DE2360893A1 - CYCLOPENTAN DERIVATIVES - Google Patents

Description

Portfolio 23 380.- Dr. K / by
Case PH 25677

IMPERIAL CHEMICAL INDUSTRIES LTD. London, UK

Cyclopentane derivatives

Priority: December 7, 1972 - Great Britain.

The invention relates to new cyclopentane derivatives and more particularly to new cyclopentane derivatives which are analogs of the naturally occurring compounds known as prostaglandin FpoC, -E ₁ , -Ep and -Ap. The new compounds show a similar spectrum of pharmacological properties and are useful for similar purposes. The strength of the effectiveness of the new compounds in pharmacological terms differs from the strength of the effectiveness of the naturally occurring prostaglandins mentioned above; in particular, they are more effective as luteolytic agents than the corresponding natural prostaglandins. That is, the prostaglandin-Ep analogs of the present invention are more potent than natural prostaglandin-Ep, Die. new compounds are therefore suitable as contraceptives, for the termination of a pregnancy, for the control of the

409824/1099

Oestrus cycle, as hypotensives to relieve bronchospasm and as inhibitors of platelet aggregation or for gastric secretion. The new "Compounds according to the invention are also suitable for the Addition of semen required for artificial insemination of Domestic animals is provided, whereby the insemination success rate "is increased, in particular with pigs and Cattle.

According to the invention there is thus a 12-epi-prostanoic acid derivative the formula, ■

I-

-proposed in what

VT

.X. CCHp J- ^ R

Ϊ. CHCOR ² IR ³

for

or

H stands for a hydrogen atom or an alkanoyloxy radical / up to 4 carbon atoms, R stands for a carboxy or hydroxymethyl radical or an alkoxycarbonyl radical with up to 11 carbon atoms, R ^{2 stands} for a hydrogen atom or an alkyl radical with 1 to 4 Carbon atoms, X stands for an ethylene or vinylene radical, Y stands for an ethylene or trans-vinylene radical

- 2 -
409824/10 99

and R- ⁵ stands for: -. ·.

a branched or unbranched alkyl or alkenyl radical having 4 to 10 carbon atoms;

15 1 a radical of the formula —A .0R ■, wprin A for an alkylene radical with 1 to 9 carbon atoms and R- ^ for a An alkyl radical having 1 to 9 carbon atoms or a cycloalkyl radical with 5 to 7 carbon atoms, with the

1 5
Restriction that A and R together contain no more than 10 carbon atoms;

a radical of the formula -AR, in which A. is a direct bond or an alkylene radical having 1 to 3 carbon. stands atoms and R _ is an aryl radical which is unsubstituted or each · 1 to 3 carbon atoms or Dialkylaminoradikal wherein by halogen atoms, nitro radicals, alkyl, Halogenoalkyl- or alkoxy radicals each alkyl has 1 to 3 carbon atoms which is substituted; . . "-" -. ■ a radical of the formula -A ⁵ .A .R ^, where £ ?. denotes an alkylene radical with 1 to 3 carbon atoms which carries as substituents 0, 1 or 2 alkyl radicals each with 1 to 3 carbon atoms, A represents an oxygen or sulfur atom, a sulfinyl radical or an alkylimino radical with up to 4 carbon atoms and R 'stands for an aryl, benzyl or furfuryl radical, which is optionally substituted by hydroxy, nitro or ethenyl radicals, halogen atoms, alkyl, alkenyl, haloalkyl, alkoxy, alkenyloxy or acylamino radicals with 1 to 4 carbon atoms or Dialkylamino radicals wherein each alkyl has 1 to 3 carbon atoms is substituted; ■ _-:; . .-..'- ν--, -ν--, ν "-, -. - ■ - ■". '·; - ■

• Z C. O "T

oder'eiEL-Raälkal of the formula -A .A ^ .- R, in which. A the above -

5
specified ^i; f meaning-owns, A. for a _; Oxygen or Sohwefe "], atöm,; a ^ SuIfinyl- ,; sulfonyl ₁ imino or alkylimino radical; .with up to ζμ -.;. 4 carbon atoms, or -a di-

right -iBindüng; stands -or .--. At; and --- A: 3 ^ §ϋ§ -for one _; direct- * 8 ■ '■■>.

R; · for, an aromatic-es,]% f; terocyc.li-

Ψ 2380893

A radical with one or two 5- or 6-membered rings which contains 1 or 2 non-adjacent nitrogen heteroatoms in only one ring and optionally 1 to 3 alkyl. or Carries alkoxy radicals or halogen atoms as substituents;

where the compounds carry 0 or 1 alkyl radicals having 1 to 4 carbon atoms as substituents on one carbon atom of the trimethylene group (- (CH _O ) _X -); and where for

those compounds in which R is a carboxy radical is available, including those that are pharmaceutically or veterinarily permitted Salts thereof are included.

A suitable value for R when it stands for an alkoxycarbonyl radical having up to 11 carbon atoms is for example a methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical *

2
A suitable value for R when it is an alkyl radical is, for example, a methyl radical.

A suitable value for R when it is an alkanoyloxy radical having 1 to 4 carbon atoms is, for example an acetoxy or propionyloxy radical.

A. A suitable value for Rr when it stands for an alkyl or alkenyl radical having 4 to 10 carbon atoms is, for example, an n-pentyl, n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylheptyl or cis-pent -2-enyl radical,

A suitable value for A when it is for an alkylene radical with 1 to 9 carbon atoms is, for example, a methylene, isopropylidene, ethylene, 1,1-dimethylethylene, Trimethylene, tetramethylene or pentamethylene

5 radical, and a suitable value for R is, for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl radical. Appropriate values for

1 ε 15 the group -A .0R, where A and R ^ together no longer

_ 4 40 9: 8 24/1099

than 10 carbon atoms are therefore, for example, n-propoxymethyl, n-butoxymethyl, isobutoxymethyl, n-pentyloxymethyl, n-hexyloxymethyl, 2-n-butoxyethyl, 3-n-propoxypropyl, 4-ethoxybutyl and 5-methoxypentyl radicals.

2 ··

A suitable value for A is a methylene, ethylene,

Trimethylene, 1-methylethylene - _{CH (CH 3 ) .CH 2} ~], 1-ethylene ft) 2-methylethylene -; '[- CH ₂ .CH (CH ₃ ) -J or

1,1-Dimethyläthylen- ^ C (CH,) ₂ .CH ₂ -J radical, and a suitable value for R ₁ , if it is an aryl radical, which is optionally substituted, is for example a phenyl or Naphthyl radical, which is optionally substituted. Suitable halogen substituents in R are, for example, chlorine, bromine or fluorine atoms. Suitable alkyl or alkoxy substituents with 1 to 3 carbon atoms in R are, for example, methyl, ethyl, methoxy or ethoxy radicals, and suitable halogenoalkyl substituents with 1 to. 3 carbon atoms in R are, for example, chloroalkyl or fluoroalkyl radicals, such as, for example, trifluoromethyl radicals. Suitable dialkylamino substituents in R are, for example, dialkylamino radicals in which the two alkyl radicals are the same, such as, for example, a dimethylamino radical. Suitable substituted aryl radicals are therefore, for example, chlorophenyl, bromophenyl, fluorophenyl, chloronaphthyl, tolyl, trifluoromethylphenyl, ethoxyphenyl, nitrophenyl, dimethylaminophenyl and tetrahydronaphthyl radicals. Preferred aryl radicals contain no more than two substituents as defined above. Special values for R are therefore phenyl, 2-naphthyl, 3- and 4-chlorophenyl, 2- and 4-fluorophenyl, 3> 4-dichlorophenyl and 3-trifluoromethylphenyl radicals.

3 ■ ■■ A suitable value for A when it is for an alkylene radical with 1 to 3 carbon atoms, the 0, 1 or 2 alkyl radicals each bearing 1 to 3 carbon atoms is

- 5 ■ '"- ■" ■

409824/1099

for example a methylene, ethylene or trimethylene radical which carries 0, 1 or 2 methyl substituents, such as e.g. a methylene, ethylidene, isopropylidene or trimethylene radical. .

A suitable value for A when it is an alkyleneimino radical having up to 4 carbon atoms is, for example, a methylimino radical. '

7th
A suitable value for R · when it represents an aryl radical which is optionally substituted is, for example, e-in phenyl or naphthyl radical which is optionally substituted; Suitable halogen atom substituents in R 'are, for example, chlorine, bromine or fluorine atoms. Suitable alkyl, alkoxy, alkenyl or alkenyloxy substituents with 1 to

7th
4 carbon atoms in R are, for example, methyl, t-butyl, allyl, methoxy or allyloxy radicals. Suitable haloalkyl substituents with 1 to 4 carbon atoms in R 'are, for example, chloroalkyl or fluoroalkyl radicals, such as, for example, trifluoromethyl radicals. Suitable dialkylamino radicals, in which each alkyl has 1 to 3 carbons

substance has atoms which can be substituents in R, are, for example, dialkylamino radicals in which the two alkyl radicals are the same, such as a dimethylamino radical. Suitable substituted aryl radicals are, for example, chlorophenyl, chloronaphthyl, bromophenyl, Fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, Hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl and tetrahydronaphthyl radicals. Preferred aryl radicals contain no more than two of the substituents defined above. Specific Values for R 'are therefore phenyl, benzyl, furfuryl, 1-naphthyl, 2-naphthyl, 2-, 3- and 4-chlorophenyl, 4-bromophenyl-, 2-, 3- and 4-fluorophenyl-, 2,3-, 2,4-, 2,5- »2,6-, 3,4- and 3» 5-dichlorophenyl-, 2-, 3- and

- 6 409824/10 99

4-tolyl-, 2,3-, 3,4- and 3,5-xyIyI-, 4-t-butylphenyl-, 3-allylphenyl-, 3-trifluoromethylphenyl-, 4-hydroxyphe- nyl-, 2-, 3- and 4-methoxyphenyl-, 4-biphenylyl-, 3-dimethylaminophenyl-, 2-chloro-4-methylphenyl-, T-chloro-2-naphthyl-, 4-chloro-1-naphthyl-, 6-methyl-2-napiithyl-, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl radicals.

A suitable value for A when it is for an alkyl e »-imino radical with Ms to 4 carbon atoms is, for example, a methylimino radical. '

Suitable ¥ erte for R are, for example, pyridyl, pyrimidinyl, Quinolyl, indolyl, indolinyl, benzimidazolyl, pyridazinyl, thiazolyl, benzothiazolyl, benzofuranyl or benzthienyl radicals, especially 2-, 3- and 4-pyridyl and 5-indolyl radicals. Suitable halogen substituents in R are, for example, chlorine, bromine and iodine atoms,

• 8 and suitable alkyl or alkoxy substituents in R are for example methyl or methoxy radicals. So are particularly suitable heterocyclic radicals, for example 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-3-pyridyl, 2,5-dichloro-3-pyridyl and 5-indblyl radicals.

A suitable alkyl radical having 1 to 4 carbon atoms, which can be used as a substituent on a carbon atom the trimethylene group may be present is, for example, a methyl radical. -

Suitable pharmaceutically or veterinarily acceptable salts. are for example the ammonium salt, the alkyl ammonium salts, wherein 1 to 4 alkyl radicals, each with 1 to 6 Carbon atoms are present, the alkanolammonium salts,. which contain 1 to 3 2-hydroxyethyl radicals, or alkali metal salts, such as a triethylammonium, ethanolamionium, Diethanolammonium, sodium, potassium or ammonium salt. .. "- ,.

