JPS6219565A - 3-thiacarbacyclin and production and drug thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, 1-10C alkyl, (substituted) phenyl, etc.; R<2> and R<3> are H or tri (1-7C) hydrocarbonsilyl, etc.; R<4> is H, 1-10C alkyl, vinyl or ethynyl; R<5> is 3-10C alkyl, 3-10C alkenyl, 3-10C alkynyl which may contain O, etc.; R<8> is H when R<6> and R<7> are together single bond, and R<6> is H when R<7> and R<8> are together single bond; n is 0 or 1]. EXAMPLE:9(0)-Methano-DELTA<6(9alpha)>-3-thiaprostaglandin I1 (3-thiaisocarbacyclin). USE:An agent for cardiovacular organs, inhibitor for malignant tumor metastatis and cell protecting agent. PREPARATION:A 1,2,3-trinorcarbacyclin conjugated diene expressed by formula II [R<21> and R<31> are H or tri (1-7C) hydrocarbonsilyl, etc.] and a thioglycolic acid expressed by formula III (R<11> is H of 1-10C alkyl, etc.) are subjected to addition reaction, and, as necessary, deprotection and/or hydrolysis and/or salt forming reaction to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to novel 3-thiacarbacycleases, a method for producing the same, and a drug containing the same as an active ingredient. More specifically, thioglycolic acids are added to novel 3-thiacarbacyclines and 1+2+3-trinorcarbacycline conjugated dienes useful as pharmaceuticals, and then deprotected and/or hydrolyzed and/or salted as necessary. The present invention relates to a method for producing the 3-thiacarbacyclines through a production reaction, and a drug containing the same as an active ingredient.

<Prior art> Natural prostacyclin is a local hormone that is mainly excreted in the inner walls of arteries in living bodies, and its powerful physiological activities, such as platelet aggregation inhibitory activity and vasodilatory activity, regulate the cellular functions of living bodies. This is an important factor, and attempts are being made to directly provide it as a pharmaceutical product [P.J. Lewis, J.O. Grady (P.J., Levies J.O.).

Grady) et al.
of Prostaeyc-1in”),
Raven Press + New York (N,Y,), 198]). However, since natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, it is easily deactivated under neutral or acidic conditions, and is not a desirable compound as a pharmaceutical because of its chemical instability. For this reason, chemically stable synthetic prostacyclin derivatives that have physiological activity similar to that of natural prostacyclin have been intensively investigated at home and abroad.

Among these, derivatives in which the 6,9-position oxygen atoms of prostacyclin are substituted with methylene groups, ie, 910)-methanoprostaglandi/! .

(carbacycli/) [G.7-le-Pain (J
, R. Vans) et al., 'Prostacyclin' (
@Promtacyclin”), Ramin Press (Raven Press), New -!-
ri (N, Y,).

1979, PP3l-41] and 9O-methano-
6m(1α)-Booster Grandin! , (Incarbacyclin/) (Publication Patent Publication No. 59-210044, etc.) are known as prostacyclins with sufficient chemical stability and are expected to be used as pharmaceuticals.

Hitherto, various studies have been conducted on human nibrostaglandins in which one or two of the carbon atoms forming the skeleton of natural prostaglandins are replaced with sulfur atoms.

For example, the present inventors have developed 4-chinar prostaglandin/zine in which the methylene group at the 4-position of prostaglandin type 1 is replaced with an atom. , have been successfully synthesized and reported separately (Japanese Patent Application Laid-open No. 165383/1983).

In addition, 9(01-methano-prostaglandin 11(9)
(0)-Methanop p Stagra/Jinae.

The Δ3-double bond of [carbacyclyc/] is reduced]
9 (G-methano-3-thi7 prostadalandins), in which the methylene group at the 3-position of the compound with a heavy bond is replaced with an atom, has been reported (Japanese Patent Laid-Open No. 60-922
No. 55), but this product does not have the Δ6 or Δ(9α) double bond, which is considered to be important for the expression of prostacyclin activity.

In addition, 9(Of-methanopustaglandin/!, 9(Ol-methano-3-oxapuxtaglandin LM) in which the methylene group at the 3-position of [carbacycline] is substituted with an oxygen atom has also been reported (% Publication No. 59-157050, JP-A-57-145833, etc.).

<Disclosure of the Invention> The present inventors focused on the chemical structure of the above-mentioned carbacyclines, synthesized a new derivative in which methylene jIIJ at the 3-position was replaced with a sulfur atom, and found that such carbacyclines were chemically stable. The present invention has been achieved by discovering that 3-thiacarbacyclines have strong pharmacological activity.In other words, the present invention provides novel 3-thiacarbacyclines represented by the following formula (1). .

R' is a hydrogen atom, a C3-Cn furkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C, ~C
1, represents a dichlorofurkyl group, a substituted or unsubstituted phenyl(C, to C1)furkyl group, or 1 equivalent of a cation.

Examples of the C1-C5° furkyl group include methyl,
Ethyl, n-propyl also so-7”p-pyl, n-butyl+, 5ee-butyl, t@rt-butyl, n-
Linear or branched ones such as pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl can be mentioned.

Substituents for substituted or unsubstituted phenyl groups include, for example, hapgen atom, hytoxy group + C1 to C77 cip
C8-C which may be substituted with xy group or halogen atom
4 Furkyl group 9 C optionally substituted with halogen atom
Preferred are I to C4 alkoxy groups, nitrile groups, carboxyl groups, and (CI to Cm) alkoxycarbonyl groups. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine.

Examples of the C1-C,7 cipoxy group include acetoxy,
Purpionyloxy, n-butyryloxy, 1so
-butyryloxy, n-valeryloxy, 1ao-
Examples include valeryloxy, caproyloxy, enantiolyloxy, and benzoyloxy.

Preferred examples of the C1-C4 alkyl group which may be substituted with halogen include methyl, ethyl, n-propyl, 1so-furobyl, n-7'thyl, lipomethyl, dicoulomethyl, trifluoromethyl, and the like. I can do it. C1 optionally substituted with halogen
-C4 flukoxy group is, for example, methoxy.

Ethoxy, n-propoxy, 1so-propoxy,
Preferred examples include n-butoxy, chloromethoxy, dicoulomethoxy, trifluoromethoxy, and the like. Examples of the (C1-C,)alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

Examples include butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have ~3, preferably 1 substituent as described above.

Substituted or unsubstituted C3-C1@cycloalkyl groups include saturated or unsaturated C9-C8, preferably C6-C6 groups substituted with the same substituents as mentioned above or unsubstituted, e.g. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohemethyl, cyclooctyl, cyclodecyl and the like.

Examples of the substituted or unsubstituted phenyl (C, to C1) alkyl group include benzyl, α-7enethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituent as mentioned above or unsubstituted.

One equivalent cation is, for example, Nagi.

Tetramethylammonium, monomethylammonium,
Dimethyl 7 ammonium, trimethyl ammonium, benzene/
Ammonium ion such as silurium/monium, phenethyl ammonium, morpholinium cation, monoethanol ammonium, piperidinium cation *Na
! Alkali metal cations such as K; 1/z Ca
", 1/2 Mg", 1/2 Zn"+, 1
Divalent or trivalent metal cations such as /3Al''+ can be mentioned.

R1 is preferably a hydrogen atom, a C1-C1° alkyl group, or a cation of 1 equivalent. Particularly preferred are a water wing atom, a methyl group, and a 1,000-ton force.

R8 and R1 are the same or different, hydrogen atom, )+
Examples of the 3(C,-Cy) hydrocarbon silyl group or the @tri(C,-ct) hydrocarbon silyl group which is a group that forms a 7-cetal bond or an ester bond with the oxygen atom of a hydroxyl group include trimethylsilyl, Triethylsilyl.

(such as t-butyldimethylsilyl group)! J(Ct~C6
) alkylsilyl, di(C, ~C,)furkylphenylsilyl such as dimethylphenylsilyl group, t-7'
Tyldiphenylsilyl group such as xyphenyl (C1-C1
) Preferable alkylsilyl groups include triphenylsilyl and tripendylsilyl groups. Particularly preferred is t-butyldimethylsilyl group.

An example of a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-bouvil, 2
-ethoxy-2-propyl, (2-methoxyethoxy)
Mention may be made of the methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-dimethyl-(3,1,0)-hex-4-yl group. .

Among these, 2-tetrahydrofuranyl group is particularly preferred.

Examples of groups that form an ester bond with the oxygen atom of a hydroxyl group include (C, ~ C,) alkanoyl groups such as formyl group, acetyl group, propionyl group, butanoyl group, and pentanoyl group; Substituted or unsubstituted benzoyl groups can be mentioned. 7 Cetyl group and benzoyl group are particularly preferred.

Among these, a hydrogen atom is particularly preferred as 11 or R''.

In the above formula (1), R4 represents a hydrogen atom, a C1-C3°furkyl group, a vinyl group or an ethynyl group. C
Examples of the 1 to C8 alkyl group include the same groups as mentioned for R1. A methyl group is particularly preferred. Among these, particularly preferred as R6 are a hydrogen atom and a methyl group.

In the above formula (Il, R6 may contain an oxygen atom) vllllg or branched C1-C1o fulkyl group; straight-chain or branched C1-C8゜fulkenyl group; straight-chain or branched C3-C11l alkynyl group ; an optionally substituted C3-C111 cycloalyl group; an optionally substituted phenyl group; an optionally substituted phenoxy group; or an optionally substituted phenyl group;
It represents a straight chain or branched chain C1-C, alkyl group substituted with an optionally substituted phenoxy group or an optionally substituted C1-C8 dichlorofurkyl group.

Straight chain or branched chain C8 which may contain exa child
Cn Furkyl group, such as 2-methoxyethyl, 2-
Ethoxyethyl, propyl.

Butyl, pentyl, hexyl, heptyl, octyl, decyl, 1-methylpentyl, 1-methylhexyl, 1.
I-dimethylpentyl.

2-methylpentyl, 2-methylhexyl.

Examples include 5-methylhexyl, 2,5-dimethylhexyl, etc., preferably butyl, pentyl, hexyl,
- or (S)- or (R8) -1-methylpentyl, (8)- or +81- or (R8)
-2-methylhexyl group is mentioned.

C1-C,・Alkenyl groups include 2-butenyl group, 2
-pentenyl group, 3-pentenyl group.

2-hexenyl group, 4-hexenyl group 12-methyl-4
-hexenyl group, 2,6-dimethyl-5-heptenyl group, etc.

Cs-'-C,・alkynyl group is 2-butynyl,
2-pentynyl, 3-pentynyl, 2-hexynyl, 4
-hexynyl, 2-octynyl, 5-decynyl, 1-methyl-3-pentynyl, l-methyl-3-hexynyl,
Examples include 2-methyl-4-hexynyl group.

Examples of the optionally substituted C8-C3 dichlorofurkyl group include a cyclopropyl group, a cyclobutyl group, a dicupentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

(C1-C@) alkylcyclopentyl group, (C.

-C4) Furkylcyclohexyl group, dimethylcyclopentyl group, dimethylcyclohexyl group, chlorocyclopentyl group, bromocyclohexyl group 9M-docyclopentyl group, fluorocyclohexyl group, etc.
Preferred are cyclopentyl group and cyclohexyl group.

Substituents for the optionally substituted phenyl group and the optionally substituted phenoxy group include kt 91, a halogen atom, a hydroxy group, a C, ~C sifsiloxy group, and a C, ~ that may be substituted with a halogen atom. C, alkyl group,
A Cs-C4 phenoxy group optionally substituted with a halogen atom.

A nitrile group, a carbothousyl group, a (CI-%-C,)alkoxycarbonyl group, etc. are preferred. As the octagen atom, fluorine, chlorine, bromine, etc., and W is preferably fluorine or chlorine. Examples of the C1-C acyloxy group include 77toxy, propionyloxy, n-butyryloxy, n-butyryloxy, and nivaleryloxy.

1so-valeryloxy, caproyloxy.

Mention may be made of enantyloxy or penzoyloxy. C8-C, which may be substituted with halogen,
As the furkyl group, methyl, ethyl, n-propyl,
1so-propyl.

n-butyl, p-dimethyl, p-methyl.

