AU604156B2 - Prostaglandins of the F series - Google Patents

Description

COMMONWEALTH OIF AUSTRALIA PATENTS ACI 1952

CURET

NAM~'E ADDRESS OF APPLICANT: Kabushiki Kaisha Ueno, Seiyaku Oyo Kenkyujo 2-3 1, Koraibashi, Higashi-ku Osaka-shi,' Osaka-fu, Osaka Jaipan NAME(S) OF INVENTOR(S); t t I

LI

I Ryuzo UENO Ryuji UENO Tomb~ ODA ADDRESS FOR SERVICE: This dowricul dhwliasth Section qaid is curcCL iut DAVIES COTISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: Prostaglandins of the F series The following 4,tatement is a full description of this ivention, including the best method of perform-ing it known to me/us:- 9 04 49 4 04 O 4 4 9449 I, 4 4 99 49 9 44 4 04 94 4 4 49 .4 44 44 9 44 49 9 49 .449 0 09 44 4 BACKGROUND OF THE INVENTION The present invention relates to novel prostaglandins of the F series and vasopressors containing the same.

Prostaglandins of the F series (hereinafter referred to as PGFs) which contain a partial structure as a five-membered ring shown in the following formula

OH

NV

OH

may be roughly divided into PGFla: 094.

p 4~9.

4 in which the carbon atom at 5-position (referred to as hereinafter, such nominating is applied to other carbon) and C-6 are singly bonded, and PGF 2 a: OHl N \COCOH

OOH

j

I'

-2in which C-5 and C-6 are doubly bounded, and PGF 3 a:

OH

OH

OH

in which C-5 and C-6 are, and C-17 and C-18 are are doubly bonded. For example, PGF 2 a which exhibits marked oxytocic S. effect is clinically used to induce or promote pain at the last stage of pregnancy. Moreover, it is known to have S• vasopressor effect, however, the effect of PGF 2 a is accompanied with preceding ephemeral vasorelaxation.

Further, the typical PG effects on trachea, bronchus and intestine such as increase of airway resistance due to tracheal contraction and abdominal 'pain due to intestineal contraction, are simultaneously accompanied with vasopressor effect, therefore, there are problems to use the PGFs as Ii vasopressors.

On the other hand, prostaglandin F metaboletes in which the bond between C-13 and C-14 is saturated, and is a carbonyl group, are found to exist in human and animal metabolites. These 13,14-dihydro-15-keto-prostaglandin Fs are shown in the formulae following: -3-

OH

6~ 0 a _GOGHI 6 5 2 OH 1 03i

OH

1013 1 5 17 15 2 7~13 I 1 I I 12 1 I4 165 1 OH 0 a a and are known as the mnetabolites of the corresponding PGF 1 00,

PGF

2 a, and PGF 3 z in Vivo. These 13,14-dihydro-15-keto-PGFs scarcely exhibit any physiological activities that PGF's d o f 4inherently possess, and have been reported as the Q P4 o 4 6physiologically-, and the pharmacologically- inactive metabolites (see, Acta Physiologica Scandinabia, 66, P 506- (1988)).

SUMMARY OF THE INVENTION .4444 While evaluating pharmacological activities of the derivatives of the above metabolites, however, the pre'sent inventors have found that carboxylic-acid esters of the above metabolites themselves, 13,14-dihydro-15-keto-PGF analogues, 'which are carboxylic acids, correspo)nding salts, and corresponding esters, bearing substituents on C-3, -i:6, -17, -19, and/or -20 and 13,14-dihydro-15--keto-PGF analogues which bear a methyl group or a hydroxymethyl group instead of a hydroxy group on C-9 or C-111 show vasopressor activity, which is one of the phermaceutical activities of I 1 i I i I 4 the PGFs. The vasopressor effect of these 13,14-dihydro-15keto-PGFs may raise blood pressure without ephemeral vasorelexation which is inherent to the PGFs. Further, 13, 14-dihydro-15-keto-PGFs, which show no or extremely reduced tracheal and intestineal contraction effects those the PGFs inherently possess are found to have no.typical PG effects on trachea, bronchus and.intestine.

BRIEF DESCRIPTION OF DRAWING 8 Figs 1 27 are n.m.r. charts of 13,14-dihydro-15- 4 94 Sketo-PGFs of the present invention.

S" DETAILED DESCRIPTION OF THE INVENTION The present invention provides 13,14-dihydro-15keto-PGFs and the corresponding salts shown in the general formula and vasopressors containing the compounds; Sa 4 COOR 1

R

4

R

:i in the formula C-2, -3 double bond may or may not be located; X is

-CH

2 CH2-, -CH 2 CH -s 7\ 6 /5 6

CH

2

C

0 -CH- or 7\ -CH z \CH CH CH

C=

5 one of four possibilities shown above R1 is a hydrogen atom, an alkyl, phenyl, benzoyl, hydroxyalkyl, alkoxyalkyl, trialkylsilyl and tetrapyranyl group; R2 is a hydrogen atom or a lower alkyl group; i R 3 and R 3 are a hydroxyl, methyl or hydroxymethyl;

R

4 and R 5 are the same or different, and signify a hydrogen atom, a lower alkyl or a halogen atom; and gt Rs is either an alkyl group consisted of 4 to 9 carbons i which may or may not be branched one, contain double bonds j or may bear alkoky substituents or the group shown in the formula following: (wherein Y indicates a single bond with C-16, or an oxygen atom;. R 7 indicates a hydrogen or halogen atom or a e halgenated alkyl); excepting the compound wherein Ri, R 2

R

4 and R 5 are simultanedusly hydrogen atoms, R 6 is a n-BU, R 3 and R 3 are both hydroxyls and C-2 and C-3 are singlly bonded.

X in the general fromula represents the four types Sof the partial structure illustrated above.

A compound in which signifies CH2 CH 2

CH

2 I6 is 13,14-dihydro-15-keto-PGF~s and a compound wherein signifies C2 CH =CH is 13,14-dihydro-15-leto-PGF 2 s. Accordingly, the compounds wherein -(X)-signifies C H 2

OH

2 and

OH

2 are 13,l4-dihydro-6,15-diketo-PG 1 s, and 13, 14-dihydro-15- Sketo-5,6-dehydro-PGF 2 s, respectively.

In the present invention, R, indicates a hydrogen atom, ilkyl, phenyl, benzyl, hydroxyalkyl, alkoxyalkyl, trialkylsilylt and tetrahydropyranyl. A preferabie R, in the present invention is an alkyl group, more preferably, a' saturated or an unsaturated alkyl group which may or may not have a side chain and particularly an alkyl group which may contain 1 to 4 carbon atoms, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.

r i lisarre 0o o 00 9 9 0 «9 4 9 a 0 7 13,14-Dihydro-15-keto PGFs in this invention may be in a salt form. The salts are physiologically acceptable ones, for example, salts with alkali metals such as sodium, potassium and salts with alkaline earth metals such as calcium, magnesium or physiologically acceptable ammonium salts, for example, ammonium salts derived from ammonia, methylamine, dimetylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamin, lysine, and tetraalkylammonium salt and the like.

R2 is a hydrogen or a lower alkyl group, especially methyl.

R3 and R 3 are a hydroxyl, methyl or hydroxymethyl. When they are both hydroxyls, the compound belongs to the general 13,14-dihydro-15-keto-PGFs< In the present inventi.on, the compounds wherein R 3 and/or R 3 are/is methyl or hydroxymethyl are also considered as PGFs,

R

3 may be a-oriented or a-oriented and R' 3 may be a-oriented or 8-oriented with respect to C-9 or C-ll respectively.

R

4 and/or R 5 independently indicate a hydrogen atom, a lower alkyl group or a halogen atom. In case of a lower alkyl group, methyl group is especially preferred, and in case of halogen a fluorine atom is especially preferred. The compound in which at least one of R 4 and R is a metyl or a fluorine atom is important. Both R 4 and R may indicate the same substituents.

9 00p 9 0 00 9 9 90 r00, O 004 0a 0 8-

R

6 is an alkyl consist6d of 4 to 9 carbons, which maj contain side chains, a double bonds or alkoxy substituents. The alkoxy substittients inc-.lude such as methoxy, ethoxy and the like. Especially, n-alkyl groups consisted of 5 to 8 carbons preferred, and a n-alkyl group of 6 carbons is particularly important. Alternatively, R6 is the group shown in the formula following:

R?

~Y

wherein Y indicates a bond with C-16 or an oxygen atom', R 7 is a hydrogen atome halogen atom or halogenated alkyl 0 0 group. Preferably, Y, and R 7 are an oxygen atom, and a 41 0 00halogenated alkyl group, respectively.

0 1 The typical compounds of the present invention are, for example; carbonylic acid esters of 13,14-dihydro-15-keto-PGF; 13,14-dihydro-15-keto-lGR,S-fluoro-PGFs; p: Q ~13,14-dihydro-15-keto-16, 16-dif luoro-PGFs; 13,14-dihydro-15-keto--16R, S-methyl-PGFs 13, 14-dihydro-15-keto-16, 16-dimethyl-PGFs; 13, 14-dihydro--l5-keto-17S-methyl-PGFs; 13, 14-dihydro-15-keo-9--PGFs; 13,14-dihydro-15-keto-110-PGFs; 13, l4-dihydro-15-keto-1-dehydroxy-R-me thyl-PGFs; 13, 14-dihydro-15-keto- 1 1-dehydroxy-llR-hydroxymethyl-PGFs; 13,f 14-dihydro--15-keto-16R4 S-f luoro-11R-dehydroxy-11Rt-methyl- -9- PGFs; 13,14-dihydro--15-keto-20-methoxy-PGFs; 13, 14-dihydro--15-keto-20-methyl-PGFs; *13,14-dihydro-15-keto-20-ethyl-PGFs; 13, 14-dihydro--15-keto-20--n-propyl-PGFs; 13, 14-dihydro-15-keto-20-n-butyl-PGFs; 131,14-dihydro-15-keto-20-ethyl-16R, S-f luoro-PGFs; I 13,14-dihydro-15-keto-20-ethyl-1-dehyroxy-1R-methyl-PGFs; 13,14-dihydro-15--keto-20-ethyl-16R, S-f luoro-11-dehydroxy- 11R-rnethyl--PGFs; 9' J3,14-dihydro-15-keto-16-desbutyl-16-trif luoronethylphenoxy-PGFs.

