DE2813261A1 - OPTICALLY ACTIVE PROSTANIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Case: 26 225

PFENNING-MAA9

MEiNIG - LEMKE - Mockery

SCHLEISSHEIMER ₁ STR.

Θ0ΟΟ MUNCHIEN 40

AMERICAN CYANAMID COMPANY Wayne, New Jersey / USA

Optically active prostanoic acid derivatives and processes for their

Manufacturing.

809841/0791

Ϋ -

Derivatives, analogs and derived compounds of prostanoic acid are described which have a terminal in the ß-chain have cyclic residue and which have the pharmacological effects of prostaglandins.

The invention relates to prostanoic acids and their esters in general formula

C ₁₃ -C ₁₄ - (CH ₂ ) _w -

in the

W is a group of general formulas

Il

Il

809841/0791

R _{1 is} a hydroxyl group, a TrI- (CC.) - alkylsilyloxy group

or a C ₁ -C ^ alkoxy group;

R _{0 is} a hydrogen atom, a hydroxyl group, a TrI- (C ₁ -C.)

alkylsilyloxy group or a C ₃ -C ₅ alkanoyloxy group; Y is a trivalent group of the general formulas

\ and /

CH ₂ - R er

wherein R is a hydrogen atom, a tri- (C ₁ -C.) - alkylsilyloxy group or a CC alkanoyl group, with the proviso that when W contains a '^ ^S -CN group, R_ is a hydrogen atom;

X is a divalent group of the general formulas

pi and CL

in which R. is a C ₁ -C ₇ alky group, a hydrogen atom, a phenoxy group or a phenoxy group which is substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups;

η O or an integer from 1 to 4; m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to

Has 20;

the C ₁ -3-C _1. -rest is an ethylene group or a trana-vinylen

group;

w 0 or 1; and

Z is a divalent group of the general formulas

0 9841/0791

CXS
(CH ₉ ) -, -CH ₉ -CH = CH-CH ₀ - (CH ₉ ) -, - (CH ₉ ) -0-CH ₉ - and

(CH ₂ ) _t -S-CH ₂ -, wherein

ρ is an integer with a value of 5 to 7, q is an integer with a value of 1 to 3 and t is an integer with a value of 3 to 5, with the proviso that when Z contains a double bond, the C.- ₃ -C ...- radical represents a trans-vinylene group / the racemic mixture of these compounds, their mirror isomers and the pharmacologically acceptable cationic salts of the compounds of the above general formula in which R- represents a hydrogen atom.

The invention also relates to a process for the preparation of the compounds of the general formula

/ - (CH ₂ ) SN

'C ₁₃ -C ₁₄ - (CH ₂ ) _W -YX

- (CH ₂ ) /

in the

W is a group of general formulas

809 8 A1 / 0791

represents R, R ₂ , R, Z, the C ₁₃ -C ₁₄ radical, Y, X, w, η and m have the meanings given above, which is characterized in that a cyclopentenone of the general formula

in the

RJ is a C.-C ^ .- alkoxy group or a protective group, such as a tri- (C.-C.) - alkylsilyloxy group, and R 'is a hydrogen atom, a C -C ^ -alkanoyloxy group or a protecting group, such as a tri- (C ₁ -C ₄ ) -alkylsilyloxy group

pe, mean and

Z has the meanings given above 7 with a connection of the general formulas

and

where L is a group of the general formulas

809841/0791

-Cu-CSC-R

R ₇ «7

in which R "stands for a C -C -alkyl group, and R _{q is} a group of the general formula

in which P is a C "-Cj - alkanoyl group or a protective group, such as a group of the general formula -Si-R ₁₁ , in which R _{11 is} a tri-lower (C ₃ -C ₅ ) -alkyl group, and m , n, W and X have the meanings given above to form a compound of the general formula

where R '

w, P, n, m, X and Z have the Be given above

own interpretations, implement them and then

a) splitting off the protective groups, so that a compound of the general formula

809841/0791

^X (CH ₂ ) _W -Y

obtained, in which R-, R ", w, Y, η, m, X and Z are those given above Have meanings;

b) optionally reduced the Δ bond, so that one Compound of the general formula

obtained in which R, R_, w, n, m, Y _7, X and Z have the meanings given above; or

c) the product of steps a) and b), in which R- is a hydroxyl group stands, dehydrated, so that you get a compound of the general formula

Il
R.

'C ₁₃ -C ₁₄ - (CH ₂ ) _W -Y

809841/0791

-T-

receives, in the Z

have the meanings given above;

-, the C., .- C.-residue, w, Y, n, m and X die

d) the product from step c), if appropriate with an acetone cyanohydrin and a basic catalyst such as sodium carbonate to give a compound of the general formula

2'n

converts, in which R, Z, the C ₁₃ -C. radical, Y, X, w, η and m have the meanings given above;

e) the product of steps a) and b) with a carbonyl reducing agent, such as sodium borohydride, so that you get a compound of the general formulas

/ HCH ₂ ) HN

and

R ₂

C ₁₃ -C ₁₄ (CH ₂ ) _w -y

809841/0791

obtained in which R-, R_, the C ₁₃ -C ₁₄ radical, w, Y, m, n, X and Z have the meanings given above; or

f) the product of steps a) and b) with a stereoselective reducing agent such as lithium tri- (sec-butyl) borohydride or lithium perhydro-9b-boraphenalyl hydride, treated so that you get a compound of the general formula

- (CH ₂ ) _W -Y

obtained in which It., R ", Z, the C ₁₃ -C ₄ radical, w, Y, n, m and X have the meanings given above;

g) the 110 (hydroxy derivatives of steps e) and f) with a Oxidizing agents such as Jones reagent to a compound of the general formula

_t converts, in which R-, Z, w, Y, X, m and η have the meanings given above; or

809841/0791

fc3

h) the products of stages a), b), c), d), e), f) and g), in which R _{1 has} the meaning of the hydroxyl group, esterified to the corresponding carboxylic acid ester in which the group R _{1 is} a C.sub.1 -C.sub.1 alkoxy group; or

i) the hydroxyl groups of the above compounds are esterified to form the alcohol esters of the products of stages a) to g).

The invention also relates to the compounds of the general formula

0 0

ii Η

lp-CR ₅

in which R _{5 is} a hydroxyl group or a C -C alkoxy group, ρ is an integer with a value of 5 to 7 and d is an integer with a value of 3 to 5.

The invention also relates to the precursor compounds of the general formula

in the

809841/0791

w O or 1;

m 0 or an integer with a value from 1 to 4; η 0 or an integer with a value from 1 to 4; P is a protective group, such as a group of the general formula -Si-R--, in which R-- is a C - Cg-alkyl group, with the proviso that the sum of η and m has a value of up to 4, and
X has the meanings given above.

The invention also relates to the precursor compounds of the general formula

H (CH ₂ ) _W -CX 0-P

in the

Q Iodine, a tri-lower (C.-C-) - alkyl group, a lithium atom or a group of the general formulas

-Cu-CSC-B ₇ , CuSC 7 '? 7

\ ₇

wherein R "represents a C. -C" alkyl group; P is a protecting group, such as a group of the general formula -Si-R ₁ , wherein.R _n - is a C ₁ -C ^ -alkyl group; w O or 1;
m is O or an integer from 1 to 4; η 0 or an integer with a value from 1 to 4 with the

809841/0791

Conditions mean that the surtime of η and m have a value of 2 to 4, and X has the meanings given above.

The invention also relates to a process for the preparation of the precursor compounds of the general formula

Li® H θ / C, H ₇ -C = C-Cu ^{3 7} \

PO ^ -fCH "P 2. m

in the
w O or 1;

P is a protecting group such as trimethylsilyl group; η O or an integer from 1 to 4; m 0 or an integer with a value from 1 to 4;

with the proviso that the sum of η and m has a value of 2

to 4; and

X is a divalent group of the general formulas

«4

15 in which R _{4 represents} a C ₁ -C ₇ -alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; which is characterized in that a compound of the general formula

809841/0791

Li

^iCH2) y

in which w, P, η, X and m have the meanings given above, with copper (I) -1-pentyne.