Preferred examples include trifluoromethyl. C1-c4 is replaced with halogen/ and looks bad
Examples of alkoxy groups include methoxy, ethoxy, n
-Propoxy.

l-oxy, n-butoxy, chloromethoxy,
Preferred examples include dichloromethoxy, trifluoromethoxy, and the like. Examples of the (Ct-Cm) alkoxycarbonyl group include methoxycarbonyl, methoxycarbonyl, phthoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group or substituted phenoxy group can have ~3 substituents, preferably 1, as described above. An optionally substituted phenyl group, an optionally substituted phenoxy group, an optionally substituted C1 to C11
1 Linear or branched chain substituted with a dichlorofurkyl group 1ilc, -C, Among the furkyl groups, the optionally substituted phenyl group and the optionally substituted phenoxy group are preferably the same as those listed above. be able to. As the C8-C3゜cycloalkyl group, a primary one can be suitably used as it is, and as for the t substituent, the same substituents as the above-mentioned substituted phenyl group and substituted phenoxy group can be mentioned. Straight chain or branched chains C1 to C,
Alkyl groups include methylpentyl, propyl, 1
so-propyl, butyl.

15o-butyl, 5ee-butyl, t-butyl.

Examples include pentyl group, and the substituent may be bonded to any position thereof.

Among these, R' is butyl and bebutyl.

1-methylpentyl, 2-methylhexyl.

Cyclopentyl, cyclohexyl, 2,6-dimethyl-5-hebutenyl, l-methyl-3-pebutenyl, and 1-methyl-3-hexynyl are preferred.

In the compound represented by the above formula CI), RA,
R? are jointly a single bond, then R6 represents a hydrogen atom, or R1 and RA are jointly a single bond, then R. represents a hydrogen atom. In other words, R・R?
A compound in which RA represents a hydrogen atom together with a single bond is a 3-thiacarbacycline represented by the following formula (1-1). At this time, the 3D configuration of the 2nd type tightening in the 5th place is (g) - configuration, (2)
-represents configurations and mixtures thereof in arbitrary proportions. Preferably, it is a 3-thiacarbacycline represented by the following formula Cl-1' (having an eye configuration).

A compound in which R1 and ah jointly represent a single bond and R. represents a hydrogen atom is a 3-thiaisocarbacycline represented by the following formula (I-2).

In the compound represented by the above formula (I), n represents O or 1. In the case of n = O, the natural chamber arrangement at position 15 is expressed by the following formula [l-3] and the following formula (1-
4) Represents either one of the non-natural configurations at position 15 represented by or a mixture thereof in any proportion. Among these, the natural extended configuration at position 15 represented by the above formula (I-3) is preferred. Also in the case of n=1, the (8)-configuration at the 16th position, (S
)-configurations and mixtures thereof in any proportion.

The configuration of the 8-, 9-, 11-, and 12-positions of the 3-17 carbacycles represented by the above formula (I) is a particularly useful stereoisomer because it is a natural prostacyclin type. The present invention also includes stereoisomers having different steric configurations at each position, or mixtures thereof in arbitrary proportions.

Preferred specific examples of the novel 3-thiacarbacyclines represented by the above formula (1) provided by the present invention include the compounds shown below.

(1) 9(01-methano-Δ6(9α)-3-thiaprostagra/Zin I, (3-thiaisocarbacyclyc/) (2) 20-methyl-9(0)-methano-Δ・( 9α
)-3-Chiaprostagra/Jin! .

(3) 16-methyl-9 (Ol-methano-Δ・0α)
-3-Thiaprostagra/Zin I.

(4) (3) (16R) integral (5) C3) (368) integral (6) 16.16-cymethyl-9(o)-methano-Δ@
(Ia) 3-thiaprostaglandin I (7) 1
7) + Roux 9 (011l / -△""'-3-
Chi7 Prosta Grunge/■.

(8) ■-20-dimethyl-9(ol-meta/-△@(
9a)-3-Thiaprostagra/Zin I.

(9) (8) (17R) integral (10) (8) (178) integral (11) 15-methyl-9+01-methano-Δs(I
a)-3-Thiaprostagra/Zin! (12) 17.18-dehydro-9(01-methano-Δ
Mountain a) 3-Thiaprostagra/Jinae.

(13) 20-impropylidene-17-methy.

-9(0nometano-Δ・(9α)-3-thiaprostaglandin I (14) 18s18y19*19-tetradehydro-
16-Methyl-9(a)-methano-Δ・(9α)-3-
Chi7 prostagrangey I.

(15) 18.18,19. j9-? toladehyde l
'-16,20-dimethyl-9(0)-methano-Δ・
(9α)-3-thiaprostaglandin■.

(16) (14) , (t6s) of Ω5) (17
) (14), (15), 16 (to) one (18)
) 16917, 18.19.20-Pentanoru 15
-cyclopentyl-9(01-methano-△・(@α)-
3-Thiaprostaglandin! .

(19) t6s17. ts*t9+zo-pentanol-15-cyclohexyl-9+01-methanol-△6(9
α)-3-Thiaprostaglandin ■1 (20) 17.18,19.20-tetratrue16
-(P-fluorophenoxy)98-methano-Δ'(9
″)-3-Thiaprostagra/Zin I.

(21) 17118, 19.20-Tetra True 16
-cyclohexyl-9(Ol-methanol-△・(9α)-
3-Chi7 Brawl Stars Grunge/! 1 (22) 15-deoxy-16-hydroxy-9+O
f-methanol△6(9α)-3-thiaprostagra/gin! .

(23) ] ]5-deoxy-16-hydroxy16
-Methi” 9 iol 1 p 7 6a (sg)
-3-Thiaprostaglandin■.

(24) (22) , (23>, (26) of (168) integrated (25) (22) , (23)
, (16R) of (26) 15-deoxy-16-hydroxy-16-vinyl-9(ol-methano-6(9α)-3-thiaprostaglandin ■ (27) 9 (01- Methano-3-thiaprostaglandin I, (3-thiacarbacycline) (28) 2
0-Inpropyl-9(o)-methano-3-thi7 prostaglandi y I.

(29) 16-Methyl-9(o)-methano-3-thiaprostagra/jinae.

(30) (29) (16S) Integration (31) (29) (16R) Integration (32) 16116-Dimef-Rou 9 (01-/(Evening)/-3-Thiaprostaglandin I.

(33) 17-methyl-9(o)-methano-3-17
Pujista Grange 7I.

(34) 17*20-sil 4-tk-9(Q
-/l'/3-17 booster grunge y i.

(35) (34) (17R) integral (36) (34) (178) integral (37) 15-Methyl-91ot-methano-3-thiaprostaglanshiff I.

(3B) 17.18-dehydro-9(0-methano-3-
Chi 7 proscugra/ji y l.

(39) 20-impropylidene-17-methyl-9
(Q-methano-3-thiaprostaglandin I.

(40) (39) (17R) integral (41) (39) (178) integral (42) 18.1B, 19.19-tetradehydro-
16-Methyl-9(01-methano-3-thiaprostaglandine, (43) 18.18,19.19-tetradehydro-
16120-dimethyl-9(01-meta/-3-thiafrostagrangeyl.

(44) (42) s (16g) of (43) (
45) (42) 1 (43) (16R) integral (4
6) 16.17t1B11912G-Pentanoru 1
5-cyclopentyl-9(0-methano-3-thiaboostaglandinl! (47) 16*1f,18,19.20-pentanol)5-cyclohexyl-9(01-methano-3-
Thia-prostaglandin I.

(48) 17d8vlSL20-Tetra True 16-
72 Noxy〇 (0-methano-3-thiaprostaglanshif!.

(49) 15-deoxy-16-hydropoxy-9 (Q
-Methano-3-thiaprostaglanshif I.

(50) 15-deoxy-16-hydroxy-16-
Methyl-9 (0-methano-3-thiaprostagra/Schiff 1 (51) 15-deoxy-16-hydroxy-16-
Vinyl-9(ol-methano-3-thiaprostaglanshiff I.

(52) (49)? (5G) I (51) (
168) Integral (53) (49) + (50) w
(51) of (16R) integral (54) (1) to (53)
Methyl ester of (55) Ethyl ester of (1) to (53) (56) Glyster of (1) to (53) (57) Sodium salt of (1) to (53) (58)
Potassium salts (59) of (1) to (53) (1) to (5)
8) t++15- or 11.16-bis-(1-butyldimethylsilyl)ether (60) 1l-(t-butyldimethylsilyl-16-) of the compound having a hydroxyl group at the 16th position of (1) to (5B) ) Limethylsilyl ether (61) 11115-bistetrahydropyranyl ether (62) of (1) to (58) 11.15-diacetate (63) of (1) to (56) (1) to (56) ) of 11115-zipe/shade (64) Enantiomers of the compounds of (1) to (63) (
65) Positions 8, 9, and 11 of compounds (1) to (63)
Examples include stereoisomers at position 1 and 15, but are not limited thereto.

The tr-3-thiacarbacyclines of the present invention represented by the above formula (I) are the 1,2-thiacarbacyclines represented by the following formula (II).
．． 3-) Linorcarbacycline conjugated dienes have the following formula (lit) H8-C)f, -C0OR”...
It is produced by subjecting a thioglycolic acid represented by (In) to an addition reaction and, if necessary, subjecting it to deprotection and/or hydrolysis reaction and/or salt formation reaction.

The formula (II) is one of the raw materials in the production method of the present invention.
1,213-) IJ /lucarbacycline conjugated dienes represented by ) are easily produced by methylenating the aldehyde of enals represented by the following formula [lv]. Methylenation is carried out by Wittig using methylidene triphenylphosphor/.
) Reaction (New Experimental Chemistry Course, Vol. 14, No. 1, pp. 224-2)
43 p. 1 Edited by the Chemical Society of Japan, see Maruzen ■) Reaction with a reagent obtained from titanium tetrachloride-zine-momethane-zinc [El Pombardo (L.

Lombardo) #Tetrahedron Letters (
Tetrahedron Lettara),
Volume 23, page 4293, 1982; Takai K.
, Takai) et al.

Tetrahedron Letters
etters) + 3978, p. 2417]. The above formula ([
The enals represented by V] can be obtained by a method known per se [T. Mane et al.

Tetrahedron Letters
etters) + vol. 25, 5 (p. 187, 19
1984], allylcyclopentano group 7 represented by the following formula (V) can be produced through several steps. Moreover, the 7lylcyclopene 1// group represented by the above formula (V) can be easily produced by a method separately proposed by the present inventors (see Japanese Patent Application Publication No. 1987-44336).

The amount of thioglycolic acid used in the addition reaction of the thioglycolic acid represented by the above formula (III) to the dinorcarbacycline conjugated diene (1,L3-) represented by the above formula [■] is 112% 3- The amount is 0.5 to 30 equivalents, preferably 1 to 15 equivalents, based on the trinorcarbacycline conjugated diene. The reaction temperature at this time was -30'C
to 200°C, preferably 30°C to 100°C, and the reaction time is 10 minutes to 30 hours, preferably 30 minutes to 3 hours.

In order for the reaction to proceed smoothly, α! Particular preference is given to using radical initiators such as α'-azobisisobutyronitrile. How much is used?

l, 0.001 to 1 equivalent relative to the 2,3-trinorcarbacycline conjugated diene, preferably 0, +11 to 0
．． It's 10 points. The reaction may be carried out in a solvent,
It may be carried out without a solvent.

The reaction solvents used are ether solvents such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and chloroform.

Halogenated solvents such as carbon tetrachloride and dichloromethane;
Among them, carbon tetrachloride and benzene are particularly preferred. In this reaction, 3-typhinecarbacyclines represented by the following formula (1-2') and 3-thiacarbacyclines represented by the following formula (I-1') and the following formula (Vl-: 2-True 4-methyl-3-thiaisocarbacyclines represented by the formula (1-2'
) is obtained as the main product. After the reaction, these mixtures can be isolated by a common separation method such as silica gel column chromatography, silica gel thin layer chromatography, or high performance liquid coumadography after a conventional extraction operation.

The product thus obtained can be further subjected to a deprotection reaction and/or a hydrolysis reaction and/or a salt formation reaction as required.