Though PGFs are usually named according to the skeleton of prostanoic acid as named hereinbefore, these may be named based Qn ItJPAC nomenclature. According to it, for F.example, PGFjq is nomin~ated as 7-[(J.R,2R,3RO5S)-3,5dihydroxy-2( -3-hydroxy-J.-octenyl)-cyclopentyl] 11 heptanoic acid; PGF 2 a is ii(Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-((E-3)3hdoyl acid; 13,14-dihydro-15-keto-20-ethyl-PGF 2 i isopropyl. ester is isopropyl(Z)-.7-[(lR,2R,3R~sS)-3,5-dihydroxy-2-(3-oxo-1decyl) cyclopenty. I-hept-S-enoate;i and 13,14-diydro--15-keto-20-methyl-PGF 2 a methyl ester is methyl (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-(3-oxo-l-nonyX)cyclnopentyl)-kept--enoate.

l3tl4-Dihydro-l5-'keto-PGFs of the present invention, 10 rapidly shows great vasopressor activity without ephemeral vasorelaxation which is inherent to PGFs. Further, 'iay are found to show no effect on trachea, bronchus and intestine such as increase of airway resistance due to contraction of trachea, and abdominal pain or diarrhea due to contraction of intestine, which are inherent to PGs, and found to have low toxicity. Therefore, they are extremely useful as a vasopressor. In addition, according to such vasopressor activity, they can be used as a remedy for essential hypotension, symptomatic hypotension, orthostatic hypotension, acute hypotension accompanied with various diseases and conditions, and can be used as a adjunctive remedy for shock and the like.

t In order to prepare 13,14-dihydro-15-keto-PGFs of the present invention, as shown in the attached sythetic charts, the commercially available (-)-Corey lactone is used as the starting material and subjected to Collines oxidation to give aldehyde which is allowed to react with dimethyl (2-oxoalkyl)phosphonate to give a,8unsaturated ketone After reduction, a carbonyl group of the resulting saturated ketone is protected. An alcohol obtained after the removal of p-phenyl benzoyl from ketone is reprotected by THP, and lactone is redeuced to lactol, and then an a-chain is introduced by Wittig reaction.

13,14-Dihydro-15-keto-PGF 2 s in wchich is 11 CH CHi 6 can be obtained after reduction of lactone to lactol which is subsequently reacted with (4cjarboxybutyl)triphenylphosphorane, and 13,14-dihydro-15keto-PGF~s, in which is

OH

2

OH

2 ca be\ /5\ndb rain rm-o oo-ehrotie afte oylzto ewenC5 6du bn hw eo 4,9 H and be obandtrhydrcxlgopon-tuiong Noofucnmd orJ4dhyr- 4idie tha is to4- ay ,l5additoPsin whb.o ich atom isa ioin atmo n iutnou ylzto ewe 012 -I S. PnPA i ^v*j-'Pr.P-ft aMHO e-t-mv- t I n 12 and the hydroxyl-group on C-9, with DBU, and hydrolysis of th& resulting enol ether with acid to produce 6-keto group.

The synthesis of 13,14-dihydro-15-keto-5,6-dehydro-

PGF

2 s in which is

OH

2

S/

involves 1,4-addition of monoalkylcopper complex or dialkylcopper complex of the following formulae; R4 R

RR

Oo

U

to 4R-t-butyldimethylsilyloxy-2--cyclopenten-l-one, alkylation of the resulting copper enolate after 1,4addition with 6-alkoxycarbonyl-l-iodo-2-hexyne or its derivativesi and reduction of the resulting 13,14-dihydro- 2 types, for example, with sodium borohydride.

13,14-Dihydro-lS-keto-PGF in which R 3 is a methyl group can be obtained after reactingPGA types, which can be prepared by Jones oxidation of the hydroxyl: group or C 9 of 11-tosylate derivatives of PGF types, with dimethylcopper complex, and by reducing the resulting llei-methyl-PGE2 with sodium borohydride. Alternatively, it can be obtained by fl7 13 protecting the carbonyl group'of the saturated ketone (4) pr'epared after reduction of the unsaturated ketone convering the alcohol obtained after removal of pphenylbenzoyl group from the saturated ketone to the corresponding tosylate, treating the tosylate with DBU, converting the resulting unsaturated lactone to the corresponding lactol, introducing an a-chain by Wittig reaction, oxidizing the resulting alcohol (9-position) to a the corresponding PGA, reaction of the product (PGA) with S dimethylcopper complex to introduce a methyl group at the 11-position, and reducing the resulting 11-methyl PGE with, for example, sodium borohydride.

So. 13,14-Dihydro-15-keto-PGFs in which R 3 is a hydroxymethyl group can be synthesized by adding methanol to thus obtained corresponding PGA types using benzophenone as a photosensitizer and reducing the resulting 11hylroxymethyl PGE type, for example, with sodium borohydride.

13,14-Dihydro-15-keto-PGFs in which either R 4 or R is other than a hydrogen atom and R 6 is other than n-butyl may be obtained by using the corresponding dimethyl (2oxoalkyl)phospnonate to obtain a,8-unsaturated ketone For example, 13,14-dihydro-15-keto-PGFs in which R 4 is a fluorine atom, R 6 is n-butyl, and Rg is a hydrogen atom, can be obtained by using dimethyl (3-fluoro-2oxoheptyl)phosphonate, and those wherein R 4 and Rg are both hydorogen atoms and R 6 is hexyl, may be obtained by using 14 dimethyl (2-oxononyl)phosphonate.

S* The synthetic methods of the compounds in the present invention'may not be limited to ones described i above, and the suitable means for protection of th? respective functional groups, oxidation, reduction and the like may be optionally employed.

Prostaglandins F of the present invention can be used as medicaments for animal and human, and, in general, used for systemic or local application by oral administration, intravenous injection, subcutaneous Lnjection and the like. The dosage varies depending on animal, human, age, weight, conditions, therapeutic effect, administration route, treatment time and the like.

The solid composition for oral administration of the present invention includes tablets, powder, granules and the like. In such solid composition, one or more active ingredient may be mixed with at least one inactive diluent, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate and the like. According to the conventional manner, the composition may contain additives other than inactive diluent, for example, lubricant such as magnesiun stearate, disintegrant such as fibrous calcium gluconate, stabilizer such as etherfied cyclodextrin such as a, 8- or y-cyclodextrin, dimethyl-a-, dimethyl-8-, trimethyl-8- or hydroxypropylcyclodextrin, branched cyclodextrin such as glucosyl-, 15 maltosyl-cyclodextrin, formulated cyclodextrin, cyclodextrin containing sulfur, mitthoprotol, phospholipid and the I like. When the above cyclodextrins are used, clathrate j compound with cyclodextrin may be often formed to enhance j stability. Alternatively, phospholipid may be used to form liposome, often resulting in enhanced stability.

Tablets or pills may be coated with film soluble in the stomach or intestine such as suger, gelatin, Shydroxypropyl cellulose, hydroxypropylmethyl cellulose i phthalate and the like, or with more than two layers.

S'Further, they may be formed as capsules with absorbable substances such as gelatin.

Liquid composition for oral administration may contain pharmaceutically acceptable emulsion, solution, I suspension, syrup, elixyr as well as generally used inactive I diluent, for example, purified water, ethanol, vegetable oil such as coconut oil. Such composition may contain adjuvants such as wetting gent and suspension, sweetening agent, flavoring agent, preservatives and the like other than inactive diluent. Such liquid composition may be used by directly enclosing in soft capsules.

Other compositions for oral administration, which may contain one or more active ingredient, include spray formulated by known method.

Injection for parenteral administration according to the present invention includes steril, aqueous or nonaqueous solution, suspension, emulsion and detergent.

16 Such aqueous solution and suspension include, for example, injectable distilled water, physiological saline and Ringer. Non-aqueous solution and suspension include, for example, propylene glycol, polyethylene glycbl, vegetabel oil such as olive oil, alcohols such as ethanol, i polysorbate and the like. Such composition may contain adjuvants such as preservatives, wetting agent, emulsifier, dispersant and the like. These are sterlized, for example, by filtration through bacteria-holding filter, compounding with germicides or irradiation of UV rays. These may be used by producing sterile solid composition and dissolving in sterile water or sterile solvent for injection before use.

The present inve6tion will be illustrated in the following example.

Example 1 synthesis of dimthyl(7-methoxy-2-oxoheptyl)phosphonate: (CH0) O 0H 0 Methyl 6-methoxy-caproate: Sodium hydride (NaH) (50 6.12 g) suspended in tetrahydrofuran (THF) (60 ml) was added to a solution of (15.0 g) in THF (200 ml), and kept at 60 °C *until gas evolution stopped. After cooling, a solution of 17 methyl iodide (12 ml) in THF (35 ml) was added and kept overnight at room temperature. The crude product obtaind after the usual work-up was chromatographed to give 6methoxy-l-hexanol. Yield; 8.16 g 6-Methoxy-hexanol (8.16 g) 'as oxidized with Jones reagent (2.67-M, 53 ml) in acetone (100 ml) at -10 OC to give 6.17 g of 6-methoxy-caproic acid.

6-Methoxy-caproic acid (6.17 g) was dissolved in dry methanol (90 ml) containing hydrogen chloride (catalytic amount) and held overnight at room temperature. The solvent Swas distilled off from the reaction solution under reduced pressure to give methyl 6-methoxy-caproate. Yield; 5.68 g Dimethyl (7-methoxy-2-oxoheptyl)phsophonate: A solution of dimethyl methylphosphonate (8.88 g)in PHF (60 ml) was cooled to -60 OC, to which n-butylithium (1.55 M, 46.2 ml) was added dropwise. After addition, the solution was stirred at -60 OC for 30 minutes. A solution of mithyl 6-methoxy-caproate 5.65 g) in THF (50 ml) was added dropwise to the resulting solution and held at -60 °C overnight, and at room temperature for 2 hours. After the reaction solution was cooled to 0°C, the reaction was neutralized by addition of-acetic acid (4 ml). The crude product obtained after the usual work-up was chromatographed (dichloromethane/methanol (5 Synthesis of dimethyl (2-oxononyl)phosphonate: i i; il- I li_ 18

II

(CH 30)2-P 0 I0 A solution of dimethyl methylphosphoanate (24.3 ml) in THF (500 ml) was cooled to to which nbutyllithium (1.6 M, 136 ml) was added dropwise. After addition, the solution was stirred for one hour, and then ,1 ethyl octanoate (28.5 ml) was added dropwise. The reaction At t Swas stirred at -78 oC for 10 hours. Acetic acid (12.5 ml) K was added to the reaction cooled at 0 oC, and the solution was brought to room temperature and concentrated under I reduced pressure. The residue was diluted with ethyl acetate, and the solution was washed with brine and dried.

The crude product obtained after concentration under reduced pressure was chromatographed (hexane/ethyl acetate 1/1) to I give dimethyl (2-oxononyl)phosphonate. Yield; 30.2 g (83 S(3) Synthesis of dimethyl (3,3-dimethyl-2oxoheptyl)phosphonate: 0 (CH30)2 -'P 0 Ethyl 2,2-dimethyl-caproate: A solution of isobutyric acid (45 g) in THF was I 19added to LDA prepared at -78 dC according to the conventional manner and stirred for one hour. A solution of butyl iodine (107 g) in dry HMPA was added, and stirred at -78 OC for one hour, and at room temperature for additional one hour. The crude product obtained after the conventional work-up was distilled.