The invention also relates to a process for the preparation of precursor compounds of the general formula

3AI® H

ET NcH ₂ ) ^ CX PO ScH)

in the
w O or 1;

P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4;

m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and
X is a divalent group of the general formulas

Λ. " ^a Λ

809841/0791

wherein R _{4 represents} a C. -C ~~ alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; which is characterized in that a compound of the general formula

Li

^N c = c

H // itj \ _i-i y

♦ 2 'W >> I I

P- (T ^ - (CH ₂ ) ST

in which w, P, n, m and X have the meanings given above, with a tri-lower (C. -C, -) -alkylaluminum compound, such as trimethylaluminum.

The invention also relates to a process for the preparation of the precursor compounds of the general formula

(C ₄ H ₉ ) SN H.

\ cH ₂ ) _w -CX

P-O H ^

in the

w O or 1;

P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4; with the Provided that the sum of η and m has a value of 2 to 4; and

2O X is a divalent group of the general formulas

809841/0791

C and

/ X ₄ / -

wherein R. represents a C _{-C 7} -AlXyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; which is characterized in that a) an aldehyde of the general formula

O = CX
(CH ₂ ) /

in which X, η and m have the meanings given above, with a Grignard reagent of the general formula HC = C-MgJ, in which J stands for a chlorine atom or a bromine atom, and w Signifies 0 or 1; to a compound of the general formula

HC = C- (CH ₂ ) _w · ^ X HC

^ X

converts, in which w, n, m and X have the meanings given above own;

b) introduces a protective group, so that a compound of the general formula

HC = C- (CH ₂₎ -CX

809841/0791

obtained, in which w, P, n, m and X have the meanings given above, after which one

c) treated the compound in the presence of bisazobutyronitrile with tri-n-butyltin hydride.

The invention also relates to a process for the preparation of the precursor compounds of the general formula

¹ V / "

po ^ (CH ₀ r ί

2 m

where w is 0 or 1;

P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4 with the proviso that the sum of η and m has a value from 2 to 4; and
X is a divalent group of the general formulas

and C

V and C

wherein R. is a C ^ C ^ alkyl group, a hydrogen atom, a Phenoxy group or one with halogen atoms, trifluoromethyl groups and / or methoxy groups represents substituted phenoxy group; which is characterized in that one

a) an aldehyde of the general formula

809841/0791

O = C X

with a Grignard reagent of the general formula HC = C- (CH ") MgJ, in which J stands for a chlorine atom or a bromine atom and w stands for 0 or 1, to a compound of the general formula

HC = C- (CH ₂ JC X

converts, in which w, n, m and X have the meanings given above;

b) introduces a protective group, so that a compound of the general formula

obtained, in which w, P, n, m and X have the meanings given above, after which one

c) treating the protected compound in solution with diisoamylborane and anhydrous trimethylamine oxide; and

L5 d) the protected compound in the diisoamylborane and trimethylamine oxide solution treated with iodine so that you get a

809841/0791

Compound of the general formula

p-c / Nch> £

receives, in the w, P, n, m and X the meanings given above own.

The invention also relates to a process for the preparation of precursor compounds of _the general formula

Li ©

in the

w 0 or 1;

P is a protecting group such as trimethylsilyl group; η O or an integer from 1 to 4; m is 0 or an integer with a value from 1 to 4, with the proviso that the sum of m and η has a value from 2 to 4; and

X is a divalent group of the general formula

V and V

R ₄

8098A1 / 0791

in which R represents a C ₁ -C 4 -alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; which is characterized in that a compound of the general formula

Li. Ά

(CH ₂ '} -

in which w, P, X, η and m have the meanings given above, treated with a solution of phenylthio copper.

The invention also relates to a process for the preparation of the compounds of the general formulas

wherein

Z is a divalent group of the general formulas - (CH ^) -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) -, - (CH ₂ ) _t -O-CH ₂ - and - (CH ₂ ^ - S-CH ₂ -, where ρ is an integer with a value of 5 to 7, q is an integer with a value of 1 to 3 and t is an integer with a value of 3 to 5; R ^ is a hydroxyl group or a C -.- C _g -alkoxy group; R. a C ^ -C ^ -alkyl group, a hydrogen atom, a phenoxy group or one with halogen atoms, trifluoromethyl groups and /

809641/0791

13th

or methoxy groups substituted phenoxy group, ' η O or an integer from 1 to 4; m 0 or an integer with a value from 1 to 4 with the Provided that the sum of η and m has a value of 2 to 4, which is characterized in that one Compound of the general formula

in which Y is a trivalent group of the general formulas

and

wherein R- represents a hydrogen atom, a tri- (C -.- C.) -alkylsilyloxy group or a C -C -alkanoyl group, and Z, R ₁ , n, m, Y and X have the meanings given above Heating dehydrated.

The invention also relates to the pharmacologically acceptable salts of the compounds of the above general formulas, in which R _{1 represents} a hydroxyl group, with pharmacologically acceptable metal cations, ammonium cations, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are those of the alkali metals, such as lithium, sodium and potassium, and those derived from the alkaline earth metals such as magnesium and calcium, although also cations of other metals, for example those of aluminum, zinc and iron, Katio- suitable according to the invention

809841/0791

represent.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methyl-hexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, oL -Phenyläthylamin, ß-phenylethylamine, ethylenediamine, diethylenetriamine and the aliphatic, cycloaliphatic and araliphatic amines, which contain up to and including 18 carbon atoms, and heterocyclic amines, for example piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, for example 1-methyl-piperidine, 4-ethyl-morpholine, 1-isopropyl pyrrolidine, 2-methyl-pyrrolidine, 1,4-dimethylpiperazine, 2-methyl-piperidine and the like, and amines that contain water-solubilizing or hydrophilic groups, for example mono-, di- and triethanolamine, ethyl diethanolamine, N-butyl ethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1, 3-propanediol, 2-amino-2-methyl-1-propanol _/

20 tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-

tert-amylphenyl) diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the same.

Examples of pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium,

Benzyltrimethylammonium and phenyltriethylammonium cations and the like.

The compounds of the invention can be on various Because of being administered for different purposes, for example intravenous, intramuscular, subcutaneous, oral, intravaginal, rectal, buccal, sublingual, topical and in the form of sterile implants that allow a longer effect.

809841/0791

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For this purpose, because of the increased water solubility, it is preferred that the
Group R _{1 is} a hydrogen atom or a pharmacologically acceptable

represents bares cation. Sterile solutions or suspensions can be used for subcutaneous or intramuscular injection
of acids, salts or esters in aqueous or non-aqueous
Use media. For oral or sublingual administration, tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions, which are prepared using conventional pharmaceutical carrier materials, binders and / or auxiliary substances, are used. For the rectale or
For vaginal administration, conventionally prepared suppositories are used. As tissue implants, one can use a

sterile tablet or a sterile silicone rubber capsule

or use some other object that contains the substance to be used contains or is impregnated with it. In certain cases it can be advantageous to use the compounds according to the invention in the form of clathrate compounds with substances such as 0 (-Cyclo-

2O dextrin, to be administered.

The prostaglandins are a family of closely related compounds isolated from various animal tissues that simulate smooth muscle, reduce arterial blood pressure, combat the mobilization of free fatty acids caused by epinephrine, and exert other pharmacological and autopharmacological effects in mammals. In this regard, reference is made to Bergstrom et al. (J. Biol. Chem. 238 (1963) 3555) and Horton (Experientia, 21 (1965) 113) and the references cited therein. All of the so-called natural prostaglandins are derivatives of
Prostanoic acid of the formula

809841/0791

-Zl-

8 CH ₂ CH ₂ CH ₂

\ 2 / CH ₀ .CH ₀ / CH ₀ / CH- \ / ² N / ² X / ² X / ³

H ^CH 2 ^CH 2 ^CH 2 ^CH 2

Those on the carbon atoms in the 8 and 12 positions bonded hydrogen atoms are in the trans position. However, the natural prostaglandins only represent one of the possible optical isomers. The compounds according to the invention include all possible optical isomers.