In the case where the protecting group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, removal of the protecting group (deprotection reaction) of the water r11 group can be carried out using, for example, acetic acid, p-)luenesulfone al
Pyridinium p-toluenesulfonate, cation exchange resin, etc. as a catalyst, for example, water, methanol, ethanol, or tetrahydrofura in which water, methanol, ethanol, etc. coexist, ethyl ether, dioxane, 7
This reaction is suitably carried out using setone, 77 tonitrile, etc. as a reaction solvent. Reaction temperature is usually -78℃~+50℃
The process is carried out at a temperature range of 10 minutes to 3 days. When the protecting group is a +7 (C, ~cy) hydrocarbon group, for example, acetic acid, p-toluenesulfone, pyridinium p-)
The reaction is carried out in a reaction solvent in which an acid such as luenesulfonate is mixed with the catalyst at a similar temperature, or a fluorine-based compound such as tetrabutylammonium fluoride, cesium fluoride, 7-hydrofluoric acid, fluorinated water-pyridine, etc. Using reagents, tetrahydrofuran, ethyl ether, dioxa/
, 7-cetone, 7-cetonitrile, etc., as a reaction solvent, at the same temperature and for a similar period of time as above. When the protecting group is a group that forms an ester bond with the oxygen atom of the hydroxyl group, for example, hydroxyl, potassium hydroxide, an aqueous solution or water-alcohol mixed solution of calcium hydroxide, or sodium methoxide, potassium methoxide. methanol containing sodium ethoxide, ethanol fI! This can be carried out by hydrolysis in liquid i.

The hydrolysis reaction of the ester group at the 1-position can be carried out using a conventional method, such as an aqueous solution or water-alcohol mixed solution of caustic soda, caustic potash, or lucium hydroxide, or an alcohol-water mixture containing sodium methoxide, potassium methoxide, or sodium ethoxide. It can be carried out by hydrolysis in a liquid. Alternatively, for example, using an enzyme such as lipase, it can be prepared in water or a solvent containing water from 0℃ to 0.0℃.
It is carried out at a temperature range of 10 minutes to 24 hours. Post-treatment after the hydrolysis reaction and n11 are diluted hydrochloric acid.

After neutralization with an acid such as oxalic acid, it is carried out in a conventional manner.

The compound having a carboxyl group produced by the above-mentioned hydrolysis reaction is then further subjected to a salt-forming reaction, if necessary, to give the corresponding carbo/acid salt. The salt-forming reaction is known per se, and involves mixing carboxylic acid with a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc., or ammonia, trimethylamine, monoethanolamine, morpholine, etc. in a conventional manner. This is done by causing a sum reaction. In addition, the ester salt can also be obtained directly by hydrolyzing the above-mentioned ester.

The above formula (1-2') is produced by adding thioglycolic acids represented by the above formula [1u] to the linolcarbacycline conjugated die/group expressed by the above formula [1]. 3-thiacarbacyclines represented by the above formula ([-1') and 2-thiacarbacyclines represented by the above formula (Vl-1)
- The mixture of true 4-methyl-3-typhine carbacyclines can be prepared by deprotection and/or hydrolysis without separation at this stage, followed by conventional silica gel column chromatography, silica gel thin layer p-mado, etc. It may be isolated by using general separation means such as chromatography or high performance liquid chromatography.

The thus obtained 3-thiacarbacyclines prepared by the above formula CI), especially the 3-thiacarbacyclines in which R1゜R1 is a hydrogen atom, have antiplatelet aggregation activity,
It has pstaglandin-like activity such as vasodilation and is useful as a cardiovascular agent in mammals including humans. That is, they are useful, for example, as platelet aggregation inhibitors, in the treatment or prevention of thrombus formation.

Furthermore, since it has a blood pressure lowering effect, it is also useful as a therapeutic agent for hypertension. These compounds have effects on patients, such as antianginal, hemogastric dilatation, and hypotension.

Antithrombotic, antiarteriosclerosis, antimyocardial infarction, antiendotoxic shock, antipulmonary arterial hypertension, antistroke, anti) Lanche/
Toy Schemic Attack (transient Is
chemical attack), anti-platelet aggregation, anti-cancer, anti-deep vein thrombosis or anti-peripheral blood '11Fl
It can be administered for sclerotic diseases. The active compounds of the invention can also be administered to suppress malignant tumors or metastasis of malignant tumors. The compounds of the invention can also be used as antithrombotic agents during organ transplantation, vascular surgery or extracorporeal circulation. Furthermore, these compounds have cytoprotective effects, preventing liver damage, kidney damage, brain damage, and gastric ulcers.

It is also effective in treating or preventing duodenal ulcer.

These compounds can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, etc., for the above-mentioned purposes, but are preferably administered orally or intravenously. It is best to administer it internally.

For oral administration, solid or liquid preparations can be provided. Examples of solid preparations include tablets, pills,
Available in powder or granule form. In such solid formulations, one or more active substances are present in at least one pharmaceutically acceptable carrier, such as the commonly used sodium bicarbonate, calcium carbonate.

Potato starch, cane sugar, mannitol.

Mixed with carboxymethyl cellulose, etc. The preparation is carried out according to a conventional method, but the preparation may contain additives other than those mentioned above, such as an F8 detergent such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include, for example, emulsions, SG agents,
Including suspensions, syrups or xyls. These formulations can include commonly used pharmaceutically acceptable carriers, such as water or liquid paraffin.

Coconut Oil 1 Fraction Oily bases such as coconut oil, soybean oil, and corn oil can also be used as carriers.

For oral administration, M-soluble preparations may be used, and for enteric-coated preparations, solid preparations such as those described above may be added with cellulose acetate phthalate, hydroxyfurovir methyl cellulose phthalate, styrene maleic anhydride copolymer, or It is manufactured by applying an enteric coating by spraying an organic solvent or an aqueous solution of an enteric substance such as methacrylic acid or methyl methacrylate copolymer. M-soluble solid preparations such as powders and granules can also be wrapped in capsules.

The pharmaceutically acceptable carrier in the present invention includes other adjuvants that are normally used.

Contains fragrances, stabilizers, or preservatives.

Liquid preparations may also be administered in capsules made of an absorbable material such as gelatin.

The 3-thiacarbacyclines of the present invention can also be administered intranasally, in which case nasal drops are usually used. As a nasal solution, a solution prepared by dissolving or emulsifying a base of hydroxypropylcellulose or lactosenate and a 3-thiacarbacycle in saline or an isotonic glucose solution is preferably used.

Solid preparations for rectal administration include herbal medicines containing one or more active substances and prepared by methods known per se.

Preparations for transdermal administration include common ointments, films, and the like.

Preparations for parenteral administration (subcutaneous, intravenous, intramuscular) are sterile aqueous or non-aqueous solutions, l! ! Provided as a clouding or emulsifying agent. Non-aqueous solutions or suspensions include, for example, propyl glycol, polyethylene glycol or Oli-7'M! Pharmaceutically acceptable carriers include 5 vegetable oils, injectable organic esters such as ethyl oleate. Such formulations may also contain preservatives, wetting agents, and emulsifying agents.
Auxiliary agents such as dispersants and stabilizers may be included. These solutions, S clouding agents, and emulsifying agents can be sterilized at °C by, for example, passing them through a bacteria-retaining filter, adding a bactericidal agent, or irradiating them as appropriate. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use.

The compound of the present invention is α, β or r-cyclodextrin) I
It can be used by forming an inclusion compound with IJ or methylated Ikp-dex.

The dosage of the compound of the present invention is determined according to the condition of the subject to be administered.
It varies depending on age, gender, constitution, route of administration, etc., but usually 1
The daily weight per day is 0, O1d'~]00#, and 1
μ#~109 is preferred. Such a dose may be administered once or several times a day, for example, in divided doses of 2 to 6 times.

The present invention will be explained in more detail below using examples.

Example 1 Methyltriphenylphosphonium bromide 90011
f (2.5 rnmol) and Calicum t-gutoxide 338 Tag (3.06 mmol) were added to a ft flask, and the mixture was purged with nitrogen, cooled on ice, and dried tetrahydrofuran.
□N16517 was added. aIW colored yellow
After stirring Solution J at room temperature for 40 minutes, 1.2.3.4.5-penta/ru-5-formyl-9(0)-methanol-(9
α)-Prostagra/Zin I, 11.15-bis-t-
Butyldimethylsilyl ether [Compound (1)) 960
ay (1,9 mmol) of tetrahydrofuran (8-
) solution and stirred at room temperature for 40 minutes. n-hexane (40 m/) and saturated 7-hexane chloride solution (25 N/
) was added thereto, and after suction filtration through Celite, the mixture was shaken in a liquid separation tray. After re-extracting the aqueous layer with n-hexane, the combined organic layers were extracted with dilute hydrochloric acid and saturated sodium bicarbonate solution.

After sequentially washing with saturated brine, it was dried over magnesium sulfate and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography to obtain 2% ethyl acetate-n-
1.2.3 of 886cm (yield 92%) in the bath outlet part
-) Rinorou 9 (01/ p 7 64. *+*a
)-P9 Star 157')71°11.15-Bis-t-
Butyldimethylsilyl ether [compound (ii)] was obtained.

NMR (a CDC, 4): 0.7-1.0 (21H), 2.7-3.3 (I
H,br).

3.72 (IH, q, J=8b).

3.8-4.1 (I H,br L 4,7-5.2
(2H, m).

5.3-5.6 (3H, m).

6.50 (I H, dd; J=18H2,10H
z) neat -r IR (λ, c+a): ax 1260.1110,970,900,835°Mas
s (FJ■, m/e): 504 (M), 44
7 Example 2 Profitability (%A 1.2.3-) Rinoru 9 (01-Methanol-△4・
-(9α)-Prostaglandin I, 11115-bis-t-butyldimethylsilyl ether (compound (II)
) 240q (0.48 mmol) was dissolved in 2.5 d of carbon tetrachloride.

Methyl thioglycolate 420 pi (4,8 mmo
l) then α,α′-azobisisobutyronitrile 4
- was added, and the mixture was heated and stirred at 70 to 80°C for 1 hour.

Water (15117) was added, and after extraction with ether (2×15d), the combined seed layers were washed with water, dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was carefully separated by silica gel column chromatography, and the fraction eluted with 2% ethyl acetate-n-hexane contained 9(ol-methano-3-thiaprostaglandin I, methyl ester 11.15-bis-t- Butyldimethylsilyl ether (compound (fi)
t)) 25319 (yield 8.5%) was obtained.

NMR< a CDCIm): MS O,? -1,0 (21H), 3.19 (2H,a
).

3.25 (2H, m), 3.5-3.8 (IH,
m).

3.70 (3H, s'), 3.8 4.2 (IH, m
).

5.26 (IH, t, J=7Hz), 5.42 (2
H, m) 5at IR (λ I cN'″l): ax 1740.1252, 1118.1002, 967°8
34.772 Mass (El, m/e): 610 (M)
, 553,447,373 Then, in the elution part of the same elution solvent system, 2-true 5-methyl-9 (Ol-methano-Δa<*a>-4-thiaprostagra/Zin I, methyl ester 11. 50 μm (yield: $17%) of 15-bis-t-butyldimethylsilyl ether (compound) was obtained.

NMR (δCDCA!, ); M.S. O,75-1,0 (21H).

1.34 (3H, d: J-'IHz).

3.1-3.4 (3H, m), 3.5-3.8
(IH,br).

3.70 (3H+s)+ 3.8 4.2
(IH9br).

5.2-5.6 (3H, m) n@at -r IR (λ IcII): ax 1740.1255, 1115, 1002, 968°8
35.772 Mass (EI, m/a): 610 (M)
, 595,553,447,373 Then, 9(0)-methano-Δa(@a) was added to the bathing part of the same elution solvent system.
3-Thiaprostagra/Zin I, methyl ester 1
1,15-bis-t-butyldimethylsilyl ether (
Compound m(φ) 135~ (yield 46%) was obtained.

NMR (δCDC6*): TMS 0.7-1.0 (21H), 2.5-3.2 (
3H, m).

3.23 (2H,s), 3.5-3.8 (I
H, m).