Yield; 50 g .680/25 mmHg i* o, Dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate: A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78 to which n butyllithium (1.6 M, 196 ml) was added dropwise. After stirring at -78 OC for one hour, a solution of ethyl 2,2dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78 oC for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0 OC and acetic acid (18 ml) was I added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130 was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72g (26 S(4) Synthesis of dimethyl (3-fluoro-2oxoheotyl)phosDhnate: Methyl 2-fluorocaproate: 0

(CH

3 0) z- P 0 K Methyl 2-bromocaproate (40 g) was added to anhydrous potassium fluoride (23 g) in acetamide (23 g) kept at 105 OC. The mixture was vigorously stirred at 105 0 C for 6 hours. The c..ude product obtained after the conventional work-up was distilled. Yeiled; 20 .g (71 66 0 nummHg 09 Dimethyl (3-fluoro--2-oxoheptyl)2hosphonate:, Dirnethy. methyiphosphonate (8.38 g) was dissolved in dry THF (250 ml) and cooled to -78 OC. n-Butyllithiun 63 V 42 ml) was added dropwise, and the reaction was stirred for 10 minutes. The above methyl fluorocaproate C(200 g) in THF (10 ml) was added dropwise. After addition, the mixture was stirred at -78 0 C for 45 minutes, and then at room temperature for additional 45 minutes. The crude woof 0404 product obtained after the conventional work-up was 0 chromatzographed (hexane/ethyl acetate=l/l) Yield; 5.04 g (62 g) Synthesis of dimethyl (4S)-methyl-2--oxohepbylphosphonate;, 46 0

(CH

3 0) 2

-P

0 0113 Ethyl 3S-:methy-ca.iroate,,: i C--i L 21 Sodium ethoxide was prepared from sodium metal (7.61 g) in absolute methanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise, and the solution was heated to 2-Bromopentane (50 g) was added and the resultant was refluxed for 24 hours. According to the conventional work-up, diethyl (2-pentyl)-malonate (62.7 g) was obtained. Diethyl (2-pentyl)malonate was added to 50 aqueous solution of potassium hydroxide, and heated for 3 Shours while water/ethanol was distilled off. Ater cooling, the resultant was acidified with concentrated hydrochloric t* acid, and subsequently extracted with ethyl acetate. The product obtained after concentration under reduced pressure I was heated at 180 °C until gas evolution stopped. After distillation, colorless 3RS-methyl-caproic acid was obtained. Yield; 27.7 g (35 b.p. >200 °C/760 mnHg 3R,S-Methyl-caproic acid (27.7 g) was dissolved in ethanol (160 ml), and cinchonidine (64 g) was dissolved thereto with heating. The salt obtained after concentration under reduced pressure was recrystallized six times from methanol to give colorless needlelike crystals. Yield; 14.4 g, 3 1 -3.3 (c=13.6 in benzene, lit. -3.1 0 The above 3S-methyl-caproic acid (3,94 g) was converted into ethyl ester using ethanol and catalytic amount of sulfuric acid. Yield; 4.04 g (84 Dimethyl (4S-methyl-2-oxoheptyl)phosphonate: The title compound was synthesized according to the 22 conventional method with using ethyl 3S-rnethyl-caproate and dimethyl methylphcsphonate.

Example 2 (cf. Synthetic scheme 1) Synthesis of 13,14-dihydro-15-keto-,PGF 2 a ehtyl ester R =Et Synthesis of lS- 2 -oxa-3-oxo-6R-(3-oxo-l--transoctenyl) -7R- (4-Lphenylbenzoy) oxy-cis-bicyclo -octane Dimnethyl (2-oxoheptyl)phosphoiaate (8.9 ml) was added dropwise to a suspension of NaH (60 1.76 in THF (200 ml) and stirred for 30 minutes. To the generated phosphonate anion was added aldehyde in TEF (400 ml), 44 which was obtained by Collins oxidatton of (-)--Corey lactone (15 The reaction solution was kept overnight at *roomq temperature and acetic acid was added thereto. After the usual work-up, a,O-unsaturated ketone was obtained, Yield; 11.8 g (62 Synthesis of 1S- 2 -oxa-3-oxo-6R-(3,3-ethylenedioxy- -octyl) -7R- (4-phenylbenzoyl)oxy-cis-bicyclo- (3 3,0) octane The unsaturated ketQne'(3) (11.8 g) was hydrogenated with using 5% palladiUm/carbon (0.300 9) in ethyl a.cetate (100 ml) to give ketone The ketone (4) (11.8 g) was dissolved in toluene (200 ml), to which were added ethylene glycol. and p-toluenesulfonic acid (catalytic 23 amount). The solution was refluxed overnight while water produced was azeotropically distilled off. After the usual work-up, ketal was obtained. Yield; 11.8 g (91 Synthesis of 1S-2-oxa-3-oxo-6R- (3,3-ethylenedioxy-loctyl)-7R-hydroxy-cis-bicyclo-(3,3,0)octane The compound (11.8 g) was dissolved in methanol (100 ml) and THF (20 ml), and potassium carbonate (3.32 g) was added thereto. The reaction mixture was stirred at room temperature for 7 hours. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane= 1/3 to give alcohol Yield; 6.78 g (90 Sy~thesis of tetrahydropyranyl ethei To the dichloromethane solution (100 ml) of the compound 6.78 g) was added dihydropyran (4 ml) and ptoluenesulfonic acid (catalytic amount). The reaction was stirred for 20 minutes, After the usual work-up, the resulting crude product was chromatographed (ethyl acetate/hexane 2/1) to yield the tetrahydropyranyl ether Yield; 8.60 g (100 This operation was repeated and 14.67 g of the product in total was obtained, Synthesis of lactol (8)i Diisobutylaluminium hydride (DIBAL-H) ml) was added dropwise to the tetrahydropyranyl ether (7) 124 (14.67 g) in dry toluene (100 R11) t -78 OC and stirred for minutes. After the usual work- Ip, lactQ1 was obtained.

Synthesis of 13,14-dihiydro-ll-(2-tetrahydropylany1)LOx -15,15-ethylenedioxy-PGFga Sodium hydride (60 11.1 washed with pencane was suspended in DMSO (150 ml), and stirred at 60 70 *C for 3 hours. The generated sodium methylsulfinyl carb~inion op, was cooled, and (4-carboxybutyl)tripheylphosphonium bromide (65.6 9) in DMSO L added to the carbanion solution. The reaction mixture was stirred for 30 minutes. The lactol (d) in DMSO (80 ml) was added to the generated ylide, After 4 ai sti rring overnight, the reaction solution as poured onto ice/water, and the pHi value was adjusted to 12 with 5 sodium hydroxide solution and extracted with ether. The aqueous layer was adjusted to pH1 4-5 with 4 N hydrochloric 4 acid and extracted with ethyl acetate. The comxnbined ethyl acetate layers were washed with brlnef and dried over magnesium sulfate. The solvent from F ie ethyl acetate extracts~ was distilled off under reduced pressure to leave a crude product. The crude product was dissol.ved into ether, and the insoluble matteOrs were filtered off, and the fViltrate W~as concentrated under reduced pressure to give the compound Yield;- 15,17 g (85%)0 Synthesis of 13,14-dih)dro-l- (2-bet rahydrOpY1nylOX

J

-,15,15-ethylenedioxy-PGF,a et:hyl aster Carboxylic, acid (12.1 g) was treated by DBU (4.9 ml) and ethyl iodide (2.4 ml) in anhydrous acetonitrile (100 ml) at 60 0 C for 2 hours. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane 1/3 to give ethyl ester Yield, 1' 8.52 g (63 a(2-8) Synthesis of 13,l4-dihydrD-l5-keto-PGF, 2 Q ethyl ester 0 The compound (10) (0.200 g) in a mixed solvent (acetic acid T1JF water (5 ml) was kept at 50 OC Sfor 4 hours. The solvent was distilled off under redauced pressure, and the resulting crude product' was chromatographed (ethyl acetate/hexane to give 13,14- 0 dihydro-15-keto-PG 2 az ethyl, ester (124. Yield, 0.054 g (41 NMR spectrum of l3,l4-dihydro-5-keto-PGF 2 a ethyl ester (11) is shown in Figure 1. Mass (SIMS) m/z 383 365 (M+1-18) Example 3 Synthetic scheme X) j Syntheais of 13,.4-dihydro-15-keto-PGF. ci methyl 11 ester R Me:, in the same manner as described in Example 2, except~ that carboxylic acid was converted into the corresponding methyl ester (10) with diazomethane, 2,3,14- 2 methyl ester (11) was synthesized.

-26- NMR spectrum of 13,14-dihydro-15-keto-PGF 2 i methyl ester (11) is shown in Figure 2. Mass (SIMS) NaC. added, m/z 391 (m .351 (m+1-18) Example 4 (cf. Synthetic scheme I) Synthesis of 13, 14-dihydro-l5-keto-PGF~a ethyl V ester R=EL: Synthesis of 13,14-dihydro-15,15-ethylenedioxy-ll-(2tetrahydropylanyl)oxy-PGF~a ethyl ester (12): l3,14-dihydro-l5,15-ethylenediocy-ll-(2tetrahydropylanyl)oxy-PGF 2 a ethyl ester (10) (3.50 g) was hydrogenated with using platinum oxide in ethanol (150 ml) and hydrogen. After the usual work-up, 13,14-dihydro--15,15e thylened ioxy-"ll-(2- te trahyd ropy ranyl oxy-PGFci ethyl ester j (12) (3.50 g) was obtained.

Synthesis of 13,14-dihydro-15-keto-PGFca ethyl ester (13): Dihydro-PGF~a derivative (12) (0.10 g) in a miixed solvent (acetic acid water/ TEF 3/1/1) (10 ml) was kept at 50 0 C for 6 hours. The solvent was distalled off under reduced pressure, and the resulting crude product was chromatographed (ethyl acetate/hexane 2/1) to give 13,14c ethyl ester Yield; 0.0455 g (62.

NMR spectrum of 13,14-dihydro-15-keto-PGF~a ethyl ester (13) is shown in Fig~ure 3.

S-27- Example 5 (cf. Synthetic scheme II) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-

PGF

2 a methyl ester (26): a a.

a ar ta 9* mm a mm-, ma~ U a aa mm; a *a a a am a, a 94 9 a~ Synthesis of 1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3-oxo-1trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo- (3,3,0)octane (14): Dimethyl (3R,S-fluoro-2-oxohepty7)phosphonate(10.23 g) in THF was added to sodium hydride suspension in THF, and the mixture was stirred for 20 minutes at room temperature. To the above mixture was added the THF .solution of aldehyde obtained after Collins oxidation of (-)-Corey lactone 15.00 After stirring at room temperature for 2 hours, the reaction solution was neutralized with acetic acid (15 ml). Subsequently, the residue obtained after the usual work-up was chromatographed (ethyl acetate/hexane=1/2) to give enone Yield; 10.45 g (53 Synthesis of 1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,Shydroxy-l-octyl)-7R-(4-phnylbenbenzoyl)oxy-cis-bicyclo- (3,3,0)octane (16): Enone (14) (10.45 g) was hydrogenated in ehtyl acetate (50 ml) using 5 palladium/carbon (1.0 g) and hydrogen to give ketone Yield; 9.35 g (89 Ketone (15) (9.35 g) was reduced in absolute a. e •a a 0 i 28 methanol (200 ml) with using sodium borohydride (1.15 g) to give colorless oil Yield, 6.50 g (69 1S-2-oxa-3-oxo-6R- 4R,S-fluoro-3R,S-t-butyldintethylsilyloxy-l-octyl )-7R-hydroxy-cis-,bicyclo- (3,3,0)octane (18).