The compounds according to the invention, which correspond to formula A given in the following FIG. 1, in which R ₁ , Z, R ₀ , Y, m, n, w and X have the meanings given above, have the same configuration as the natural prostaglandins with respect to the configuration at carbon atoms 8 and 12 and are identified by the prefix nat. The enantiomer represented by the general formula B corresponds to the mirror isomer or the ent configuration.

A cyano group in the 11-position, which is bound via a dashed line (C ₁₁ CN), has by definition

a 0 (configuration, while that of a solid line

bonded cyano group (C ₁₁ CN) than in the ß-configuration

is to be regarded as bound.

The compounds according to the invention which correspond to the general formula C, in which R ₁ , Z, Y, m, n, w and X have the meanings given above, have the same configuration as that at carbon atoms 8, 11 and 12 natural prostaglandins and are therefore designated with the prefix nat. The enantiomers which correspond to the general formula D represent the mirror isomers and have the ent configuration. One tied in the 9 position via a dashed line

809841/0791

Hydroxyl group (C _g OH) has the o (configuration, while the solid line (C_OH) for the ß-configuration

stands.

The compounds according to the invention which have the structure corresponding to the general formula E, in which R ₁ , Z, R 1, Y, m, n, w and X have the meanings given above, have the configurations at carbon atoms 8, 11 and 12 have the same configuration as the natural prostaglandins and are marked with the prefix nat. The enantiomers which correspond to the general formula F have the mirror image configuration or the ent configuration. One over a dashed line
the carbon atom attached to the 11-position

(C- R ₂ ) has the 0 (configuration, while the selected

15 solid line (C ,, R “) stands for a ß-configuration.

The compounds according to the invention which have the structure of the general Formula G correspond, in which R-, Z, R ", Y, m, n, w and X have the meanings given above, with regard to the configurations at the carbon atoms 8, 11

and 12 the same configuration as the natural prostaglandins and are therefore denoted by the prefix nat. The enantiomers corresponding to the general formula H, have the mirror image or the ent configuration. A dashed line to the carbon

atom in the 11-position bonded substituent (C ₁ , R _? ) has the OC configuration, while the solid line
(C ₁₁ R) stands for the ß-configuration.

The configuration of groups Y and X is carried out via the R
and denotes the S configuration, as is customary. For example, the compound of the general formula C is designated as follows: nat-15S, 16S-15-dihydroxy-9-oxo-15, 16-t'riraethylene-13-trans-10-prostadienoic acid, while its enantio-

809841/0791

- 24 -

meres (Formula D) as ent-15R, loR-IS-dihydroxy-Q-oxo-IS, 16-trimethylene-13-trans-10-prostadienoic acid referred to as.

The racemate (1: 1 mixture of compounds C and D) is called nat-15S, 16S- (and ent-15R, 16R) -15 ~ dihydroxy-9-oxo-15, lo-trimethylene-IS-trans-10-prostadic acid. In Similarly, the compounds represented by general formulas I to N have the following configurations.

FIGURE I

- (CH ₂ ), (CH ₂ ) _n .

(A)

y- (CH ₂ ) _w -c ₁₄ -c ₁₃

(C)

809841/0791

- (CH ₂ ) W-

(D)

OH

C ₁₃ -C ₁₄ -

(E)

(CH ₂ ),

(CHj) _n .

R ₁ -CZ OH ι

Y- (CH ₂ ) _W -C ₁₄ -C ₁₃

(F)

(G)

C ₁₃ -C ₁₄ (CH ₂ ) WY

8098-1 / 0791

.36 SO

nat-15S, 16R

(D

ent-15R, 16S

Racemate
nat-15S, 16R f (and

ent-15R, 16S)

(J)

809841/0791

nat-15R, 16S

(K)

HO ₂ C

ent-15S, 16R

(L)

nat-15R, 16R (Μ) "

ent-15S, 16S

Racemate nat ~ 15R, 16S \ (and '

ent-15S, 16R)

Racemate nat-15R, 16R (and
ent-15S _f 16S)

8098 A 1/0791

»A

In the above general formulas (J to N), the hydroxyl group bonded to the carbon atom at the 11-position becomes referred to as "llo (-hydroxy") while the hydroxy group is at the carbon atom in the 9-position is referred to as "9ot-hydroxy" will.

In the above general formulas, W has the meanings given above.

The compounds of the present invention can be represented by the reactions shown in the following reaction scheme

xO become. In the reaction scheme, n have m, X, w and Z

the meanings given above, while R ' _{1 stands} for a straight-chain or branched (C ₁ -C ₁ J) -alkoxy group or a tri-lower (C - C.) - a.lkylsilyloxy group, R ¹ for a hydrogen atom, a tri-lower group - (C ₁ -C.) - alkylsilyloxy group or a

C "-C, - alkanoyloxy group and R" .. and R "for hydroxyl groups stand.

809841/0791

35

REACTION SCHEME _- A

X HCiC- (CH ₂ ) _w -MgJ (J is Cl or Br)

(ID

(I)

1IC5C- (CH _{2) W is} -C

(CH ₂ )

X /

HCaC- (CH ₂ ) _W -C (CH ₃ J ₃ SiO

(III)

(IV)

The isomers are separated.

H ' ^X (CH ₂ ) -C (CH ₃ J ₃ SiO

(V)

(C ₄ Hg) ₃ SnH

(C ₄ H ₉ ) ₃ S _n> H

(CH ₃ )

■ ^(CH 2 ^} n

- (CH ₂ ) _m

(VI)

809 8.41 / 0791

REAKTI0NS5CHFMA A (continued)

(V3> 2 6

LiH

"(CH ₀ )

(CH ₂ ) _W -C

«Λ ^ V * 11% V ^ -Π) / ^ ^ S

(CH ₃ ) ₃ Si0 (VII)

Li ^ (CH ₃ )

Al (CH ₃ ) 3

¹¹ / ^ * ^(C »2) rT

. / v _rH

(VIII)

CuL

(CH ₃ ) ₃ SiO

L «-C = CC ₃ H ₇ or

»09841/0791

- (CH ₂ ) η

(IX)

REACTION SCHEME A (continued)

Alles "

trans

(CH ₂ J _n -

(CH ₂ ) -C

HO ^V CH ₂ - (CH ₂ J _n , (XIII)

Il

Jk .. Z-C-R

trans

η.

(CH ₂ IC

HO

^(CH 2> n

- (CH

REACTION SCHEME A (continued) (XI) + (VIII), (IX) or (X); 0 °

(XIV)

R and R ₁ are hydrogen atoms

(XIII)

trans

! (CH ₂ )

m ⁴

-C

trans

(CH ₂ )

(CH ₂ ) _W -C HO '^ CH ₂ -

(CH ₂ ) _m

J

(XVIII)

H ·.

5-CR ₁

trans

(CH ₂ ) _W -C

(XVII)

809841/0791

HO '^ CH ₂ - (CH ₂ )

rf.rkttONSSSCHEMA A (continued)

XIV

^H0 ^ / ^H I!

trans

(XIX)

(CH ₂ ) -C

HO

- (CH ₂ )

(XIII)

OH. ..H H "

trans

(XX)

HQ. H J)

trans

(XXI)

(CH ₂ )

. X

(CH ₂ ) _W -C

HO ^ CH ₂ - (CH ₂ ) _B y 2'W "V HO

- (CII ₂ ),

Il

trans

(XXII) _{| Κ}

809841/0791 i ₂ - (CH ₂ ) _m y

REACTION SCHEME A (continued)

(XXI)

HO ^ H If

trans

(XXIII)

(XIX)

(XXIV)

(CH ₂ ) _W -C

HO ^% * CH ₂ - (CH ₂ )

According to Reaction Scheme A above, a ketone (I) is obtained with a Grignard reagent (II) such as acetylene magnesium chloride (II, w = 0) or propargyl magnesium bromide (II, w = 1) to the corresponding one acetylenic alcohol (III) implemented. When X is not a -CH- group, two isomeric become acetylenic Formed alcohols. These isomers can be separated using procedures known per se, for example through fractional crystallization, fractional distillation and various chromatographic methods. The single ones Isomers can then be added to the other reactions according to Reac-

8098A1 / 0791

- 3β -

tion scheme A are subjected.

