000, 940, 830, 770 cm ^-1 .

(2) (Z) -1-iodo-3- (1-ethoxyethyloxy) -1-propene (1.59 g,
To a solution of (6.22 mmol) in ether (16.6 ml), a solution of t-butyllithium in pentane (6.47 ml, 1.7M, 10.7 mmol) was added dropwise at -78 ° C, and the mixture was stirred for 40 minutes, then continuously. (2-thienyl) Cu
Tetrahydrofuran solution of (CN) Li (28.05m
1, 0.25M, 7.01 mmol) was added. -78
After stirring at C for 10 minutes, (3R, 4R) -2-methylene-3-[(3S) 3- (t-butyldimethylsiloxy) -4-cyclopentylbut-1ynyl] -4- (t.
An ether solution (20 ml) of -butyldimethylsiloxy) cyclopentan-1-one (1.209 g, 4.15 mmol) was added dropwise. After heating to room temperature over about 1 hour with stirring, the reaction solution was poured into a mixed solution of hexane-saturated ammonium chloride aqueous solution with stirring. The organic layer was separated and the aqueous layer was extracted with hexane. The resulting organic layer was dried with anhydrous magnesium sulfate and subsequently filtered. The crude product obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (developing solvent; hexane:
Purified by ether = 10: 1), 2-decarboxy-2,3,17,18,19,20-hexanor-4-
(1-ethoxyethyl-oxy) -16-cyclopentyl-13,14-didehydro -PGE ₂ 11,15- bis (t-butyldimethylsilyl ether) 1.36 g
Got

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 0.10, 0.11, 0.12 (3s, 12
H), 0.88 (S, 18H), 1.10-2.86.
(M, 23H), 3.37-3.77 (m, 2H),
4.04-4.46 (m, 4H), 4.73 (q, J =
7.2 Hz, 1 H), 5.42-5.76 (m, 2
H).

(3) The compound (0.798) obtained in (2)
g, 1.32 mmol) of tetrahydrofuran (6.6
ml) solution was cooled to -78 ° C and L-Selectri
de (1.71 ml, 1M tetrahydrofuran solution,
1.71 mmol) was added dropwise. After stirring at −78 ° C. for 1 hour, the temperature was raised to room temperature over about 1 hour. To this 3
After adding a 5% hydrogen peroxide aqueous solution (3 ml) dropwise, the mixture was stirred at room temperature for 15 minutes. Saturated ammonium chloride aqueous solution (50
(ml) and ether (50 ml) were added, the organic layer was separated, and the aqueous layer was extracted with ether (30 ml). After drying the obtained organic layer with anhydrous magnesium sulfate,
Filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; hexane: ether = 5: 1) to give 2-decarboxy-2,3,17,18,19, 20-hexanor-
4- (1-Ethoxyethyloxy) -16-cyclopentyl-13,14-didehydro-PGF ₂ α 11,1
5-bis (t-butyldimethylsilyl ether) 59
0 mg was obtained.

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 0.08 (s, 12H), 0.85 (s, 18)
H), 1.08-3.04 (m, 24H), 3.36-
3.76 (m, 2H), 3.92-4.48 (m, 5
H), 4.75 (q, J = 7.2 Hz, 1H), 5.5
2-5.74 (m, 2H).

(4) The compound obtained in (3) (590 mg,
0.970 mmol) of i-PrOH (0.97 ml)
And ether (0.97 ml) solution, pyridinium p
-Toluene sulfonate (12.1 mg, 0.048 m)
mol) was added and the mixture was stirred at room temperature for 10 hours. Ether (20 ml) followed by saturated aqueous sodium hydrogen carbonate solution (3
(0 ml) was added, the organic layer was separated, and the aqueous layer was extracted with ether (2 × 10 ml). The obtained organic layer was dried over anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography to give 2-decarboxy-2,
There were obtained 357 mg of 3,17,18,19,20-hexanor-4-hydroxy-16-cyclopentyl-13,14-didehydro-PGF ₂ α11,15-bis (t-butyldimethylsilyl ether).