Alcohol (16) (6.50 g) was. converted to the corresponding t-butyldimethylsilyl ether (17) in anhydrous DMF (30 ml) with t-butyidimethylsilyl chloride (6.27 g) and imidazole (5.67 Yi.cj.d; 8.80 g (100 9 t-Bulthyldimethylsilyl ether (17) (8.80 g) was dissolved in methanol (80 ml). Anhydrous potassium carbonate (2.09 g) was added to the solution. After the reaction solution was stirred at room temperature for 4 lA 0 0 hours, alcohol (18) as colorless oil was obtained after the conventional treatment. Yield; 4.41 g (67 Synthesis of 13,14-dihydro-16R,S-fluoro-15R,S-tbutyldimethylsilyloxy-11R-(2-tetrahydropyranyl)bxy-PGF,,a mthy~ l ester (22).

Alcohol (18) (4.11 g) was treated with dihydropyran (4.10 ml) and p-toluenesuJlfonic acid (catalitic amount) in dichloromethane (50 ml) at room temperature for minutes. After the usual work-up, the obtained residue was chromatographed (ethyl acetate/hexane 1/4 to give tetrahydropyranyl ether (19) as a colorless oil. Yield; 5.08 g (100 29 Tetrahydropyraryl ether (19) (5.08 g) was reduced with DIBAL-H 20 ml) in anhydrous toluene (60 ml) at -78 0 C to give lactol (20) as a colorless oil.

According to the conventional method, ylide was prepared from (4-carboxybutyl)triphenylphosphonium bromide (18.51 and previously prepared lactol (20) in DMSO was added thereto. The resultant was stirred at room temperature for 2.5 hours. After the usual work-up, the obtained crude product was dissolved in ether, the insoluble matters were'filtered off, and the filtrate was concentrated j under reduced pressure to give a crude carboxylic acid I Yield; 8.0 g The crude carboxylic acid (21) (2.00 g) was converted to the corresponding methyl ester (22) in ethr with diazomethane. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane 1I 1/4 to give 13,14-dihydro-16R,S-fluoro-15R,S-t-.

butyldimethylsilyloxy-llR-(2-tetrahydropyranyl)oxy-PGF 2 a Smethyl ester (22) (0.550 g).

Tetrahydropyranyl ether formation of the compound SSynthesis of bis-tetrahydropyranyl ether (23): Alcohol (22) (0.550 g) was treated in anhydrous dichloromethane (30 ml) with dihydropyran (0.5 ml) and several pieces of p-toluzc'esulfonic acid at room temperature for 30 minutes. The crude product obtained after the usual 30 work-up was chromatographed (ethyl acetate/hexane 1/6 to give bis-tetrahydropyranyl ether (23) as a colorless oil. Yield; 0.580 g (92 Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-PGF 2 a methyl ester (26): Bis-tetrahydropyranyl ether (23) (0.580 g) was treated overnight in anhydrous THF (20 ml) with tetrabutylanmuonuin fluoride 10 ml) at room temperat're. The crude product obtained after the usual t 0, g work-up was chromatographed (ethyl acetate/hexane 1/3 to give alcohol (24) as a colorless'oil. Yield; 0.300 g (62 Alcohol (24) (0.300 g) was oxidized'with Jones reagent (2.67-M, 1.04 ml) in acetone (20 ml) at -10 OC. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane 2/7) to give ketone as a colorless oil. Yield; 0.280 g (94 Ketone (25) (0.280g) in a mixed solvent (acetic acid water/ THF (25 ml) was kept at 55 oC for 2 hours. The solvent was distilled off under reduced pressure and the resulting crude product was chromatographed (ethyl acetate/hexane 2/3 1/1) to give 13,14-dihydro-15keto-16R,S-flUoro-PGF 2 a methyl ester Yield; 0.123 g (63 NMR spectrum of 13,14-dihydro-15-keto-16R,S-fluoro- PGF2a methyl ester (26) is shown in Figure 4. Mass (SIMS) -j ii 44 31 m/z 387 349 +1-18) Example 6 (cf. Synthetic scheme III) Synthesis of 13,14-dihydro-15-keto--16R,S-fluoro- 11R-dehydroxy-.llR-methyl-PGF 2 Qa methyl ester (37): 15R,S-t-Butyldimethylsilyloxy-13,14-dihydro-16R,Sfluoro-PGF.)z methyl ester (29); Lactone (18) (2.313 g) obtained according to IExample was reduced in toluene (25 ml) with using DIBAL-H 15 ml) at -78 0 C to give lactol (27) as a colorless Vt ~oil.

Sodium hydride (60 %,1.84 g) washed with dry ether was suspended in, anhydrous DMS0 (20 ml), and kept at 70 *C for one hour to generate sodium methylsufiny. carbanion. A V solution of (4-carboxybutyl)triphenylphosphonium bromide (10.19 g) in DMSO (30 ml) was added to the generated carbanion cooled at room temperature and stirred at room temperature for 10 minutes to yield ylide. To the ylide was I added above lactol (27) in DNSO (50 ml) and stirr~ed for hours. The crude product obtained after the usual work-up was converted to the corresponding methyl ester with diazomethane, subseqUenthly chromatographed (ethyl acetate/hexane =2/3 3/2) to give ester (29) as a colorless oil. Yield; 1.00 g (34 t) Synthesis of 15R,S-t--butyldimethylsilyloxy-13,14dihydro-16R,S-fluoro-1lR-p-toluenesulfonyloxy-PGF.,ca methyl -32ester S-t-Butyldimethylsilyloxy-l3, 14-dihydro-l6R,Sfluoro-PG 2 i methyl ester (29) (0.430 g) was treated in anyhydrous pyridine (20 ml) with p-tlouenesulfonyl chloride (3.01 g) at room temperature for 2.5 hour~s. The crude product obtained af ter the usual work-up was chromatographed ii (ethyl acetate/hexane 1/3) to give the tosylate (30) as a colorless oil. Yield; 0.417 g (74 15R,S-t-ButyldimeL-hylsilyloxy-13,14-dihydro-16R,S- V fluoro-PGA methyl ester (31): The tosylate (30) (0.417 g) was oxidized with Jones reagent (2.67-Mf 0.9 til) in acetone (25 ml) at.-20 0 C. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane 1/5) to give a PGA derivative (31) as a colorless .cil. Yield; 0.234 g (75 Synthesis of 15R,S-t-butyldimethylsilyloxy-13,14dihyro-1 6R, S- flIuo ro-l 1R-dehyd roxy-1 R-me thy -PGE, methyl ester (32): Copprr iodide (0.233 g)was suspended In anhydrous ether (30 ml)t to which was added dropwise methyllithium 1.56 ml) at -10 O 0 C. A solution of the enone (31) (0.281 g) in anyhydrous ether (20 ml) was edded to the above mixture. After stirring at -10 OC for 40 minutes, acetic acid (0.6 ml) was added to stop the reaction. The crude product obtained after the usual work-up was chromatographed -33- (ethyl acetate/hexane to give a 11R-methyl compound as a colorless oil. Yield; 0.192 g (66 Synthesis of 15R,S-t-butyldimethylsilyloxy-13,14dihydro-16R,S-fluoro-1R-dehydroxy-1R-nethyl-PGFcz methyl ester (33): llR-Methyl-PGE 2 derivative (32) (0.234 g) was reduced in dry methanol (15 ml) with using sodium it borohydride (0.178 g) at 0 OC. The crude product obtained after the usual work-up was chromatographed (ethyl ft Iacetate/hexane to give 9c-hydroxy derivative (33) as a colorless oil. Yield; 0.133 g (57 13,14-Dihydro-16R,S--fluoro-15-keto-11R-dehydroxy-11Rmethyl-PGFqac methyl ester (37): 9ci-Hydroxy derivative (33) 0.302 g) was converted to the corresponding tetrahydropyranyl ether (34) according to the conventional manner. Yield; 0.352 g (100 I llR-Methl-PGF a derivative (34) (0.353 g) was converted to alcohol (35) with using tetrabutylamnonium fluoride 4 ml) in anhydrous THF (15 ml). Yield;, 0.261 g (92 Alcohol (35) (0.261 g) was oxdzdwith Jones reagent (2.67-M, 0.5 ml) in acetone (15 ml) at -15 0 C. The crude product obtained after the usual work-up was chromatographed (ethyl acetate/hexane 1/7) to give ketone Yield; 0.262 g (87

I

1 0 '4 t~ II 0 I I* I I I

A

34- Ketone (36) 0.226 g) in a mixed solvent (acetic acid water /,ATHF 10/3.3/1) (20 ml) was kept at 45-50 0

C

for 3 hours. The solvent was concentrated under reduced pssure and the resulting crude product was chrornatographed (ethyl acetate/hexane= 1/3 to give 13,14-dihydro-iS-keto- 1,6R,S-fluoro-llR-dehydroxy-lR-methyl-PGF 2 amhyesr Yield; 0,171 g (92 NMR spectrum of 13,14-dihydro-15-keto-16R,S-fluorollR-dehydroxy-lR-methyl-PGF 2 a methyl ester (37) is shown in Figure 5. Mass (SIMS) m/z 385 367 Example 7 (cf. Synthetic scheme IV) Synthesis of 13,14-dihydro-15-keto-20-ethyl- PGFqci methyl ester (45) R =Me lS-2-oxa--3-oxo-6R-(3-oxo-l-Lrans-'decenyl)-7R-(4phenylbenzoyloxy) -cis-bicyclo 3, 0)octane (38): The solution of dimethyl (2-oxononyl)phosphonate (3.50 g) in dry THF (50 ml) was added dropwise to NaH 0.570 g) in THF (100 ml) and the reaction mixture was stirred for 40 minutes. A THF solution (60 ml) of aldehyde obtained from (-)-Corey lactone (1).was added dropwise to the phcsphonate anion in THF. After stirring overnight, acetic acid (5 ml) was added under ice-cooling and the compound (38) was obtained according to the conventional manner.

Synthesis of 1S-2-oxa-3-oxo-6R-(3-oxo-l-decyl)-7R-(4phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane (39): Unsaturated ketone (38) was hydrogenated in ethyl acetate (150 ml) with using 5% palladium/carbon (0.120 g) to give the compound (39).

