JPS6314746A - Carbacyclin derivative, production thereof and remedy containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:A carbacyclin derivative of formula I (Z is -COOH, -CONH2 or -CH2OH; A is -CH=CH- or -CidenticalC-; B is (substituted) indanyl, (substituted) benzodioxanyl, (substituted) benzodioxolanyl or 2,3,5,6,7,8- hexahydrobenzodioxolanyl) or its alkali addition salt. EXAMPLE:15alpha-hydroxy-15-(benzodioxan-6-yl)carbacyclin. USE:It has antiulcer, anticoagulation and vasodilating activities and is useful as a drug. It has high chemical stability. PREPARATION:A compound of formula II (R<1> is lower alkyl; R<2> is hydroxyl protecting group) is made to react with a compound of formula III (Y is H or halogen) and the resultant compound of formula IV is reduced to obtain a compound of formula V. The product is subjected to dehydrohalogenation reaction when Y is halogen and to deprotection reaction of OH group and COOH group to obtain a compound of formula I wherein A is triple bond.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel prostacyclin derivative useful as a medical drug.

(Prior art and problems) Conventional prostacyclin derivatives are not necessarily satisfactory in terms of stability, and also have a wide range of medicinal effects and systemic effects, and it is necessary to improve the stability and selectivity of drug efficacy as a compound. is desired.

Prostacyclin (PGI It is unstable and more stable prostacyclin derivatives have been investigated.

In the above formula, the oxygen (-o-) at the 6.9-position is returned to the element (-CI
A derivative of carbacycline with a structure substituted with 2-) has been synthesized (Stanlcy, M, Rol) crts
& Feodor Scheinmann Eds,
”New 5 synthetic routes.

Prostaglandins and Illrom
boxanes” Academic Press (
(1982), p. 221-231).

Furthermore, it is known that prostaglandins lose their activity by converting the 15-position hydroxyl group into 15-keto prostaglandin by 15-hydroxyprostaglandin dehydrogenase (Jarabak).

J, l Braithwaite, 5.5. , Ar
ch, Biochem.

Biophys, 1976, 177, 245).

Furthermore, it has been reported that introducing a triple bond at position 13 can suppress inactivation by 15-hydroxyprostaglandin dehydrogenase [Josef F.
r1ed, D, Ni, Mitra, M, Nagara
jan, M, M.

Mohvotra, J., Med, Chem.
23. 234-237p (1980).

(Structure of the Invention) Under these circumstances, the present inventors have conducted extensive studies with the aim of providing prostaglandin derivatives that are chemically stable and have high drug efficacy selectivity. The present invention was achieved based on the discovery that a compound having a structure in which is substituted with a bicyclic group has various excellent properties that meet the above objectives.

121 The compound of the present application has the general formula ■: (wherein, Z is -COOHl-coNll, or -
CH, OH, A is -CH=CH- or -C=C-, B is an indanyl group that may have a substituent, a benzodioxanyl group that may have a substituent, or a benzodioxanyl group that may have a substituent. a benzodioxanyl group, or 2.3.5.6
．． 7.8-hexahydrobenzodioxanyl group, respectively. same as below. ) or a pharmaceutically acceptable alkali addition salt of these compounds.

In the present application, the bonded chain ~ indicates any monoisomeric bonded chain of structurally acceptable isomers such as α, β configuration isomers, cis/trans isomers, etc.

Compounds with a structure in which a bicyclic compound is introduced into the ω chain (lower chain) of prostaglandins or compounds with a similar structure have not been known so far, and therefore, the compound of general formula (2) is also novel. It is a substance.

As can be deduced from its characteristic structure of having a bicyclic compound in the ω chain, the compound of the present application is less susceptible to ω oxidation of the ω chain, and the hydroxyl group at the 15th position is 15-hydroxyprostaglan. By blocking attack by zine dehydrogenase with steric hindrance, the dehydrogenation reaction is prevented, and therefore the degree of deactivation due to modification to 15-keto prostaglandin is reduced. Furthermore, in the case of compounds containing this bicyclic substituent or a heteroatom, 15
It is determined that the 15-hydroxyl group is stabilized by hydrogen bonding with the hydroxyl group at the 15-hydroxyprostaglandin dehydrogenase position, making it less susceptible to inactivation by 15-hydroxyprostaglandin dehydrogenase.