3.72 (3H+ a), 3.8 4.2 (I
Hlm ) *5.30 (IH, be ), 5.45 (
2H, m) IR (λn@1.cIL-1): ax 1740.1255, 1118.1002, 966°8
35, 773 Mass (EI, m/e): 610 (M
), 595,553,478,447°407, 37
3 Example 3 (V) IV) 9(01
-Methano-Δs(Ia)-3-thiaprostaglandin I, methyl ester 11.15-bis-t-butyldimethylsilyl ether (compound (Vl) 82W9 (0,
134 mmol) to 1M tetrabutyl 7/monium fluoride dotetrahydride qfuran solution 0.9 wLl
was added and stirred at room temperature overnight. Add 1014 ml of saturated aqueous ampentium chloride solution and add ethyl acetate (2X 10 id
), the organic layer was washed with saturated brine and dried over magnesium sulfate.

After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography to yield n-hex/ethyl acetate (
1:3) 36 Da (yield 70%) of 9(0)-
Methanol-Δ・(9α)-3-thiaprostagra/gin■
, methyl ester [compound (■)] was obtained.

NMR (a CDCl5): TMS 0.90 (3H, t, J=5flz).

2.5-3.2 (3H, m), 3.20 (2H,
s).

3.4 3.8 (IH,m), 3.70 (3H-
s).

3-8 4-2 (I H1m) + 5.30 (
IHIbs).

5-45 (2H+m) IR (λ, IR): ax 3380.1740, 1438.1280°1132.
1085.1005.968Mass (El,
rn/e): 382 (M”), 364, 346, 2
58 Example 4, (y6 (v
ii) 9 (Of-MechnoΔ'(1α)-3-thiaprostagra/gin!, methyl ester (compound ~I)
30w9 (0,079mmol) with methanol 0.5
d and 0.08 d of 2N sodium hydroxide solution (
0.16 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours.

After adding 10 d of water and making it acidic with dilute hydrochloric acid, ethyl acetate (2X
121j), and the organic f- was washed twice with saturated brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography to yield n-hexane-ethyl acetate (3 nia; vinegar a O, 2
9 (01
-Methano-Δa(Ia) 3-thiaprostaglandin 1. [Compound (Vi+)] was obtained.

NMR (a CD”!): TMS 0.9 (3H, t, J=5m).

2.78 (2H, t, J=7b).

2.7-3.2 (IL br )e 3,20 (I
H,Il,).

3.4-3.8 (I H,m)e 3.8 4.2 (I Hlm) *5.2 5.6
(6Hlm; 3H disappeared with DtO) n@at IR (λ HC11l-'): ax 3370.2800~2300.1715°1082.
970 Mass (EI, m/e): 350 (M-H
, O), 332 Example 5 9 (G-methano-3-thiaprostaglandin!, Methyl ester 11.15-t-butyldimethylsilyl ether [Compound (+10) 100 #(0,163
rnmol) was added with 0.9 d of IM-tetrabutylammonium fluoride-tetrahydrofuran m solution, and the mixture was stirred at room temperature overnight. Saturated heptammonium chloride aqueous fil
After adding 01lj and extracting with ethyl acetate (2X10m),
The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained 1A residue was purified by silica gel column chromatography, and 49 das (yield 78%) was found in the n-hexane-ethyl acetate (1:3) eluate.
No9 (Q) 5' / 3 f 7 Cl
Staglandin ■, methyl ester [compound (V11+
)) I got it.

NMR (a CDC15): M.S. 0.88 (3H, t, J=5Hz).

3.20 (2, s), 3,26 (2) 1. m).

3.4-3.8 (IH, m), 3.69 (3H, s).

3.8-4.2 (IH, m).

5.26 (1) 1. t, J=7[z).

5.44 (2H, m) IR (λWas', cIIL-'): 3380
．． 1740, 1278.113B.

1008.965 Mass (El, rn/e): 364 (M-
H,0), 346.258 Example 6 9 (01-methano-3-thiaprostaglandin ■,
Methyl ester [compound (VliD) 45~(0,
Dissolve 12 mmol) in 5 m of methanol and 2N hydroxide) IJ solution 0.12117 (0,2
4 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. water 10
Add d and acidify with dilute hydrochloric acid, then add ethyl acetate (zxl
ziu), the organic layer was washed twice with saturated saline, &
Dry M was carried out with magnesium chloride. After evaporation of the solvent, the resulting residue was subjected to silica gel column chromatography to obtain n-hex/-ethyl acetate (3N; acetic acid 0.25%).
9 (0) of 39119 (yield 488%) in the elution part
-Methano-3-thiaprostagra/Zin II (compound (
1×) was obtained.

NMR<, CDC1a): MS 0.88 (3H,t, J=!lx)+3.19 (
2H,s), 3.25 (2H,m).

3.4 38 (IH9m), 3.8 4.2 (IH
1 mL 5.26 (I H, t, J = 7 Hz).

5.43 (2Hlm) + 5.6-5.9 (3H, br; disappeared with D, O) I
R(1"", ca-'): ax 3380.2800-2300. 1715°1080
, 968 Mass (EI, m/e): 350 (M
-Mountain 0), 332 Example 7 (i-]) (!1-1) Example 1
By the same method as (17S)-1t2t3t4t5
-Pe/Tafuru 5-Formyl-1F.

20-dimethyl-9(0)-methano-Δ6(9α)-prostaglandin I, 11115-bis-t-butyldimethylsilyl ether [Compound (1-1)) 2544
(0.48 mmol) as the starting material, (17 g
) -1t2,3-) Reno, Lou 17.20-
Dimethyl-9(Of-methano-Δ6·39α)-frostaglandin I, 11, 15-bis-t-7′-tyldimethylsilyl ether [Compound (II-1)) 2
To 301? (yield 90%).

NMR (a CD”) 2MS O,7-1,0 (24H), 2.7-3.3 (11
(,br L3.5-4.3 (2H,m), 4.
7-5.2 (2H, m).

5.3-5.7 (3H, m).

6.51 (IH, dd; J=18mm, 1011z
) eat IR (λ, α-1): ax 1110.967.835.775 Mass (EI, m/e): 532 (M)
, 475 Example 8 (i-2) (II-2) By the same method as in Example 1, (17R)-17,20-dimethyl-1,2,3,4,5-pentano,ru-5-formyl −
9 (01-methano-Δ6(9α)-prostagrafdi/
I, 11115-bis-t-butyldimethylsilyl ether (compound (+-2)) 322 jv (0,60m
mol) as a starting material, 11213-)linol-910i-methano-Δ49.(9α)-prostagrafdiyI, 11.15-bis-t-butyldimethylsilyl ether (compound (1l-2)) 281 da(yield) Rate 88
%) was obtained.

NMR (δCDCJs): MS O,71,0(24)=2.7 3.3 (tH,b
r).

3.5-4.3 (2H, m), 4.7-5.2
(2H,m)+5.3-5.7 (3H,m).

6.50 (IH, dd; J=th (11z, 10h)e
at IR (λ 1 cm-'): ax 1258.1110,965,837,775 Maam
(KI, m/e): 532 (M), 47
5 Example 9 (+-3) (II-3) By the same method as in Example 1, 16-methy7 and 1+2.3+
4*5-pentanol-5-formyl-9fol-methano-6m(11α)-purustabrangin I.

11.15-bis-1-//butyldimethylsilyl ether compound (1-3)) 480 Da (0,,92 mmol
) as a starting material, 1,2,3-1-linol-9
(0-Methano-Δ4-(9α)-Prustabrangin I.

11.15-bis-t-butyldimethylsilyl ether [compound (+1-3)] 462 µ (yield 91%) was obtained.

NMR (δCDCl5): MS O,? -1,0 (24H), 2.7-3.3 (IH
,br,).

3.5-4.3 (2H, m), 4.7-5.2
(2H, m).

5.3-5.6 (3H, m).

6.51 (IH, dd; J=18&, 10b)ea
tIR(λgcIL-'): mmX 1252, 968. 835. 772Mass (
EI, m/e): 518 (M), 461 Example 10 (l-4) (II-4) 1+2,3t4+LIL by the same method as in Example 1.

17*18*19,20-Big True 15-Cyclope/
Chil-5-formyl-9(O)-meta/-Δ6(9α)
-Boostaglandin I, 11, 15-bis-1-
Butyldimethylsilyl ether (compound (1-4))
Using 400~(0.79 mmol) as the starting material, 1
12, Li2, 17elL19.20-octanolu 1
5-cyclopentyl-9 (01-methano-△4I・0α
)-glostaglandin I, 51, 15-bis-1
-//Gutyldimethylsilyl ether compound (IJ-4
)) 353 Da (yield 89%) was obtained.

NMR (δCDC1*); MR O,7-1,0(18H)+2.7-3.3 (I
H,br).

3.5-4.0 (2H, m), 4.7-5.3
(2H, m).

5.3-5.7 (3H, m).

6.50 (I H-dds to 18h-I GHz
) neat IR (λ, Bei-1): ax 1258.1112,968.83! 'i, 775Ma
ss (EI, rn/s): 502 (M),
445 Example 11 (1-s) (if-5) l + 2 t 3 v 4 e 5 by the same method as in practical application 1
t16.17.18, 19.20-Big True 15-
Cyclohexyl-5-formyl-9(0)-methanol-△
-(9α)-Prostagra/Zin I, 11115-bis-t-butyldimethylsilyl ether (compound (1-5
)) Using 50 Qq (IJ, 97 mmol) as the starting material, 112.3116117118,19.20-
cyclohexyl-15-cyclohexyl-90-methanol-△
41(9α)-Prostaglandin I+11+15-bis-2-butyldimethylsilyl ether (compound (IJ
-5)) 426■ (yield 85%) was obtained.

NMR (a CD””): MS O,? -1,0(1B)1), 2.7-3.3(I
K, br).

3.5-4.0 (2H,rn), 4.7-5.
3 (2H, m)e5.3-5.7 (3H, m)
.

6.51 (1) f-dd; J=18 k-101
1z) neat - IR (λ, 1): mmX 1256.1112.967.835,775Mass
(E I * m/ @) “516 (M”), 45
9 Example 12 (1-6) (il-6) By the same method as Example 1') (16S) -112°3+4+
5-pentanol-15-deoxy-5-formyl-16
-Methylpustagrange/Engineering.

1l-t-Butyldimethylsilyl ether 15-trimethylsilyl ether (compound (1-6)) 520 Wq
Using il (1 mmol) as the starting material, (168)
-1,2t3-) dinor-15-deoxy-16-methyl-9(0-methano-to4,5(Icl)-prostaglan shift 1.1l-t-butyldimethylsilyl ether 15-triphthylsilyl ether 466 da (yield 90
%) was obtained.

NMR (δ1 effect 3): 0.7-1.0 (12H), 1.18 (3H, s
).

2.7-3.3 (IH,br), 3.5-4.0
(IH, mL4.7-5.2 (2H, m), 5.
3-5.8 (3H, m).

6.50 (I H, dd; , r=i 8flz,
10flz) Mass (EI + m/e
) :476(ML 461,419 Example 13 By the same method as Example 1, (16R)-112,3
,415-pentanol-15-deoxy-5-formyl-16-methylp-a staglandin I, 11-t-
Butyldimethylsilyl ether 15-) IJ Methylsilyl ether (Compound (1-7) 3520 IQ
Starting from (Immof), (16R) −
1,2,3-)dinol-15-deoxy-16-methyl-9(O)-methano-Δ number! -(9α)-Prostagra/Zin I, 11-t-butyldimethylsilyl ether 15-) IJ methylsilyl ether 440 da (yield: 485%) was obtained.

NMR (aCD""): TMS O,7-1,0(12H), 1.18(31-1,
s).

2.7-3.3 (IH, br).

3.5-4.0 (IH,m), 4.7-5.
2 (21, m).

5.3-5.8 (3H,m)t 6.50 (IH,dd; J=18&, 10
[1z) Mass (El, m/e): 4
76(M”), 461.419 Example 14 (fil-1) (iv-1) (V-1) In the same manner as in Example 2, (178) 11213-trinor-17,20-dimethyl-9( 0)-methane-△'
u(Iαゝ-boostaglandin I, 11.15-bis-t-butyldimethylsilyl ether (compound (if-
1)) The following compound was obtained using 23019 (0.43 mmol) as a starting material.