The acetylenic alcohol (III) is converted into the corresponding trimethylsilyl ether in the usual way. The silylated Derivative (IV) is then treated with diisoamylborane (which is obtained in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, Sodium borohydride and boron trifluoride etherate) and then treated with anhydrous trimethylamine oxide. Then the resulting solution and a solution of iodine in tetrahydrofuran at the same time added to an aqueous solution of sodium hydroxide, whereby the l-iodo-3-trimethylsilyloxy-trans-1-alkene (V) receives.

The vinyl iodide (V) is converted to the trans-vinyl lithium derivative (VII) at a temperature of about -78 ° C by treatment with either one equivalent of n-butyl lithium or two equivalents of t-butyl lithium in hexane or toluene, while maintaining the configuration. For this treatment, it is preferred to work at -78 ° C. for about an hour, then at -40 ° C. for about an hour and finally at about ⁰ ° C. for about an hour. For the subsequent preparation of the lithium alanate reagents (VIII) it is preferred to use n-butyllithium, while for the lithium cuprate reagents (IX) or (X) tert-butyllithium is used as the reagent of choice. The same vinyl lithium derivative (VII) can be obtained from l-tri-n-butylstannyl-3-trimethylsilyloxy-trans-lalken (VI) form by treatment with n-butyllithium in hexane solution at -40 to 0 ⁰ C. The compound (VI) can also be easily prepared by adding tri-n-butyltin hydride in the presence of bisazo-isobutyronitrile to the acetylene (IV) and then vacuum distillation at a sufficiently high temperature (about 170 ° C.) carried out in order to isomerize any cis-vinyl tin compound present to the corresponding trans-vinyl tin compound.

809841/0791

To prepare the alanate reagent (VIII) or the like, 1 mol equivalent of a tri-lower (C -C ₅ ) alkylaluminum compound (for example, trimethylaluminum) is added to it in the form of a solution in a solvent such as hexane at about 0 ° C

5 vinyl lithium derivative. After about 15 to 45 minutes with this one

The required blocked cyclopentenone (XI) is added at temperature and the reaction mixture is stirred for about 18 hours at room temperature. The mixture is treated in the cold with aqueous hydrochloric acid, whereupon the pro-

10 duct wins through extraction. In the series of 11-deoxy

derivatives, the protective trialkylsilyl group is removed by treatment with an acetic acid / tetrahydrofuran / water mixture (4/2/1) at room temperature for about 20 minutes. The ester group can then be saponified in the usual way. In the

15 series of 11-oxy derivatives are split through the silyl groups

Treat with an acetic acid / water / tetrahydrofuran mixture (20/10/3) for about 4 hours at about 40 ° C. The alkyl esters the compounds of the 11-oxy series are made by this Treatment does not interfere and cannot be treated with basic treatment because of the instability of the ll-hydroxy-9-ketone not be chemically saponified. However, the esters can be cleaved with baker's yeast in a manner known per se.

For the preparation of the asymmetric lithium cuprate (IX) or the like, a solution of 1 mol equivalent is added

25 of a copper (I) -1-alkyne, preferably copper (I) -1-pentyne, in anhydrous hexamethylphosphorus oxide, preferably in 3 to 5 molar equivalents thereof, and anhydrous ether 1 molar equivalent of the above-mentioned vinyl lithium compound solution (VII), which has been cooled to about -78 ° C. Man

The solution is then stirred at -78 ° C. for about 1 hour. Man

can also be a cuprate reagent that has a p-thiophenolate ligand (L = -S- / JA) contains, which is obtained by first forms lithium thiophenolate by adding 1 equivalent n-Butyllithium in hexane to a solution of thiophenol in ether

809841/0791

admits. Then, a solution of one equivalent of tri-n-butylphosphine-copper iodide complex in ether and returns the obtained solution of Phenylthiokupfer at -78 ⁰ C under an inert gas to the solution of the vinyl lithium compound (VII).

The mixture is then kept at -78 ° C. for one hour.

1 molar equivalent of the required cyclopentenone (XI) is then added to one of these cuprate solutions at -78 C. After some Hours at -20 ° C, the reaction mixture is treated with an aqueous ammonium chloride solution and the isolated blocked or protected product (XII) in the usual way. The cleavage of the protective groups is then described in the above Way done.

The products are finally purified in the usual way by chromatographic methods.

In those cases in which X is not a -CH "group and m ^ η -1, two isomers are formed which differ in the configuration at carbon atoms 15 or 16. Both isomers are in the form of racemates and can with the help of customary chromatographic methods

20 are separated.

For the preparation of the symmetrical lithium cuprate (X), 1 mol equivalent of that dissolved in anhydrous ether is added Copper (I) iodide tributylphosphine complex at approx -78 ° C to 2 molar equivalents of a solution of the vinyl lithium compound mentioned (VII) in hexanes, which has cooled to -78 ° C. Treated after about an hour at this temperature one the lithium cuprate (X) with the required cyclopentenone (XI), as described above with regard to the conjugate addition of 1-alkynyl lithium cuprate (IX).

In order to ensure a trans structure in the case of the compounds (XII), (XIV) or (XIII), these product conditions can be used

809841/0791

which are known from the literature to be cis-8-iso-PGE. equilibrate to a mixture containing about 90 % of the trans product (see EG Daniels et al., JACS 90 (1968) 5894). These conditions include treatment with potassium acetate in aqueous methanol for about 96 hours at room temperature. The cis and trans products can be separated chromatographically.

Most of the for the preparation of the compounds of the invention Cyclopentenones used have been described in the literature or can be formed using procedures

analogous to those already described. Appropriate advice is given in the following examples. The synthesis Cyclopentenones not previously described are also explained in the examples.

15 The treatment of the 11-hydroxy derivatives of the general formulas (XIV) or (XIII), in which R ″ represents a hydroxyl group, with dilute acid leads to dehydration of the β-ketol system and the formation of the corresponding Δ derivatives (XVI) or (XV) (prostaglandins of type A). A preferred one

The procedure is to have a treatment for about

20 hours at room temperature in a tetrahydrofuran / water mixture (2/1), which contains 0.5N hydrochloric acid. Under these conditions, the tetrahydropyranyl or trialkylsilyl esters are subject to hydrolysis, if

apply this procedure to the conjugate initially formed Addition product (XII) ends up. A longer treatment with acid or preferably a treatment with a dilute base, for example sodium carbonate in aqueous methanol or an amine, such as piperidine, causes the Conversion of the compounds (XIV) or (XIII) to the Δ derivatives (XVIII) or (XVII) (prostaglandins of type B). The Δ derivatives (XVI) and (XV) can also be prepared by that one is a conjugate addition of the cuprate (IX) ■

809841 / 07S1

(L = -C ^ cC ₃ H ₇ ) to the cyclopentenone (Xl) (R 'is here
for the trimethylsilyloxy group) in the manner described above and the solution formed during 1 to 2
Hours at a temperature of ⁰ ° C. Under these conditions, both the conjugate addition and the cleavage of the C ^ -trimethylsilyloxy group take place. After the protective groups have been split off in the manner described above, the Δ derivatives (XVI) and (XV) are isolated and separated by chromatography.

The 9-keto derivatives (XIV) or (XIII) of the invention can be converted into the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product obtained is a mixture of the 90 (- and the 9ß-hydroxy derivatives (prostaglandins of the series Fd and Fß: from (XIV) and (XXI) (XIX) or ( XX) and from (XIII) (XXII)) The 90i and 9β derivatives can be separated with the aid of known chromatographic procedures.

If the reduction with lithium perhydro-gb-boraphenalyl hydride (HC Brown and WC Dickason, J .. ACS 92. (1970) 709) or with lithium tri (sec-butyl) borohydride (HC Brown and S. Krishnamurthy, JACS 94 ( 1972) 7159), the product obtained is predominantly the 9-hydroxy derivative
(XIX) or (XXI) in which the 9-hydroxy group is in the cis position to the side chain bonded to the carbon atom in the 8 position and to the 11-oxy group, if such is present. According to the usual convention, an of-substituent is in the 8, 9, 11 or 12-position behind the plane of the paper, while the β-substituent in these positions is in front of the plane of the paper. This is usually done for the

Case of the ßC-substituent through a bond, for the

Case of the ß-substituent by a «= 2s £ 3 bond and for the If both possibilities are addressed, represented by one.