The main compounds included in the general formula (1) are illustrated below.

(1) 15α-hydroxy-15-(benzodioxan-6-yl)carbacycline (2) 15β-hydroxy-15-(benzodioxan-6-yl)carbacycline (3) 13.14-dehydro-15α- Hydroxy-15-(indan-2-yl) carbaliclin (4) 13.14-dehydro-15β-hydroxy-
15-(indan-2-yl)carpariclin (5) 15α-human 1]oxy-15-(benzodioquinyl-2-yl)carbacycline (6) 15β-hydroxy-15-(benzodioxane-2- yl)carbacycline (7) 15α-hydroxy-15-(indan-2-yl)carbacycline (8) 15β-hydroxy-15-(indan-2-yl)ruvacycline (9) 15α-hydroxy-15-( 6-Methylbenzodioxan-2-yl)carbacycline (10) 15β-hydroxy-15-(6-methylbenzodioxan-2-yl)carbacytalline (11) 15α-hydroxy-15-(6-medoxybenzo dioxan-2-yl)carbacitalin (12
) 15β-hydroxy-15-(6-medoxybenzodioxan-2-yl)carbacycline (13) 1
5α-hydroxy-15-(2,3,5,6,7,8-
hexahydrobenzodioxan-2-yl)carbacycline (14) 15β-hydroxy-15-(2,3,5,
6,7,8-hexahydrobenzodioxan-2-yl)carbacycline (15) 15α-hydroxy-15-(benzodioxan-2-yl-methyl (16) 15β-hydroxy-15-(benzodioxan-2 -yl-methyl (17) 15α-hydroxy-15-(2-methylbenzodioxan-2-yl) carbacycline (18) 15β-hydroxy-15-(2-methylbenzodioxan-2-yl) carbazycline ( 19) 15α-hydroxy-15-(indan-2
Carbacycline-1-yl (20) 15β-hydroxy-15-(indan-2
Carbacycline-1-yl (21) 15α-hydroxy-15-(indan-2
-yl)carbacyclinamide (22) 15β-hydroxy-15-(indan-2
-yl)carbacyclinamide (23) 15α-hydroxy-15-(indan-6
-yl) carbacycline (24) 15β-hydroxy-15-(bean-6
-yl) Carbacycline (25) 15α-Hydroxy~15-(Indan-1
-yl)carbacycline (26) 15β-hydroxy-15-(indan-1
-yl)carbacycline (27) 15α-hydroxy-15-(5-nitroindan-2-yl)carbacycline (28) 15β-hydroxy-15-<5-nitroindan-2-yl)carbacycline (29 ) 15α-hydroxy-15-(5-methoxyindan-2-yl)carbacytalin (30) 15β-hydroxy-15-(5-methoxyindan-2-yl)carbacycline (31) 15α-hydroxy-15- (5-chloroindan-2-yl)carbacycline (32) 15β-hydroxy-15-(5-chloroindan-2-yl)carbacycline (33) 15α-hydroxy-15-(benzodioxolan-5-yl) Carbacycline (34) 15β-hydroxy-15-(benzodioxolan-5-yl)carbacycline (35) 15α-hydroxy-15-(2-methylindan-2-yl)carbacycline (36) 15β-hydroxy-15 -(2-Methylindan-2-yl)carbacitalin The compounds (1), <2>, ..., (36) above are hereinafter referred to as Compound 1, Compound 2, ..., Compound 36
It can be quoted as

In the production of the compound of the present application, the starting material, a compound represented by the general formula (2): (In the above formula, R' represents a lower alkyl group and R2 represents a hydroxyl group protecting group, respectively) can be prepared using the method U of Shibasaki et al. Org, C
hem.

19B4.4096p), 1-alkenyl-cis-bicyclo[3,3,0]octene derivatives are subjected to hydrogenation, desilylation and oxidation reactions using a metal carbonyl compound [Mw(Co)x] or its complex as a catalyst. can be obtained as follows.