(178)-17,20-dimethyl-9(Ol-methano-3-thiaprostaglandin■, methyl ester 11
．． 15-bis-1-butyldimethylsilyl ether [Compound (+i+-1)) 27~(yield 10%) NMR (a CDCj?s>: TMSO, 71,0 (24H), 3418 (2H, mL
3.24 (2H, m L 3.5-4.2 (2H,
m).

3.70 (3H9SL 5.25 (IH, t; J=7k).

5.3-5.6 (2H, m) eat IR (λ, C1a-'): ax 1740, 1252. 1116. 10G3. 9
66°835, 774 Mass (El, m/e): 638 (M
), 581 (178)-2-True5+17e2o-)dimethyl-9to-methano-Δ・(9α)-4-thiaprostaglandin I, methyl ester 11,15-bis-t-butyldimethylsilyl ether (compound ( 1v-1))4
9 das (collected vehicle 18%) NMR (delta): 0.7-1.0 (24H).

1.34 (3) 1. d; J=7&).

3.1-3.4 (3M, m), 3.5-4.2
(2H, m).

3.71 (3H, I), 5.2-5.6 (3H
, m) n@at IR (λ t C11-'): m凰X Mass (EI, m/.): 638 (M), 5'81 (178)-17,20-dimethyl-9(0)- Methanol-Δs(1")-3-thi7p-staglandin I, methyl ester 1i15-bis-t-7' tyldimethylsilyl ether [compound (V-1)) 137 m9 (collected vehicle 50
%) NMR (δCDC1*): TMS 0.7-1.0 (24H), 2.5-3.2 (3
H,m)+3.22 (21,s), 3.5-4
．． 2 (2H, m).

3.72 (3H, s), 5.30 (IH, bs).

5.3-5.6 (2H, m) H@at IR (λ IcR″″I): ax 1740.1254, 1116, 1002°967.8
35,773 Masa (EI, m/a): 638 (M)
, 581 Example 15 (1t-2) (+1l-2) (IV
-2) (V-2) In the same manner as in Example 2, (17R) -1,2,3-trinor-17,20
-dimethyl-9(ol-methano-to4...(9α)-frostaglandin I, 11115-bis-1-butyldimethylsilyl ether (compound (il 2)) 2
Using 50 Mg (0.47 mmol) as a starting material, the following compound was obtained.

(17R)-17,20-dimethyl-9(01-methano-3-thiaprostagra/zinko, methyl ester 11
, 15-bis-t-butyldimethylsilyl ether [Compound (m-2)) 29 # (Yield 10%) NMK (Yield 10%): 0.7-1.0 (24H), 3.18 ( 2H,s
).

3.23 (2H, m), 3.5-4.2 (2H
, m).

3.70 (3H, s).

5.25 (IH, t; J=7b).

5.3-5.6 (2H, m) IR (λ @cIL): ax 1740.1252. +116.1002°966.8
35,775 Mass (El + m/e): 638 (M)
, 581 (17R)-2-/ru5.17.20- ) dimethyl-9(Q-methano-ΔsOα)-4-thiaprostaglandin I, methyl ester 11115-bis-t-butyldimethylsilyl ether [ Compound (IV-2))
47 da (yield 16%) NMR (bow gc, ls): 0.7-1.0 (2,4H).

1.34 (3H, d; J=7tlz).

3.1-3.4 (3H, m), 3.5-4.2 (2H,
m), 53.71 (3H,a), 5.2-
5.6 (3)1. m) Mass (EI, m)
/e): 638(M), 581 (17R)-17,20-dimethyl-9+01-methano-△6(9αゝ-3-thi7 prostaglandi/■, methyl ester 11+15-bis-t-7'thi I dimethylsilyl ether [Compound (V-2)] 145■ (yield 4
8%) NMR (J CD""): MS 0.7-1.0 (24M), 2.5-3.2 (3
H, m).

3.22 (2H,s), 3.5--4.2 (2
H,m).

3.72 (3H, s), 5.29 (IL ba).

5.3-5.6 (2H, m) IR (λ.ax 'α): 1740.1254.1116.1002°967.8
35.775 Mass (El, m/e): 638 (M
), 581 (stream side 16 (++-3) (1li-3) (I
V-3) (V-3) 1,2.3-) dinor-16-methyl 9 (01
-Meta/-△4. a(9α)-prostagrangeyI,
11.15-bis-t-butyl dimethyl ether [compound (if-3)) 460 mg (0.89 mmol
) was used as a starting material to obtain the following compound.

16-Methyl-9(0)-meta/-3-thiabrostaglandine, methyl ester 11.15-bis-1-butyldimethylsilyl ether [Compound (ul-3)]
33MJ9 (yield 6%) NMR (δCDC4): MS O,71,1(24H), 3.20 (2i(,s
)+3.25 (2H,m), 3.5-4.2 (
2H,rn L3.71 (3H,s).

5.25(1)i, t; J=7mu).

5.3-5.6 (2H, m) IR (λ, cm)・ax 1740.1250,1117. +002°966.8
35,774 Mass (EI + m/a): 624 (M)
, 567 2-Flu 5.16-di/ + /L, -9(Q-
11/-Δ'(9σ)-4-Chia booster grunge yl
, methyl ester 11+15-bis-t-butyldimethylsilyl ether [Compound (IV-3)) 83 das (yield 15%) NMR (a CDC7Is): MS 0.7-1.1 (24H).

1.33 (3H, d; J=7Hz).

3.1-3.4 (3H, m), 3.5-4. '
2 (2H, m).

J, 70 (3)1+ a), 5.2-5.6 (
3H+m)IR(1"lLt+cm-')
:ax 1740, 1254. 1113. 1002°96
7, 835. 774 Mass (EI, m/e): 624 (M”
), 567 16-methyl-9(0)-methano-Δ6(9α)-3-
Thiaprostaglandin ■, methyl ester 1].

15-bis-t-butyldimethylsilyl ether [Compound (V-3)) 306~ (yield 55%) NMR (a C
DCl5): MS O,7-1,1 (24M), 2.5-3.2 (31
, m).

3.23 (2H,a), 3.5-4.2 (2H
, m).

3.70 (3H,,s), 5.29 (IH, bs).

5.3-5.6 (2)1. m) IR (λ packed HC&-'): 1740.1254. 111? , 1002°965.
835,775 Mass (EI + m/e): 624 (M
), 567, Example 17 (1i-4) (tit-4) 1-4
) (V-4) 1 + 2 t 3 t 16 in the same way as Example 2
t 17 * 18 * 19 +20-year old Kutanoru 15-shiku ρbenru 9 (01-methano-Δh・(
9α]-frostaglandin I, il+15-bis-t
-Butyldimethylsilyl ether [Compound (it-4)
]3s oda (0,70peng01) as the starting material,
The following compound was obtained.

16s17+18e19t20-pe/taflu 15-cyclopentyl-9 (Q-methano-3-thiaprostaglandin ■, methyl ester 1] 9) 5-bis-t-butyldimethylsilyl ether [compound-?ll (l1l-
4)) 22■ (Yield "J! & 5%) NMR (δ♀Nishiki'l): 0.86 (9H* @), (1,89 (9H1s)
+3.19 (2H,s), 3.25 (2H,m
).

3.73 (3H, s), 3.75 (IH, m) + 3.8
5 (IH, m).

5.29 (IH, t, J==7Hz).

5.48(2)1. m) IR (λn@1.cII&-1): ax 1740.1252.1116,967°835, 7
74 Mass (EI, m/e): 593 (M-
CH,), 551,5392, +6.17,18.19
920-Hexanol-15-cyclopentyl-5-methyl-9(O)-methano-Δ@(11α)-4-thiaprostaglandin I, methyl ester 11.15-bis-
t-7'Tyldimethylsilyl ether [Compound (Iv-
4) ) s 1w (yield 12%) NMR (6CDCl5.: MS 0.86 (9H, s), 0.89 (9H, s).

2.96 (IH,br), 3.0-3.4 (3
H, m).

3.70 (I Hl m ) + 3-73 (3
)1. s).

3.85 (IH, m), 5.4-5.6 (3H, m)e
at IR(λ @ Cjl-') : aX 1740.1250.1114,965°835.77
5 Mass (E I + m/e): 551 (M-
'Bu), 539 16+17t18w19,20-pentanol-15-cyclopentyl-9(0-methano-△・(9α)-3-1,7 prostagra/zinl, methyl ester 11.15-
Bis-t-phthylne methylsilyl ether [compound (
V-4) ) 2134 (yield 5450%) NMR (δ
CDCl5): MS θ, 87 (9H, a), 0.89 (9H,'s).

2.74 (2H, t, J=8Hz).

2.94 (IH=br), 3.24 (2H-s
) + 3.72 (IH, mL 3.74 (31 (, s)
+3.82 (IH, m), 5.33 (IH, bs).

5.49 (2H, m) eat IR (λ g CIL-' ): ax 1740.1256.1118.867°835, 77
4 Mass (EI, m/e): 593 (MC
M, ), 551,539 Example 1B (ll-5) (1il-5) (IV-
5) (V-5) In the same manner as in Example 2, L2-L16-17*IL19
゜20-year-old ctanol-15-cyclohexyl-9to+
-Metano-△'+'(1"ゝ-Prostagrangeyr,
tt.

15-bis-t-butyldimethylsilyl ether [Compound (If-5)] 400 W (0.78 mmol
) was used as a starting material to obtain the following compound.

]6. 】F+18.19.20-Penkutu-15-cyclohexyl-9+Of-methanol 3-thiaprostaglandin I, methyl ester 11915-bis-monobutyldimethylsilyl ether (compound < +t+-5)
)33■ (yield 7%) NMR (a CD"3 ): MS 0.86 (9H, @), 0.89 (9H, s).

3.20 (2H, s), 3.25 (2H, m).

3.5-4.1 (2H,rn), 3.72 (3
)1. fi ).

5.28 (IHoL J==7b).

5.3-5.7 (2H, rn) n@at-breath IR (λ, 1): ax 1740.1250.111? ,967°835.77
5 Mass (EI, m/e): 622 (M”), 607,565.5392116.1
7. ]]8. +9.20-hexano-15cyclohexyl-5-methyl-9(01-methano-△・(9α)-
4-thiaprostaglandin ■, methyl ester 11.
15-bis-t-butyldimethylsilyl ether [Compound (IV-5)) 68 IQ<Yield $14%) NMI soil (δCDC13): TMSO,7-1,0(18)1), 2.96 ( 1)1
．． br).

3.0-3.4 (3)i, m), 3.5-4
．． 1 (21(, m).

3.72 (3H=s) + 5.3 5.7
(319m)IR(J ``s1t+am-')
:m&x 1740.1252,966.836,774 Maas
(g engineering, m/e): 565 (M-'Bu),
539 16.1? , 18119.20-pentanol-15-cyclohexyl-9(0)-methano-Δ6(9α)-3-
Thiaprostagra/gin 11 methyl ester 11115
-bis-t-7' methyldimethylsili! Reether [Compound (V-5)) 267■ (yield 55%) NMR (d C
D"): TMS O, 7-1, 0 (18H), 2.5-3.2 (3)
1. m).

3.24 (2H,l), 3.5-4.1 (21
-1, mL3.72 (3H, s), 5.32 (IH, b
s).

5.45 (2Hem) IR (λn@1. Sue'): ax 1740.125? ,967.835,775Mass
(EI + m/e): 622 (M) +
565,539 Example] 9 (H-s) (+1i-6)
In the same manner as in Example 2, (16S)-1,2,3-trinor-15-deoxy-16-methyl-9toI-methano-Δ*II(Iα)-brostagrange/1.1 l
-t-butyldimethylsilyl ether 15-trimethylsilyl ether [compound (++-6)) 452 da(0,
95 mmol) as a starting material, the following compound was obtained.

(168)-15-deoxy-16-methyl-9tol
-Methano-3-Chiaprusta Brandin! .