01841 / 07-1

The 13-dihydro derivatives according to the invention (in which the C - C . -Rest represents an ethylene group) can be achieved by reducing

13th
tion of the Δ function of the corresponding 13-protenic acids or their esters. This reduction can be brought about by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at room temperature.

The ll-0xo-9 «-hydroxy derivatives (XXIII) and (XXIV) (prostaglandins of series D) can be easily obtained by oxidation of the corresponding 9o (-hydroxy derivatives (XXI) and (XIX) with the Jones reagent at -35 ° C in acetone. This oxidation is selective and gives the compounds (XXIII) or (XXIV), which only contain small amounts of the 9-oxo derivatives (XIII) or (XIV) are contaminated, from which they can be separated by chromatographic methods.

The prostane carboxylic acids and prostene carboxylic acids according to the invention can be converted into the corresponding alkyl esters in the customary manner by treatment with a suitable diazoalkane. The preparation of the diazoalkanes using various methods is well described, including for example on CD. Gutsche (Organic Reactions, VIII (1954) 389) may be referred. Some of the esters of the invention can be can also be prepared directly by using the appropriate cyclopentenone ester (see XI). The different esters

One can also use various methods known per se via the acid chloride (whereby the free alcohol groups are first treated with suitable protective groups, such as trialkylsilyl groups, Tetrahydropyranyl groups or the like), or the mixed anhydrides and treating them

Prepare intermediate products with the appropriate alcohol. By treating the prostaglandic acid in a solvent, such as dioxane, at a temperature in the range from 0 to 15 ° C. with one molar equivalent of a trialkylamine, preferably

809841/0791

Triethylamine, tributylamine or the like, and then one Molar equivalent, isobutyl chlorocarbonate or the like can to make the mixed anhydrides. The mixed anhydride formed is then mixed with the appropriate alcohol converted to the derivative (see Prostaglandins, 4 (1973) 738).

An alternative method is the prostaglandic acid with one molar equivalent of the trialkylamine and one Excess of the appropriate alcohol in an anhydrous solvent, such as methylene chloride, to react, then a Add molar equivalent of p-toluenesulfonyl chloride (whereby one if necessary, a second molar equivalent can be added), whereupon after stirring at room temperature for about The product was worked up in the usual manner for 15 minutes to an hour (see US Pat. No. 3,821,279). A third approach includes common use of dicyclohexylcarbodiimide (see DE-OS 23 65 205 and Chemical Abstracts 81 (1974) 12-98 g).

The esterified alcohol derivatives (C _g ^OR o / where R ^ a

Alkanoyl group and R_ an alkanoyloxy group and / or R, represent an alkanoyl group) is also obtained in a customary manner using methods known per se from the appropriate alkanoic anhydride or the corresponding acid chloride.

Some of the ketones (I) according to the invention are obtained according to reaction scheme B below

809841/0791

2B13261

REACTION SCHEME B

(XXV)

(XXVI)

(R) _κ

HO -

CH ₂ - (CH ₂ J _1n .

(XXVII)

(CH ₂ ),

CH ₂ - (CH ₂ ) _m (XXVIIl)

where η and m have the meanings given above and the remainder

809841/0781

stands for a phenoxy group, optionally with a or more halogen atoms, trifluoromethyl group and low molecular weight (C -C.) - Alkyloxy groups is substituted.

As can be seen from Reaction Scheme B above, reacting an epoxide (XXV) with a substituted one gives or unsubstituted phenol (XXVI) in the presence of a catalytic amount of aqueous sodium hydroxide and a phase transfer catalyst, such as methyltricaprylylammonium chloride and the like, at 70 to 80 ° C the phenoxy-substituted Alcohol (XXVII), which in turn is substituted with an oxidizing agent such as pyridinium chlorochromate in methylene chloride to form the phenoxy Ketone (XXVIII) is oxidized.

The other ketones (I) used according to the invention are known from the literature or can be made more known per se Procedures are produced (G. Lardelli, U. Lamberti, W. T. Walles and A.P. de Jonge, Rec. Trav. Chem. Holland, 1967, 86, 481; Ng. Ph. Buu-Hoi, T. B. Loc, and Ng. Dat Xuong., Bull. Soc. Chem. France (1958) 174; and G. H. Posner, Organic Reactions 19 (1972) 1).

The compounds of the formulas (XXIX) and (XXX) are obtained by heating the corresponding 15-hydroxy compounds (to 100 to 200 ^° C.), which causes water to be split off.

09841/0791

• Μ. _

(XXIX)

(XXX)

The invention also relates to the various intermediates which are used according to the invention. They correspond to the general formulas given below K and L.

809 8-41 / 0791

(I trens H

(CH ₂ ) _W -C

CRg) SiO

(K)

(CH ₅ )

2'n

LiCu

in the w, n, m and X <? - 3 meanings given above, R _ft a lower (C - C _g ) alkyl group,

Q is an iodine atom, a tri-lower CC ^ -C,) alkyl tin group Lithium atom or a group of the following formulas

Cu-CC-R ₇ , -Cu-Si '\\ and
? t © ^

ti ©

R ₇ »7

represents, wherein R "represents a lower (C -C) alkyl group.

When the compounds of the invention are formed from racemic starting materials, two racemates are obtained. In In appropriate cases, these racemates can be separated by careful application of customary chromatographic procedures. In more difficult cases it may be necessary to

809841/0791

to use high pressure liquid chromatography and to employ recycling methods (see G. Fallick, American Laboratory (August 1973) 19-27 and those therein mentioned publications. Additional information regarding high speed liquid chromatography and the devices required for their application are available from Waters Associate, Inc. Maple Street, MiIford, Mass., USA, available).

It is also possible to use the individual enantiomers of the 11-oxy derivatives via the conjugate addi-

xO tion method by starting from a split into the optical isomers 4-oxy-cyclopentenone (see (XI), where R ' _{2 is} a tri-lower alkylsilyloxy group). The products (XIV) and (XIII) obtained are obtained in the form of their optically active isomers after the protective groups have been split off in the manner indicated above.

The racemic 4-hydroxy-cyclopentenones can be converted into the Split enantiomers (XXXI) and (XXXII) by adding them to an optically active center via the ketone function having reagent converted into a derivative. The received

A mixture of diastereoisomers can then be obtained by fractional crystallization, by chromatography or by high speed liquid chromatography, which can be combined with recycling techniques if necessary, separately will. As suitable optically active reagents for the formation of the

25 derivatives of the ketone can be 1-tf-aminoxy-V-methylpentanoic acid hydrochloride (from which the compound (XXXIII) is obtained), (R) -2-aminoxy-3,3-dimethylbutyric acid hydrochloride and 4-e (-methylbenzyl-semicarbazide insert. After the diastereoisomeric derivatives have been separated and the keto groups have been re-formed

pe the enantiomeric 4-hydroxycyclopentenones are obtained

(XXXI) and (XXXII). A suitable method for resolving a racemic 4-hydroxycyclopentenone via the oxime,

809841/0791

as (XXXIII) has already been described (R. Pappo, P. Collins and C. Jung, Tetrahedron Letters (1973) 943).

ο ο

S-C-OH

HO

(XXXI)

(XXXII)

HO '

COOH CH ₃ HC-CH ₂ CH-CH ₃

N 0

S-C-OH

(XXXIII)

An alternative method for the preparation of the enantiomers 4- (R) -Hydroxycyclopentenone comprises the key stage selective microbiological or chemical reduction of the trion (XXXIV) to the 4- (R) -hydroxycyclopentanedione (XXXV). Many microorganisms are able to effect this asymmetrical reduction, the most useful of which is Dipodascus is unincleatus. This reduction can also be carried out chemically by catalytic hydrogenation in a customary manner (for example in methanol at a hydrogen pressure of 1 kg / cm) below Use of a soluble rhodium catalyst with chiral

809841/0781

Phosphine ligands such as (1,5-cyclooctadiene) bis (o-anisylcyclohexylmethylphosphine) rhodium (I) tetrafluoroborate in the presence of an equivalent of an organic base, such as triethylamine, cause.