201 To produce the compound of the present application, first, a compound of the general formula (1) is mixed with a compound represented by the general formula (2): (wherein, B is the same as above, and Y represents hydrogen or a halogen group. The same applies hereinafter). Avoiding the reaction, the general formula ■: (R1,
A compound (R1, Y, B are the same as above) is produced. This reaction can be carried out in a conventional manner by Wittig reaction. Inert solvents used in this reaction include ethers such as ethyl ether, tetrahydrofuran, and dimethoxyethane, hydrogen ash such as hexane and benzene, amides such as dimethylformamide and dimethylacetamide, dimethyl sulfoxide, Examples include hexamethylphosphoramide (HMPA). The base used is an organolithium compound such as n-butyllithium, phenyllithium or lithium diisopropylamide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, or sodium hydride-dimethylsulfoxide (
Gymzyl anion) can be given.

The 15-oxo compound represented by the general formula ■ is cis (Z)
Because it is obtained as a mixture of isomer and trans (E) isomer,
If necessary, the cis isomer and the trans isomer are separated by a method such as column chromatography.

Next, by reducing the compound of general formula (1), a 15-hydroxy compound represented by general formula V: (wherein R1, R1, Y and B are the same as above) is obtained. A hydrogenation reagent such as sodium borohydride, lithium aluminum hydride, or selectide can be used in this reduction reaction.

The 15-hydroxy compound represented by the general formula V is a mixture of α-hydroxy form and β-hydroxy form.
Separate into body. In particular, in the case of a compound in which Y is a halogen atom in the general formula V, a dehydrohalogenation reaction,
By carrying out the deprotection reaction of OH and COOH groups,
A compound in which A is a triple bond (-C=C-) in the general formula (2) can be obtained. In this case, dehydrohalogenation and deprotection are carried out in the presence of an alkaline reagent such as potassium t-butoxide or potassium butyrate. Particularly when potassium t-butoxide is used, dehydrohalogenation and ester hydrolysis proceed simultaneously. still,
Examples of the protecting group R2 for the -OR group include a tetrahydropyranyl group. Among the compounds represented by the general formula V, in the case where Y is a hydrogen atom, the hydroxyl group is deprotected to form the 11-hydroxy form, and then, if necessary, the 15α-hydroxy form and the 15β-hydroxy form are combined. Perform separation. This separation is also performed by chromatography or the like. Deprotection of the hydroxyl group at position 11 can also be carried out in a dilute acetic acid solution. In this case, after the deprotection reaction is completed, the ester group -COOR'' can be hydrolyzed with an alkali to lead to a compound of general formula I.Among the compounds of general formula II, compounds in which Y is a halogen atom are Obtained by reacting a compound in which Y is II in the general formula (■) in the presence of an alkali using N-chlorzicinimide (NC5), N-promsuccinimide (NBS), etc. as a halogenating agent. For example, C Substituent B in general formula I is an indanyl group, a penzodioxanyl group, a penzodioxolanyl group, and 2.
3.5.6.7.8-hegylyhydrobenzodioxanyl group and any one or more positions of these bicyclic groups substituted with a lower argyl group, lower alkyloxy group, nitro group, or halogen group These are compounds described in the literature.

Among these, uncommon compounds were synthesized as follows.

(i) When B is a 2-methylindanyl group, it can be obtained as follows.

(i) When B is a 2-methylbenzodioxanyl group, it can be obtained as follows.

02.3 1eolI *I J, Am, Chem, Soc, 73917
(1961); C, D, H [JRD.

H, E, WINBERG *2 J, Med, Chem, 8446 (196
5); A, M, Monroe.

G, W, H, POI'I'ER *3 J, Med, Chem, 10880 (19
67); A, M, Monroe.

G, W, H, POITER (i) When B is 2.3.5.6.7.8-hexahydrobenzodioxanyl group, C, A, 57.1
6633C and goods.

It is obtained as follows according to the method described in No. 13320a.

The compound represented by the general formula I and its pharmaceutically acceptable alkali addition salt exhibit 1. remarkable anti-ulcer effect, platelet aggregation inhibiting effect, and vasodilatory effect, as described below;
It is chemically stable and is expected to be effective as an anti-ulcer agent, a thrombus aggregation inhibitor, or an antihypertensive agent. The compound of the present invention can be administered either orally or parenterally, and the dosage is 100 μg to 10 μg per adult per day.
The desired therapeutic effect can be expected by administering 00 μg.