Synthesis of 1S-2-oxa-3-oxo-.6R-(3,3-ethylenedioxy-ldecl -7R- (4-phenylbenzoyl )oxy-cis-bicyclo( 3,3,0 )octane Saturated ketone ethylene glycol (10 ml) and t, t p-toluenesulfonic acid (catalytic amount) were dissolved in benzene (200 ml), and the solution was heated at reflux for Li24 hours using a Dean-Stark Trap. After the usual work-up, the compound (40) was obtained. Yield; 3.90 g (53 basd on the compound 4 Synthesis of 1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxydecyl)-7R--hydroxy-cis--bicyclo(3,3,0)octane (41): Ketal (40) (3.90 g) was dissolved in dry methanol 1(150 ml) and stirred with potassium carbonate (1.30 g) for 6 LIhours. Acetic acid (0.9 g) was added while cooling with ice. The crude product obtained after the Usual work-up was ~chromatographed to give the compound YLield; 2.18 g Synthesis of 20-ethyl-15,15-ethylenedioxy-13_,14dihydro-PGF!)a m~ethyI ester (44): 36- Lactone (41) (1.22 g) was reduced in dry toluene ml) with using DIBAL-H (7.6 ml) at -78 OC. After stirring for 45 minutes, methanol (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ether and filtered. The filtrate was concentrated under reduced pressure to give lactol (42).

Sodium hydride (60 1.15 g) washed with dry ether was suspended in DMSO (30 ml) and kept at 65 -70 OC for one hour to generate methylsulfinyl carbanion. A solution of (4-carboxybutyl)triphenylphosphonium bromide (6.4 g) in DMSO was added to the carbanion at room temperature to generate ylide, and the solution was stirred for 40 minutes. Lactol (42) in DMSO was added dropwise and the resultant was stirred overhight. The solution was poured into ice/water, the pH value was adjusted to 12 with aqueous potassium carbonate and the resultant was extracted with ethyl acetate. The aqueous layer was adjusted to pH 4 with diluted hydrochloric acid while cooling with ice and extracted with ether. The combined ether layers were dried and concentrated under reduced pressure to give the compound The crude product (43) was converted into the corresponding methyl ester (44) with diazomethane, which'was chromatographed. Yield; 1.29 g (82 Synthesis of 13,14-dihydro-15-keto-20-ethyl- PGFia methyl ester 37 Ketal (44) (1.06 g) was dissolved in a mixed solvent (acetic acid/water/THF 3/1/1) (18 iid) and kept at 0 C for 3 hours. The solvent was disciaed off and the resulting crude product was chromatographed to give ethyl-13,l4-dihydro-15-keto-20-ethyl-PGF methyl ester Yield; 0.868 g (74 NMP. spectrum. of 123,14-dihydro-15-keto-20-ethyl-

PGF

2 a methyl ester (45) is shown in Figure 6.

Example 8 Synthesis of 13,14-dihydr-16,16-dimethyl-15-ketot1: PGF 2 i e hyl ester (46):

OH

(46) C 0 0 E OH 0 In the same manner as described in Examples I to 7 l3,l4-dihydro-5-k eto-l,166-dmethyl-PGF 2 q ethyl ester (46) was obtained with using (-)-Corey lactonQ and diniethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, NMR spectrum of l3jl4-dihydro-15-keto-16fldimethyl-PGF 2 ethyl ester (46) is shown in Figure 7. Mass (DT) m/z 410, 392 374 Example 9 Synthesis of 13,l4-dihydro!-15Sketo-2O-nethoxy-I PGFc metyl ester r; i I' 38

OH

(47) OH 0- In the same manner as described in Example to 8, l3,14-dihydro-15-keto-20-nethoxy-PGF 2 a methyl ester (47) was prepared with using (-)-Corey lactone and diethyl (7rnethoxy-3-oxoheptyl)phosphonate.

NMR spectrum of 13,14-dihydro-l5-keto20--methoxy-

PGF

2 a methyl ester (47) is shown in Figure 8.

ar d ~Example t IP Synthesis of 13,14-dihydro-15-keto-17S-meh 1-

PGF

2 a ethyl ester (101)%

OH

COE t (101) 0OH 0 CHI In the same manner as described in Exanple 1 to 9, l3,14-dihydro-L5-keto-27s-methyl-PGFcia ethyl estor (101) Was prepared with using (-)-Corey lactone and dimethyl (4S- Methyl-2-oxoheptyl)phosphonate.

NMR spectirum of 13,l4-dihydro-15-keto-17S-'raethyl-

PGF

2 0c ethyl ester (101) is shown in Figure 9. Mass (DI) m/z 396 378 18)0 360 Example 11 (cf, Synthetic scheme IV) Synthesis of 13,14-dihydro-15-keto-20-ethyl- 39 PGF-cz ethyl ester (45) R=Et: Procedure described in Example 7 was repeated to prepare 20-ethyl-l3,14-dihydro-K-L5-keto-PGF 2 a ethyl ester except that carboxylic acid (43) was converted into the corresponding ethyl ester (44) with using ethyl iodide ard DBU in acetonitrile at 50 *C.

NMR spectrum 13l-iyr-5-ec-0ehl el~ ester (45) is shown in Figure 10. Mass (DI) rn/z 410 (),392 374 1xample 12 (cf. Synthetic scheme IV) Synthesis of 13,14-dihydro-15-keto-20-ethyltat PGF,. isopropyl ester Riso-Pro: Procedure di -cribed in Example 7 was repeated, exept that carboxylic acild (43) was converted into the corresponding isopropyl. ester (44) with using isopropyl iodide and DBU in acetonitlile at 50 OC and 20-ethyl--13fl4- 2 a isopropyl ester (45) was obtained.

NMR spectroeq of 2344-d'&hydro-15--keto-20-ethyl-

PGF

2 a isopropyl ester (45) is shown in Figure 11. Mass (DI) m/z 424 406 388, 347 Example 13 (cf. Synthetic scheme TV) Synthesis Iof 13, 14-dihydro-15--keto-20-th1

PGF

2 a n-butyl ester (45) R~n-FPu: Procedure described In Example 7 was repeated to prepare 20-ethyl-13,14-dihydro-J.5-keto-PGF 2 o n-butyl ester excpt that carboxyl.ic acid (43) was converted into the corresponding n-butyl ester (44) with usi.ig n-butyl iodide and DBU in acetonitrile at 50 OC.

K NMR spectrum of 13,14-dihydro-15-keto-20-ethyl- PGF a n-butyl ester (45) is shown in Figure 12. Mass (DI) 420 402 (M 376, 347 Example 14 (cf. Synthetic scheine IV) Synthesis of 13,14-'dihydro-l5-keto-20-ethyl-PGF~a mnethyl. ester (48): HO COOMe HO 0(48) 23,14-Dihydro-15-keto-20-ethyl-PGPca methyl ester R=Met (0.0505 g) was hydrogenated in ethanol with using PtO 2 to give 13,J.4-dihydro-J5-keto-20-ethyl- PGFja methyl ester (48) (0.0166 g\.

NMR spectrum of 20-ethyl--13,14-dihydro-15-keto- PGFla methyl ester (48) is shown in Figure 13. Mass (DI) rn/z 398 380 362, 349 Exa~mple 15 (cf. Synthetic scheme V) Synthesis of,13,14-'dihydro-15-keto-20-ethyl-11Rdehydtoxy-1R-rnetfiyl-PGF~a methyl Oster (57): Tosylation of 1S-2-oxa--3-oxo-6R-(3,3-ethylenedioxy-ldecyl) -7R-hydroxy-cis-bicyclo(3,'3,0) octane synthesis of tosylate (49)- 4 -41- Alcohol (41) (1.723 g) was treated with ptoluenesulfonyl chloride (12.893 g) in pyridine (5 ml) at 0 OC to give tosylate (49).

Yield; 1.812 g (74 (15-2) Synthesis of 1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-ldecyl)-cis-bicyclo(3,3,0)-7-octene Tosylate (49) (1.812 g) was dissolved into toluene (1.9 ml) and DBU (5.6 ml), and the solution was kept at C for 7 hours. The crude product obtained after the usual work-up wa~s chromatographed (hexane/ethyl aceta~te to give olefin Yield, 0.7594 g (63 (15-3) Reduction of 1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-ldecyl)-cis-bic~clo(3,3,0)-7-octene (50) with DIBAL-H; synthesis of lactol (51): Olefin (50) (0.7594 9) was reduced with DIBAL-H 6.2 ml) to give lactol (51).

(15-4) Synthesis of methyl 20-ethyl-15,15-ethylenedioxy-9S hydroxy-cisA 5

_A

10 -prostanoa~e (53)4 Lactol (51) was allowed to react with y'iide obtained from (4-carboxybutyl)triphenylphosphonium bromide' and sodium 'nnethylsulfinyl carbanion in DMSO to give prostanoic acid The resultant was esterified with diazomethane to give the corresponding methyl prostanoate Yield, 0.6600 g (67 C. -42- (15-5) Synthesis of 13,14-dihydro-20-ethyl-15,15ethylenedioxy-PGA, methyl ester (54): Methyl prostanoate (53) (0.6600 g) was oxidized 1with Jones reagent in acetone (40 ml) at 20 0 C. After V chromatography (hexane/ethyl acetate 13,14-dihydro- I 20-ethyl-15,15-ethylenedioxy-PGA 2 methyl ester (54) was obtained. Yield, 0.6182 g (99 t%) (15-6) Synthrosis of* 13,14-dihydro-20-ethyl-15,15- V ethylenedioxy-11R-dehydroxy-11R-methyl-PGE 2 methyl ester Enone (54) (0.6100 g) was allowed to react with dimethylcopper complex obtained from copper iodide (0.8380 q) and methyllithium 5.8 ml) in ether (15 ml) to Ii give 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-llR- IA dehydroxy-JR-methyl-PGE 2 methyl ester Yield, 0,5720 g (94 (15-7) Syn~hesis of 13,.4-dihydro-15-keto-20-ethyl.-11Rrethyl-PGF 2 a methyl ester (57): U Ketone (55) (0.4023 g) was reduced with diisobutylalumlnium (2,6-di-tert-butyl-4-methyl)-phenoxide in toluene to give alcohol Alcohol (56) (0.2016 g) was kept in a mixed solvent (acetic acid/water/THF 3/1/1) ml) at 50 0 C for one hour. After the usual procedure, 13, J4-dihydro-15-keto-2o-ethyl-llR-dehydroxy-llR-methyl- 43 L 4F

P

2 a methyl ester (57) was obtained. Yield; 0.0960 g NMR spectrum of l3,14-dihydro-l5-keto-20-ethyl-1lRdehydroxy-llR--methyl-PGF 2 a methyl ester (57) is shown in Figure 14. Mass 394 (DI) m/z 394 375 358, 344 Example 16 Synthesis of 13,14-dihydro--15-keto-20-n-butyl- PGF,a methyl ester V 110 0(58) In the same manner as described in Examples 7 to 14, 13,14-dihydro--l5-keto-20-n-butyl-PGF 2 a methyl ester (5f8) was obtained with using dimethyl (2-oxoundecyl)phosphonate prepared in the same manner as preparation of dimethyl (2oxononyl)phosphonate in Example 1 and (-)-Corey lactone.