': ■' ■ " ⁷ "

403824/10 99

A preferred group of 12-epi-prostanoic acid derivatives embraces the compounds of formula I wherein R is a Carboxy or methoxycarbonyl radical, X is a Ethylene or cis-vinylene radical,

for / "" "" ^ v - "" · or

HO '

HC

Y stands for a trans-vinylene radical, R stands for Is hydrogen atom and R ^ is an alkyl radical with 5 to 9 carbon atoms, a benzyl radical or a phenoxymethyl or naphthyloxymethyl radical which possibly by one or two methyl radicals on the methyl part or substituted by a halogen atom or an alkyl or alkoxy radical having 1 to 3 carbon atoms on the phenyl part is.

Particularly preferred 12-epi-prostanoic acid derivatives of the invention are: 20-ethyl-9c ^ 11o (., 15-trihydroxy-5-cis, 13-trans-12-epi-prostadienoic acid, 20-ethyl-11cC, 15-dihydroxy-9 -oxo-5-cis, 13-trans-12-e £> i-prostadic acid, 9oc, 11oc, 15-trihydroxy-5-cis, 13-trans-12-epi-prostadic acid, 11oc, 15-dih. hydroxy -9-oxo-5-.cis, 13-trans-12-epi-prostadienoic acid, 20-ethyl-9o6., 11cc, 15-trihydroxy-5-cis, 13-trans-12-epiprostadienoic acid methyl ester, 16- ( 3-chlorophenoxy) -11cC, 15-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-pr o stadienoic acid, 16- (3-chlorophenoxy) -9oC , 11oc ·, 15-trihydroxy-17,18,19,20-tetranor-5-cis, ί 3-trans-12-epi-prostadienoic acid and 16- (3-chlorophenoxy) -3d, 11Λ, 15-trihydroxy-2 -methyl-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid.

The 12-epi-pro-stage acid derivatives of the invention can by methods known per se in the art for the preparation of analogous compounds. So

- £ 8 09824/1099

is therefore according to the invention still a method for Preparation of a 12-epi-prostanoic acid derivative according to the invention proposed, which is carried out in that one

a) for compounds in which R is a carboxy radical '

ρ
and R stands for a hydrogen atom, with the exception of those compounds in which R stands for a radical of the formula -AR, where A stands for a direct bond, hydrolysis of a compound of the formula:

- - '""' ■■ · ■■: Ii

. GH (OR ⁹ ) R ³ ■ "■ '■■. ·""."'

or a mixed anhydride thereof wherein R, 'R, X and Y have the meanings given above,

_r 0H ■■ ■ ^:. "■ '

or

.Ör9. . _:

Q ". ■■ -.

and R · ^{7 is} a tetrahydropyran-2-yloxy radical or an alkoxydialkylmethyl radical having 4 to 8 carbon atoms, for example a 1-methoxy-i-methylethyl radical, where the compound Ö or 1 alkyl radical having 1 to 4 carbon atoms as a substituent on one carbon atom contains the trimethylene group, whereupon, if a salt is desired, the product is reacted with a base; or ■

b) for those compounds in which R is a carboxy radical stands, - .

- Q - -

409 82A / 10 99

stands for \ I 'and R ^{3 stands} for a

■ 6h

Radical of the formula -A ² R, in which A ^{2 is} a direct bond, or R ^ is a radical of the formula

3 5 8

-A .Ar. R is as defined above, implementation of a lactol of the formula:

III

wherein Y has the meaning given above and R the has the meaning given immediately above, with a (4-carboxybutyl) triphenylphosphonium salt, for example the bromide, which has 0 or 1 alkyl radical with 1 to 4 carbon atoms as substituents on the carbon atom 1, 2 or 3, in the presence of a strong base, whereupon, if a salt is desired, the product with a Base is implemented; or

c) for those compounds in which R is an alkoxycarbonyl radical with up to 11 carbon atoms, reaction of an acid of the formula:

X.CCH ₂ ) ,. COOH

.CHCOH) .R ³ '\ where X, Y and R have the meanings given above

- 10 - 409824/1091

zen and

has one of the meanings given first above, 'where the compound O or 1 alkyl radical having 1 to 4 carbon atoms as a substituent on a carbon atom the tr! methylene group contains, with a diazoalkane with 1 to 10 carbon atoms; or a salt thereof, for example ' a silver or sodium salt, with an alkyl halide having 1 to 10 carbon atoms; or

d) for those compounds in which R is a hydroxymethyl radical stands and

{stands for \ 'I,

1 GH.

1 reduction of an ester of the formula I, wherein R is a Alkoxycarbonyl radical, for example an alkoxycarbonyl radical having 1 to 11 carbon atoms, with, for example a complex metal hydride such as lithium aluminum hydride; or

e) for those compounds in which R is a radius

n h 7 ^ ^ 8 U-

kai of the formula -A ..A .R or -A - '. A .R stands in which A stands for a sulfinyl radical or h? stands for a sulfinyl or sulfonyl radical, oxidation of the corresponding xhio compound, where A and k? stands for Schv / efel, for example with sodium periodate; or

/ ■

f) for those compounds in which R is an alkoxycarbonyl radical stands, reaction of a compound of the

409824/10 99

Formula II, wherein

Fr and X die

Have the meanings given above, where the compound has 0 or 1 alkyl substituent having 1 to 4 carbon atoms on carbon atoms 2, 3 or 4, with an alkanol having 1 to 10 carbon atoms in the presence a strong acid such as toluene-p-sulfonic acid, and »when a 12-epi-prostanoic acid derivative is desired

-ι
where R is a carboxy radical, hydrolysis of the ester thus obtained, for example with potassium hydroxide or potassium carbonate; or ■

g) for those compounds in which X is a trans-vinylene radical is, separation of a mixture of the 5-trans-12-epi-prostanoic acid derivative and the corresponding 5-cis isomer; or

h) for those compounds in which R is an alkyl radical is, reaction of the corresponding 12-epi-prostane

2 acid derivatives of the formula I, in which R is a hydrogen atom stands, with an alkyl halide having 1 to 4 carbon atoms, for example an alkyl iodide, in the presence a strong base such as sodium hydride; or

i) for those compounds in which

IO

for

HO formula I, in which

stands, reduction of a compound of

O ₁

for

stands,

for example with a complex metal hydride, e.g.

12 -

0-9824 / 10 99

Lithium tri (lower alkyl) hydride, for example lithium tri-s-butyl hydride, or . a borohydride, for example Sodium borohydride; or

j) for those connections in which

stands for ζ \ J, ¥ water splitting off from a

■■ '"■■ · o.

bond of the formula I, wherein _{t is}

stands, for example with a substituted garbodiimide in the presence of a copper salt as a catalyst, such as NjN'-dicyclohexylcarbodiimide in the presence of Copper (II) chloride.

The hydrolysis at. Method (a.) Can take either acidic or basic conditions are carried out, for example in aqueous acetic acid, or an aqueous or alcoholic solution of an alkali metal carbonate, such as z ·. B. potassium carbonate in methanol. The procedure can also at room temperature or at an elevated temperature up to 60 ° C. ·

A suitable mixed anhydride is a mixed anhydride with a lower alkanoic acid such as a lower alkanoic acid of up to 8 carbon atoms, for example Acetic acid. . -.

The compounds of formula II used as starting material used in the process of the invention can be prepared as follows:

7-acetoxymethylene ~ 5-chloro-5-cyanobicyclo / 2,2,1_7hept-2-en (VI) is added by 0.1η hydrochloric acid in aqueous acetone

- 13 409 824/1 0 99

5-chloro-5-cyanot) icyclo / 2,2, iy> iept-2-en-7-anti-carboxaldehyde (VII) hydrolyzed. Dor aldehyde VII is reacted with a phosphonate reagent of _{the formula (CPL 5} O) ₂ ^{PO.CH.COR · 3} , where K ^{J is} , for example, the n-heptyl or "3-chlorophenoxymethyl radical, to give an enone VIII which is reduced, for example, with zinc borohydride or aluminum triisopropoxide to the mixed epimers of the enol IX. The chloronitrile substituents on the C-5 are hydrolyzed to give the ketone X which is subjected to the Baeyer-Villiger oxidation to form lactone XI Lactone XII is saponified with sodium hydroxide and neutralized with acetic acid, and the product is treated with potassium triiodide to give an iodohydrin XII which is treated with tributyltin hydride to give the decoded lactone XIII. The lactone XIII is reacted with dihydropyran , whereby the bisether XIV is formed, which is reduced to "Lactol XV" with diisobutylaluminum hydride. The lactol XV is reacted with a (4-carboxy butyl) -triphenj'iphosphoniumsalz, whereby a compound XVI is formed, ie a starting material ■

al of the F-radicals of the formula II, in which

HO "

stands for \ JL ',

X stands for cis-vinylene, Y stands for trans-vinylene and R ^{p stands} for n-heptyl or 3-chloropheno: cymethyl.

Alternatively, the ketone X can be prepared by converting the aldehyde VII to an acetal thereof, such as e.g. Dirnethylacetal XVII, subsequent saponification of chloronitrile to acetalalketone XVIII and hydrolysis of acetal to ketoaldehyde XIX, which with a phosphonate reagent is implemented according to the above regulation, whereby a '

- 14 409824/109 9

711. O. COCIL,

VI

CIIO

CN '

VII

COR ³ . "-.--." H _n Λ CN ". ^ CH (OH) R ⁵ IX ■ v / T Τ " -, 'Cl S.
.CN VIII \

GH (OH) R-

XI

-> ι

XII

XIII

Q. H ί OH) V?

. 40.g8.24 / i0

χ · ΐν

- ^

OH

XV

HO

CH (OP.9 ') r3

XVI '

-COOH

409824/1099

- 16 - '

/ f '-2 3BO 8

Ketoenone XX is formed, which in turn reduces to ketone X. will. . . '

The starting material of the F - ^ - series of the formula -II, in which *

stands for \ j,

Ν. »

can be obtained from the corresponding compound XVI by acylation the same can be obtained with an acid anhydride in pyridine, a 9-ester-i-mixed anhydride being formed ..

The starting material of the Ε series of formula II, wherein

stands for \ J-_,

-. HO can be obtained from the corresponding compound XVI by oxyda-.tion with Jones reagent (chromic acid in acetone). .

The starting material of formula II, wherein X is the ethylene radical can be obtained by hydrogenating the bis-ether XVI .:

The starting material of the formula II, "in which Y stands for the ethylene radical, can be obtained by hydrogenation the compound XIII or XIV and use of the hydrogenation product instead of the compound XIII or the compound XIV for the remainder of the above sequence of reactions.

The lactol of the formula III, which is used as a starting material in Method according to the invention is used, can be obtained

40 982.4 / 1099

VII "->

CH (OCH ₃ ) ₂

-Cl

CN XVII · K ^ ^ CH (OCH) ₂

XVIII

Hv. CHO

XIX

COR

- ^ X

409824 / T 09

: ■ - ■ is -

are by "'reduction of the corresponding lactone XIII, for example with Diisobutylaiuminiumhydrid.

The mixture of 5-trans and 5-cis isomers, which * is used as starting material in the process according to the invention, can be obtained, for example, by reacting a lactol XIV with the ylide which is derived from a (4-carboxybutyl ) - triphenylphosplionium salt, for example the bromide, has been obtained by butyllithium in a solvent such as sulfolane, and "by subsequent hydrolysis of the protective group R-". Although this reaction gives almost exclusively the 5-cis compound when the ylid mater is produced using a sodium base, the use of butyllithium results in a mixture of cis and trans isomers, which is up to 40 % of the trans- Contains isomer.