Pharmacological test examples and production examples are listed below, but the present invention is not limited to these, and it goes without saying that modifications within the scope of the present invention are included within the scope of the present invention.

(Anti-ulcer effect) Ethanol ulcer A, Robert (Gastrocnterology 7
7, 433-443), rats were fasted for 24 hours and then 1 m! One hour after the ethanol administration, the stomachs were removed, the total length of damage caused to the glandular stomach was measured, and the anti-ulcer effect was compared. The test drug was orally administered 30 minutes before ethanol administration.

(Hypertensive lowering effect) The hypotensive effect was investigated using anesthetized rats according to the method of Sogabe c') et al. Male Wistar rat (200
~300g > under urethane anesthesia (1.2g 7kg
, i, V, ), and blood pressure was simultaneously measured from the femoral artery using a pressure transducer (Nihon Kohden R-5).The test drug was dissolved in physiological saline and injected from the femoral vein. Administration (0.1 mL/100 g body weight).Drug efficacy was evaluated based on the MBP16 value (when the test drug lowered the mean blood pressure by 15 mm).
This was done by comparing and examining doses for lowering Hg (mg/kg, i, v, ).

(1) Hirofumi Sogabe “Introduction to Experimental Hypertension” P, 227
(Eikodo) 1968 (Anti-platelet aggregation effect) Under ether anesthesia, 0.9 volume of blood was collected from the abdominal aorta of a rat into a syringe containing 0.1 volume of 3.8% trisodium citrate solution. Platelet aggregation was measured using a platelet aggregation measuring device (Chronolog, Model C530, USA) according to the method of C. Cardinal (1). Place in a cuvette, keep warm at 37°C, add 10 μP of a drug solution containing 1 μg to 1 mg/ml of the test drug dissolved in physiological saline, and after 2 minutes add 5 μP of collagen reagent.
! was added and the aggregation curve was recorded. The size of aggregation was expressed as a resistance value, the maximum aggregation rate when only the solvent was added was taken as 100%, and the maximum aggregation rate when the test drug was added was expressed as inhibition %.

”'J, Pharmaco1.Method, q,
135-158 (1980) Table 3 Stability test of the present compound Take about 1.5 mg of the test compound, dissolve it in a small amount of methanol, and adjust the pH to 5, 2, 7, 2, 7, 4, 9.
, 2 and observed changes under each condition. pH 5.2 (0.2M potassium hydrogen phthalate).

2N-NaOH), pH 7,2 (0,2M KH, PO
, +0.2N-NaOH), 9.2(0.2M-nsp
o4+o, 2MKCJ2"0.2N-NaOH) pH 7.4<0.2M at 37°C, Kl
(tPOa+0.2N-NaOH) was carried out at room temperature. The confirmation method was to extract the test solution with ethyl acetate when using a buffer solution with a pH of 5, 2, 7, 2, 7°4, and observe the change by thin layer chromatography of the extract. In the case of pH 9.2, the test solution was diluted with water, adjusted to pH 4 with 10% Hc1, extracted with ethyl acetate, and changes were observed by thin layer chromatography of the extract. The results are shown in Table 4.

[Formulation Examples] The compound of general formula (I) is used as it is or in the form of a pharmaceutically acceptable alkali addition salt, mainly in the form of granules, tablets or capsules, according to a conventional method. Examples of formulations are listed below.

Tablet description Compound 5 0.10mg
Crystalline cellulose 10.0g lactose
70.0 g starch
35.0 g Methyl cellulose 3.0 g Stear 1, Etolic acid 7) / Cium 2, Total volume
120.0 g The above mixture was prepared in a conventional manner at a rate of 100μ of Compound 5 per tablet.
Tablets containing g.

Capsule Compound 7 0.20mg
crystalline cellulose to, o g lactose
65.0 g starch
23.0 g Polyethylene Beginner P-Rule 60002.
0i Total amount 100.0 g Add the above mixture to 2 portions of Compound 7 per capsule according to a conventional method.
Capsules containing 00g.