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.88, 0.10 (2s, 12H), 0.
88, 0.89 (2s, 18H), 1.02-2.08
(M, 14H), 2.19-2.27 (m, 1H),
2.48-2.71 (m, 2H), 3.12 (br
s, 2H), 3.87 (dd, J = 6.3, 12.1H)
z, 1H), 4.08 (t, J = 4.1Hz, 1H),
4.21-4.44 (m, 3H), 5.57 (dt, J
= 5.0, 10.9 Hz, 1H), 5.74-5.85
(M, 1H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
32.1, 129.3, 84.8, 80.3, 73.
6, 62.7, 57.4, 52.7, 45.3, 44.
7, 42.9, 36.4, 32.7, 32.5, 26.
8, 25.8, 25.7, 25.0, 18.4, 18.
1, -4.4, -4.8, -4.9, -5.0. [Α] _D ^36.0 −4.04 ° (c = 6.34, chloroform)

(5) Compound obtained in (4) (310 m
g, 0.578 mmol) and Bu ₄ N.HSO ₄ (19.
6 mg, 57.8 mmol) of toluene (2.9 ml)
A solution of -25% aqueous sodium hydroxide solution (2.9 ml) was added with 2-bromoacetic acid t-butyl ester (0.233).
(ml, 1.45 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The organic layer was separated, and the aqueous layer was extracted with hexane (15 ml). The obtained organic layer was washed with a saturated aqueous ammonium chloride solution (10 ml) and then dried using anhydrous magnesium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure and then subjected to silica gel column chromatography (developing solvent;
Hexane: acetic acid ethyl ester = 10: 1) to give 3-oxa-13,14-didehydro-17,1.
8,19,20-tetranor-16-cyclopentyl-
PGF2α t-butyl ester 11,15-bis (t
Butyl dimethylsilyl ether) was obtained.

(6) Compound (171 m) obtained in (5)
g, 0.263 mmol) pyridine (1.31 ml)
The solution was added with methanesulfonyl chloride (0.033
(ml, 0.420 mmol) was added and the temperature was raised to room temperature, followed by stirring for 5 hours. A saturated aqueous sodium hydrogen carbonate solution (20 ml) and hexane (30 ml) were added to this, and the mixture was stirred for 10 minutes, then, the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then filtered. The toluene (1.31 ml) solution of the crude product obtained by concentrating the filtrate under reduced pressure was added with n-Bu ₄ NCl (1.19).
g, 5.25 mmol) was added, and the mixture was stirred at 40 ° C. for 5 hours. After adding saturated saline, the mixture was extracted with hexane. The obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. To a solution of the crude product obtained by concentrating the filtrate under reduced pressure in THF (1.4 ml) was added an aqueous solution of hydrofluoric acid (0.73 ml) at 0 ° C., and the mixture was stirred for 4 hours while warming to room temperature. The reaction mixture was poured into ethyl acetate (3 ml) -saturated aqueous sodium hydrogen carbonate solution (3 ml) with stirring, the organic layer was separated, 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;
Purified with hexane: ethyl acetate = 20: 1) to give 3-
Oxa-9-deoxy-9β-chloro-13,14-didehydro-17,18,19,20-tetranor-16
-Cyclopentyl-PGF ₂ α t-butyl ester 6
4 mg was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 1.02-2.05 (m, 13H), 1.4
7 (s, 9H), 2.13-2.32 (m, 2H),
2.35-2.47 (m, 2H), 3.93-4.04
(M, 1H), 3.97 (s, 2H), 4.09-4.
23 (m, 2H), 4.29-4.37 (m, 1H),
4.35 (dt, J = 7.0, 1.8 Hz, 1H),
5.63-5.78 (m, 2H).

(7) Compound (58.2 m) obtained in (6)
Lithium hydroxide monohydrate (27.6 mg, 0.659 mmol) was added to a methanol (4 ml) -water (0.36 ml) solution of g, 0.131 mmol), and the mixture was stirred at room temperature for 7.5 hours. After adding ethyl acetate (18 ml), 0.1N hydrochloric acid aqueous solution was added little by little to adjust the pH to 5. Ammonium sulfate (5 g) was added thereto, and the mixture 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; ethyl acetate: methanol = 5:
Purification by 2) yielded 50.0 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 1.04-2.49 (m, 17H), 3.9
4-4.05 (m, 1H), 4.06-4.48 (m,
4H), 4.13 (s, 2H), 5.50-5.87.
(M, 5H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
73.4, 130.6, 127.6, 84.8, 84.
2, 76.0, 66.7, 66.5, 62.1, 58.
5, 54.3, 44.1, 43.5, 36.5, 32.
6, 28.4, 25.1, 24.9.