It is pointed out that the optical active connection can be obtained in that either the corresponding racemate is separated or the reaction sequences described above are carried out, with one starts from an optically active intermediate such as an optically active ketone of formula X.

As already stated above, the compounds according to the invention have a profile of pharmacological properties, which differs from that of the naturally occurring prostaglandins FpoC and -Ep. So is for example each C-15 epimer of 20-ethyl-11a., 15-dihydroxy-9-oxo-5-cis, 13-trans-12-epi-prostadienoic acid in a luteolytic test on a hamster (oral dose) almost 20 times as active as the natural prostaglandin Fpcc, but has less than 1/25 of the stimulation activity from prostaglandin Fpoc to smooth muscle. Similarly, i6- (3-Chlorophenyi) -11oc, 15-. dihydroxy-9-o2co-i7,18,19,20-tetranor-5-cis, 13-trans-i2-

409824/1; 099 BAD

ftö

epi-prostadienoic acid 'about 50 times the luteolytic activity (with subcutaneous dosing) and half the stimulating activity on the smooth muscle of prostaglandin F ₂ Oi. .

At. the compounds according to the invention were not found to have any toxic effects at the luteolytically effective doses.

As already stated above, the compounds according to the invention are suitable, for example, for inducing childbirth. For this purpose they are used in the same way as is known for the naturally occurring prostaglandin E ^ and -Ep, that is to say by administering a sterile, essentially aqueous one. Solution containing 0.01 to 10 pg / ml, preferably 0.01 to 1 μβ / ταΐ, of the active compound by intravenous, extraovular or intraamriotic infusion until movement begins. For this purpose, the compounds of the invention can also be used in combination or simultaneously with a uterine stimulant, such as oxytocin, in the same manner as is known for prostaglandin-F ₂ Oi, in combination or simultaneously with oxytocin, in order to achieve the ' Induce movement.

If a compound of the invention is used for the control of the oestrus cycle in animals, then it can it in combination or at the same time with a gonadotrophin, such as PMSG (pregnant mare serum gonadotrophin) or HCG (human chorionic gonadotrophin) can be used to speed up the onset of the next cycle.

Thus, according to the invention, there is still a pharmaceutical or a veterinary composition which contains a 12-epi-prostanoic acid derivative according to the invention together with a pharmaceutically or veterinarily acceptable diluent or carrier.

- 20 -

4 0 9 8 2 4/1099

The compositions can take the most varied of forms such as tablets or capsules for oral administration, Aerosol sprays for inhalants, sterile 'aqueous or oily solutions or. Suspensions for parents teral administration or administration by infusion, or suppositories for anal or vaginal use.

The compositions according to the invention can be prepared by the usual methods. They can also contain conventional excipients. They preferably consist of sterile, essentially aqueous solutions which contain between 0.01 and 10.0 g / tal of a compound according to the invention.

The invention is illustrated in more detail by the following examples. Throughout the examples, the. Rp values on silica gel plates produced by Merck in "Darmstadt were delivered. The stains were either by fluorescence under UV radiation or by spraying the plates with a solution of cerium ammonium nitrate determined in sulfuric acid. The mass spectrum data for the compounds of the F series refer to per- (trimethylsilyl) derivatives, i.e. usually the tetra-tri-

1 methylsilyl derivatives of compounds in which R is for Carboxy- or hydroxymethyl and tri-trimethylsilyl derivatives for compounds in which R denotes an alkoxycarbonyl radical stands. The mass spectrum data for the Ε-series compounds normally refer to the tris (trimethylsilyl) -9-methoxime derivatives.

example 1

A solution of 112 mg (0.19 mmol) i6- (3-chlorophenoxy) -9o ^ -hydroxy-11oc, 15-bis (tetrahydropyran-2-yloxy) -17,18,19, 20-tetranor-5-c.is, 13-trans-12-epi-prostadic acid in 6.6 ml a 2: 1 mixture of acetic acid and water vmrde 1 st

40982A / 1099

stirred at 5O ⁰ C. The solvents were evaporated in vacuo, with 16- (3-chloropheiioxy) -9ct, 11-Λ, 15-trihydroxy-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid as Mixture of C-15 spimers was obtained. Thin-layer chromatography on silica gel plates from Merck in Darmstadt, using a mixture of 3 % acetic acid in ethyl acetate as the development joint, separated the C-15 epimers, which had Rp values of 0.3 and 0.4 . The NMR spectrum of each isomer (in deuterated acetone) showed the following characteristic bands (S values):

4.0, .4H, Multiplet, ^ CH (OH) ^at ·. C-9 and C-11,

and -CH ₂ O-

4.48, 1H, multiplet, C-15 proton 5.40, 2H, multiplet, cis-olefinic protons 5.6, 1H, multiplet

. trans-olefinic protons 6,1, 1H,. Quartet J '

6.8-7.4, 3H, multiplet, aromatic protons.

The mass spectrum of the more polar epimer had M ⁺ = 712.3202 (calculated for C ₅₄ H ₆₁ OgSi ₄ Cl = 712.3235).

The one used as the starting material for the above process 16- (3-chlorophenoxy) -9ot-hydroxy-11cc, 15-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13-trans-12 ^ epi-prostadic acid can be obtained as follows:

178.4 g (0.80 mol) γ-acetoxymethylene ^ -chloro - ^ - cyanobicyclo / 2,2,1_7hept-2-en and 800 ml (0.08 mol) of an aqueous 0.1N hydrochloric acid in 800 ml of acetone were refluxed 21 st heated in a nitrogen atmosphere. The mixture was cooled and adjusted to (approximately) pH 4 by adding solid sodium bicarbonate. Then became Acetone removed under reduced pressure. 400 ml of methylene dichloride were added, the mixture became with solid Sodium bicarbonate neutralizes the organic layer

- 22 409824/1099

was separated and the aqueous layer ■ was added with 200 ml Extracted ethylene dichloride. The combined extracts were washed twice with 300 ml of water each time and dried, and the solvent "was evaporated, leaving 5-chloro-5-cyanobicyclo / 2,2,1_7hept-2-en-7-anti-carboxalaehyd was obtained as a dark oil which partially solidified on cooling. ··;

The M-IR spectrum in deuteriochloroform showed the following characteristic features (cT values):

1.6-2.9, / 3H, complex multiplet, C-6 and C-7 pro

tone

3.45, 1H., Multiplet 1 . ', / V. "

''' Y C-1 and C-4 protons

3.85, 1H, multiplet J.

6.2-6.6, 2H, multiplet, olefinic protons 9.6-9.7, 1H ,. Doublet, aldehyde proton

A solution of 9.07 g (31 mmol) of dimethyl r2-oxoprop3 '"l-3- (3-chlorophenoxy) phosphonate in 68 ml of anhydrous 1,2-dimethoxyethane was at -78 ⁰ C with 11.6 ml of a 2.29 molar solution of n-butyllithium in hexane, the mixture was stirred for 10 min, and to this mixture a solution of 4.02 g (22 mmol) of S-chloro-S-cyanobieyclo- / 2., 2, 1_7hept-2-en-7-anti-barboxaldehya in 10 ml of 1,2-dimethoxyethane was added .. The reaction mixture was then allowed to warm to room temperature, and after it had been stirred for 5 'it was neutralized with glacial acetic acid were evaporated under reduced pressure, and .the residue was taken up in 120 ml of methylene chloride and washed with a 1: 1 solution of common salt and water. The saturated aqueous phase was extracted with 2 × 50 ml of methylene dichloride, the organic Layers were combined and dried and the solvent was evaporated in vacuo. The residue was deposited on Florisil silica ("Flor isil "is a registered trademark) chromatographed, with methylene dichloride as solvent

- - .- 23 -. . ' : 409824/1099

medium was used. The enone, 5-chloro-5-cyano-7-anti- (3-oxo-4-m-chloro-phenoxybut-1-trans-enyl) -bicyclo / 2,2,1_7hept-2-ene, was obtained as a solid . Mp 93-107 ° C. Rp = 0.3 (5p % toluene in methylene dichloride). .

The NMR spectrum in deuteriochloroform showed the following characteristic features (S values):

1.81, 1iV Quartet'Ί

'> · C-6 protons

2.80, 1H, Quartet J.

3.14, 1H, wide singlet,)

■ χ / ο «τ ν, ■ + _σ · -, ₊ V ^C ~ ¹ - ^and C-4 protons. 3.48, 1H, broad singlet, J.

4.85, "2H, singlet, -CH ₂ -O- '

5.20-6, '60, 2H, multiplet, C-2 and C-3 protons 6.65-7.30, 6h, multiplet, aromatic and trans-

olefinic protons.

7.56 g (21.7 mmol) of the enone and 44 ml of a 1.11 molar -Solution of aluminum tri-isopropoxide in toluene were added in 191 ml of a 2: 1 mixture of toluene and isopropyl alcohol to ' dissolved and the solution was slowly distilled. The mixture that which had distilled off was continuously replaced by a 2: 1 mixture of toluene and isopropanol. After 1 st the reaction mixture was cooled and treated with 75 ml of saturated aqueous sodium hydrogen tartrate solution for 10 min long stirred. The mixture was washed with 4 × 50 ml of ethyl acetate extracted, the combined extracts were dried and the solvent was evaporated under reduced pressure, where 5-chloro-5-cyano-7-anti- / 3-hydroxy-4 -. (3-chlorophenoxy) -but-1-trans-enylZ-bicyclo / ^, 2,1_7hept-2-en was obtained. Rp = 0.3 (methylene dichloride).

The IMR spectrum in deuteriochloroform showed the following characteristic features (cf values):

3.90, 2H, multiplet, -CH ₂ -O- '_. 4.46, 1H, broad singlet, -CH (OH) - · 5.4-6.1, 2H, multiplet, trans-olefinic proto-.

nen

- 24 409824/1099

6.1-6.5, '2H, multiplet,. C-2 and C-3 protons 6,6-7., 3, A-H, multiplet, aromatic protons.

5.08 ml (42 mmol) of 8.6N potassium hydroxide were added to a solution of 7.26 g (20.8 mlfol) of the linole in 72 ml of dinethyl sulfoxide, and the mixture obtained was stored for 18 hours in an inert Atmosphere stirred. The reaction mixture was then acidified to pH 1 with η hydrochloric acid and extracted with 4 × 70 ml of ether. The combined extracts were washed with 3 × 50 ml of water and dried, and the solvent was evaporated under reduced pressure, the enol ketone being 7-anti- (3-hydroxy-4-m-chlorophenoxy-but-1 -trans-enyl) -bicycle - / ^, 2,1_7hept-2-en-5-one was obtained. Rg, = 0.4 (10 % ethyl acetate in methylene dichloride). The WIR spectrum in deuteriochloroform showed the following characteristic features' ((S "values):

1.9, 2H, Multiplet ,. C-6 protons trans-olefinic protons 3.9, " 2H, 'Multiplet, -CH ₂ -O- ' > C-2 and C-3 protons 4.5 ,: 1H, wide singlet ,. -CH (OH) -. J 5.75, • 2H, Multiplet, 4H, multiplet, aromatic = protons. 6, i2 ,; 1H, ^ Multiplet, 6.62, 1Ή, Multiplet, 6, .7-7.3

5.30 g (17.4 mmol) of the enplketone were dissolved in 53 ml of ethanol, 20.8 ml (52 mmol) of a 10% sodium hydroxide solution were added, and the mixture was cooled to ^{0 ° C. while stirring.} Then 6.1 ml (52 mmol) of 30 # strength hydrogen peroxide were added and the mixture was ^{stirred for 1 hour at 0} ° C. and then for 2 1/2 hours at room temperature. The mixture "was diluted with 100 ml of water and extracted with 150 ml of methylene dichloride. The pH of the solution was adjusted to 7.4 with glacial acetic acid, a solution of sodium- / 4oc-hydroxy-5cC- (3-hydroxy-4- m-chlorophenoxybut-1-transenyl) -cyclopent-2-en-1oC-yl7 _aC etate was obtained in aqueous ethanol.