The conversion of the Hydroxyeyelopentanedione (XXXV) into a Enol ether or an enol ester (XXXVI, where D is an alkyl group, preferably an isopropyl group or a Aroyl group such as a benzoyl group or an arylsulfonyl group such as a 2-mesitylenesulfonyl group) for example by treating with isopropyl iodide and a base such as potassium carbonate in refluxing acetone for 15 to 20 hours or by treatment with a base, such as triethylamine, and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylene

15 sulfonyl chloride in a non-prototropic solvent

at a temperature of about -10 to -15 ° C. The reduction of (XXXVI) with excess sodium bis (2-methoxyethoxy) aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, for example at

20 -60 to -78 ° C, followed by mild acid hydrolysis

(representative conditions: aqueous dilute hydrochloric acid, pH = 2.5; or oxalic acid, sodium oxalate in Chloroform) at room temperature for 1 to 3 hours gives the 4- (R) -hydroxycyclopentenone ester (XXXVII). The Esters (XXXVII) can also be obtained after protecting the hydroxyl group in the manner described above subject the conjugate addition reaction conditions described above. The product of conjugate addition after splitting off the protective groups of the 11- and 15-Hy-

30 droxy! Groups form a methyl ester, which is based on enzymatic or microbiological means, for example with baker's yeast or by treatment with Rhizopus oryzae, to the corresponding Can hydrolyze carboxylic acid.

809841/0791

403

A more detailed description of these procedures, which are known per se can be found in the following references: C-J-Sih et al-, J-A.C.S. 1973, 95, 1676; J.B. Heather et al, Tetrahedron Letters (1973) 2213; R. Pappo and P. W. Collins., Tetrahedron Letters (1972) 2627; and R. Pappo, P. Collins and C. Jung, Ann. N. Y. Acad. May be. 180 (1971) 64. Regarding for the method using baker's yeast see C. J. Sih et al. J. A. C. P. 94 (1972) 3643).

Z-CO ₂ CH ₃

HO '

(XXXV)

(XXXVI)

Z-CO ₂ CH ₃

(XXXVII)

Methods for making the required cyclopentanetriones (XXXIV) are also known and generally include the treatment of a long-chain 1-oxo ester (XXXVIII) with methyl or ethyl oxalate and a base, such as Sodium methylate in methanol followed by treatment with dilute hydrochloric acid in aqueous methanol with the effect of dealkoxalylation of the intermediate (XXXIX) (see J. Kutsube and M. Matsui, Agr. Biol. Chem. 33 (1969) 1-78; P. Collins, C. J. Jung and R. Pappo, Israel Journal of Chemistry 6 (1968) 839; R. Pappo, P. Collins

809841/0791

and C. Jung, Ann. N. Y. Acad. May be. 180 (1971) 64; C. J. Sih et al., J. A. C. P. 95 (1973) 1676 (see Ref 7); and J.B. Heather et al., Tetrahedron Letters (1973) 2313).

1!

CH ₃ -C-CH ₂ -Z-CO ₂ CH ₃

(XXXVIII)

(XXXIV)

H +

CH ₃ O ₂ C

CO ₂ CH ₃

CO ₂ CH ₃ NaOCH.

The intermediate keto esters (XXXVIII) can be prepared in a variety of ways that are known per se. A useful one Process is given below and comprises the alkylation of the sodium salt of ethyl acetoacetate (XL) in the usual way with the appropriate side chain precursor (XLI, X = Xl, Br, J, preferably Br or J) followed by a decarbethoxylation and re-esterification, each of which is carried out in the usual manner.

809841/0791

Well ©

(XL) (XLI)

0 0

H "

.C. ^ Z-CO ₂ H .Cv ^ CO ₂ Cj

^ ^ CH ₂ ' ² CH ₃ ^ Ν »' ^{2 2}

Z-CO ₂ C ₂ H ₅ (XLII).

f (XLIII)

(XXXVIII)

The side chain precursors (XLI) in which Z represents a group of the formula - (CH ₃ ) - are commercially available and can be prepared by the procedure of BE-PS 786 215.

The precursors in which Z represents a group of the following formula - (CH ^) .- _{O-CH 3} - can be prepared from the monotetrahydropyranyl derivative (XLIV) by the conversion reaction given below. For example, the compound (XLIV) is converted into the lithium alcoholate by treatment with butyllithium, which is then 0-alkylated with ethyl bromoacetate to give the compound (XLV) which is obtained by des-O-tetrahydropyranylation, mesitylation and reaction

809841/0791

with lithium bromide gives the desired compound (XLVI).

(These and all of the conversions described above can be carried out in the usual way, including, for example can use the reactions described in BE-PS 786 215).

THP-O- (CH ₂ ) _t -0H

(XLIV) ^!

THPO- (CH ₂ ) _t -O-CH ₂ -CO ₂ C ₂ H ₅ (XLV)

HO- (CH ₂ ) ^ 0-CH ₂ CO ₂ C ₂ H ₅ (XLVII)

HsO- (CH ₂ ) ^

(XLVIII)

Br- (CH ₂ ) _t -O-CH ₂ CO ₂ C ₂ H ₅ (XLVI)

It is also possible to split the racemic 4-hydroxycyclopentenone (XLIX) microbiologically. Thus, treatment of the 4-0-alkanoyl or -aroyl derivatives (L, R- ₈ = an aryl group or an alkyl group) of the racemate (XLIX) (preferably the 4-0-acetyl and 4-0) Propionyl derivatives) with

a suitable microorganism, for example a representative of the species Saccharomyces, for example 1375-143, prefers the de-O-acylation of the 4- (R) -enantiomer, see above

809841/0791

that the compound (LI) is obtained, which is then chromatographed on the unreacted 4- (S) -O-acyl enantiomer (LII) is separated. Upon separation, mild hydrolysis of the 4- (S) derivative (LII) gives the 4- (S) -hydroxycyclopentenone (LIII) - (See N. J. Marsheck and M. Miyano, Biochima et Biophysica Acta, 316 (1973) 363 for others Examples).

H0 ^J (XLIX)

Z-COOH

Il

(R ₁₈ C) ₂ O

Z-COOH

Il

Z-COOH

HO *

(LI)

R ₁ oC-cr

Z-COOH

coon

(LIII)

It is also possible to use the individual 4-hydroxycyclopentenones (LI) and (LIII) directly through selective microbiological.

809841/0791

to produce hydroxylation of the corresponding cyclopentenone (LIV) unsubstituted in the 4-position. For example, it has been reported that selective 4- (R) -hydroxylation can be achieved with Aspergillus niger ATCC 9142 (LIV, Z = (CH „) ₆ ) (see S. Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters ( 1973) 4959). This hydroxylation can also be accomplished with other microorganisms.

0 0

(LIV)

An alternative method of splitting is to use the IO alcohol group of the racemic Hydroxyeyelopentenons an ester derivative (LV) (where R "is a hydrogen atom or an alkoxy group and η 'are 0 or 2 and Z are those given above Have meanings).

Z-C-O-RJ

(LV)

15 These derivatives can be obtained from the corresponding free hydroxycyclopentenone by ordinary treatment with oxalyl chloride, succinyl chloride, succinic anhydride and the like. The treatment of the corresponding acid or diacid (R "- = hydrogen) with optically active amines, for example

way 1 - (-) - ol-methylbenzylamine, d - (+) - Of-methylbenzylamine, Brucine, dehydroabietylamine, strychnine, quinine, quinchonine,

809841/0791

Quinidine, ephedrine, (+) - tf-amino-1-butanol and the like, and fractional recrystallization of the resulting mixture of diastereoisomers, followed from cleavage of the 4-oxy-ester group of the individually isolated diastereoisomers gives the separated ones enantiomeric 4- (R) - and 4- (S) -hydroxycyclopentenones (LVI) and (LVII) or their corresponding esters. The split The oxalic acid ester (LV, η = 0) can be brought about by treatment with lead tetraacetate in pyridine solution. In terms of An example of a similar application of oxalic acid esters (acidic oxalic acid esters) can be found in J.G. Molötkovsky and L.D. Bergelson, Tetrahedron Letters No. 50 (1971) 4791. Regarding the use of a succinic acid ester, may on B. Goffinet (DE-OS 22 63 880) and Chem. Abstracts 79 (1973) 7815 ζ can be referred to.