Example 2 3-oxa-9-deoxy-9β-chloro-13,14
- didehydro -16,17,18,19,20- Pentanoru-15- (1-norbornyl) production of -PGF ₂ α

[0037]

[Chemical 9]

(1) In the same manner as in (1) of Example 1, (3S) -3- (t-butyldimethylsiloxy) -4-
(3S) -3 instead of cyclopentylbut-1-yne
-(T-Butylsiloxy) -3- (1-norbornyl)
(3R, 4R) -2-methylene-
3-[(3S) 3- (t-butyldimethylsiloxy)-
3- (1-Norbornyl) prop-1-ynyl] -4-
(T-Butyldimethylsiloxy) cyclopentane-1-
Got on.

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 0.07, 0.10, 0.13 (3s, 12
H), 0.88, 0.89 (2s, 18H), 0.98
-1.97 (m, 10H), 2.19-2.21 (m,
1H), 2.33 (dd, J = 7.4, 17.9 Hz,
1H), 2.72 (dd, J = 6.5, 17.9 Hz,
1H), 3.50-3.57 (m, 1H), 4.21-
4.31 (m, 1H), 4.46 (d, J = 1.4H
z, 1H), 5.56 (d, J = 2.7Hz, 1H),
6.14 (d, J = 3.0 Hz, 1H).

(2) Using the compound obtained in (1), the same procedure as in (2) of Example 1 was repeated to obtain 2-decarboxy-2,
3,16,17,18,19,20-heptanor-4-
(1-Ethoxyethyloxy) -15- (1-norbornyl) -13,14-didehydro-PGE ₂ 11,1
5-bis (t-butyldimethylsilyl ether) was obtained. ¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm:
0.07, 0.09, 0.10, 0.12 (4s, 12
H), 0.88, 0.89 (2s, 18H), 1.04
−1.68 (m, 10H), 1.21 (t, J = 7.0
Hz, 3H), 1.31 (d, J = 5.3Hz, 3
H), 2.09-2.76 (m, 7H), 3.42-
3.70 (m, 2H), 4.04 to 4.33 (m, 3
H), 4.42 (d, J = 1.4 Hz, 1H), 4.6
3-4.76 (m, 1H), 5.49-5.72 (m,
2H).

(3) Using the compound obtained in (2), (3) of Example 1 was carried out in the same manner to give 2-decarboxy-2,
3,16,17,18,19,20-heptanor-4-
(1-Ethoxyethyloxy) -15- (1-norbornyl) -13,14-didehydro-PGF ₂ α 11,
15-bis (t-butyldimethylsilyl ether) was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.07, 0.09, 0.10 (3s, 12
H) ,, 0.89 (s, 18H), 1.10-1.82
(M, 13H), 1.20 (t, J = 7.0Hz, 3
H), 2.04-3.01 (m, 6H), 3.44-
3.71 (m, 2H), 3.99-4.28 (m, 4
H), 4.41 (d, J = 18 Hz, 1H), 4.10
-4.79 (m, 1H), 5.57-5.72 (m, 2)
H).

(4) Using the compound obtained in (3) and in the same manner as in (4) of Example 1, 2-decarboxy-2,
3,16,17,18,19,20-heptanor-4-
Hydroxy-15- (1-norbornyl) -13,14
- didehydro -PGF ₂ α11,15- bis (t-butyldimethylsilyl d - ether) was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.04, 0.06, 0.76, 0.084
(4s, 12H), 0.86 (s, 18H), 1.07
-2.09 (m, 13H), 2.12-2.28 (m,
2H), 2.48-2.69 (m, 2H), 3.60.
(Br s, 2H), 3.87 (dd, J = 6.3H)
Z, 12.1 Hz, 1 H), 4.02-4.39 (m,
3H), 4.39 (d, J = 1.8Hz, 1H), 5.
55 (dt, J = 5.1, 10.7 Hz, 1H), 5.
71-5.84 (m, 1H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
31.9, 129.1, 85.0, 83.3, 80.
1, 73.3, 66.6, 57.3, 53.5, 52.
7, 44.6, 42.9, 40.5, 36.9, 31.
0, 30.4, 26.8, 26.0, 25.8, 18.
2, 17.9, -4.3, -4.7, -4.9, -5.
1. ^{_{[Α] D 36.0 -3.33 ° (}} c = 5.06, chloroform).