A09824 / 1099 BAD ORlGfNAL

The solution of sodium / 4oi-hydroxy-5ct- (3-hydroxy-4-m-chlorophenoxybut-1-tr ansenyl) -cyclopent-2-en-1ol-yl7-ac et ate (17.4 ml -iol) in aqueous ethanol (2: 1, 153 ml) was cooled in Sis, and then an ice-cold solution of 26 g (0.16 mol) potassium iodide and 13.1 g (52 mmol) iodine in 52 ml water was added . The mixture was ^{stirred for 18 hours at 0} ° C., the excess iodine was destroyed by adding solid sodium bisulfite, and the solution obtained was extracted with 3 × 100 ml of ethyl acetate. The combined extracts were dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel using 10 % ethyl acetate in .Methylene dichloride as the eluent, wherein 2,3,3ass, 6assietrahydro-50 <- hydroxy-4 "- (3-hydroxy-4-m-chlorophenoxybut-1-trans -enyl) -6ß-iodo-2-oxocyclo'penteno / b7furan was obtained. R "= 0.5 (50 % ethyl acetate in methylenedi- chloride). The NMR spectrum in deuteriochloroform showed the following characteristic bands (£ values):

5.32, 1H, doublet. C-6ass proton 6.90, 2H, multiplet, olefinic protons 6.7-7.3, 4H, multiplet, aromatic protons.

3.14 g (6.8 inMol) 2,3,3ass, 6ass-Tetrahydro-5 <X / -hydroxy-4o <- (3 -rhydr 0x37 - 4-m- chlorophenoxybut-1-trans-enyl) -6ß- iodo-2-oxocyclopenteno / b / furan and 2.46 g (8.5 "in moles) tri-n-butyltin hydride were dissolved in 30 ml of anhydrous benzene and the resulting solution was refluxed for 48 hours. The benzene was evaporated under reduced pressure, and the remaining oil was rubbed 5sial with 2 ml of n-pentane, where the epimeric diols, 2,3,3ass, 6ass-tetrahydro-5othydroxy-4oi - (3-h.ydroxy-4-m-chlorophenoxy-but-1 -trans-enyl) Z-oxocyclopent-eno / b / furan were obtained. Rp = 0.4 (ethyl acetate). The NMR spectrum in deuteriochloroform. showed the following characteristic features (<£ values):

3.92, 2H, multiplet, -CH ₂ .0-

- 26 4098247 10 99

4.25, 1Η, wide singlet ,. C-5 [beta] proton
4,52, 1H, broad singlet, -CH: CH.CH (OH) -5,10, ΊΗ, 'multiplet, C-öaß ^ proton:
5.90, 2H, multiplet, olefinic protons
.6,7-7,3, 4H, multiplet, aromatic protons.

To a solution of 1.85 g (5.5 mmol) of the epimeric diols in 50 ml of methylene dichloride under a nitrogen atmosphere were successively 5.6 ml of redistilled 2,3-dihydropyran and a solution of 0.5 ml of a 1?:> solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran added. .

After 10 min, 3 drops of pyridine are added, first and foremost
100 ml of ethyl acetate were added. The solution was washed successively with saturated sodium bicarbonate solution and saturated saline solution
"and dried. Evaporation of the solvents gave a
Mixture of the epimeric bis-tetrahydropyraiiyl ethers as a clear oil, Rp- = 0.6 (ethyl acetate). ■ -

To a solution of 2.53 S (5.0 mmol) of the epimeric bis-tetrahydropyranyl ethers in 45 ml of dry toluene were added
3.06 ml of a 1.9-6 molar solution of diisobutylaluminum hydride in toluene were added under a nitrogen atmosphere at -78 ° C. After 15 min \ furde that Realition by dropwise addition of 4 ml of methanol, quenched, and after a further I5 ^£ \ yurden at room temperature for '30 min - a 1 oil: 1 Gcmischs of saturated brine and .Water was added and then the mixture was extracted with 3 x 50 ml of ethyl acetate. The Extract was washed with saturated sodium chloride solution and dried, and the solvents were evaporated, leaving a mixture of the epimers of the lactol ; -2-Hydroxy-2,3,3ass, 6ass-tetrallydro-5oi- (tetrahydropyran-2-3riOxy) -4oc- / 3- (tetrahydropyran-2-yloxy) -4-m-chlorophenoxybut-1-trans-e ^ l / '- cyclopenteno / b / furan _t received

. "- 27 - ■

became. Rp = 0.4 (ethyl acetate).

8.8 g (20 mmol) of finely powdered (4-carboxybutyl) tri-Tjhenylphosphoniumbrornid were under vacuum for 1 st to 100 ⁰ C heated. The evacuated reaction vessel was filled with a dry nitrogen atmosphere, the solid was dissolved in 20 ml of dimethyl sulfoxide, and the solution was cooled to room temperature. To this solution, 19 ml (47 mmoles) of a 2 molar solution of kethanesulfinylmethylsodium in dimethyl sulfoxide were added dropwise, followed by the addition of a solution of 2.0 g (4.4 mmoles) of the mixture of the. . Epimers of lactol in a mixture of 20 ml of dimethyl sulfoxide and 4 ml of toluene connected. The solution was stirred for 1 st, and the solvent was removed by evaporation under reduced pressure at room temperature below 4O ⁰ C. The residue was shaken with 50 ml of water and 10 ml of ether, and the aqueous

away-

ge phase was / separated and extracted 4 times with 20 ml of ether, whereupon the extracts were then discarded. The aqueous solution was acidified to pH 4 with 2N aqueous oxalic acid and extracted 5 times with 20 ml of a mixture of equal parts of ether and petroleum ether (boiling point 40-60 ° C.). The organic phase would be separated off, washed with saturated sodium chloride solution and dried. Evaporation of the solvent gave the desired i6- (3-chlorophenoxy) -9oG-hydroxy-1 lot, 15-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13 ~ trans- 12-epi-prostadienoic acid as a clear oil, · R "= 0.4 (5 % methanol in methylene dichloride).

Example 2 _.

A solution of 135 mg (0.23 mmol) i6- (3-chlorophenoxy) -9-oxo-hot, 15-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid in 1 ml of tetrahydrofuran and 8 ml of a 2: 1 mixture of acetic acid and water was 1 st stirred at 5O ⁰ C.. The solvents were

- 28 409824/1099

removed in vacuo and the residue was chromatographed on silica gel thin layer plates using a mixture of 3% acetic acid in ethyl acetate as the eluent. The separated C-15 epimers of 16- (3-chlorophenoxy) -.1 1ct, 1 S-dihydroxy ^ -oxo-17,18,19, 20-tetranor-5-cis, 13-trans-12- epi-prostadic acid obtained. , Rp = 0.30 and 0.35. The NMR spectrum of each epimer in deuterated acetone showed the following characteristic features (<£ values):

3.98, 2H 4, , Multiplet, -CH ₂ .0- 4.48, -2H , Multiplet,. -CH (OH) - 5.38, 2H , Multiplet, cis-olefinic protons 5.76, 2H _r multiplet, trans-olefinic protons 6.8-7, 4H, multiplet , aromatic protons.

For the more polar C-15 epimer, M ⁺ = 667.2908 (calculated for C ₅₂ H ₆₄ NO ₆ Si ^ Cl = 667.2947).

The starting material for the above manufacture was as follows: -,

A / solution of 210 mg (0.36 mmol) i6- (3-chlorophenoxy) -9ct-hydroxy-11oc, 15-bis (tetrahydropyran-2-yloxy) -17 * 18.19, ^ O-tetranor-S- cis, 13-trans-12-epi-prustadienoic acid in 4.4 ml of acetone was treated at 0 C with 115 μΐ 8N chromic acid for 35 minutes. Isopropanol was then added, and the solution was diluted with 30 ml of ethyl acetate, washed 3 times with 10 ml of sodium chloride solution and dried. Evaporation of the solvent gave the mixed C-15 epimers of 16- (3-chlorophenoxy) -CMoxo-Hoi, 15-bis (tetrahydrppyran-2-yloxy) 17,18,19,20-tetranor-5-cis, 13 ^ trans-12-epi-prostadic acid, Rp = 0.5 (5 % methanol in methylene chloride).

Example 3

The procedure described in Example 2 was repeated, wherein i6- (3-chlorophenoxy-2-methyl-9-oxo-1to (., i5-bis (tetra-

- '- _; 29 409824/1099

hydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid was used as the starting material. The separated C-15 epimers of i6- (3-chlorophenoxy) -1 -] oi, 15-dih.ydroxy-2-methyl-9-oxo-17,18,19,20-tetranor-5-cis , 13-trans-12-epi-prostadic acid. Rp = 0.4 or 0.45- The NMR spectrum of a 3 ^ed - ^en epirner in deuterated acetone showed the following characteristic features (6 "values):

1.11, 3H , Doublet, -CH- 3.99, 2H , Doublet, -CiL ₅ -O- 4.46, · 2Η , Multiplet, -CH (OH) - 5.35, 2Η , Multiplet, cis-olefinic protons 5.79, '2H Multiplet, trans-olefinic protons 6.8-7, 4, 4Η, multiplet, aromatic protons.

M ⁺ = 681.3096 (calcd for C ₃₃ H ₆₆ ClNO ₆ Si ₃ = 681.3103).

"The starting material for the above production was obtained as follows:

The procedure described in Example 1 was repeated except that the lactol was reacted with the ylide derived from (4-carboxypentyl) triphenylphosphonium bromide, where i6- (3-chlorophenoxy) -9oU-hydroxy-2-methyr- 11cC, 15-bis- (tetrahydropyran-2-yloxy) -17,18,19,20-tetr anor-5-cis, 13-trans-12-epi-prostadic acid. Rp = 0.2 (5 % methanol in methylene dichloride).

The bis (tetrahydropyranyl ether) was oxidized according to Example 2, the mixed C-15 epimers of i6- (3-chlorophenoxy) -2-methyl-9-oxo-11oL, 15-bis (tetrahydropyran-2-yloxy) - 17, 1-8,19 »20-tetranor-5-cis, 13-trans-12-epi-prostadic acid. Rp = 0.6 (5 % methanol in methylene dichloride).

Example 4 '

A solution of 18.5 mg (0.044 in moles) of the less polar

409824/1099

C-15 spimers from. i6r- (3-chlorophonoxy) -11oi, 15-dihydroxy-9-oxo-17 j 18, 19 j 20-tetranor-5-cls, 13-trahs-12-epi-prostadienoic acid in 4 ml diglyme would be treated with 2i4 / Treated il a 1 molar solution of sodium borohydride in diglyme and stirred for 20 st at room temperature. The mixture was diluted with 10 ml of water and extracted 3 times with 10 ml of ether and the extracts were discarded. The aqueous solution was acidified to pH 4 with 2N oxalic acid and extracted with 3 × 10 ml of ethyl acetate. The combined extracts were dried, the solvent was evaporated, and the residue was chromatographed on silica gel thin-layer chromatography plates, eluting with 3% acetic acid in ethyl acetate. , 15-trihydroxy-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid. R "= 0.2 (3 % acetic acid in ethyl acetate). *.