V NMR spectrum of 13,14-dihydro--15-keto-20-n-butyl- PGFa methyl ester (58) is shown in Figure 15. Mass (DI) m/z 424, 406 18), 388, 375 Example l/ Synthesis of 13,14-dihydro-5-keto-20 2 etyl- PGF~a methyl ester

HO

co 0 -44 In the same manner as described in Exarn-',es 7 to 14 and 16, 13.,14-dihydro-15-keto-20-methyl-PGF 2 a methyl ester (59) was obtained with using dimethyl (2oxooctyl)phosphonate prepared in the same manner as preparation of dimethyl (2-oxononyl'phosphonate in Example 1, and (-)-Corey lactone NMR spectrum of '3,14-dihydro-15-keto-20-methyl-

PGF

2 z methyl ester (59) is shown in Figure 16. Mass (SIMS) m/z 383 365 347 Example 18 Synthesis of 13,14-dihydro-15-keto-20-ethyl-16R,Sfluoro-11R-dehydro-lIR-methyl-PGF 2 a methyl ester CH 3 in the same manner as described in Example 6, 13, 14-dihydro-15-keto-20-ethyl-16R, S-fluoro--llR-dehydroxy- 1lR-mbthyl-PGF 2 px methyl ester (60) was obtained with using dimethyl (3R,S-fluoro-2-oxoionyl~phosphoflate prepared in the same manner as synthesis of dimethyl (3R,S-fluoro-2oxoheptyl)phosphonate in Example 1, and (-)-Corey lactone.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl- 16R,S-fluoro-lR-dehydro-lR-methyl-PGF 2 I methyl ester is shown in Figure 17. Mass (DI) m/zA4l2 (M 4 394 (M+_18) Example 19 Synthesis of 13,14-dihydro-15-keto-20-ethyl-16R,Sfluoro-PGFga methyl ester

HO

F

HO 0 (1 H In the same manner as described in Example l3,14-dihydro-l5-keto-20-ethyl-l6R,S-fluoro-PGF 2 a methyl ester (61) was obtained with using dimethyl (3R,S-fluoro-2oxononyl)phosphonate and (-)-Corey, lactone.

t l NMR spectrum of 13,14-dihydro-15-keto--20-ethyl- 16R,S-f r-G 2 a methyl ester iz shown in Figure 18.

Mass (DI) m/z 414 396(M 1l8), 378, 358 Example 20 (cf. Synthetic scheme VI) Synthesis of 13,14-'dihydro-15-keto-9o,lla-PGF 9 methy, ester R=CH2: Alcohol (10) (0.2423 g) was converted into the j K corresponding benzoate (62) in dichioromethane (20 ml) with using diethlyl azodicarboxylate (0.1026 benzoic acid (0.0720 g) and triphenylphosphine (0.1545 g).

Yield; 0.1223 g The above benzoate (62) was treated with potassium carbonate in methanol to give 98,lla-PGF derivative (63).

The obtained 98,lla-hydroxy-PGF derivative is deketalized to 13,14-dihydro-15-keto-9a, llcz-PGF 2 methyl ester (64) Yield; 0.0236 g NM.R spectrum of 13,14-dihydro-15-keto--90-11ahydroxy-PGF 2 methyl ester R=CH 3 is shown in Figure 46 19.

Mass (DI) m/z 368 350(M+-18), 332, 319, 301 Example 21 Synthesis of 13,14-dihydro-15-keto-20-n-propyl- PGF,)a methyl ester

HO

4 HO 0 tt In the same manner as described in Examples 7 to 14, 16 and 17, 13,14-dihydro-15-keto--20-n-propyl-PGF a methyl ester (65) was prepared with using dirnethyl (2oxdeyl)phosphonate obtained in anlgu to thle synthesis of dimethyl (2-oxononyl)phosphonate in Example 1, and Corey lactone'(1).

NMR spectrum of 13,14-dihydro-15-keto-20-n-propyl-

PGF

2 a methyl ester (65) is shown in Figure Example 22 (cf. Synthetic schemes II and VII) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-

PGF

2 a (68): 22-1) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-9,1bis(2-tetrapyranyloxy)-PGFcz (67) Ester (24) (0.796 g) was stirj,,ed ovornight with lithium hydroxide (0.5 mol/l00 ml) in I.,HF (50 ril) at room temperature. After acidified with hydrochloric- acid in an ice bath, f~he solution was extracted with ethyl acetate.

The crude p'roduct (66) obtained after concentration under I4 reduced pressure was oxidized with Jones reagent in acetone at -l5 0 C to give ketone Yield; 0.330 g (22-2) Synthesis of 13,l4-dihydro-15-keto-16R,S-fluojro-

PGF

2 cz (68): Ketone (67) (0.330 g) was kept in a mixed solvent (acetic acid/water/THF (25 ml) at 45 0 C for 3 hours. After the usual work-up, the product was chrornatographed (ethyl acetate/hexane 1/3 2/3) to give 13,14-dihydro-15-keto-16R,S-.fluoro-PGF 2 a (68) as a pale yellow oil. Yield; 0.112 g PGF~aNMR spectrum of 13,14-dihydro-15-keto-16R,S-fluoro- GFa(68) is shown in Figure 21. Mass (DI) m/z 372 (M )I 354(M+-18), 336, 284, 256 Example 23 (cf. Synthetic scheme VII) Synthesis of 13,14-dihydro-15-keto-20-ethyl-16R,Sfluoro-PGFc (69):

OH

N..-~NO0H (69) 0OH 0 V In the same manner as described in Example 22', 13,14-dihydro-l,$-keto-20-ethyl-16R,S-fluoro-PGFcL (69) was prepared with using (-)-Corey ).actone and dimethy"L (3R,S-fluoro-2-.oxo-)nonyl)phosphonate obta~ner acc~ording to the conventional method.

NMP. spectrum of 13,14-dihyro-15-keto-20ethyl- 48 16R,S-fluoro-PGF 2 a (69) is shown in Figure 22. Mass (DI) J m/z 400 (M 382 18), 362, 344 Example 24 (cfL'. Synthetic scheme IV) Synthesis of 13,14-dihydro-15-keto-20-ethyl- PGFcx

OH

OH 0 13 ,14-Dihydro-20-ethyl-15 PGF a (43) 518 g) was dissolved in a mixed solvent (acetic acid/THF/water (10 ml) and held at 601C for 2 hours. After the usual. work-up, the resulting crude product was chromatographed to give 13,14-dihydro-1 5-keto- 20 -ethyl- PGF a Yield; 0.202 g NMR spectrura of 13,14-'dihydro-15-keto-20-ethy,-

PG,"?

2 a (70) is shown in Figure 23. Mass (DI) m/z 364 18), 346 Example 25 (cf. Synthetic scheme VIII) Synthesis of 13,14-dihydro-15-keto-16-desbUtyl16m-trifluoromebypheiioxy-PGF 2 a methyl ester (82): (25-1) Synthesis of IS-2-oxa-3-oxo-6R-( 4-m-trifluokomethylphencxy-3-t-butyldimethylsilyloxy-l-butyl) -7R-hydroxy- *cis-bicyclo(_3_t3, 0)octane In tht- same manner as described in Example alcohol (75) was obtained using tunsaturated ketone (71) 49 which was prepared with using (-)-Corey lactone and dimethyl (3-m-trifluoromethylphenoxy-2-oxopropyl)phosphonate obtained according to the usual method.

(25-2) Synthesis of 13,14-dihydro-15R,S-t-butyldimethylsilyloxy-9 ,ll -bis (2-tetrapyranyl )oxy-16-desbutyl-16m-trifluoromethylphenoxy-PGFja methyl ester (79): 13, 14-Dihydro-lSR, S-t-butyldimethylsilyloxy-16desbutyl-16-m--tri-fluoromethylphenoxy-PGF 2 x methyl ester (78) (0.50 g) obtained from alcohol (75) according to the usual method was converted into the compound (79) in dichloroynethane (50 ml) using dihydropyran (1.5 ml) and catalytic amount of p-toluenesulfonic acid.

(25-3) Synthesis of 13,14-dihydro-15R,S-hydroxy-9,ll-bis(2tetrapyranyl )oxy-16-desbutyl-16-m-trifluoromethylphenoxy- PGF.~Q methyl ester The above compound (79) was converted into the compound (80) using tetrabutylammonium fluoride in TIIF ml). Yield; 0.42 g (77%) (25-4) Synthesis of 13,14-dihydro-15-keto-9,11-bis(27 tetrapyranyl )oxy-16-desbutyl16-m-tri-fluO -'methyl~henoxy: PGF.,a methyl ester (811A: The compouna (80) (0.42 g) was oxidized with Jones reagent in acetone (15 ml) at -35 0 C to give ketone (81).

YielO; 0.18 g (43%) I- 50 S(.25-5) Synthesis of 13,14-dih',dro-5-keto-16-desbutyl-16-m- K trifluoromethylphenoxy-PGFga methyl ester (82): The compound (81) (0.18 g) was dissolved in a mixed I solvent (acetic acid/TEF/water 3/1/1) (15 mI) and kept at 0 C for 2 hours. The crude product obtained after the usual work-up was chromatographed to give 13,14-dihydro-15keto-l6-desbutyl-16-m-trifluoromethylphenoxy-PGF 2 0 methyl ester Yield; 0.123 g (93%) K NMR spectrum of 13,14-dihydro-15-keto-16-desbutyl- 16-m-trifluorometbylphenoxy-PGF 2 a methyl ester is shown in Figure 24. Mass (DI) m/z 472, 454, 436, 423 Example 26 Synthesis of 13,14-dihydro-15-keto-16RS-fluoro-20methyl-PGF 2 i methyl ester (83):

OH

cooe (83) OH 0 In the same manner as described in Example l3,l4-dlhydro-15-keto-1.6RS-fluoro-20-methyl-PGF 2 a methyl ester (82' was obtained with using (-)-Corey lactone and dimethyl (3R,,S-fluoro-2-okcooctyl)phosphonate.

NMR spectrum of 13,14-dihydro-.5-keto--16RS-fluoro- 2 0 nethyl ester (83) is shown in Figure Mass (DI) m/z 400, 382, 364, 362 Example 27 (cf. Synthetic scheme IX) I -I I I 51 Synthesis of 13, 44-diydro-15-keto-16,16-difuloro-

PGF

2 i methyl ester (96): (27-1) Synthesis of 1S-2-oxa-3-oxo-6R-(4,4-difluoro-3-oxo-ltrans-octenyl )-7R-(p-phenylbenzoyl )oxy-cis-bicyclo- (3,3,O)octane (84): (-)-Corev lactone (6.33 g) was oxidized wtih Collins reagent to give aldehyde Separately, thalliun ethoxide (4.26 g) was dissolved in benzene, to which was added a solution of diwethyl (3,3-difluoro-2-oxoheptyl)phosphonate (4.64 g) in benzene, and the solution was stirred for 30 minutes# The crude product obtained after the usual work-up was chomatographed (ethyl acetate/hexane :t1/2) to give the compound Yield; 3.88 9 (27-2) Synthesis of 1S-2-oxa-3-oxo-6R-(4,4-di fjltto--,-RShydroxy-l-octyl -7R-(p-phenylbenzoyl )oxy-cis-bicyclo- (3,3,0)octane (86): Enone (84) (3.88 g) was hydrogenated in ethyl acetate (40 ml) with using 5% palladium/carbon (0.39 g) to give the compound The above compound was reduced in a mixed solveot (THF itteohanol 30/70 ml) with usiag NnBH 4 to give alcohol Yield; 4.02 g Synthesis of IS-2-oxa-3-oco-6R-(4,4-diflUoro-3RS-t -52 butyldimethylsilyloxy-l-octyl )-7R-hydroxy-cis-bicyclo- (3,3,0)octane (88): Alcohol (86) (4.02 g was converted into the corresponding silylether (87) in DMF with using tbutyldirethylsilyl chloride and imidazole. The product was tconverted to the compound (88) with potassium carbonate (1.14 g) in methanol (80 ml). Yield; 2.89 g (83%) (27-4) Synthesis of l3,14-dihydro-15-keto-16,16-difluoro- PGFa methyl ester (96); In the same manner as described in Example 5f using the compound (88) (2.89 the synthetic intermediate (92) was obtained. Yield; 3.0 g In the same manner as described in Example 5, Isirg the compound (92) (0.44 13,14-dihydro-15-k,eto-16,.6dlfluoro-PGF 2 a methyl ester (96) was obtained. Yield; 0.683 NMU spectrum of l3,l4-dihydro-!.,c-keto-l6,l6diflUoro-PG1F 2 methyl ester (96) is shown in Figure 26.