[Examples 1-2] 15α-hydroxy-15-
) carbacycline (compound 1) and 15β-hydroxy-15-(benzodioxane-6-
Carbacycline (Compound 2) In a 200 ml flask, dissolve 18.0 g of methyl 3.4-dihydroxybenzoate in 60 mj2 of acetone, then add 5.2 mj2 dibromoethane and 7.5 mj2 potassium carbonate.
g and heated under reflux for 10 hours. After cooling, filter
The solvent is distilled off. Dissolve the residue in ether, wash the ether solution with water, 5% sodium hydroxide solution, and saturated brine, add hexane, and leave overnight. The resulting crystals were collected by filtration to obtain 15.2 g (73.3%) of the desired product.

(b) 11α-tetrahydropyranyl-15-year-old xo-15-(benzodioxan-6-yl)carbacycline methyl ester 1.068 g of Na1 was added to a 50 ml flask of 1, and was heated with N-pentane under an atmosphere. After washing, THF (tetrahydrofuran) 1.3mf! , and cooled to 0@C. Add to this solution 0.873 [2-(benzodioxyxan-6-yl)-2-oxo]ethyldimethyl obtained in (a).
A solution obtained by dissolving 1.0 g in 6 ml of THF was added thereto, and the mixture was stirred at 0°C for 20 minutes under N atmosphere. Furthermore, the general formula ■ is added to this reaction solution.
A solution of 0.45 g of aldehyde (where R2 is THP (TEI-lahydropyran)) in 8 ml of THF is added dropwise at O''C and stirred for 30 minutes at room temperature. After the reaction, saturated ammonium chloride solution is added and ether extraction is performed. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue is purified by silica gel chromatography (ether: n-hexane = C4). 0.350 g of the oily target product ( 0.54%).

IR (cm-') 2940.2870.1740.
1670.1620.1580°1500, 1438 NMR (S CDC15) 7.45-7.75 (m,
3H) 6.8 (dd+m) 5.2 (t, IH) 4
．． 55 (bs, III) 4.22 (s, 4B)
3.6 (s, 3H) 3,4 (m, IH) 0.10 of the compound obtained in (b) in a 25 ml flask
After adding 1 ml of methanol, 0.002 g of sodium borohydride was added at -25°C (dry ice/restored tetrachloride) and stirred for 15 minutes under N2 atmosphere. Furthermore, after adding acetone at -25°C and stirring at room temperature for 20 minutes,
Add saturated ammonium chloride to neutralize (pH 7.0). After methanol is distilled off under reduced pressure, the residual liquid is extracted with ether, and the ether extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (ether: n-hexane = 2:
1), the oily target product 0.100 g (99,
2%).

IR(am-'neat) 3450. 2950.
2B80. 1740. 1600°1510, 144
O NMR(&CDCj!s) 6.9(s, 3H)
5.75 (bs, 2H) 5.1-5.6 (m, 2
H) 4.8 (bs, 111) 4.31 (s, 4H)
3.8 (s, 3H) 3,4-3.7 (m, 01) Add 5 ml of a mixture of acetic acid: water: tetrahydrofuran (3:1:1) to a 25 ml eggplant-shaped flask, and then (c) Add 0.350 g of the compound obtained above and stir at 45-50°C for 5 hours. The solvent is distilled off using an aspirator, and the residue toluene is added and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (ether:n-hexane=4:1). 15α-hydroxy-15-(benzodioxane-6-
IR) Carbacycline Methyl Ester IR(am-1'neat) 3350. 2940.
2870. 1730. 1580.

1500, 1440. 1380. 12B0. 1
240.

MS (m/e) 428 (M”) 149 (b.P) 15β-hydroxy-15-(
0.060 g (28.9%) of benzodioxan-6-yl)carbacycline methyl ester was obtained.

IR (cm””neat) 3440.2940.28
60.1734.1582゜1506, 1438.14
01.1308.1287MS(m/e) 441(M
”-H, O), 15α obtained in 188 (b, P) (d)
-hydroxy-15-(benzodioxan-6-yl)
Add 0.4 ml of 10% sodium hydroxide solution to carbacycline methyl ester and incubate at 0"C for 2 hours, then at room temperature for 1 hour.
Stir for 0 hours. The reaction solution was cooled with ice water and adjusted to pH 7.0 with 10% hydrochloric acid. After the temperature is reduced to 0, the solvent is distilled off under reduced pressure. Add saturated brine to the remaining aqueous layer, cool with ice water, and adjust the pH with 10% hydrochloric acid.
Adjust to 3-4 and extract with ethyl acetate. After drying the ethyl acetate extract over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Oily 15α-hydroxy-15-(benzodioxan-6-yl) carboxylicin 0. 01
0 g' (25.9%).