Methyl ester 1l-t-7'Tyldimethylsilyl ether] 5-) IJ methylsilyl ether [Compound (i+l-6)) 22W9 (yield 4%) NMR (a
CDCl5) 21″MS 0.7-1.0 (12H), 1.18 (3)1.
s).

3.20 (2H, s), 3.26 (2H, m)
.

3.5-3.9 (IH, m), 3.70 (3H,
s )=5.26 (I H,t ; J=7Hz).

5.3-5.8 (2H, m) Maaa (EI, m7m) 258
2(M), 567.525 (16S-2-Tru-15-Deocy5゜16-dimethyl-9(0)-methano-8(9α)-4-thiap-staglandine, methyl ester 1l-t -Butyldimethylsilyl ether 15-trimethylsilyl ether (compound (IV-6)) 66 lv (yield 12%) NMR (/J CD""): TMSO,?t,o (12H), 1.18 (3H -a
)+1.33 (31(,d; J=711z).

3.1-3.4 (3H, m), 3.5-3.9
(I H, m).

3.71 (3H,s), 5.2-5.8 (3
t(,m)Mass(EI,m/e)
:5fi7(MC)l, ), 525 (168)-15-deoxy-16-methyl-9+01
-Meta/-Δ-(9α)-3-thiaprostagra/Zin 11 Methyl ester 1l-t-:l;/Tyldimethylsilyl ether 15-) Limethylsilyl ether [
Compound (V-6) ) 3329 (yield 60%) NMR (δCDCJ, ): TMSO,7-1,0(121), 1.18 (3H,s
).

2.5-3.2 (3)i, m), 3.22 (
2H,a).

3.5 3.9 (IH, m), 3.71 (3H,
s).

5.30 (3H, bs)t 5.3-5.8 (2
H, m) Mass (El, m/e): 58
2(M), 567.525 Example 20 (It-7) (1i1-7) "" (IV-7) (V-7) In the same manner as in Example 2, (16R) -1,2,3 -Trinor-]5-deoxy-16-methyl-9(0)-methano-41.(9α)-frostagra/Zin I, 11-1
-Butyldimethylsilyl ether 15-trimethylsilyl ether [Compound (ll-7)) 420np(0
, 88 mmol) as a starting material, the following compound was obtained.

(16R)-15-deoxy-16-methyl-9(01
-Methano-3-thiaprostaglandin I.

Methyl ester 1l-t-7'Tyldimethylsilyl ether] 5-Trimethylsilyl ether [Compound (m
-7) ) 27 I9 (yield 5%) NMR (a♀寥s
): 0.7-1.0 (12H), 1.18 (3H,s
).

3.20 (2H, s), 3.25 (2H, m)
.

3.5 3.9 (IH9m), 3.70 (3H+
s).

5.26 (1)ilL; J=71(z)-5
, 3-5, 8 (2H, m) Mass (EI, m/e): s82 (M)
, 567.525 (16R)-2-Trudeoxy-5,16-dimethyl-9 (01-methano-△6(-)-4-thiaprostaglandin ■, methyl ester 11-1-butyldimethylsilyl ether 15- Trimethylsilyl ether [Compound (IV-7)] 64 das (yield 12%) NMR (a ”DCls): MS O,7-1,0(12H), 1.18 (3H,s
).

1.34 (3H, d; J=71h).

3.1-3.4 (3H, m), 3.5-3.9
(I H, m) + 3.71 (3H, a), 5
．． 2--5.8 (3H, m)Mass (EI,
m/e ): 567 (M-CB, ), 525 (16R)-15-deoxy-16-methyl-9(0)
-Meta/-△a(Iα)-3-17p Stagra/Zin I, methyl ester 1l-t-7'Tyldimethylsilyl ether 15-trimethylsilyl ether [Compound (V
-7)) 3401Ig (yield 66%) NMR (a CDCl5): MS 0.7-1.0 (+2H), 1.19 (3H,
@).

2.5-3.2 (3H, m), 3.22 (2H
,s).

3.5-3.9 (IH, m), 3.71 (3)
1. sfu.

5.30 (IH,be), 5.3-5.8 (2
H, m) Maaa (EI * m/e): 582
(M), 567.525 Example 21 (V-1) (V+-1) (178)-1
7,20-dimethyl-9(0)-methane-Δ・(IIα
)-3-thiaprostaglandin I, methyl ester 1
1.15-bis-t-7' methyldimethylsilyl ether [Compound (V-1)) 1301149 (0.20mm
ol) in 31 acetonitrile and 200μ of pyridine under cooling with water. and pyridinium poly(hydrodiene fluoride) (HF-Pyridlne) 0.4
ml and stirred at room temperature for 1.5 hours. After adding 1 omt of saturated sodium bicarbonate solution and extracting with ethyl acetate (2x1o*j),
Organic I- was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off. When the obtained residue was purified by silica gel column chromatography, n-hexane-
Ethyl acetate (1:3)+? 67■ at the exit (yield 82%)
(178)-17,20-dimethyl-9(0)-methano-Δ6(1α)-3-thiaprostagraf 97 I
, ) 4-Le $ Stell [Compound '11!5 (Vi-
1)) was obtained.

NMR (a CD”s): MS O, 7-1,0 (6H), 2.5-3.2 (3H,
m).

3.20 (2H,a), 3.5-4,3 (2
)1. rn)+3.70(3H,s), 5.30
(IH, br).

5.3-5.6 (2H, m) neat IR (λ * cIl-'): ax 3380.1740, 1282, 1132.967Ma
ss (Er + m/e) :4]0(M)+
392.374 LOL Example 22 (V-2) (Vi-2) Example 21
Similarly, (17R)-17゜20-dimethyl-9
(01-methano-Δa(eα)-3-thiaprostagra/Zin I, methyl ester 11゜15-bis-t-7'
Tyldimethylsilyl ether [Compound (V-2)]
Using 14019 (0.22 mmol) as a starting material, (17R)-17,20-dimethyl-9(0-methano-△@0α)-3-thiaprostaglandin l, methyl ester [Compound (Vl-2)] 77 da (yield: 485%)
) was obtained.

NMR<, CDCIm>: MS 0.7-1.0 (6M), 2.5-3.2 (3
H,m).

3.19 (2B, sun+ 3.5 a, a
(2H9m) +3.70 (3H,a), 5
．． 29 (IH, bs).

5.3-5.6 (2H, m) neat −+ IR (λ ICIL): ax 33B0, 1738, 1282, 1132.966 Ma
as (EI, m/e): 410 (M”), 3
92,374 Example 23 In the same manner as in Example 21, 16-methyl ray 9 (01
-Methano-Δ6(9α)-3-thiaprostagra/Zin I, methyl ester 11.15-bis-t-butyldimethylsilyl ether [Compound (V-3)] 3θO# (
16-methyl-
9(0)-methano-Δ3 thiaprostaglandin I, methyl ester [compound (vi-3) 3152
DA (yield 80%) was obtained.

NMR (a CDC15): MS O,? -1,1 (6H) + 2.5-3.2 (3H,
m).

3.20 (2H,a), 3.5 4,2 (2H
, m).

3.71 (3H,s), 5.30 (IH,bs
).

5.3-5.7 (2H, m) IR (J neat, cR-r); ax 3380, 1740. 1282. 1130°10
86, 967 Mass ('WI e m/@): 396 (M
), 378,360 Example 24 (V-4) (Vi-4) In the same manner as in Example 3, 16.17118.19.20-pentanol-15-cyclopentyl-9 (01-methano-ΔN0α
)-3-17 prostagrange/11 methyl ester 1
1.15-bis-t-butyldimethylsilyl ether (
Compound (V-4) )210IQ (0.35 mmol
) as starting material, 16g17*IL19.20
-Pentano-15-cyclopentyl-9 (Of-methano-Δ"(Sα)-3-thi-7 prostaglandin I, methyl ester [compound (Vl-4)) 101■ (yield 76%) was obtained.

NMR (a CDC15>: MS 2.5-3.2 (3H, m), 3.21 (2H
,s).

3.5-4.1 (2H, m), 3.70 (3)
1. s).

5.30 (IH, bs), 5.3-5.7 (2H, m)
net IR(λ*Cm-'): aX 3380.1738,1438,1280°1130.
1082.967 Mass (E I I m/e): 380 (M
), 362,344 Example 25 (V-5) (Vi-5) In the same manner as Example 21, 161171181]9t20
-pe/taflu 15-cyclohexyl-9(Of-methano-Δa(ea) 3-thiaprostaglandin 11
Methyl ester l'l, 35-bis-t-butyldimethylsilyl ether [compound (VS)) 262 mg (0
, 42 mmol) as the starting material, 16.17.1
8119120-pentanol-15-cyclohexyl-
9(0)-Methano-Δ6(9α)-3-thiaboostaclandin 11 methyl ester [Compound 6 (Vl-5)) 1
4119 (yield 85%) was obtained.

NMR (δCDCIm) MS 2.5 3.2 (3H9m), 3.20 (2H+
s).

3.5-4.1 (2H, m), 3.69 (3H,
a).

5.29 (IH, bs), 5.3-5.7 (2
H, m) nett −+ IR (λ, cIR): ax 3380.1?40,1438,1282°1132.
1082.967 Maaa (El, m/e): 394 (M)
, 376.358 Example 26 In the same manner as in Example 3, (168)-15-deoxy-
16-methyl-9(ol-methano-Δ6(””ゝ-3-
Thiaprostaglandin I, methyl ester 1l-t-
7'Tyldimethylsilyl ether 15-) U methylsilyl ether [Compound (■-6)) 3154 (0,
54 mmol), (168)-15-det't
'/ -16-) 4-Lou 9 (Ol-/ 1No△@(Ia) 3-thiaprostaglandin 11 methyl ester [Compound (Vi-6) 31751115
1 (yield: 4182%).

NMR (a CD”8): M.S. 0.88 (3H, t; J=5 degrees).

1.19 (3H,ti)t 2.5-3.2 (3H
, m L3.20 (2H,s), 3.5-3.9
(IH, m).

3.70 (3H,s), 5.31 (IH,bs
).

5.3-5.8 (2H, m) Mass (EI, m/e): 378 (M-
H,0), 360 Example 27 In the same manner as in Example 3, (16R)-15-deoxy-
16-Methyl-9(01-methano-△・(9α)-3-
Thiaprostaglandin 11 methyl ester 1l-t-
7'Tyldimethylsilyl ether 15-)limethylsilyl ether [Compound (■-7)] 3229 (0,5
(16R)-15-deoxy-1
6-Methyl-9(0)-methano-bs(ea)-3-thiaprostaglandin 11 methyl ester [Compound (V
l-7) 3170 Da (yield 78%) was obtained.

NMR (δCDC4): TMS 0.89 (3H, t; J-5tlz).

1.18 (3H, @), 2.5-3.2 (3H
, m).

3.20 (2H,s), 3.5-3.9 (I
H, m).

3.70 (3)1. m), 5.30 (I
H, ba ) ts, a-s, s (2H, m) Mass (El, m/e): 378 (M
-H, O), 360 Example 28 (+1l-1) (Vii-1) (17
S)-If, 20-dimethyl-9(Of-methano-3-
Thiaprostaglandin If methyl ester 11115
-bis-1-butyldimethylsilyl ether [compound (
1H-1) ) 23 ag (0,036 mmol)
was desilylated in the same manner as in Example 3 to obtain (178)-
17,20-dimethyl-9(0)-methano-3-thiaprostaglanshiff I, methyl ester [compound (vH-
1), 312 If (yield 82%) was obtained.

NMR (aCDCI Hatake): TMS 0.7-1.0 (6H), 3.20 (2H,a
).

3.25 (2H, m), 3.5-4.2 (2H
, m).

3.70 (:4H,s).

5.25 (IH, t; J=H1z).

5.3-5.6 (2H, m) IR (λn@1.儂-I): aI 3380.1740.1276.1137°1006.
966 Mass (EI e m/e): 392 (M-H
, O), 374 Example 29 (il+-2) (Vii-2) (17R
) -17,20-dimethyl-9-methanol 3-thiaprostaglandi/It methyl ester 11.15-bis-t-7' tyldimethylsilyl ether [compound (l
l+-2)) 28 da (0,044 mmol) was desilylated in the same manner as in Example 3 to form (17R)-17
, 20-dimethyl-91ot-methano-3-thiaprostagra/gin■, methyl ester [compound (wit-2
) 15 mg (yield: 85%) was obtained.