The NMR spectrum in deuterated acetone showed the following characteristic features (£ values):

3.85-4.36, 4H, multiplet, C-9 and C-11 protons,

and -CH ₂ .0-

Multiplet, C-15 proton multiplet, ci-olefinic protons multiplet, trans-olefinic protons

6.8-7.4, 4H, multiplet, aromatic protons,

(M-CH ₃ ) ⁺ = 697.3003 (calcd for G ₃₃ H ₅ 697.3 PO) ..; -

Example 5 "

4, 46, 1H, 5, 42, 2H, 5, 77, · 2H,

The procedure% described in Example 1 vürde repeated 9ct-hydroxy-1iGC _i 15-bls (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi-prostadienoic acid as a starting material ver \ -; was completed. The separated Cr15 epimers of 9oi, 1106,15-trihydroxy-5-cis, 13-trans-12-epi-prostadic acid were obtained. R "= 0.30 or O ₅ 35 (3 % acetic acid in

... - ^; 31 ■ - ■ ■ ■ - ■. ■■

Ethyl acetate). The NMR spectrum of each epimer in deuterated Acetone showed the following characteristic features (6 values):

0.87, 3H, triplet,. -CH ₇

4.10, 3H, multiplet, -CH (OH) -5.3, 2H-, multiplet, cis -olefinic protons

5.50, 1H, quartet, Ύ . ,

? ■ trans-olefinic protons. 5.90, 1H, Quartet, J.

M ⁺ = 642.3987 (calcd for C ₃₂ H ₆₆ O ₅ Si ^ = 642.3989).

The bis-tetrahydropyranyl ether used as the starting material was followed by that described in the second part of Example 1. Process prepared via the following intermediates:. . .

the enone, Rp = 0.5, (methylene dichloride). The NMR spectrum -in deuteriochloroform showed the following characteristic features (£ values):

Triplet, -CH ₃ -

Triplet, -CO-CH ₉ -CH ₉ -. ■ ■ ■

double doublet, C-6 endo proton

Triplet, -COCH ₂ -

Quartet, -CH: CH.CO-

Multiplet, I _n ^ ^ _n ^ "u. '

V C-2 and C-3 protons. Multiplet, J

Quartet, ■ -CH: CH.CO-

the enol, Rp = 0.3 (methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (S values):

0.85, .3H, 1.57, 2H, 1.80, 1H, 2.55, 2H, 6, -04, 1H, 6.22, 1H, 6.47 ^% • 1H, ■ 6.76, 1H,

0.85, 3H, Triplet, -CEU 1.70, 1H, Quartet, C-6 endo proton 4.04, 1H, Multiplet, -CH (OH) - 5.64, 2H, Multiplet, . trans-olefinic protons 6.17, 1H, Multiplet, i C-2 and C-3 protons 6.45, / IH, Multiplet, J - 32 - 4098 2 4/1099

the enol ketone, Rp = 0.2 '(10 $ ethyl acetate / methylene dichloride). The "NMR spectrum" in deuteriochloroform showed the following characteristic features ((j-values):

0.85, 3H, Triplet, ■ -CH ₃ 4.00, 1H, Multiplet, -CH (OH) - 5.50,. 2H, Multiplet, trans-olefinic protons 6.10, 1H, Multiplet, > C-2 and C-3 protons 6.60, IH, Multiplet, J

the iododiol, Rp = 0.4 (50% ethyl acetate in methylene dichloride). -The NMR spectrum in deuteriochloroform showed the following characteristic features (£ values):

0.85, 3H, · triplet, -CH ₃

4.08, 1H ₁ multiplet, 7 _{OT ((H)} . ^> _CHJ .

4.36, 2H, multiplet, J ~. · ^ ~

5.31, 1H, doublet, C-6ass proton

5.73, -2H, · multiplet, / olefinic protons

the diol, R "= 0.2 (50 % ethyl acetate in methylene dichloride). The NMR spectrum in deuterated chloroform showed the following characteristic features (6 values):

Triplet, -CH ₃

Multiplet, T, _ _{CH (0H)} _ ·. Multiplet, J.
Triplet, C-6ass proton multiplet, olefinic protons

the bis-tetrahydropyranyl ether, Rp = 0.8 (5 ^ methanol in methylene chloride). The NMR spectrum in deuterated chloroform showed the following characteristic features (S values):

Triplet, -CH ₃ .
Triplet, - .C-öaß-Proton Multiplet, olefinic protons

- 33 - ■

4098 24/1099

0.86, 3H, 4.10, 1H, 4.20, 1H, 5.07, 1H, 5.70, 2H,

0, 87 3H, 5, 06, 1H, 5, 65, 2H,

the lactol, rp = 0.40 (ethyl acetate).

Soi-Hydroxy-1 Id, 15-bis (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi-prostadienoic acid, Rp = 0.2 (5 % methanol in methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features ■ (£ values):

0.89, 3H, multiplet, -CH _3. -5.4, 4H, multiplet, olefinic protons

Example 6

• The procedure described in Example 2 was repeated, using 9-Oxo-Hot, i5-bis (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi-prostadienoic acid as starting material. The separate 'C-15 epimers of 11 et, 15-dihydroxy-9-oxo-5-cis, 13-trans-12-epi-prostadienoic acid were obtained.' R "= 0 * 35 or 0.5 (3 % acetic acid in ethyl acetate). The IMR spectrum in deuterated acetone showed the following characteristic features (6 values):

0.88, 3H, triplet,

4.09, 1H, multiplet, 1 _ _{CH (0H)} _ 4.44 ,. 1H, multiplet, J "". -5,38, 2Ά, multiplet, cis-olefinic protons 5,62, 2H, multiplet, trans-olefinic protons

M ⁺ . = 597.3683 (calculated for C ₃₀ H ₅₉ NO ₅ Si ₃ = 597.3701).

The 9-oxo-bis (tetrahydropyranyl ether) used as starting material i Rp = 0.4 (ethyl acetate), was replaced by the in the second part of example 2 described method by oxidation of 9-hydroxy-bis (tetrahydropyranyl ether) obtain.

Example 7

The procedure described in Example 1 was repeated,

- 34 - 40982471099

0.89, ■ 3H, Triplet, 1.13, 3H, Doublet, Vi, '3H, Multiplet, 5.4, 2H, Multiplet, 5.50, 1H, Quartet, 5.92, 1H, Quartet,

9ot.-Hydroxy-2-methyl-'bis- (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi ^ prostadienoic acid was used as the starting material. The separated C-15 epimers of 9oC, 11cC, 15-trihydroxy-2-methyl-5-cis, 13-trans-12-epi-prostadic acid were obtained. Rp = 0.20 or 0.25 (3 % acetic acid in ethyl acetate). The MR spectrum of each spimer in deuterated acetone showed the following characteristic features (<5 values):

, - (CH ₂ ) ₄ -CH ₃
2-methyl ■

-CH (OH) -

cis-olefinic protons

trans-olefinic protons

M ⁺ = 656 ^ 4102 (calculated for C ₃₃ H ₆₀ O ₅ Si ₄ = 656/4145).

"The bis-tetrahydropyranyl ether used as the starting material v / Was by that described in the second part of Example 3 ". Process via the 2-methyl bis (tetrahydropyranyl ether) obtain. Rp = 0.25 (ethyl acetate).

Example 8

The procedure described in Example 2 was repeated using 2-methyl-9-oxo-1100,15-Ms- (tetrahydropyran-2-yloxy) 5-cis, 1'3-trans-12-epi-prostadienoic acid as the starting material . The separated C-15 epimers of 1 "1oL, 15-pihydroxy-2-methyl-9-oxo-5-cis, 13-trans-12-epi-prostadienoic acid were obtained. R _p = 0.4 or vi. 0 , 5 (3 % acetic acid in ethyl acetate) The NMR spectrum of each isomer in deuterated acetone showed the following characteristics (6 values):

CX, 87, 3H, triplet, g ₄₃

1.13, 3H, doublet, 2-methyl 4.08, 1H, multiplet, C-9 proton

■ "-'-- 35 409824/1099 ^

4.46, 1H, multiplet, C-15 proton 5.40, 2H, multiplet, cis -olefinic protons 5.63, 2H, multiplet, trans-olefinic protons.

M ⁺ = 611 _; 3853 (calculated for C ₇₅₁ H ₆₁ NO ₅ Si ^ = 611.3857).

The 9-oxo-bis (tetrahydro ~ pyranyl ether) used as starting material, Rp = 0.2 (50 ⁰ A ethyl acetate in toluene), was oxidized according to the second part of Example 2 of 9-hydroxy-bis-tetrahydropyranyl ether, which is described in Example 7 obtained. . ■

Example 9

The procedure described in Example 4 was repeated using the less polar C-15 Eplmer of 11ot.j15-dihydroxy-9-oxo-5-cis, 13-trans-12-epi-prostadienoic acid as starting material. This gave 9β, 11cC, 15-trihydroxy- ~ 5-cis, 13-trans-12-epi-prostadienoic acid. Rp = 0.2 (3 % acetic acid in ethyl acetate). The MR spectrum in deuterated acetone showed the following characteristic features (6 values):

0.88, 3H, triplet, -CH ₃

4.2, 3H, Mul.tiplet, -CH (OH) -

5.42, 2H, multiplet, ice-olefinic protons

5.60, 2H, "Multiplet, trans-olefinic protons.

M ⁺ . = 642.3962 (calculated for C ₃₂ H ₆₆ O ₅ Si ₄ = 642 ^ 3989).

Example 10

The procedure described in Example 1 was repeated. gets, using 20-ethyl-9 ^oU iiyd.roxy-11 QL, 15-bis- (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi-prostadienoic acid as starting material. The separated C-15 epimers of 20-ethyl-9 <*, 11 <λ, 15-trihydroxy-5-cis, 13-trans-12-epi-prostadienoic acid were obtained. Rp = 0.3 and 0.4 (3 % acetic acid in ethyl acetate). The NMR spectrum of a

- 36 -A0982 4/1099

each isomer (in deuterated acetone) showed the following characteristic bands (O values):

0.85, 3H, triplet, methyl.

- 4.1, 3H, multiplet, • CH (OH) '·

5.2-6.0, 4H, multiplet, olefinic protons.

The one used as the starting material in the above procedure 20-ethyl-9oC-hydroxy-11 &, 15-bis- (tetrahydropyran-2-yloxy) S-ciSjiS-trans - ^ - epi-prostatic acid can be obtained as described in the second part of Example 1 through the following intermediates:

the Εηοη, ν 5-chloro-5-cyano-7-anti- (3-oxodec-1-trans-enyl) -bicyclo / 2,2, i / tiept-2-en, Rp = 0.8 (methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (<5 values):

0.85, -3Hf. Triplet, methyl group

'1,55, 2H> broad triplet, -CO.CH ^^

2.55, 2H »triplet, -CO-CH ₂ -CH ₂ -,

6.01, IH, "double doublet, -CH = CH-CO-

6.22, 1H,

6.44, 1H, multiplet, J protons

6.6-7.0, 1H, multiplet, p

, J

the enol, 5-chloro-5-cyano-7-anti- (3-hydroxydec-1-trahsenyl) bicyclo ^ 2.2, i7hept-2-ene, R _p = 0.5 (methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (S values):

Triplet, methyl

broad, ^ CH (OH) ■.