MS (m/e) 396 (M”-H*O) 149 (b
．． p. ) Similarly 0. 048 g of 15β-hydroxy-15-(benzodioxan-6-yl)carba°
Hydrolyze nyclin methyl ester to obtain oily 15
β-hydroxy-15-(benz'dioxan-6-yl)carbacycline 0. 020 g (41%) was obtained.

M. S. (m/e) 396 (M”-11.0) 1
49 (b.p.) [Examples 3-4] 13, 14-dehydro-15α-hydroxy-15-
(indan-2-yl)-carbacycline (compound 3
) and 13,14-dehydro-15β-human 'lx-15-(indan-2-yl)-carbacycline (
Compound 4) 2.74 ml of dimethylmethylphosphonate in a 100 ml three-bore flask was added to TllF20mj! Solution, add 15.8 ml (15.8 ml) of n-butyllithium at -78°C.
．． 6M. Hexane solution) was added dropwise and stirred for 30 minutes,
2-Indanecarboxylic acid methyl ester3. 70g
IHF26. Add 3ml solution dropwise at -78℃,
Stir for an hour. After the reaction, a saturated aqueous ammonium chloride solution is added, the temperature is returned to room temperature, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate). Colorless oil 3. 89 g was obtained.

NMR (& , CDCffi s) 7.15 (s.4
H) 3.85 (s.3H) 3.72 (s.3H)
3.24. 3.08 (2s.2H) 3.33~3
．． 08(d+m.5H)IR(cm""neat) 2
944. 2B48. 1707. 1458. 12
57.

1182, 1029, 807. 756MS (m/
e) 268 (M+) 116 (b.p.) 25m I
! ．． Sodium hydride in a double diameter flask of 0. 09
[2-(Indan-2-yl)
2-oxo-1-chloro]ethyldimethylphosphonate 0
.

630g of DMell. After adding 0 ml of the solution and stirring for 30 minutes, add 0.315 g of tochlorsuccinimide.
Stir for an hour. After the reaction, add saturated ammonium chloride,
Ether extraction is performed, and the ether extract is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1).

0.351 g (49.0%) of a yellow target product was obtained. Melting point 57.3-58.4° CNMR (&, CDCl2
s) 7.11 (s.4H) 4.93. 4.63(d
．． LH) 3,91 (s.IH) 3.73 (s.3H)
3.34-3.65 (m.1■) 3.273, 14
(d. 4H) IR (cm-'neat) 2944. 1728.
1460. 1378. 1266.

11B0. 1035. 840, 750.

MS (m/e) 303 (M”) 115 (b.p.)
25m2 two-diameter hula7. DMEO. A suspension of 1 ml of 2-(ingen-2-yl) was prepared at 0°C by adding 0.08 g of sodium hydrinyl F.
2-year-old xo-1-lyrol]ethyldimethylbosphonate 0
．． A solution of 114 g dissolved in 2 ml of DMEI was added and stirred at 0°C for 20 minutes and at room temperature for 20 minutes.
and cooled to aldehyde of general formula I (where R3 is THP).
A solution of 0.051 g dissolved in DMEl, 2mj2 was added, and the mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours, and then further stirred for 5 hours.
Stir at 0°C for 4 hours. After the reaction, saturated ammonium chloride solution is added at room temperature and extracted with ether. The ether extract is washed with saturated saline and then dehydrated with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography (ether: n-hexane = 1:
Purify in step 4). “6.02 from the Res Polar part
Obtain 2 g of the target product (trans isomer).