The splitting of the racemic 9-hydroxy derivatives (their Enantiomers are illustrated by the following formulas LVIII and LIX) can be achieved that one the racemate whose hydroxyl groups in positions 11, 15 or 16 are preferably protected with trialkylsilyl groups has, (for example by first converting the two hydroxyl groups to form the corresponding 9-oxo derivative and reduction of the 9-carbonyl derivative in the manner described above), into the corresponding phthalic acid half-ester converts, splits off the protective groups of the hydroxyl groups in the 11- and 15-positions and the dicarboxylic acid (i.e. the compound LX) with an optically active amine (e.g. 1- (-) -Ck-methylbenzylamine, D- (+) - <* - methylbenzylamine, Brucine, dehydroabietylamine, strychnine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine, Amphetamine, (+) - 2-amino-1-butanol, (-) - 2-amino-1-butanol and the like) to a mixture of the diastereoisomeric bis-salts. The diastereoisomers formed are then separated by fractional crystallization, whereupon the individual components are acidified and saponified

809841/0791

to the corresponding enantiomeric 9tf-hydroxy derivatives (LVIII) and (LIX) converts their oxidation, which is carried out after the hydroxyl groups in 11- and 15-positions has preferably protected with tetrahydropyranyl groups or trialkylsilyl groups, after the cleavage Protecting groups gives the corresponding enantiomeric 9-oxo derivatives (LXII) and (LXIII). If necessary, you can the 11- and 15-hydroxyl groups before saponification of the phthalic ester convert to tetrahydropyranyloxy groups. (Regarding one of the procedures described above, see E. W. Yankee, C. H. Lin and J. Fried, Journ. Chem. Soc. (1972) 112O, referenced).

JL. Z-C-OH

y y

Another method comprises the conversion of the racemic 9C (-hydroxy-derivatives "(such as the prostate acid ester, the alcohol of which

809841/0791

functions in positions 11, 15 or 16 are preferred are protected via trialkylsilyl ether groups) in the diastereoisomeric carbamates, including an optically active Isocyanate, e.g. B. (+) - l-phenylethyl isocyanate or (-) - l-phenylethyl isocyanate, used, followed by removal of the protecting groups. The separation of the diastereoisomers formed, For example, the compounds (LXIV) and (LXV), one can by fractional crystallization or by customary chromatographic methods or, if necessary, by high speed liquid chromatography, the if necessary, includes recycling techniques. Treatment of the separated diastereoisomeric carbamates with bases gives the corresponding diastereoisomeric alcohols, for example (LVIII) and (LXVI). You can make these connections in turn to the corresponding 11-oxo compounds oxidize, which are claimed according to the invention (LVII b) and (LXVI b).

809841/0791

PH ϊ

Ϊ Z-C-OH

(LVIII)

(CHJ _n -

CH- (CH ₂ )

ItV '

(LXVI)

COOH

-O

A *, -z-fc-

OH

(CH ₂ ).

H ₂ - (CH ₂ )

OH

(LVIII b) CH ₂ - (CH ₂ ),

(LXVI b)

809841/0791

AAS

HO

(LXI)

HO

(LXIV)

OÜ41 / O701

It is also possible to resolve the racemic 9Of-hydroxy derivative, preferably as a prostate acid ester, to be achieved by using the 9'-hydroxyl group (preferably the hydroxyl groups beforehand in the manner described above

in positions 11, 15 or 16 via trialkylsilyl ether groups) with an optically active acid via the Esterified acid chloride and then the protective groups of the alcohol groups on carbon atoms 11, 15 or 16 splits off. Suitable optically active acids are aqueous acid, menthoxyacetic acid, 3ot-acetoxy-Δ-ethic acid acetoxy-Δ-etianic acid), (-) -ot-methoxy-Of-trifluoromethylphenylacetic acid and (+) -d-methoxy-t (-trifluoromethy! phenylacetic acid and the same. The diastereoisomeric esters formed, for example the compounds of the formulas

15 (LXVII) and (LXVIII) are then obtained by fractional crystallization or separated by chromatography, if necessary using high speed liquid chromatography. By saponifying the individual diastereoisomers, the enantiomeric 9c (-hydroxyprosten-

acids (LVIII) and (LXVI).

CH ₃ O 0

HO '

(LXVII)

809641/0701

CH, O O

³ ΙΊΙ

C ^ Hc-C-C-O ¹ I.

/ Z-CO ₂ C ₂ H ₅

(LXVIII)

χ:

Although the procedures described above have been illustrated on compounds which have a llo (hydroxyl group, can also be carried out with representatives of the 11-deoxy series.

Another method of splitting that is less useful than the methods described above based on the 90 <-hydroxy derivatives based, which, however, can be applied particularly well to the 11-deoxy compounds according to the invention see the derivative picture of the keto function of the racemi 9-Oxo-prostenic acids or their esters, including conventional means for the formation of ketone derivatives used, which an optically have an active center. The resulting mixture of the diastereoisomeric derivatives can then be obtained by fractional crystallization or separated by chromatography and, if necessary, by high speed liquid chromatography will. The individual diastereoisomeric keto derivatives, for example the compounds of the formulas (LXIX) and (LXX) are then made by the usual cleavage techniques, which, however, do so use mild conditions that the sensitive 11-hydroxy-9-keto system, if such is present, it is not impaired, into the individual enantiomeric 9-oxo derivatives be converted, for example into the compounds of the formulas (LXXI) and (LXXII). (The application

809841/0791

These mild conditions are unproblematic with the derivatives unsubstituted in the 11-position. Reduction of the keto group of the enantiomeric 9-oxo derivatives in the manner described above then gives the corresponding enantiomeric 9tf-hydroxy derivatives or 9β-hydroxy derivatives. Examples of the optically active reagents which are suitable for the formation of ketone derivatives are 1-oC-aminoxy-Y-methylpentanoic acid hydrochloride (E. Testa et al. HeIv. Chimica Acta 47 (3), (1973) 766), Methylhydrazine and 4- <rt-methylbenzylsemicarbazide. A useful method for cleavage of the oximes such as those of formulas (LXIX), and (LXX) comprises treatment of the oxime at a temperature of about 60 ⁰ C for about 4 hours in a water / tetrahydrofuran mixture (1/2), the is buffered with ammonium acetate and contains titanium trichloride.

(LXIX)

(CH ₂ ) _n

CH ₂ - (CH ₂ )

II-C * -CH ₇ -CH-CH

(LXK)

809841/0781

(LXXI)

(LXXII)

-CH ₂ - (CH ₂ :

Further useful agents for the formation of ketone derivatives are optically active 1,2-glycols, for example D - (-) - 2,3-butanediol, or 1,2-dithiols, for example L - (+) - 2,3-butanedithiol. These compounds are used to convert the racemic 9-oxo derivatives into the diastereoisomeric 9,9-alkylenedioxa- or to convert 9,9-alkylenedithia derivatives. The separation of the diastereoisomers by means of chromatographic methods, followed by regeneration of the separated ones Enantiomeric 9-oxo derivatives by ketal cleavage can be achieved with the aid of methods known per se will. Both the formation of the ketals and the cleavage of the ketals must be achieved with the help of methods that the ll-oxo-9-keto system does not affect it, however no problem with the compounds unsubstituted in the 11-position represents.

The manufacture of the necessary cyclopentenones that a Having sulfur atom in the o (chain is indicated by the reaction scheme C explained. According to reaction scheme C, in which t has the meanings given above, gives the

5 Treatment of 2-furyllithium (LXXIII) with a Uj-chloraldehyde (LXXIV) the chlorine alcohol (LXXV). Treatment of the
Chlorine alcohol (LXXV) with ethyl mercaptoessxgate results in the hydroxyester (LXXVI), which is hydrolyzed with a
Sodium formate / formic acid mixture the 3-hydroxy-cyclopene

tenon (LXXVII) returns. Treatment of Cyclopentenone (LXXVII) with sulfuric acid gives the required 4-hydroxy-cyclopentenone (LXXVIII), which after treatment with chlorotrimethylsilane and hexamethyldisilazene in pyridine the bis-silylated cyclopentenone (LXXIX) yields.