Multiplet, -CH = CH.CH (OH) -

■ Multiplet, ■> _c _ ₂ _ _{and c} _3. _proton multiplet, J.

the enol ketone, 7-anti- (3-hydroxydec-1-trans-enyl) -bicyclo- / 2.2, i7hept-2-en-5-o'n ·, R _p = 0.4 (10 % ethyl acetate in Me-

- 37 409824/1099

0.84, 3H, 4.05 1H, 5.63, 2H, 6.18, 1H, 6.43, 1H,

ethylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (ό "values):

0.87, 3H, Triplet, methyl 3.99, 1H, Multiplet, ^ CH (OH) 5.47, 2H, Multiplet, -CH = CH.CH (OH) - 6.10, 1H, Multiplet, \ C-2- and C-3-P 6.60, ' 1H, ' Quartet, J. -

the iododiol, 2,3,3ass, 6ass-tetrahydro-5oc-hydroxy-4oC- (3-.hydroxydec-1-trans-enyl) -6ß-iodo-2-oxocyclopenteno / b7furan, Rp = 0.5 (50 % Ethyl acetate in methylene dichloride). The NMR spectrum • in deuteriochloroform showed the following characteristic bands (o values):

0.86, 3H, triplet, methyl
. 4.0-4.4, 3H, multiplet, ^ qI (OH) and ^ CHJ 5.32, 1H, multiplet, 6ass-hydrogen 5.72, 2H, ■ multiplet, olefinic hydrogens

the diol, 2,3,3ass, 6ass-Tetrahydro-50O-hydroxy-4ol- (3-hydroxydec-1-trans-enyl) -2-oxqcyclopenteno / b / furan, R "= 0.2 (40 % ethyl acetate in Methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (<5 values):

0.86, 3H, triplet, methyl

4.0-4.3, 2H, multiplet, ^ CH (OH) 5.08, 1H, triplet, 6oUProton 5.70, 2H, multiplet, olefinic protons

the Lact'ol, 2,3,3ass, 6ass-Tetrahydro-5 * - (tetrahydropyran-2-yloxy) -4Λ- / 3- (tetrahydropyran-2-yloxy ) -dec-1-trans-eny l7-2-hydroxycyclopenteno / b7furan, Rp = 0.2 (ethyl acetate). The NMR spectrum in deuteriochloroform showed the following characteristic features (<5 values):

0.85, 3H, triplet, methyl

- 38 -

409824/1099

5.5 »2H, Mulitiplet, olefinic protons"

20-Äth7l-9o ^£ --h7drox7-1 lot, 1 5-bis- (tetrah7cirop7ran-2-7lox7) S-ciSj ^ -trans - ^ - epi-prostadienoic acid, R "- = 0.3 (ethyl acetate). The NMR spectrum showed the following characteristics (6 values): ... "".

0.85, 5H, Triplet, methyl Protons 5.5, 4H, Mulitiplet, olefinic example 11

The procedure described in Example 1 was repeated, using 20-ethyl-9-oxo- _N 11 <X, 15-bis- (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epl-prostadienoic acid as starting material was used. The C-15 epimers of 20-ethyl-110C, 15-dih7drox7-9-oxo-5-cis, 13-trans-f2-epi ^: -prostadien- ^ acid, R ₅₁ = 0.4 and 0 , 5 (3 % acetic acid in ethyl acetate). The NMR spectrum in deuterioacetone showed the following characteristic features (d values):

0.85, / 3H, - triplet, Metli7l .'- .. '■ ■ ■ 4.1 and 4.4, · 2H, multiplets, -GH (OH) - ■ 5.5, 4H, milliplet, olefinic protons.

The starting material was obtained by oxidation, as described in the second part of Example 2, of 20-Äth7l-9oUh7drox7-11Λ, 15-bis- (tetrah7drop7ran-2-7loX7) -5-cis, 13-trans-12- epi-prostadienoic acid, which is described in the second part of Example 10, prepared. Rp = 0.3 (50 % acetic acid in toluene).

Example 12 ^;

A solution of 5 mg of the more polar C-15 epimer of 20- 'ß.Vay ± -9oL, 11 ot, 15-trih7dr 0x7-5-0 is _r 13-tr ans-12-epi-pro stadienoic acid in 10 ml Methanol was treated with an excess of diazomethane at 0 C. -After 5 min the lo-

- 39 - 40 98 2 4 / T0 99

solvent-evaporated in vacuum, whereby 2O-ethyl-9oi, 1ioC, 15-trihydroxy - ^ - ciSj ^ -trans - ^ - epi-prostadienoic acid-Hiethylester was obtained. Rp = 0.3 (ethyl acetate).

Example 15

The procedure described in Example 2 was repeated using 9-oxo-10C, 15-bis (tetrahydropyran-2-yloxy) -13-trans-12-epi-prostenic acid as starting material. The separated C-15 ExDiraeren of 11oC, 15-dihydroxy-9-OXO-13-trans-12-epi-prostenic acid were obtained. R " = 0.3 or 0.5 (2 % acetic acid in ethyl acetate). The NMR spectrum in deuterated acetone showed the following characteristic features (<5 values):

0.85, 3H, Triplet, Methyl protons 4.10, 1H, Multiplet, C-11 proton 4.50, 1H, Multiplet, C-15 proton 5.63, 2H, ' 'Multiplet, trans-olefinic. Protons

M ⁺ = 599.3844 (calculated for C ₃₀ H ₆₁ NO ₅ Si ₃ = 599.3857).

The 9-oxo-HoC, 15-bis- (tetrahydropyran-2-yloxy) -13-trans-12-epi-prostenic acid used as starting material was obtained as follows:

A solution of 174 mg (0.33 mmol) of 9 ⁰ ^ -hydroxy-11 oC, 15-bis- (tetrahydropyran-2-yloxy) -5-cis, 13-trans-12-epi-prostadic acid in 3.5 ml of absolute ethanol containing 87 mg of 5% palladium-on-charcoal catalyst was hydrogenated for 5-1/2 st at room temperature. The catalyst was filtered off and the filtrate was evaporated in vacuo to give ^ o ^ hydroxy-HoL, 15-bis- (tetrahydropyran-2-yloxy) -13-trans-12-epi-prostenic acid. Rp = 0.7 (ethyl acetate). -

The .901 hydroxy compound was treated with chromic acid by the The method of Example 2 is oxidized, the desired

- 40 409824/1099

9-Oxo-i 1 (X 1, 15-bis (tetrahydropyran-2-yloxy) -13-trans-12-epi-prostenoic acid. R "= 0.3 (5 % methanol in methylene dichloride). -

Example 1 ~ 4

The procedure described in Example 2 was repeated, using as starting material 9o ^ -hydroxy-1ioL, 15-bis- (tetrahydropyran-2-yloxy) -13-trans-12-epi-prostenic acid, which was used according to the second part of Example 11. This gave 9 "-, 11a, 15-trihydroxy-13-trans-12-epi-prostenic acid. R _p == 0.3 and 0.4 (3 % acetic acid in ethyl acetate). M = 644.4150 (calculated for C ₃₂ H ₆₈ O ₅ Si ₄ = 664.4145). ".

Example 15 '

The procedure described in Example 1 was repeated, with 9oi-Hydro3cy-i6-phenyl-1ia, _s i5-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13- trans-12-ep.i-prostadienoic acid was used as the starting material. The separated C-15 epimers of goLjHajiS-trihydroxy-iophenyl-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid were obtained. Rp = 0.3 and 0.4 (3 % acetic acid in ethyl acetate). The NMR spectrum in deuterioacetone showed the following characteristic features (6 values):

2.80, - 2H, ■ 'doublet, -CH ₉ Ph

3.9-4.4, 3H, multiplet, "-GH (OH) -. 5.40, 2H, multiplet, cis-olefinic protons 5.51, 1H, Quartet, ")." ■■ · - ■

, _ _Λ ^ _ττ . · "■■ ν trans-olefinic protons

5.9t, 1H, Quartet, J.

7.22, 5H, multiplet, * aromatic protons. · (M-CH ₃ ) ⁺ «647.3443 (calculated for C ₃₃ H ₅₉ O ₅ Si ₄ = 647.3441).

The bis (tetrahydropyranyl ether) used as starting material was by the in the second part, of example 1

• ■■■. ' ^: - · - 41 - ·

409824/1099 ~

MS

Written procedures received through the following intermediate stages:

the enone, Rp = 0.6 (methylene dichloride). The NI-IR-Sp eis.tr um in deuteriochloroform showed the following characteristic features (cS values):

1.77, 1H,. double doublet, C-6 endo proton 2.76, 2H, multiplet, C-6 exo and C-7 protons 3.05, 1H

, J

Multiplets, C-1 and C-4 protons 3.44, 1HJ

3.85, - 2H, singlet, -CH-Eh
6.08, 1H, quartet, -CH: CH.CO-.

''' γ multiplets, C-2 and C-3 protons 6.45, 1H, J

6.85, IH, Quartet, -CH: CH.CO-; ^r 7.22, 5H, multplet, aromatic protons

the enol, R _p = '0.4 (methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (6 - fourth):

C-6 endo proton -CHpPh, C-6 exo- and C-7-

Protons

-CH (OH) -.

trans-olefinic protons

C-2 and C-3 protons aromatic proton

the enol ketone, Rp = 0.5 (10 % ethyl acetate in methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (ί values):

1.80, 2H, multiplet, C-6 protons

2.76, 2H, doublet, -CH ₂ Ph

4.26, 1H, multiplet, -CH (OH) -

5.59, 2H, multiplet, trans-olefinic protons

- 42 - 4098 24/1099

1.75, 1H, Multiplet, ) 2.80, 4H, Multiplet, J- multiplet, 4.37, 1H, Multiplet, Singlet, 5.70, 2H, Multiplet, 6.22, 1H, " 7 7
6.46, 1H, J. 7.27, 5H,

O , 12, 1H, O .53 / 1H, π , 21, EXT

Multiplets, C-2 and C-3 protons Multiplet, aromatic protons

the iododiol, Rp = 0.5 (50 % ethyl acetate in methylene dichloride). The NMR spectrum in Deuteriochlorof orrn showed the following characteristic merlanals (6- ¥ erte):

2.86, 2H, doublet, -CH ₂ Ph ^

4.33, 3Π, multiplet, 'C-5ß-,' C- & t- and Seitenlcet-

ten ~ CH (OH) protons

5.35, 1H,. Doublet, C-6ass proton 5.78, 2H, multiplet, olefinic protons 7.3, 5H, multiplet, ■ aromatic protons

the diol, R _p = 0.4 (ethyl acetate). The WIR spectrum in deuteriochloroform showed the following characteristic features ((S values): "■■ _." ·

Doublet,. -CH ₀ Ph
Multiplets, -CH (OH) - ''

Triplet, C-15 proton '■■ ..-' Multiplet, olefinic protons Multiplet, aromatic protons

the 'bis (tetrahydropyranyl ether), Rp = 0.7 (ethyl acetate). the lactol, P ^ p = 0.6 (ethyl acetate); .

9c (-Hydroxy-16-phenyl-11ov., 15-bis- (tetrahydropyran-2-yloxy) 17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid ·, R ₁₅ , = 0.5. (5 % methanol in methylene dichloride).