Mass (DI) m/z 404, 386, 368, 355 8xample 28 (cf. Synthetic scheme X) Synthesis of 13,14-dihydro5-1keto-167desbutyl-16m-trifluoromethylphenoxy-PGF 2 a (100): (28-1) Synthesis of tetrapyranyl ether (O)z The crude carboxylic acId (77) was converted to the corresponding tetrapyranyl ether (97) in dichl3oromethane 53 with using excessive amount of dihydropyran and ptoluenesulfonic acid as a catalyst. Yield; 0.63 g (28-2) Synthesis of alcohol (98): The above tetrapyranyl ether (97) (0.63 g) was converted to the corresponding alcohol (98) in THF with using tetrabutylammonium fluoride, Yield; 0.38 g (28-3) Synthesis of ketone (99): The above alcohol (98) (0.38 g) was oxidized with 6 9 Collins reagent to give ketone Yield; 0.34 g (2 8-4) Synthesis of 13,14-dihydro-15-keto-16-desbutyl-16-mq .trifluoromethylphenoxy -PGF 2 a (100): The above ketone (99) (0.34 g) was kept in a mixed solvent (acetic acid/THF/water 3/1/1) at 45 50 Oc for hours. After completion of the reaction, the reaction 4w 4 solution was concentrated. The resulting residue was chromatographed to give 13,14-dihydro-15-keto-16-desebutyl- 16 -m-trifluoromethylphenoxy-PGF 2 a (100). Yield; 0.1 g ""NMR spectrum of 13,14-dihydro-15-keto-16-desbutyl- 16-m-trifluoromethylphenoxy-PGF 2 a (100) is shown in Figure 27. Mass (DT) m/z 458, 441, 423 NMR data of the ir termediates obtained in the above Examples 6 27 is shown below: 6 OA,5 (6H, 0.88 (9H, 0.75 1405 1.05 54 2.5 (23H, 2,42 (3H, 3.63 (3H, 3.4 4.7 (4H, 5.37 (2H, 7.28 (2H, d, J=9Hz), 7.75 (2H, d, J=9Hz).

(31) 0.05 (6H, 0.88 (9H, 0.75 1.05 (3H), 1.05 2.7 (20H, 3.63 (3H, 3.5 3.85 3.85 4.1 (0.5H, 4.4 4.65 5.35 (2H, 6.09 (1H, dd, J=6Hz, J=3Hz), 7.53 (1H, dd, J=6Hz, 3Hz).

(39) 0.87 (31, t, J=6Hz), 1.05 3.0 (22H, 4.93 5.25 (21, 2.2 8.1 (9H, m) (41) 0.87 (3H, t, J=613,) 1.0 3.0 (23, 3.88 (4H, 3.6 4.2 4.91 (1H, dt, J=6Hz, J=3Hz) (62) 0.88 (3H, 1.05 -2.4 (30, 3.60 (3H, s), 3.88 (4H, 3.2 4.3 (31, 4.6 (1H, bS), 5.11 (IHi, 5.40 (2H, 7.3 8.1 (5H, i).

(63) 0.89 (3H, 1.0 2.4 (311, 3.62 (3H, s), 3.87 (411, 3.3 4.2 (4H, 4.55 (11, bs), 5.42 (28, m) (88) 0.05 (6H, 0.87 (91, 0,75 1.0 (31TI, l,0S 3.0 (17, 3.35 3.80 3!97 (11.

4.88 (11, dt, J=6Hze H=31z).

(92) 0.08 (61, 0,88 (9H, 0.77 ls.5 (3H) (29H, 3.63 (3H, 3.3 4.2 (51, m), 4.62 (2,H m)i, 5.40 (21, m).

55 Experiment 1 Male Wister rat (8-week old) was anesthetized by intraperitoneally'administering urethane (1.25 g/kg).

Polyethylene tube was inserted into femoral artery and connected with pressure transducer to measure blood pressure.

The test drugs were dissolved in ethanol, diluted with Ringer's solution before use and a dose of 1 mg/kg was administered into tale vein. The maximum concentration of ethanol was As reference, ethanol-Ringer's solution without containing test drugs was used and the effect was checked in each experiment without failing. The rate of change in blood pressure was determined by average of dta per group.

The results are shown in Table 1.

I I 11t c

L,

-56- Table 1 Test Dr-i Change in Blood Pressure(% 1 +12 2 +17 )3 +14 4 +27 +18 9 96 +44 7 +26 98 7 9 +41 +18 11 12 +16 13 8 14 +32 7 16 +14 17 18 +13 19 8 Table 1 (continued) Test Drug Change in Blood Pressure M%' 21 +16 22 7 23 24 +24 26 0 Test Drugs 13,14-dihydro-15-keto-PGF 2 i methyl ester 13,14-dihydro-1-et-G 2 a ethyl ester 13,14-dihydro-15-keto-9a-PGF 2 a methyl ester 13,14-dihydro-15-keto-16,lG6-dimethyl-PGF2 a ethyl ester 13,14-dihydro-l5-keto-16R,S-fluoro-PGFa 13,14-dihydro-15-keto-6RS-fluQio-PGF2 a methyl cstar 13,l4-dihydro-l5-keto-l6,16-difluoro-PGF2 a metkhyl ester 13,14-dihyd9-ro-15-keto-16R,S-fluoro-11Rflethyl-

PGF

2 i methyl ester l3,l4-dihydro-l5-keto-16R,S-fluoro-20-methyl-

PGF

2 c± methyl ester 13,14-dihydrolS-keto-6R,Sfluor)20-ethyl-PGF2 a (11) l3,l4-dihydro-15-keto-16RS-fluoro-20-ethyl-

PGF

2 methyl ester (12) 13,14-dihydro-15-keto-16R,S-fluoro-20-ethyl12-l-methyl-

PGF

2 0 r,,,thyl ester

I

58 (13) 13,14-dihydro-15-keto-17S-methyl-PGF 2 a ethyl ester (14) 13,14-dihydro-15-keto-20-methyl-PGF 2 z methyl ester 13,14-dihydro-15-keto-20-ethyl-PGF 2 m l 1314-dihydo-15-keto-20ethyl-PGF e (16) 13,14-dihydro-15-keto-20-ethyl-PGF 2 a methyl ester (17) 13,14-dihydro-15-keto-20-ethyl-PGF 2 a ethyl ester (18) 13,14-dihydro-l5-keto-20-ethyl-PGF 2 a isopropyl ester (19) 13,14-dihydro-15-keto-20-ethyl-PGF 2 a n-butyl ester 13,14-dihydro-15-keto-20-ethyl-PGF 2 a methyl ester (21) 13,14-dihydro-15-keto-20-n-propyl-PGF 2 a methyl ester (22) 13,14-dihydro-15-keto-20-n-butyl-PGF 2 t 'methyl ester (23) 13,14-dihydro-15-ketc'-16-desbutyl-16-(mtrifluoromethylphenoxy)-PGF 2 a methyl ester (24) 13,14-dihydro--15-keto-PGFla ethyl ester 13,14-dihydro-15-keto-20-ethyl-PGFla methyl ester (26) Ringer's solution As is obvious from the above results, 13,14of the F series of the present invention distinctly show vasopressor effect.

Further, it has been found that those containing halogen such as fluorine or lower alkyl group such as methyl or phenoxy especially show surprisingly great vasopressor effect.

Experime~it 2 Measurement of pulse: Male Wister rat (8-week old) was anesthetized by intraperitoneally admnistering urethane (1.25 g/kg). A I nC- rrasi__ra*u~ i 59 tachometer was operated by R wave of electrocardiogram of exterminal derivation. The effect of the tested PGEs on pulse is' evaluated by the value calucurated from the following formula: pulse after pulse before administration administration x100 pulse before administration The results are shown in Table 2.

Experiment 3 Trachea contraction: Trachea was enucleated from Std Hartley guinea pig, longitudinally incised heterolateral side to trachea unstriated muscle, then transversely truncated. The resulting ring-shaped trachea tissue (7 pieces) were connected like chain with string and suspended in a magnus tube into which Krebs buffer containing enzyme was filled.

The each test drug was dissolved in ethanol and then diluted with distilled water, which was applied to Krebs buffer in S the magnus tube. The concentration of ethanol was S controlled at less than The contraction by the test drug was indicated by EC 50 which is a concentration of the drug showing 50% contraction when the contraction by 30 mM KC1 is assumed 100%. The results are shown in Table 2.

Experiment 4 Airway resistance: Male Std Hartley guinea pig was anesthetized by intraperitoneally administering urethane (1.5 g/kg. After I; 60 cannulation in trachea, 0.3 mg/kg of parachronium was ihtravenously adminis.ered to immobilize, and artificial respiration was conducted using a respirator. The change in the inner pressure of the airway was recorded using oronchospasm transducer. The test drug was intravenously administered through the polyethylene tube inserted in the V external jugular vein. The drug which raised the inner resistance of the airway when administered at the dose or 1 mg/kg was evaluated as positive for airway resistance raising activity, The results are shown in Table 2.

Experiment Enteron contraction: Ileum was removed from male Wister rat and suspended in a magnus tube. Contraction was induced several times with acetylcholine at the concentration of 1 x 10 6 g/ml. After more than two contractions with same intensity were obtained, the test drug was administered in the same manner as in Experiment 3. Contraction by the test drug was indicated by EC 50 which is a concentration of the test drug showing 50% contraction, when the contruction induced by 1 x 6 g/ml of acetylcholine iq assumed 100%.

The results ire shown in Table 2.

Experiment 6 Acute toxicity: Using Male Slc-ddY mouse (5 weeks old), acute toxicity upon oral administratio. (LD 50 w; examined. The 61 results are shown in Table 2.