NMR<S, CDC1s) 7.20(s, 4H)
6.22.6.06(d, IH, >5.21(bt, 1
11) 4.68 (bs, LH) 3.65 (s, 3H
) 3.35°3.20 (d, 4H) 4.35~3.
05 (m, 4H) 2.77-1.15 (m, 21H)
IR(cm-'neat)2932.2g54.173
4.1695.1440°1350, 1320.124
B, 1197.1167, 1119.1074°10
20,972.867,750 (d) 11α-tetrahydropyranyl-14-chloro-15αβ-hydroxy-15-(ingen-2-yl)carba In a 25 ml eggplant-shaped flask, add the compound obtained in <c) 0 Add 22g of ゜ and 2.2ml of methanol, and heat to 0℃.
Add 10.005g of sodium borohydride,
Stir for a minute. Furthermore, after adding a small amount of acetone and stirring for 30 minutes, saturated ammonium chloride solution was added to adjust the pH to 7.0.
The solvent is removed under reduced pressure. Add saturated brine to the residue and extract with ether. The ether extract is washed with saturated brine, dehydrated with anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (n-hexane = 2:1). Oily object 0
, 180 g (81.5%).

NMRCS, CDCl, )7.10 (s.41()
5.75, 5.61 (d.IH) 5, 25 (bt
．． IH) 4. 63 (bs. LH) 3. 63
(s. 3H) 4. 21-3, 20 (m. 5H
) 2. 64-3. 20 (mad. 511) 2
．． 63-1. 00 (m. 2IH) 'IR (cm-'neat) 3418, 3004.
2932. 1731, 1437.

1356, 1317. 121B. 1200.
1170. 1119, 1074.

1020, 975 (2) Compound 0. 240 g was dissolved in 5mj7 of a mixture of acetic acid:water:tetrahydrofuran (3:1:1) and stirred at 45°C for 8 hours. After the reaction, the solvent is distilled off under pressure,
After azeotroping the residue with toluene, silica gel column chromatography (ethyl acetate: n-hexane = 1:1
). 0. from the Res Polar part. 071
g (34.8%) of oily 14-chloro-15
α-hydroxy-15-(indan-2-yl)carbacitalin methyl ester was obtained.

1HMRCS, CDCl ->7.12 (s.4H)
5.78. 5.61 (d.IH) 5, 24 (bt
．． IH) 3. 63 (s. 3H) 4. 29～
3. 44 (mad. 2M>2, 72~3.14
(d+m. 5H) 2. 71-1. 01 (m.
17H)'IR(cm-"neat) 3394.3
004, 2932. 2842. 1725.

1437, 1218. 1080. 900. 75
0.104g (51
．． 7X) oily 14-chloro-15β-hydroxy-
15-(Indan-2-yl)carbanycline methyl ester was obtained.

NMR (S, CDCj2 s) 7.10 (s.41
1) 5.69. 5.51 (d.IH) 5, 29 (b.
t. IH) 3.65 (s.311) 3, 39-4.
30 (mad. 2H) 2, 61 ~3. 38<
mad. 5 Summer I) 1.0-2.61<m. 17H
)IR(cm-'neat) 3370. 3004.
2932. 2836, , 1725.

1437, 1215. 10g3, 900. 75
14-chloro-15α-hydroxy-1 obtained in 3(e)
5-(Indan-2-yl)carbazycline methyl ester 0. 030 g with 2 ml of DMSO and 'fHF
Add 1 m j2 and add 0.0 m of potassium-t-butoxide.
038 g was added and stirred at room temperature for 10 hours. After reaction, 0
Cool to °C, adjust to pH 4 with 10% hydrochloric acid, and extract with ethyl acetate. Wash the extract with saturated brine and dry over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by Prevaratip thin layer chromatography (ethyl acetate). 0.021 g (79,0%) of the target product 13
．． 14-dehydro-15α-hydroxy-15-(indan-2-yl)carbacycline was obtained.

NMR (1; , CDCR->7.'01 (s,
4H) 4.93-5.40 (bs+bt, 4H) 4
．． 20-4.41 (d, IH) 3.50-4.10 (
m, IH) 2.90 (bs.

5H) 1.30-2.70 (m, 15H) IR (c
m””neat) 3376, 2932.2668.2
524.1710°1434, 1377, 1248.1
116.1086.1044.975 Similarly (e)
14-chloro-15β-hydroxy-15-(indan-2-yl)carbacitalin methyl ester obtained in
．． 030 g, 13.14-dehydro-15β
-Hydroxy-15-(indan-2-yl)carbacycline 0.013 g (48.9%) was obtained.