Example 16 -, ---..._

The procedure described in Example 2 was repeated, v / obei 9-Oxo-16-phenyl-1 ioc, 15-bis (tetrahydropyran-2-yloxy) -17,18,19,2Q-tetr £ nor-5-cis, 13-trans-i2-e.pi-prostadienoic acid

4 0 9 8 2 4/1099

2.82, 2H, 4.16, 1H, -4.35, - IH, 5.03, 1H, 5.68, 2H, 7.22, 5H,

was used as the starting material. The C-15 epimers of Hot, 15-dihydroxy-9-oxo-16-phenyl-17, '18, 19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid were obtained. Rp = 0.45 and 0.55 (3 % acetic acid in ethyl acetate) The NMR spectrum in deuterioacetone showed the following characteristic features (6 values):

2.80, ZH, Doublet, -CH ₂ Ph 4.35, 2H, Multiplet, -CH (OH) - 5.34, ZH, Multiplet, cis-olefinic protons 5.60, 2H, Multiplet, trans-olefinic protons 7.22, * 5H, Singlet, aromatic protons

M ⁺ = 617.3383 (calculated for C ₃₂ H ₅₅ NO ₅ Si ₃ = 617.3388)

The starting material can be oxidized, as described in the second part of Example 2, of 9 ⁰ 16-phenyl-1ia, 15-bis (tetrahydropyran-2-yloxy) -17, 18,19,20 tetranor-5-cis , 13-trans-12-epi-i) rostadienoic acid, which is described in the second part of Example 15, can be produced. Rp. = 0.35 (5 % methanol in methylene dichloride).

Example 17

That. The procedure described in Example 1 was repeated, except that 9c <-hydroxy-16- (2-naphthyloxy) -1 ία, 15-bis- (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis , 13-trans-12-epi-prostadienoic acid was used as the starting material. The separated C-15 epimers of 9ot, 11 (Xj15-trihydroxy-16- (2-naphthyloxy) -17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid, Rp = 0.2 and 0.3 (3 % acetic acid in ethyl acetate) obtained. M ⁺ = 728 ^ 3781 (calculated for C ^ gHg ^ OgSi ^ = 728 _; 3773). The NMR spectrum in deuterio-chloroform showed the following characteristic features (6 values):

4,10, 4H, Multiplet,.-CHp.O- and C-9- and C-11-

Protons

'- 44 -

409824/1099

4.58, 1H, Multiplet, 5.45, 2H-, Multiplet, 5.66, ■ 1H, Quartet, ~) 6.20., 1H, Quartet, J.

cis-olefinic protons, trans -olefinic protons 7.1-7.9, 7H, multiplet, aromatic protons

The bis (tetrahydropyranyl ether) used as starting material was followed by that described in the second part of Example 1 Procedure obtained via the following intermediates:

the enone, "Rp = 0.5 (2 % ethyl acetate in methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (S values):

1.70,. 1H, double doublet, C-6 endo proton - 4.86, 2H, singlet, -CH ₂ O-

6.1-6.6, 3H, multiplet, C-2 and C-3 protons and • - - -CHrCH.CO-

6.9-7.9, 8H, multiplet, aromatic protons and

'. ^; -CHiCH.CO-the enol, Rp = 0.3 (10 % ethyl acetate in methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (6 values):

/ 1.76, '1H, double doublet, C-6 endo proton 4.04, 2H ₁ multiplet, -CH ₂ -O-.4.56, 1H, - multiplet,' -CH (OH) -5 , 5-6,6, 4H, multiplet, trans-olefinic and

C-2 and C-3 protons

7.1-7.9, 7H, multiplet, aromatic protons

the enol ketone, Rp = 0.3 (10 % ethyl acetate in methylenedi- 'chloride).

the iododiol, Rp = 0.4 (50 % ethyl acetate in methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (<5 values):

409824/1099

Multiplet, -CH ₂ O- and C-6β protons Multiplets, -CH (OH) protons

Doublet, C-6ass proton 5.9, 2H, multiplet, olefinic protons 7.1-7.9, 7H, multiplet, aromatic protons

the diol, R _p = 0.4 (5% methanol _in? methylene dichloride). The NMR spectrum in deuteriochloroform showed the following characteristic features (6 values):

4.05, 3H, 4.41, 1H, 4.63, 1H, 5.26, 1H,

4, 02, .2H, Multiplet, 4, 22 IH, Multiplet, 4, 58 1H, Multiplet,

C-5β-Pro "1; on

-CH (OH) - within a ~ "chain

5.00, 1H,. Multiplet, C-6ass proton ■ 5.5-6.2, 7H, multiplet, aromatic protons

"the bis (tetrahydropyranyl ether), R" = 0.3 (50 % ethyl acetate in toluene).

the lactol, Rp = 0.6 (ethyl acetate) -

-Hy droxy-16- (2-naphthyloxy) -11oC, 15-bis- (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid , Rp = 0.4 (5 % methanol in methylene dichloride).

Example 18

The procedure described in Example 2 was repeated using 16- (2-naphthyloxy) -9-oxo-1 lot, 15-bis- (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis , 13-trans-12-epi-prostadienoic acid was used as the starting material. The C-15 epimers of 1 lot, 15-dihydroxy ~ 16- (2-naphthyloxy) -9-OXO-17,18,19,20-tetranor-5-cis, 13-trans-12-epi- Prostadic acid obtained. Rp = 0.3 and 0.4 (3 % acetic acid in ethyl acetate). The NMR spectrum in deuterated acetone showed the following characteristic features (<i- ¥ erte) s

- 46 - '409824/1093

-CH ₀ O- and -CH (OH) -

cis-olefinic protons trans-olefinic protons aromatic protons.

4.10, 3H , 9, , Multiplet, / 4.56, 2H , Multiplet, J. 5.42, 2H ,. Multiplet, 5.86, 2H , Multiplet, 7.1-7 7H, multiplet,

M = 683j3477 (calculated for C ₃₆ H ₅₇ NO ₆ Si ₃ = 683.5493). "

The starting material can be oxidized, as described in the second part of Example .2, from 9 ° i - hydroxy- ~ 16- (2-naphthyloxy) -11 oil, 15-bis (tetrahydropyran-2-yloxy) 17 , 18,19,2D-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid, which is described in the second part of Example 17, can be obtained. R " = 0.3 (ethyl acetate).

Example 19 -

i6- (3-chlorophenoxy) 9a, 1.1cC, 15-trihydroxy- '. 17,18,19,20-tetranor-5-cis, 13-tra'ns-12-epi-prostadic acid . 0.003

Sodium Phosphorus at B.P. '2.90

acid sodium phosphate B.P. 0.30

water suitable for injection; until 100

The sodium phosphate BP was dissolved in approximately 80 % of the water and the prostatic acid derivative was then added. After it had dissolved, the acidic sodium phosphate BP was then added. The solution was made up to volume with injectable water and the pH was adjusted to between 6.7 and 7.7. the

'' Bf = British Pharmacopedia

- 47 -

40982A / 1099

Solution was filtered to remove particulate matter, sterilized by filtration, and pre-sterilized neutral glass ampoules filled under aseptic conditions. Immediately before use, the content was the ampoule with sodium chloride B.P. diluted to one Preparation for intravenous infusion.

The prostatic acid derivative can of course be replaced by an equivalent amount of another prostanoic acid derivative according to the invention be replaced.

Example 20

The procedure described in Example 19 was repeated, the sodium phosphate & afe B.P. and the acidic sodium phosphate B.P. have been omitted. Ampoules were obtained containing a sterile, aqueous solution of i6- (3-chlorophenoxy) -9oi, 1 lot, 15-.tr ihydr oxy-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadic acid. You became in the same manner as used in Example 19.

The 12-epi-Prostadienäurederivat can by an equivalent Amount of another 12-epi "prostatic acid derivative according to the invention can be replaced, whereby other sterile, aqueous solutions are obtained.

- 48 -

409824/1099

Claims (1)