NMR (a CDC15): TMS 0.7-1.0 (6H), 3.20 (2H, s
) t3.26 (2H, m), 3.5-4.2 (2H, m
)-3,71(3)1.8).

5.26 (I H,t; J=7Hz)5.3-
5.6 (2H, m) eat IR (λ, cWL-'): m Todoroki X 3380, 1740. 1278. 1139°10
06, 966 Mass (El m m/e): 392 (M-
H, O), 374 Example 30 (+1i-3) (vll-3)16
-Methyl-9(O)-methano-3-thiaprostaglandin ■, methyl ester 11.15-bis-t-butyldimethylsilyl ether [Compound (Ill-3)]
32sF (0,051 mmol) was desilylated in the same manner as in Example 3 to obtain 16-methyl-90-methanol-3.
-Thiaprostaglandin! , methyl ester [compound (Vl-3)) 15# (yield 76%) was obtained.

NMR (δ♀寥j): 0.7-1.1 (6H)-3,20(2H1s)+
3.25 (2H,m L a,s-4,2(2H,m
).

3.70 (3H, s).

5.26 (IH, t; J=7Hz).

5.3-5.6 (2H, m) neat -1.

IR(λ, ca).

1X 3380.173g, 1276.1136°1006.
965 Maas (EI, m/e): 378 (MH, 0), 360 Example 31 (1li-4) (vll-4) 16t
17s18+19120-pentanol-15-cyclope/tyl-9(0)-meta/-3-thiaprostaglandin I, methyl ester 11w15-bis-t-butyldimethylsilyl ether [compound (i+1-4)) 20Q
(0,033 mmol) was desilylated in the same manner as in the method of Example-13, and 16,17,18t19,20-pentanol-15-cyclopene 1,000-9 (01-methanol-3-
Thiaprostaglandin I, methyl ester [compound (
Vl+-4) ) 10 Da (yield 82%) was obtained.

NMR <, C storage>: 3.21(2H,s), 3.26(2t(,m).

3.5-4.1 (2H, m), 3.70 (3H
,a).

5.26 (IH, t; J=7Hz).

5.3-5.6 (2H, m) neat IR (λ 1CIL-'): ax 3380.1740, 1278, 1136°1008.
965 Mass (E I + m/@) ”380 (M
”), 362..344 Example 32 (+1i-5) (vii-s)1
6.17118119120-pentanol-15-cyclohexyl-9 (01-methano-3-thi7 prostaglancy I, methyl ester 11.15-bis-t-butyldimethylsilyl ether [compound (1il-5)
) 31jll (0,050 mmol) was desilylated in the same manner as in Example 3, and 16.17118119t2
0-pentanol-15-cyclohexyl-9 (Ol-methano-3-thiaprostaglandin!, methyl ester (compound 1l-5)) 17~ (yield 85%) was obtained.

NMR (δCDC7!3): M.S. 3.20 (2H, a), 3.25 (2H, rn).

3.5-4.1 (2H, m), 3.69 (3)
1. s).

5.26 (IH, t; J = 7■z) s 5.3-5.6 (2L m) neat -m IR (λ, CI rim °: ax 3380, 1738. 1280. 1128. 1
082°Mass (EI * m/e): 37
6(MH,U), 358 Example 33 (168)-15-deoxy-16-methyl-9(Ol
-Methano-3-chiplostaglandin.

Methyl ester 1l-t-7'Tyldimethylsilyl ether 15- ) Dimethylsilyl ether [Compound (i
if 6) 322IQ (0,038mmol)
was desilylated in the same manner as in Example 3 to obtain (168)-
15-deoxy-16-methyl-9(0)-methanol 3
-Thia 7'l = Staglandine, methyl ester [Compound (vii-6)] lzw9 (yield 80%) was obtained.

NMR (δCDC13): M.S. 0.88 (3H, t; J=5Hz).

1.20 (3H,s), 3.21 (211,s
).

3.27 (2H, m), 3.5-3.9 (IH,
m).

3.70 (3H, a).

5.25 (IH, t; J=7b).

5.3-5.8 (2)1. m) Masa (EI + m/e): 378 (M-H
, O), 362 Example 34 (ll+-7) (Vl+-7) (16
R)-15-deoxy-16-methyl-9(Q-meta/
-3-17 pstaglandinye.

Methyl ester 1l-t-methyldimethylsilyl ether] 5-trimethylsilyl ether [compound (III-
7) ) 2711 g (0,046 mmol) was desilylated in the same manner as in Example 3 to obtain (16R)-15-
Deoxy-16-methano-9(o)-methano-3-thiaprostagra/zin, methyl ester [compound (Vi
+-7) ) 15 Da (yield 84%) was obtained.

NMR (a CDC4): M.S. O, 88 (3H, t; J=5mm).

1-19(3)1+s), 3.21(2H1s)-3
, 26 (2H, m), 3.5-3.9 (] H, m
).

3.70 (3H, s).

5.26 (IH, t; J=7b).

5.3-5.8 (2H, m) Mass (gI + m/s): 378 (M-u
, o), 360 Example 35 (vi -1> (veil-1) (1
7S)-17,20-dimethyl-9(0-meta/-△@
(9a)' 3-Thiaprostagra/Jinko, methyl ester [Compound (Vl-1)) 40 Da (0,098 m
mol) was hydrolyzed in the same manner as in Example 40,
(17S)-17,20-dimethyl-9(Q-methano-
△s(+1α)-3-chi7 pstagrange y r,
(Compound (viii-1>) 35 #<Yield 90
%) was obtained.

NMR (δCDCl, ); MS O,75-1,0(6)[,m), 2.5-3.2
(3H, m) + 3.20 (21, s), 3.5-4.3
(2H, m).

5.30 (IH, ba) + 5.3-5.6 (2
H, m).

5.6-5.9 (3K, br; disappeared with DtO)
neat −+ IR (λ, cm): ax 3380, 2800-2300. 1715°108
2, 968 Maaa (EI, m/*): 378 (M-
Hρ), 360 Example 36 (vi-2) (viil-2) (1
7R)-17,20-dimethyl-9((J-methano-△
8(′α)-3-thiapdistaglandin II methyl ester [compound (vi-2)) s o ay(o,
t2mmol) was hydrolyzed in the same manner as in Example 4, and (17R)-17,20-dimethyl-9(0-methano-Δ·(″αkun--Thiaboostagra/Zin I!
[Compound (veil-2)) 41 # (yield 87
%) was obtained.

NMR (δ♀renal s): 0.75-1.0 (6H, m).

2.5-3.2 (3H,m), 3.20 (2
)(,s).

3.5-4.3 (2H, m), 5.30 (IH
, bs).

5.3-5.6 (2L m).

5.9 6.2 (3H= br # disappears with DtO)
neat −r·IR(λ rca).

ax 3380.2800~2300.1712°1080,
967 Mass (EI * m/s): 378 (M-
H, 0), 360 Example 37 (vi-a) (v+1i-3)1
6-Methyl-9(Of-methano-Δ1(”α)-3-thiaprostaglandine, methyl ester [metallic compound (V
l-3) ) 1 ] 5II9 (0.29 mmol
) was hydrolyzed in the same manner as in Example 4 to obtain 16-methyl-9+Of-methanol△@0")-3-thiaprostaglandin I, (compound (v+1l-3)) 9
4a5i+ (yield 85%) was obtained.

NMR (aCDCls): MS 0.75-1,1 (6H), 2.5-3.2 (3
1, m).

3.20 (2H,a), 3.5-4.2 (2)
i, m).

5.29 (IH, bs).

5.3-5.8 (5)1. m; 3H disappears with D, O) neat IR (λ*CIL-') e ax 3380.2800~2300.1715°1082.
970 Mass (II + m/e): 364 (M-1
8), 346 Example 38 (Vl-4) (vii-4)
16+17t18w19+20-pe/Tafuru 15-cyclo 1pe/Chiru 9 (OI-methano-Δ・(9α)-
3-thiaprostaglandin I, methyl ester (compound (Vi-4)) 7619 (0.20 mmol
) was hydrolyzed in the same manner as in Example 4 to obtain IL17
118119e20-Penta True 15-Cyclope/
Chil-9 (Q-methanolΔ'(9α)-3-thiaprostaglandin!, [Compound (viil-4)) 62
# (yield 85%) was obtained.

NMR (δCDC4): M8 2.5-3.2 (3H, m), 3.20 (2)1
．． s).

3.5-4.1 (2H, m), 5.30 (IH,
ba).

5.3-5.6 (2H, m).

5.8-6.2 (3H, br; disappears with D, O) n
eat IR (λ, ctn-'): ax 3380, 2800-2300. 1714°108
2, 968 Mass (EI e m/e): 366 (M
L 348,330 (Stream side 39 (Vl-5) (viii-5) IL1
7,18119920-pentanol-15-cyclohexyl-9(0)-methano-Δ6(”α)-3-thiaprostaglandin!, methyl ester (compound (Vi
5) ) 1009 (0.25 mmol) in Example 4
It was hydrolyzed in the same manner as in the method of 1(i117118+
19+20-pentanol-15-cyclohexyl-9 (
0)-methano-Δ60α)-3-thiaprostaglandin I, (compound <viii-5>) 76 da (yield: 80%) was obtained.

NMR (aCDCl5): MS 2.5-3.2 (3H,m), 3.20 (2
H,a).

3.5 4.1 (2H, m), 5.30 (IH
, bs).

5.3-5.6 (2H, m) IR (λ, α): ax 3380.2800-2300.1715°1082.
966 Mass (EI, m/e): 380 (M), 362,344 Example 40 (tss)-1s-deoxy-16-methyl-9(O)
-Methano-△・(9α)-3-thiaprostagra/di/
I, methyl ester [compound 1-6)) 11319 (
0.29 mmol) was hydrolyzed in the same manner as in Example 40 to obtain (168)-15-deoxy-16-methyl-9(ol-methano-Δ60")-3-thiaprostaglandin Ii (compound ( vnl-6) 390m9(
A yield of 81%) was obtained.

NMR (-CDC also): M.S. O, 88 (3H, t; J±5m).

1.18 (3H,s), 2.5-3.2 (3H
, m).

3.20 (2H,a), 3.5-3.9 (I
H, m).

5.30 (IH, bm).

5.3-5.8 (5H, m; 3H disappears with DtO)
Mass (EI, ITI/@): 364 (M
-H,O), 346 Example 41 (16R)-1s-deoxy-16-methyl-9D-methano-Δ60α)-3-thiaprostaglandin ■, methyl ester (compound (vl-7)) 12o# (0
. Jin I, (compound (viil-7))
9619 (yield 84%) was obtained.

NMR (δCDCA!s): M.S. 0.88 (3H, t; J=5mm).

1.18 (3H, s L 2.5-3.2 (3H,
m)+3.20 (2H9s)e 3,5-3.9
(I H-m).

4.9-5.2 (3H, m; disappeared with D, O).

5.30 (IH, bs), 5.3-5.8 (2
H, m) Mass (EI, m/@): 364 (MH, 0), 346 Example 42 (Vl+-1) (IX-1) (17
8)-17,20-dimethyl-9(O)-methano-3-
Chiafrostaglandin! , methyl ester [compound (
Vll-1) ) 8 ml (0,020 mmol
) was hydrolyzed in the same manner as in Example 6 to obtain (17g
)-17,20-dimethyl-9(Ol-methano-3-thiaprostaglandin It (compound (lX-1)) 7
DA (yield 90%) was obtained.

NMR (aCD”a): MS 0.75-1.0 (6H,m), 3.20 (2
H,a)t3.25 (2H,m), 3.5-4
．． 2 (2H, m).

5.25 (IH, L; J=7&).