(5) Using the compound obtained in (4), the same procedure as in (1) of Example 1 was carried out to obtain 3-oxa-9-deoxy-9β-chloro-13,14-didehydro-16,1.
7,18,19,20- Pentanoru -15- (1-norbornyl) -PGF ₂ αt- butyl ester.

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 11.5-26.5 (m, 19H), 1.49
(S, 9H), 3.98 (s, 2H), 3.85-4.
58 (m, 4H), 4.49 (d, J = 1.5Hz, 1
H), 5.63-5.94 (m, 2H).

(6) Using the compound obtained in (5), (5) and (6) of Example 1 were carried out in the same manner to give 3-oxa-9-deoxy-9β-chloro-13,14-didehydro-1.
6,17,18,19,20-pentanol-15- (1
- to obtain a norbornyl) -PGF ₂ α.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 1.25-1.76 (m, 10H), 2.0
9-2.55 (m, 7H), 4.05-4.47 (m,
5H), 4.13 (s, 2H), 5.57 (br s,
3H), 5.50-5.86 (m, 2H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
73.6, 130.6, 127.7, 85.3, 82.
8, 76.1, 66.4, 66.3, 58.6, 54.
6,52.8, 43.6, 43.5, 40.5, 37.
0,30.9,30.4,28.4.

Example 3 3-Oxa-9-deoxy-9β-chloro-13,14
-Didehydro-17,18,19,20-tetranor-
Production of 16-cyclohexyl-PGF ₂ α

[0050]

[Chemical 10]

(1) In the same manner as in (1) of Example 1, (3S) -3- (t-butyldimethylsiloxy) -4-
(3S) -3 instead of cyclopentylbut-1-yne
Using (-t-butyldimethylsiloxy) -4-cyclohexylbut-1-yne, (3R, 4R) -2-methylene-3-[(3S) -3-in the same manner as in Example 1 (1).
(T-Butyldimethylsiloxy) -4-cyclohexylbut-1-ynyl] -4- (t-butyldimethylsiloxy) cyclopentan-1-one was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm; 0.07 to 0.14 (m, 12H), 0.8
9 (s, 18H), 1.03 to 1.80 (m, 13
H), 2.33 (dd, J = 17.9 Hz, 7.4H)
z, 1H), 2.71 (dd, J = 17.9 Hz, 6.
4Hz, 1H), 3.41 to 3.54 (m, 1H),
4.22 to 4.32 (m, 1H), 4.47 (t, J =
6.8 Hz, 1 H), 5.55 (d, J = 2.5 Hz,
1H), 6.14 (d, J = 2.7 Hz, 1H). IR (neat): 2930, 2850, 1735, 1
640, 1460, 1360, 1250, 1220, 1
100, 1000, 940, 830, 770 cm ^-1 .

(2) Using the compound obtained in (1), the same procedure as in (2) of Example 1 was repeated to obtain 2-decarboxy-2,
3,17,18,19,20-hexanor-4- (1-
Ethoxyethyloxy) -16-cyclohexyl-1
3,14-Didehydro-PGE ₂ 11,15-bis (t
-Butyldimethylsilyl ether) was obtained.

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 0.10, 0.11, 0.13 (3s, 12
H), 0.89 (s, 18H), 1.07-1.78.
(M, 19H), 2.15 (dd, J = 7.5, 18.
0H ₂ , 1H), 2.25-2.76 (m, 5H),
3.42-3.72 (m, 2H), 4.04-4.51
(M, 4H), 4.65-4.76 (m, 1H), 5.
48-5.72 (m, 2H).