Patent claims: 12-epi-prostanoic acid derivatives of the formula: where ^:. ι . *. (CH ₂ ) ₃ R ^J .CH (OR ² ) R ³ for ■ _, 'or HO. . stands R represents a hydrogen atom or an alkanoyloxy radical up to 4 carbon atoms, R- stands for a carboxy or a hydroxymethyl radical or an alkoxycarbonyl radical with up to 11 carbon atoms, R stands for a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms X stands for an ethylene or vinylene radical, Y for an ethylene or trans-vinylene radical and R- stands for the following: a branched or unbranched alkyl or alkenyl radical having 4 to 10 carbon atoms; a radical of the formula -A ¹ . OR ^, where A ^{1 stands} for an alkylene radical with 1 to 9 carbon atoms and R ^ for an alkyl radical with 1 to 9 carbon atoms or a cycloalkyl radical with 5 to 7 carbon atoms 1 5 • men stands, with the restriction that A and R ^ together contain no more than 10 carbon atoms; a radical of the formula -A ² R, where A ^{2 is} a di- - 49 - 409824/1099 so direct bond or an alkylene radical with 1 to 3 carbon atoms and Fi / stands for an aryl radical which is unsubstituted or which is substituted by halogen atoms, nitro radicals, alkyl, halofenoalkyl or alkoxy radicals each having 1 to 3 carbon atoms or dialkylamino radical, in which each alkyl 1 to 3 carbon atoms per v / eist, is substituted} a radical of the formula -A .A .R. , where kr is an alkylene radical having 1 to 3 carbon atoms which has 0, 1 or 2 alkyl radicals each having 1 to 3 carbon atoms as substituents, A is an oxygen or sulfur atom, a sulfinyl radical or an alkylimino radical having up to 4 carbon atoms • 7 and R 'represents an aryl, benzyl or furfuryl radical stands, which may be caused by hydroxy, nitro or phenyl radicals, Halogen atoms, alkyl, alkenyl, halogenoalkyl, Alkoxy, alkenyloxy or acylamino radicals having 1 to 4 carbon atoms or dialkylamino radicals, in which each alkyl has 1 to 3 carbon atoms substituted is; or a radical of the formula -A .A .R, wherein A has the meaning indicated above, A represents an oxygen or sulfur atom, a SuIfinyl-, sulfonyl, imino or • Alkyliminoradikal having up to 4 carbon atoms or a direct bond or A and A each stand for a direct bond and R stands for an aromatic heterocyclic radical with one or two 5- or 6-membered rings, which only contains 1 or 2 non-adjacent nitrogen heteroatoms in one ring and optionally 1 to. 3 carries alkyl or alkoxy radicals or halogen atoms as substituents; wherein the compounds 0 or 1 alkyl radical with 1 to 4 carbon atoms as substituents on one Carbon atom of trimethylene group (- (CHp) 3-) - ■ 50 -. 409824/1099 si;, · carries j '-. · ■■ - ■ and where for those compounds in which R is a Carboxy radical, also including the pharmaceutically or veterinarily acceptable salts thereof. ■ IZ-epi-prostanoic acid derivatives according to claim 1, wherein 1 ■: ■■■. ■ .- ■ " R is a carboxy, hydroxymethyl, methoivycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-deci'-loxycarbony radical, X is an ethylene, cis-vinylene or trans-vinylene radical, R is a hydrogen atom or an acetoxy or propionyloxy radical, Ϋ stands for an ethylene or trans-vinylene radical, R stands for a hydrogen atom or a methyl radical and where in R- ^ A for a methylene, isO-propylidene, ethylene, 1, 1-dimethylethylene, trimethylene, tetramethylene or pentamethylene radical and R stands for a methyl, ethyl, n-propyl, isopropyl, n-butyl, xsobutyl, n-pentyl or n-hexyl radical. A stands for a direct bond or a methylene, ethylene, trimethylene, 1-methylethylene, 1-ethylethylene, 2-methylethylene or 1,1-dimethylethylene radical and R ° stands for a phenyl or naphthyl radical, optionally by chlorine, bromine or fluorine atoms, methyl, ethyl, methoxy * ethoxy or dimethylamino radicals or a chloroalkyl or fluproalkyl is radically substituted by 1 to 3 carbon atoms, Ar is a methylene, ethylidene, isopropylidene, ethylene or trimethylene radical, A is an oxygen or sulfur atom or a sulfinyl or ■ 7
Methylimino radical and R stands for a phenyl or naphthyl radical, which is optionally substituted by chlorine, bromine or iodine atoms, methyl, t-butyl, allyl, methoxy, allylpxy or dimethylamino radicals or chloroalkyl or fluoroalkyl radicals with 1 is substituted up to 3 carbon atoms, or A for.an oxygen or sulfur atom or a sulfinyl, "imino or" methyl - 51 A0982A / 1099; imino radical and R is a pyridyl,. Pyrimidinyl, Quinolyl, indolyl, indolinyl, benzimidazolyl, pyridazinyl, thiazolyl, benzothiazolyl, benzofuranyl or benzothienyl radical, which may be caused by chlorine, Bromine or iodine atoms or methyl or methoxy radicals and wherein the optional alkyl substituent on carbon 2, 3 or 4 is a methyl radical is. 3. 12-epi-prostanoic acid derivatives according to claim 1 or 2, characterized in that R stands for an .n-pentyl, ' n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylheptyl or cis-pent-2-enyl radical. 4. 12-epi-prostanoic acid derivatives according to claim 1 or 2, characterized in that in R ^ das'Radikal -A .OR · ⁵ for an n-propoxymethyl, n-butoxymethyl ~, isobutoxymethyl, n-pentyloxy-methyl- , n-hexyloxymethyl, 2-n-butoxyethyl, 3-n-propoxypropyl, 4-ethoxybutyl or 5-methoxypentyl radical, R stands for a chlorophenyl, bromophenyl, fluorophenyl, chloronaphthyl, tolyl, trifluoromethylphenyl , Athoxyphenyl, nitrophenyl, dimethylaminophenyl or tetrahydronaphthyl radical 7th
stands, R 'for a chlorophenyl, chloronaphthyl, 'Bromophenyl, fluorophenyl, tolyl ,. XyIyI-, methyl- naphthyl, t-butylphenyl, methylchlorophenyl, tri-. fluoromethylphenyl, hydroxyphenyl, methoxyphenyl, Methoxynaphthyl, biphenylyl, dimethylaminophenyl. or tetrahydronaphthyl radical or R is a 2-, 3- or 4-pyridyl, 5-indolyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-3-pyridyl or 2,5-dichloro-3-pyridyl radical. 5. 12-epi-prostanoic acid derivatives according to claim 4, characterized in that in R ^ R for a phenyl, 2-naphthyl, 3- or 4-chlorophenyl, Z- or 4-fluorophenyl, - 52 - 409824/1099 3,4-dichloropheriyl or 3-trifluoromethylphenyl radical stands, R ^ for a phenyl, benzyl, furfuryl, 1-naphthyl, 2-naphthyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl-, 2-, 3- or 4-fluorophenyl-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl-, 2-, 3- or 4-tolyl-, 2,3-, 3,4- / or 3,5-XyIyI-, 4-t-Buty! Phenyl-, 3-allylphenyl-, 3-trifluoromethylphenyl-, 4-hydroxyphenyl-, 2-, 3- or 4-methoxyphenyl-, 4-biphenylyl-, 3-dimethylaminophenyl-, ^ -Chloro ^ -methylphenyl-, i-chloro-2-naphthyl-, 4-ChIOrO-1-naphthyl-, δ-methyl-2-naphthyl-, 6-methoxy-2-naphthyl- or 5,6,7,8-tetrahydro-2-naphthyl radical. 6. 12-epi-prostanoic acid derivatives according to any of the preceding Claims, characterized in that R stands for ■ a carboxy or methoxycarbonyl radical, X stands for . is an ethylene or cis-vinylene radical, or .· 'HO. · ■ ■ · - "■■ stands, Y stands for a trans-vinylene radical, R ^ stands for a hydrogen atom and R · ^ stands for an alkyl radical with 5 to 9 carbon atoms, a benzyl radical or a phenoxymethyl or naphthyloxymethyl radical, which is optionally substituted by one or two methyl radicals on the methyl moiety or by a halogen atom or an alkyl or alkoxy radical having 1 to 3 carbon atoms on the phenyl moiety, where, in the event that R ^{1 is} a carboxy radical, j. also die'pharmazeutisch or Veterinary approved salts are included. 7. 12-epi-prostanoic acid derivatives according to claim 6, characterized ■ 'characterized in that V? for an n-pentyl, n-heptyl, 3-chlorophenoxymethyl, 2-naphthyloxymethyl or 409824/10 99 Benzyl radical. 8. The 12-epi-prostanoic acid derivatives: 20- £ ethyl-9c £, 11 #, 15-trihydroxy-5-cis, 13-trans-12-epi-prostadienoic acid, 20-ethyl-11oί, 15-dihydroxy-9- oxo-5-cis, 13-trans-12-epiprostadienoic acid, 9o6,11α, 15-trihydroxy-5-cis, 13-trans-12-epi-prostadienoic acid, 11c6,15-dihydroxy-9-oxo-5-cis, 13-trans-12-epi-pro stadienoic acid., 2O-ethyl-9o (., 11 α, 15-trlhydroxy-5-cis, 13-trans-12-epi-prostadienoic acid mei ± tyl ester, 16- (3- Chlorophenoxy) -1iot, 15-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis, 13-trans-12-epi-prostadienoic acid, 16- (3-chlorophenoxy) ~ 90L _f 11ö., 15-trihydroxy-17, 18,19,20-tetranor-5-cis, ^ - trans-IS ^ epi-prostadienoic acid or i6- (3-chlorophenoxy) -9o6,11od., 15-trihydroxy-2-methyl-17 , 18,19, 20-tetranor-5-cis, 13-trans-12-epipro stadienoic acid, the pharmaceutically or veterinarily acceptable salts also being included for the compounds - which are acids. 9. 12-epi-prostanoic acid derivatives according to one of the preceding claims, characterized in that they are ammonium salts, alkylammonium salts containing 1 to 4 alkyl radicals each having 1 to 6 carbon atoms, alkanolammonium salts containing 1 to 3 2-hydroxyethyl radicals, or alkali metal salts acts, ι
stands. delt, if in the derivative R for a carboxy radical 10. 12-epi-prostanoic acid derivatives according to one of the preceding claims, characterized in that it is is -Racemate. 11. 12-epi-prostanoic acid derivatives according to one of the claims 1 to 9, characterized in that it is pharmacological effective, optically active forms; 12. Process for the preparation of 12-epi-prostanoic acid - 54 409824 / 109S derivatives according to one of claims i to 11, characterized characterized that one: a) for compounds in which R is a carboxy radical and R stands for a hydrogen atom, "with the exception of those compounds in which R stands for a radical 2 6 2 ■ "■ of the formula -AR, where k is a direct bond, hydrolysis of a compound of the formula: Y.CHCOR ⁹ ) R ³ 1 5 or a mixed anhydride thereof, wherein R, R, X and Y have the meanings given above, for or and R stands for a tetrahydropyran-2-yloxyradikäi or an alkoxydialkylmethyl radical with 4 to 5 carbon atoms, the compound 0 or 1 ■ alkyl radical with "1 to 4 carbon atoms as a substituent on one carbon atom of the trimethylene group, whereupon, if a salt is desired is, the product is reacted with a base; or ^; ■ b); for those compounds in which R stands for a garboxy radical, - 55 - 9824/109 "9 SG for 2 ° ^h ■ 25 represents and R stands for a radical of the formula -A R, 2 2 wherein A is a direct bond, or R is ο 5 8 a radical of the formula -A .A .R as defined above is, implementation of a lactol of the formula: - III Y.CH (OH) .R ^3- . wherein Y has the meaning given above and R ^ has the meaning given immediately above, with a (4-carboxybutyl) triphenylphosphonium salt, which 0 or 1 alkyl radical with 1 to 4 carbon atoms as substituents on the carbon atom 1, 2 or 3, in the presence of a strong "base, whereupon, if a salt is desired, the product is reacted with a base; or c) for those compounds in which R is an alkoxycarbonyl radical with up to 11 carbon atoms is, reaction of an acid of the formula: -.X. (CH) .COOH 5 c - 2 '.
- »Υ. CH (OH) .R ³ . . ..- '· ■ 7. wherein X, Y and R ^ have the meanings given above own and 409824/10 9 9 has one of the meanings given above, where the compound 0 or T is an alkyl radical with 1 to 4 carbon atoms as a substituent on one carbon atom of the tr! methylene group contains, with a diazoalkane having 1 to 10 carbon atoms; or one Salt thereof with an alkyl halide having 1 to 10 carbon atoms; or- _d) for those compounds in which R stands for a Hydroxymethyl radical · stands and stands for / .., 1 reduction of an ester of the formula I, wherein R is a • alkoxycarbonyl radical; or . e) for those compounds in which R is a radical of the formula -A ^ .A -.R ^ or · -i? .Ap. R ⁸ stands in which-A stands for a sulfinyl radical or A ^ stands for a sulfinyl or sulfonyl radical, oxidation. the corresponding thio compound in which A and A are sulfur; or f) for those compounds' in which R stands for a Alkoxycarbonyl radical, reaction of a compound preparation of the formula II, wherein. ': |. , R, Rr, R and X have the meanings given above, where the compound 0 or 1 alkyl substituent with 1 up to 4 carbon atoms on carbon atoms 2, '■■ - ■.' - 57 - 409824/1099 3 or 4 bears, with an alkenol having 1 to 10 carbon atoms in the presence of a strong acid, and »if a 12-epi-prostanoic acid derivative is desired where R is a carboxy radical, hydrolysis of the ester thus obtained; or g) for those compounds in which X is a trans-vinylene radical, separation of a mixture from the 5-trans-12 ~ epi-prostate acid derivative and the corresponding 5-cis isomer; or h) for "those compounds in which R is an alkyl radical, reaction of the corresponding 2 12-epi-prostanoic acid derivative of the formula I, in which R is a hydrogen atom, .mit an alkyl halide having 1 to 4 carbon atoms, in the presence of a. starkeri Basej or _νιΛ „. . _; - i) for those compounds in which HO - stands, -Redulction of a connection HO of the formula I, in which stands; or .j) for those connections in which ι • 0 stands, elimination of water from a Compound of formula I in which for stands. - 58 - 409824/1099 13. Pharmaceutical or Veterinary Composition, thereby characterized as being a 12-epi-prostanoic acid derivative according to claim 1 together with a pharmaceutically or veterinarily acceptable diluent or contains carriers, 14. Composition according to claim 13 _}, characterized in that it has one of the following forms of administration: tablets or capsules for oral administration; for inhalation aerosols or sprays; for parenteral administration or for administration by infusion, sterile aqueous or oily solutions or suspensions; or for anal or vaginal use suppositories. 15. Composition according to claim 13 or 14, characterized in that that it is a sterile, essentially liquid solution that is between 0.01 and 10.0 ug / ml of the compound according to claim 1 contains. - 59 - 409824/1099