5.3-5.6 (2H,m)e 6.1-6.5 (3H,br; disappeared at 010)I
R (1"'te cm-'): max 3380, 2800~2300. 1714°108
0, 967 Mass (EI, m/e): 378 (M-
) 110), 360 Example 43 (Vll-2) (iX-2) (17R
)-17,20-dimethyl-9(0-methano-3-thiaprostaglanshif 1f methyl ester [compound (vl
l-2)) 10Q (0,037 mmol) was hydrolyzed in the same manner as in Example 6 to form (17R)-
17,20-dimethyl-9(O)-methano-3-thiaprostaglandin Xt (compound < +X-z)) t3f
(yield 88%).

NMR (a CDCJs): MS 0.75-1.0 (6)i, m), 3.2
0 (2H,s).

3.25 (2H, m), 3.5-4.2 (2
H,m).

5.26 (IH, t; J=7flz).

5.3-5.6 (2H, m).

5.8-6.2 (3H, br; disappears at D, 0) e
at IR(λ r CIL-'): max 3380, 2800-2300. 1715°1 0
82, 965 Maas (EI, m/e): 37B (M-
H,0), 360 Example 44 (vll-3) (+x-3)16-methyl-9(0)-methano-3-thi7 p-staglandin! , methyl ester [compound (Vll3)) 10
M9 (0,025 mmol) was hydrolyzed in the same manner as in Example 6 to give 16-methyl-9+01-methano-
3-Thiaprostaglandin! .

(Compound (IX 3)) 9'Ijp (yield 490%) to 4? , :.

NMR (δ9寥3): 0.75-1-0 (6H-m), 3.19 (2
Hls).

3.25 (2H, m), 3.5-4.1 (2H,
m).

5.1-5,6 (6I(, 3Hff in m s DtO
4 loss) IR (2"at* cm-'): max 3380.2800~2300.1712°1080.
965 Maaa (El, m/e): 382 (M)
, 364,346 Example 45 (Vll-4>(+x-4>16.
17,18919.20-pentatrue-15-cyclopentyl-9 (01-methano-3-thiaprostaglandin I, methyl ester [compound (Vll-4)) 7m9
(0,018 mmol) was hydrolyzed in the same manner as in Example 6, and 16.17118119.20-penktrue 15-cyclope/chiru-90-methanol 3-thiaprostaglandin I,C compound (iX-4) )6
DA (yield 92%) was obtained.

NMR (δCDC15): M.S. 3.20 (2) L a), 3.26 (2H, m).

3.5-4.1 (2) 1. m).

5.25 (IH = ts J = 7 Hz).

5.3-5.6 (2H, m).

6.0-6.4 (3H,br; disappears with DIO)r
beat-r IR (λ 1cIL): max 3380.2800~2300.1714°1082.
967 Mash (EI, m/e): 366 (M
)s 348.330 Example 46 (Vil-5) (IX-5) 16.1
7,18119.20-pe/Tunoru 15-cyclohexyl-9 (01-methano-3-thiabrostagrange/
I, methyl ester (compound (Vil-5)) 12 mg
(0,030 mmol) was hydrolyzed in the same manner as in Example 6 to obtain 16.17918.19120-pentanol-15-cyclohexyl-9 (0-meta/-3
- Thiapustagrange/11 [Compound (1x-5)]
10I9 (yield 85%) was obtained.

NMR (a CDCl5): MS 3.20 (2H,s), 3.26 (2H,'
m) = 3.5-4.1 (2H, m).

5.25(II(,t;J=7mm).

5.3-5.6 (21(,m) n7at -50IR(λ,aR)・aw 3380, 2800. 2300. 1712°10
80, 966 Mass (EI, m/e): 380 (M
L 348 Example 47 (168)-15-deoxy-16-methyl-9+Of
- Methanol 3-Thiaprostagra/Zin I.

Methyl ester [compound (vii-6)) s Wl
g (0,020 mmol) was hydrolyzed in the same manner as in Example 6 to obtain (168)-15-deoxy-16-
Seven days of methyl-9(υ-methanol-3-thiaprostaglandin 11 (compound (IX-6)) (yield: 89%) was obtained.

NMR (δCDCl5): M.S. 0.88 (3H, t; J=5b).

3.20 (2H, s), 3.26 (2L m).

3.5-3.9 (IH, m).

5.25 (IH, t; J=7k).

5.3-5.8 (5) L, m; 3H disappearance with D, O) eat IR (λ, α-1): m&X 3380, 2800-230G, 1714. 9
66Mass (EI + m/e): 364 (
M-HtO), 346 Example 48 (16R)-15-deoxy-16-methyl-9(01
-Methano-3-Chiaprustaburan Gin! .

Methyl ester [compound-(Vil-7)) 11 da(
0,028 mmol) was hydrolyzed in the same manner as in Example 6 to obtain (]5R)-15-deoxy-16-methyl-90-methano-3-thiaprostaglandin I,
(Compound (ix-7)) 99 (yield 87%) was obtained.

NMR (δCDC1@): M.S. O, 88 (3H, t; J=5Hz).

3.20 (2H,s), 3.25 (2H,m
).

3.5-3.9 (IH, m)+ 5.25 (1) 1. t; J=7tlZ).

s, 3-5. s (2H, m).

6.4-6.7 (31 (, disappeared in br poto)
eat IR (λ HC11-'): ax 3380.2800~2300.1714.967Ma
ms (EI, m/e): 364 (M-H2O), 346 Example 49 In vitro platelet aggregation inhibiting effect The in vitro platelet aggregation inhibiting effect of the test drug was assayed using rabbits. i.e. body* 2.5-3.5 kgO
3.8% trisodium citrate mw was collected from the ear vein of a Japanese white-breasted domestic rabbit at a ratio of 9 dishes to x, and 1
After centrifugation for 000 flO minutes, the upper layer was separated as PRP (platelet rich plasma). The lower layer is further 280OflO
After centrifugation for a minute, the upper layer separated into two layers was separated as PPP (platelet poor plasma). Platelet count is 6X10'/
Dilute alfi in μIcPPP. lA difference'flkf)
Add 25 μl of test drug to 250 μl of PRP and mix 37
ADP 1 after 2 min play/cupation at °C
μM (final) was added and the change in transmittance was recorded using an acribometer. The test drug was dissolved in ethanol to a concentration of 10 mg/-, and then diluted with a mild phosphoric acid solution (pH 7.4) before use. The aggregation inhibition rate was determined using the following formula.

−: Permeability of (phosphate buffer addition system) T: Permeability of the additive system The lowest concentration of drug at which the inhibition rate exceeds 50% is IC.

Shown as 1st shift.

The results are shown in Table 1.

wJ l machine Example 50 Tablets were manufactured, each having the following composition.

Active ingredient 20μl or 100μl milk
Sugar 28059
Yam starch 80M
9 Polyvinylpyrrolidone 1
1. Magnesium stearate
51IIF5 76ai! The active ingredient, lactose and potato starch were mixed, evenly moistened with a 20% ethanol solution of polyvinylhyloridone, and passed through a 20m mesh at 45°C.
It was then passed through a 15m mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

As active ingredient, typically the compound of Example 4 (vl
i) was used.

Example 51 Hard gelatin capsules were made containing the following composition:

Active ingredient 20μI or 100μI microcrystalline cellulose 195IIg amorphous silicic acid
5119400 Da The active ingredient in finely powdered form, microcrystalline cellulose and unpressed silicic acid are thoroughly mixed and packed into hard gelatin capsules. As the active ingredient, the compound of Example 4 (wit) is representative.
was used.

Example 52 The compound of Example 4 (v++) was dissolved in fractionated coconut oil. In addition, dissolve the skin component according to the following formulation at 1 temperature, and
Soft capsules were manufactured by a conventional method using a soft capsule manufacturing machine so that each capsule contained 50 μl of the compound (vil) of Example 4.

Prescription gelatin 10 times & glycerin 5 〃 Nrubin#! 0.08# Purified Water 14 Example 53 (Preparation of 7-pack formulation) An ampoule containing the following composition in one ampoule (5-volume) was prepared.

Active ingredients 200μI polyethylene glycol 600 200jll distilled water
The total amount of 50114 polyethylene glycol and the active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. This l111
The volume given by adding 1 L of pretreated water was filtered under sterile conditions. This production is carried out under diffused light.

Filling was carried out in a nitrogen stream and sterilization was carried out at 121°C for 20
I did it for a minute.

In addition, as the above-mentioned active ingredient, the compound of Example 4 (Vl
l) was used.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
[In the formula, R^1 is a hydrogen atom, a C_1 to C_1_0 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3 to C_1_0 cycloalkyl group, a substituted or unsubstituted phenyl(C_1 to C_2) alkyl represents a group or 1 equivalent of a cation, R^2 and R^3 are the same or different,
Hydrogen atom, tri(C_1-C_7) hydrocarbon silyl group,
or a group that forms an acetal bond or an ester bond with the oxygen atom of a hydroxyl group, R^4 is a hydrogen atom,
C_1~C_1_0 represents an alkyl group, vinyl group or ethynyl group, R^5 is a straight chain or branched chain C_3~C_1_0 alkyl group which may contain an oxygen atom; a straight chain or branched chain C_3~C_1_0 alkenyl group; Straight chain or branched C_3-C_1_0 alkynyl group; optionally substituted C_3-C_1_0 cycloalkyl group; optionally substituted phenyl group; optionally substituted phenoxy group; or optionally substituted Represents a phenyl group, a linear or branched C_1 to C_■ alkyl group substituted with an optionally substituted phenoxy group or an optionally substituted C_3 to C_1_0 cycloalkyl group. R^6 and R^7 jointly represent a single bond, then R^
8 represents a hydrogen atom. Alternatively, R^7 and R^8 jointly represent a single bond, in which case R^■ represents a hydrogen atom. n represents 0 or 1. ] 3-thiacarbacyclines represented by: 2, R^7 and R^8 jointly represent a single bond, R^9
3-thiacarbacyclines according to claim 1, wherein is a hydrogen atom. 3, R^6 and R^7 jointly represent a single bond, R^8
3-thiacarbacyclines according to claim 1, wherein is a hydrogen atom. 4. 3-thiacarbacyclines according to any one of claims 1 to 3, wherein n is 0. 5. 3-thiacarbacyclines according to any one of claims 1 to 3, wherein n is 1. 6. Any one of claims 1 to 5, wherein R^1 is a hydrogen atom, a methyl group, or 1 equivalent of a cation.
3-Thiacarbacyclines described in Section 3. 7. The 3-thiacarbacyclines according to any one of claims 1 to 6, wherein R^2 and R^3 are both hydrogen atoms. 8. The 3-thiacarbacyclines according to any one of claims 1 to 7, wherein R^4 is a hydrogen atom. 9. The 3-thiacarbacyclines according to any one of claims 1 to 7, wherein R^4 is a methyl group. 10, R^5 is butyl group, pentyl group, 1-methylpentyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, 2,6-dimethyl-5-heptynyl,
1-methyl-3-pentynyl group, or 1-methyl-3
The 3-thiacarbacyclines according to any one of claims 1 to 9, which are -hexynyl groups. 11. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] [In the formula, R^2^1, R^3^6 are the same or different, and hydrogen atoms, tri- (C_1 to C_7) represents a hydrocarbon silyl group or a group that forms an acetal bond or an ester bond with the oxygen atom of a hydroxyl group, and R^4, R^5, and n are the same as defined above. ] 1,2,3-trinorcarbacycline conjugated dienes represented by the following formula [III] HS-CH_2-COOR^1^1...[III
] [In the formula, R^1^1 is a hydrogen atom, C_1 to C_1_0
It represents an alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, or a substituted or unsubstituted phenyl (C_1-C_2) alkyl group. ] The following formula [I] is characterized by subjecting thioglycolic acids represented by the following to an addition reaction and, if necessary, to deprotection and/or hydrolysis reaction and/or salt formation reaction. There is▼・・・・・・〔 I
] [In the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7, R^8 and n are the same as defined above. ] A method for producing 3-thiacarbacyclines represented by: 12. The method for producing 3-thiacarbacyclines according to claim 11, wherein the addition reaction is carried out in the presence of a radical reaction initiator. 13. A circulatory agent, malignant tumor metastasis inhibitor, or cytoprotective agent comprising an effective amount of 3-thiacarbacyclines represented by the above formula [I] and a pharmaceutically acceptable carrier.