Table 2 Drug 18 Drug 16 Blood Pressure f+ Pulse*- Trachea* Contraction Airway Resistance Enteron Contraction

LD

50 (oral) 2000 mg/kg >2000 mg/kg increase more than decrease more than no change observed

:EC

50 1- 10- s0:5 1 io 6

EC

5 0 i nrease airway resistance Drug 1, PGF 2 a As is obvious fromn the above regluts, 13,14did not show ephemeral decresase in pulse as well as bloo)d pressure which PGF 2 i usually shows, Further, 13,14-dihydito-l5-keto-20-alkyl PGFs are found to show no effect on puls~e. 13f14-Dihydro-l5-keto-PGFs shown

I

62 no or extremely reduced effect on trachea or enteron contraction without showing side-effect such as increase in airway resistance. Therefore, 13,14-dihydro-15-keto- PGFs are useful as vasopressor with no or little sideeffects. Particularly, 13,14-dihydro-15-keto-20-alkyl-PGFs are free from side effect, slight increase in pulse and specifically show vasopressor activity. Moreover, their toxicity are extremely weak, that is, no death was caused by oral administration of 2,000 mg/kg of the compound.

I

Synthetic scheme I 0 C il~ Y111 0 PhPli -4 -0 0- 0 0 PhYh 1 0 0. 0~ OTill 0 0 00 0 0 Oil li1p 0 Oil COo OT0 0 Synthetic scheme I (continued) Oil OTI P- 0 0 ORt 110 0 0 i) 110

COOR

0TIIP 0 0 LWj (12) 110 01 PhPh- TIIP= o o 000 000 000 0 2 S 1 0 0 -2 0 0 2 0 2 02020 00 0 0 0 00 0 0 0 0 -e nr_ Synthetic scheme II 0 KII~/Oil Phl'li (1) 0

F

PhPhi (1) S F Ln '0

F

6:o 011 PhIPh (16) 0 ri OS! -I- (19) 0 -Y I PliPh -(171) 0)

UTII

lp OSt i 0

F

Ol OSI Oil 118 OTII (21) C C OC'" 000 0C- C~ C C 0 C i -4 Ct C C, C c, ~i 0 0 00 0 Synthetic scheme II (Continued) off

F

Urrrr' OS,!+ (22)

GTIIP

1'I-

OTUIP

(24)

OTIIP

F

OTUP? 0 011 0 (25) (26) o 03 Dot~ a a a o 09 0O a ~CI. I Synthetic scheme III (18) (27) 110 IIO .OS'- (28) 0 OsI+ (31) if

F

p-'rs

-F

I

US i 4 0 C11 os, -t OS1 (32) OTHP Oc Coli C I oil (35) 0 0 S\COOMC COOlie (33) 1-1- Ci.

(340 OT1IP coli 1-36) 110 cooli 0 (37) 0 0 e Co1 C a C, 0 0 0 0 O 0 0 Synthetic scheme IV Oi 0I 0 Ph Ph (39) I PhPh (38) 0o 0 0 Ph Ph Oil 0 0 0 0 01 0 (44).

11 0 0 (42) Oil 011, 0 W4) 0 CC C e C C CC C 0 0 C C C C 0 00 0 0 0 0 n 0 0 0 0 C 00 0 o o 0 Snthetic scheme V 0 110 0 0 (41 0 TsO 0 0 (49) 0 0 110 N~~NNCOO~l1 0 0 (53) 0 0 1 0 0 0 O o 0 0 (52) 110 C13 0 0 (55 (56) 0 0 0 (:54) 110 CII3 0 (57) o- 00000 C 0 6 0 1 o 00 0i 0 0 0 00 0(t 08 00 0 Synthetic scheme VI rTIIi 0 0 .00) Ph Y-o 0THP 0 0 (62) ItoO I Tlp 0 0 A,63) 110 0 (64) St OC>~ t ~O 004 C, C 4 0 4 0 0 4 4 o 44 0 4 4 4 4 4 4 4 Svnthetic scheme VII COO~Ie (24) OTIIP j (66)

OTIIP

OTIIP .0 (67)

-I

110 0 (68) o 01, Synthetic scheme VIII O0 0 o-Q I'hII'h (71) 00 -Y 0 0CF3 PhPh (72) 0YO PhPli 0il (73) 0 0-

Q

O-S. CI

O

0 S i+ CF 3 (77),

(ITIIP

0Th!' Oil

CF

3 0.

oil 0-311+0 CF 2 (75) 0il ~ll -SI+ CFa (78)

OTIIP

OTIIP 0 -CF3 (81) Oil OTlIP -i

CF

3 (7 6) OT7lP !T11 P 0-31+

CF

3 Oil ~hI 0 (82) Synthetic scheme IX 0 0

IFF

o1 -s'i+ (8 8)

EF

PhPh (86) 0

IF

00 0 -Si PhPh (87)

OYG

'Ph Ph (85) 0K

F

UTIP 0-Si+ OTIIP -Si+ 0il OTIIP 0-Si+ Oil (92)

OTIIP

OTIEP 0-Si+ (93)

OTIIP

(94)

OTIIP

F ''om OTIHP 0 Oil 0T1IP 0 C C 0 0 Synthetic scheme X Mf O-Si 3 OTH?1 OTIP O-i+ CF7

OTIIP

TTP Oil

F

(99) Oil off 0oQ (100) C 0I C

Claims (8)

1. 13,14-Dihydro-l5--keto-PGFs represented by the general formula: 0 11 R 4 in which a bond between C-2 and C-3 Js a single or a double bond, X is a gJroup; -CH 2 -CH 2 ~CH 2 -CH 2 ,C-CH 2 -CH 2 or -U CH=:CH- C !C- R, is a hydrogen atom or a Cl 1 4 aldcYl, phenyl,, benzoyl, hydroxyalkyl, al1koxyalkyl, trialkylsilyl or tetrahydropyranyl group; V< 2 is a hydrogen atom or a lower alkyl group; R 3 is ai hydroxyl group;4 Rl 3 1 is a hydroxyl or hydroxyniethyl group; R 4 and R$ are the same or different, and signify a hydrogen atom, a hal~ogen atom, or a lower alkyl group; and when the R 4 and R 5 are both a hydrogen atom, R 6 is a group: -(CtI 2 )-CH3 (wherein m is an inte 'ger of 4 -(CH2) 4 -Cg 3 o -CH-(C11 3 )CH 2 CH 2 CfI 3 Or -0 ~R 7 (where R 7 is a 0, 76 hydrogen or halogen atom or a halogenated alkyl group); or when at least one of R 4 and R5 is a halogen atoui ~r a lower alkyl group, R 6 is a group: -(CH 2 )n-CH 3 (wh-..taiii n is an integer of 3 -(CH 2 4 -OCH 3 -CH(CH 3 )CH 2 CH 2 CH 3 or -0-a R7 or a salt of said 13, 14-dihydro-15-keto-PGFs.

2. 13, 14-DJihyclro-15-keto-PGFs of the Claim I being 13,14-dhydro-5-eto-2- ethy-PGFS represented by the formula: M -1 4COOR 1 1 4 t f 5 4 t5 1 2 2 22 wherein X, R 1 R 2 1 R 3 R8y, R 4 and RS are the same as defined in claim 1; or a salt thereof,

3. 13,14-Dihydro-15-keto-PGFs of the Claim I being 33, 14-dihydiro-15-keto-l6-substitutei-PGFs represented by the formula: R Rj r/ COO R I~ LZ I 0 wherein X, R 1 R2, R 3 R 3 R 4 and R 5 are the same as defined in claim I providing that the at least one of the groups R 4 and S is a halogen atom or a lower alkyl 9OO7d~d,P?.DA1'.O3Ob 22a 8, pa 77 group; or a salt thereof.-

4. 13,1l4-Dihydro,-15-keto-PGFs of the Claim 1 being 13,14-dihydro-15-keto-16-desbutyl-16-phenoxy-PGFs represented. by the formula: 000 00~~ 00 ci 00 0 0 0 01 04 wherein X, Rl, R 2 R 3 R 3 R 4 R 5 and R 7 are the same as defined in claim 1; or a salt thereof. A 13,14-dihydro-15-keto-PGF according to Claim 1, wherein at least one of~ the groups R 4 and R 5 are methyl or fluor'ine.

6. A Method for the treatment of hypoteision or shok which comprises administering to a subjeoct in need ofi such treatment a therapeutically effective amount of a vasopressor of the formula: R 3 R 2 COORi R 4 R in which a bcnd bet~ween C-'2 and C-3 is a single or a double bond; X represents a group selected from -OH 2 CH2-s -CHz H 2 7\6 I7\r 0112 G I 1' I I90-730, PiAS!AT,3,2220-8. rap, 77 78 -CH2 or CHz S/

7.\ CH =CH C=C R 1 is a hydrogen atom or a C 1 4 alkyl, phenyl, benzoyl, hydroxyalkyl, alkoxyalkyl trialkylsilyl or tetrahydropyranyl group; R 2 is a hydrogen atom or a lower alkyl group; R3 and R 3 are the same or different hydroxyl, methy. or hydroxymethyl; ooo" R 4 and R 5 are the same or different and signify a hydrogen, halogen atom, or a lower alkyl; and I R 6 is a C 4 9 alkyl which may or may not be branched or 4 contain a double bond or an alkoxy group, or a group ol: the general formula: 44 4 7 wherein Y indicates a bond or an cxygen atom, and R7 indicates a hydrogen or halogen atom or a halogenated alkyl group; and/or physiologically acceptable salts thereof; in association with one or more pharmaceutically acceptable carriers. 7. A method according to claim 6, whicn is a method for the treatment of essential hypotension, symptomatic hypotension, orthostatic hypotension, or acute hypotension.

8. A method for effecting vasopression which 900730 .ASDAT. 038,22268-88 rsp, 78 Fl 79 comprises administering to a subject an effective amount of a vasopressor of the formula: R 3 R 2 COORi I a 13 1 0 14 R 4 Rs 1R6 0 in which a bond betwee~n 0-2 and C-3 is a single or a double bond; X represents a group selected from 0 0 ~H2 CH 2 -CH: C1 2 '01 0 7\ CH 2 C -OH 2 or -CHz ODOR0 CH CH C=C 0 00g Ris a hydrogen atom or a C1..4 alkyl, phenyl, benzoyl, hydroxyalkyl, alkoxyalkyl trialkylsilyl or tetrahydropyranyl group; R 2 is a hydrogen atom or a lower alkyl group; R 3 and R 3 1 are the same or different hydroxyl, methyl or hydroxymethyl; R 4 and R 5 are the game or different anC; signify a hydrogen, halogen atom, or a lower alkyl; and R 6 is a 0 4 -9g alkyl which may or may not be hranched or contain a double bond or an alkoxy group and a group z--f the~ general formula: R 9oa731,PJ"DAM.o3a.22268-B8. rsp,79 81 is a group of the general formiula: _aR wherein Y is a bond or an oxygen atom; R 7 is a hydrogen atom, halogen atom or a halogenated alkyl group.

16. A vasopressor composition which comprises a compound accor'ding to any one of claims 1 to in 0 00 association with a pharmaceutically acceptable car'rier. 0 0 DATED) this 21st day of August, 1990 KABUSHIKI KAISHA UENO SEIYAKU OYO KENKYUJO by its Patent Attorneys DAVIES COLLISON 13 14 9ao731,PASDATo38, 22248-88.rap,8I