NMR (SCDCρs) 7.15 (s, 4H) 5.
22 (bt, LH) 4.55-5.06 (bs, 3H
) 4.30-4.52 (d, IH) 3.60-4.
02 (m, IH) 2.99 (bs, 5H) 1.37
'-2,70 (m, 15H) IR (cm-'neat)
3370.2930.1728.1434.1377
゜1245, 1083.1041 The following compound was obtained in the same manner as in Examples 1-2.

-41+-

Claims (8)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Z is -COOH, -CONH_2 or -
CH_2OH, A is -CH=CH- or -C≡C-
B is a substituted or unsubstituted indanyl group, a substituted or unsubstituted benzodioxanyl group, a substituted or unsubstituted benzodioxolanyl group, or 2,3,5,6,7,8-hexahydrobenzodioxa Each represents a nyl group. ) or a pharmaceutically acceptable alkali addition salt of the derivative. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R^1 represents a lower alkyl group, and R^2 represents a hydroxyl group protecting group. The same applies hereinafter in this section.) Compounds represented by and general formulas: ▲Mathematical formulas, chemical formulas, tables, etc. A xolanyl group or a 2,3,5,6,7,8-hexahydrobenzodioxanyl group, and Y represents hydrogen or a halogen group, respectively.The same applies hereinafter in this section.) Production of a compound represented by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, B, ~Y are the same as above.) Method. (3) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R^1 is a lower alkyl group, R^2 is a hydroxyl protecting group, Y is hydrogen or a halogen group, B is a substituted or unsubstituted indanyl group, substituted or unsubstituted benzodioxanyl group, substituted or unsubstituted benzodioxolanyl group, or 2,
Each represents a 3,5,6,7,8-hexahydrobenzodioxanyl group. The same shall apply hereinafter in this section. ) A general formula characterized by reducing the compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, Y, and B represent the same as above. ) A method for producing the compound shown in (4) General formulas: ▲ Numerical formulas, chemical formulas, tables, etc. represents an unsubstituted benzodioxanyl group, a substituted or unsubstituted benzodioxolanyl group, or a 2,3,5,6,7,8-hexahydrobenzodioxanyl group.The same applies hereinafter in this section) A method for producing a compound represented by the general formula: ▲Mathematical formula, chemical formula, table, etc. available▼, which is characterized by subjecting the represented compound to a deprotection reaction. (5) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R^1 is a lower alkyl group, R^2 is a hydroxyl protecting group, Y is a halogen group, and B is a substituted or unsubstituted indanyl group, substituted or unsubstituted benzodioxanyl group,
a substituted or unsubstituted benzodioxolanyl group, or 2,3,
Each represents a 5,6,7,8-hexahydrobenzodioxanyl group. The same shall apply hereinafter in this section. ) is treated with an alkali to perform a dehydrohalogenation reaction and a deprotection reaction of carboxyl groups and hydroxyl groups.The general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing a compound. (6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Z is -COOH, -CONH_2 or -
CH_2OH, A is -CH=CH- or -C≡C-
B is a substituted or unsubstituted indanyl group, a substituted or unsubstituted benzodioxanyl group, a substituted or unsubstituted benzodioxolanyl group, or 2,3,5,6,7,8-hexahydrobenzodioxa Each represents a nyl group. ) or a pharmaceutically acceptable alkali addition salt of the derivative as an active ingredient. (7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Z is -COOH, -CONH_2 or -
CH_2OH, A is -CH=CH- or -C≡C-
B is a substituted or unsubstituted indanyl group, a substituted or unsubstituted benzodioxanyl group, a substituted or unsubstituted benzodioxolanyl group, or 2,3,5,6,7,8-hexahydrobenzodioxa Each represents a nyl group. ) or a pharmaceutically acceptable alkali addition salt of the derivative as an active ingredient. (8) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Z is -COOH, -CONH_2 or -
CH_2OH, A is -CH=CH- or -C≡C-
B is a substituted or unsubstituted indanyl group, a substituted or unsubstituted benzodioxanyl group, a substituted or unsubstituted benzodioxolanyl group, or 2,3,5,6,7,8-hexahydrobenzodioxa Each represents a nyl group. ) or a pharmaceutically acceptable alkali addition salt of the derivative as an active ingredient.