(3) Using the compound obtained in (2), (3) of Example 1 was carried out in the same manner to give 2-decarboxy-2,
3,17,18,19,20-hexanor-4- (1-
Ethoxyethyloxy) -16-cyclohexyl-1
3,14-Didehydro-PGF2α 11,15-bis (t-butyldimethylsilyl ether) was obtained.

¹ H-NMR (CDCl ₃ , 90 MHz) δ
ppm: 0.11 (s, 12H), 0.90 (s, 18
H), 1.07-2.77 (m, 25H), 3.42-
3.73 (m, 2H), 3.98-4.49 (m, 5
H), 4.66-4.78 (m, 1H), 5.53-
5.88 (m, 2H).

(4) Using the compound obtained in (3) and following the same procedure as in (4) of Example 1, 2-decarboxy-2,
3,17,18,19,20- Hekisanoru -4-hydroxy-16-cyclohexyl-13,14-didehydro -PGF ₂ α 11,15- give the bis (t-butyldimethylsilyl ether).

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.10, 0.11, 0.12 (3s, 12
H), 0.89, 0.90 (2s, 18H), 1.13
-2.10 (m, 16H), 3.02 (br s, 2
H), 3.83-3.92 (m, 1H), 4.05-
4.14 (m, 1H), 4.26-4.33 (m, 1
H), 4.34-4.47 (m, 2H), 5.54-
5.88 (m, 2H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
32.2, 129.3, 84.9, 84.8, 80.
2,73.4,61.2,57.4,52.6,46.
5,44.6,43.0,34.1,33.6,33.
1,26.8, 26.6, 26.4, 26.3, 25.
9, 18.3, 18.0, -4.3, -4.6, -4.
9.

(5) Using the compound obtained in (4), (5) and (6) of Example 1 were carried out in the same manner to give 3-oxa-9-deoxy-9β-chloro-13,14-didehydro-1.
There was obtained 7,18,19,20-tetranor-16-cyclohexyl-PGF ₂ αt-butyl ester.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.85-1.82 (m, 13H), 1.4
8 (s, 9H), 2.07 (brs, 2H), 2.10
-2.49 (s, 6H), 3.98 (s, 2H), 3.
94-4.06 (m, 1H), 4.08-4.25
(M, 2H), 4.29-4.37 (m, 1H), 4.
45 (dt, J = 1.4, 6.3 Hz, 1H), 5.6
7-5.83 (m, 2H).

(6) Using the compound obtained in (5), (7) of Example 1 was carried out in the same manner to give 3-oxa-9-deoxy-9β-chloro-13,14-didehydro-17,1.
8,19,20-hexanor-16-cyclohexyl-
PGF ₂ α was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz)
δppm: 0.83-1.85 (m, 13H), 2.0
6-2.55 (m, 6H), 3.98-4.52 (m,
5H), 4.15 (s, 2H), 5.60-5.85.
(M, 2H). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ ppm: 1
74.8, 130.9, 127.5, 85.0, 84.
3, 76.0, 67.2, 66.5, 60.5, 58.
6, 54.3, 45.3, 43.5, 43.3, 34.
3,33.3, 28.4, 26.4, 26.2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 31/557 ABS ACV (72) Inventor Kazuya Kamio 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceuticals Co., Ltd. (72) Inventor Tonami Toru 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Ken Muto 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceuticals Co., Ltd. (72) Inventor Naoya Ono 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Jun Goto 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Within the corporation

Claims (3)

[Claims] 1. Formula (I): [In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms,
R ² represents a cycloalkyl-substituted methyl group having 5 to 7 carbon atoms, or a bridged cyclic hydrocarbon. ] The prostaglandin derivative or its salt represented by these. 2. Formula (I): [In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms,
R ² represents a cycloalkyl-substituted methyl group having 5 to 7 carbon atoms, or a bridged cyclic hydrocarbon. ] The prostaglandin derivative represented by these or its salt is contained as an active ingredient, The renal disease improving agent characterized by the above-mentioned. 3. Formula (I): [In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms,
R ² represents a cycloalkyl-substituted methyl group having 5 to 7 carbon atoms, or a bridged cyclic hydrocarbon. ] The prostaglandin derivative or its salt represented by these is contained as an active ingredient, The ischemic heart disease improving agent or the heart failure improving agent.