The 3-hydroxy-cyclopentenones of the type (LXXVII), the 4-Hy-

droxy-cyclopentenones of the type (LXXVIII) and the bis-silylated or bis-tetrahydropyranyl-protected or otherwise
appropriately protected 4-hydroxy-cyclopentenone des
Type (LXXIX) are new and useful connections that also

if the subject of the invention, as well as the new

Intermediate products required for their manufacture.

809841/0791

REACTION SCHEME C

Il l [

Li + HC- (CH ₂ ) _t -Cl

(LXXIII)

(LXXIV)

CH- (CH ₂ ) _t Cl

OH

(LXXV)

HSCH ₂ CO ₂ C ₂ H ₅

0H

H ₂ SO ₄

(LXXVII)

I I

OH

HCO ₂ Na / HCO ₂ H (LXXVI)

(CH ₂ ) _t SCH ₂ COOH

(LXXVIII)

(CH ₃ ) ₃ SiCl

. (CR,) -, BLQ.Z.

8098A1 / 0791 (CH ₂ ) _t SCH ₂ SOOSi (CH ₃ ) ·.

(LXXIX)

The ring systems of the new compounds according to the invention can be characterized as follows:

Il

PEE type

OH

PGF ₂ type

PGF type

I!

PGA type

PGB - type

The compounds of the present invention have the following indicated pharmacological effects associated with the corresponding prostaglandin type described above are linked.

The known PGE compounds are effective compounds which, even at low doses, cause a number of biological reactions. For example, PGE ₁ and PGE are extremely effective in lowering blood pressure and stimulating smooth muscles, and also act as anti-lipolytic agents. On the other hand, these known prostaglandins have an unpleasant short biological duration of action for many purposes. In surprising contrast, the analog prostaglandin derivatives according to the invention are significantly more specific with regard to their ability to cause prostaglandin-like biological reactions and / or have a significantly longer-lasting biological effect. Therefore, these prostaglandin derivatives according to the invention are surprisingly and unexpectedly more effective than the above-mentioned known prostaglandins, at least with respect to one of the pharmacological purposes which are given below for the known compounds, which is based on the fact that they have a different or narrower range of have a biological effect than the known prostaglandins and are therefore more specific in their effect and cause fewer and fewer undesirable side effects than known prostaglandins, or that, due to their prolonged effect, they can be used less frequently and lower doses of the prostaglandin derivatives according to the invention to achieve the desired result.

The 11-deoxy-PGE compounds are still selective because that at most they represent relatively very weak stimulants for the smooth muscles. The 11-deoxy-PGE compounds have the further advantage that they are essential

809841/0791

are more stable and have a much longer "shelf life" than the corresponding 11-hydroxy derivatives, such as will be explained in more detail below.

A further advantage of the compounds according to the invention compared to the known prostaglandins is to be found therein

see that they are effective on oral, sublingual, intravaginal, buccal or rectal route in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods appropriate for the 0 known prostaglandins are typical. These properties are beneficial as they make it possible to obtain more uniform contents to effect these compounds in the body with fewer numbers, shorter given or smaller dosages and also allow patient 15 self-administration.

PGE, PGE_, PGE, and Dihydro-PGE and their esters and pharmacologically acceptable salts are extremely effective in causing various biological reactions. the end therefore these compounds are useful for pharmacological purposes. In this regard, reference is made to Bergstrom et al.

(Pharmacol. Rev. 20 (1968) 1) and the references cited therein referenced. Some of these biological responses are systemic lowering of blood pressure in the arteries Case of the PGE compounds, for example, anesthetized (with phenobarbital sodium) and treated with pentolinium Measures rats with indwelling catheters placed in the aorta and right ventricle; a stimulation the smooth muscles, which can be found, for example, by investigations on strips of guinea pig ileum, des

30 rat duodenum or gerbil colon determined; potentiation of other smooth muscle stimulants; an antilipolytic effect, which is one by the antagonism against the mobilization induced by epinephrine

809841/0791

of free fatty acids or by inhibiting the spontaneous release of glycerol from isolated rat fat bodies proves; an inhibition of gastric secretion in the case of the PGE compounds studied in dogs, their secretion stimulated by food or by an infusion of histamine; an XY effect on the central nervous system; a decrease in platelet adhesion in the case of PGE, which the adhesion of the platelets to glass is demonstrated; and an inhibition of platelet aggregation and the Thrombus formation caused by various physical irritations, such as an arterial injury, and various biochemical irritants such as those caused by ADP, ATP, serotonin, thrombin and collagen; and in In the case of the PGE compounds, a stimulation of skin growths and skin cornifications, which one observes when one looks at the Applying compounds in cultures to skin segments of embryonic chicks and rats.

Because of these biological responses, these known prostaglandins are useful in treating a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, farm animals, Domestic animals, animals in zoos and laboratories such as mice, rats, rabbits and monkeys, to investigate, prevent, combat or alleviate »

For example, these compounds, and particularly the PGE compounds, are found in mammals, including humans, suitable as a nasal decongestant. For this purpose the compounds are used in a dose of about 10 µg up to about 10 mg / ml of a pharmacologically suitable liquid carrier material or as an aerosol spray, both of which applied topically.

The PGE compounds are found in mammals, including men

/ 07

see and certain farm animals, such as dogs and Pigs, prone to excessive gastric secretion decrease, thereby reducing or avoiding gastric erosion or gastrointestinal ulcers, and thereby reducing the Healing of such pre-existing ulcers in the gastrointestinal tract is accelerated. For this purpose the connections by intravenous, subcutaneous, or intramuscular routes at a dose of about 0.1 µg to about 500 / µg / kg body weight per minute or in a total dose of daily

10 about 0.1 to about 20 mg / kg of body weight, which dose depends on the age, weight and condition of the patient or of the animal and depends on the frequency and route of administration, injected or infused. These connections can also together with various steroidal anti-inflammatory

Toric agents such as aspirin, phenylbutanzone, indomethacin and the like are used to treat the well-known ulcerative To minimize the effects of these compounds.

The PGE compounds are useful whenever it is desired to inhibit platelet aggregation,

decrease platelet adhesion and thrombus formation in mammals, including humans, rabbits and rats, to prevent. For example, these compounds are useful for treatment and preventive treatment 25 of myocardial infarctions and for the treatment and prevention of postoperative thrombosis. Be for this purpose these connections systemically, d. H. intravenous, subcutaneous, intramuscular or in the form of sterile implants to achieve administered for a longer effect. For a quick 30 treatment, especially in emergencies, an intravenous one is recommended Administration preferred. Dosages in the range from about 0.005 to about 20 mg / kg of body weight and per day are used the exact dose depending on the age, weight and condition of the patient or animal and the frequency of

809841/0791

speed and the route of administration.

The 11Of-Hydroxy-PGS compounds are particularly effective in terms of smooth muscle stimulation and also have an extremely great increase in activity the effect of other known smooth muscle stimulants such as oxytocic agents, for example Oxytocin, and the various ergot alkaloids, including derivatives and analogous compounds thereof. Therefore, for example, PGE can be used instead of or in combination with less than the usual amounts of these known Use smooth muscle stimulants to treat symptoms of paralytic ileus, for example to ease or uterine bleeding after abortions or childbirth, to encourage placenta expulsion, and during control or prevent the puerperium. The PGE compound is administered for the latter purpose immediately after the abortion or delivery by intravenous infusion at a dose in the range of about 0.01 to about 50 .ug / kg body weight per minute until the desired Effect, is achieved. Further doses are given by intravenous, subcutaneous or intramuscular injection or infusion during the puerperium, this dosage being in the range of 0.01 to 2 mg / kg of body weight and per day, the exact dose again depending on the age, the weight and the

25 depends on the condition of the patient or the animal.

The PGE compounds are useful hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, the compounds are administered by intravenous infusion at a dose of about 0.01 to about 50 .g / kg of body weight per minute or in single or multiple dosages of about 25-2500 µg / kg. Body weight per day given.

SQSS41 / 07I1

2313261

The PGE compounds can also be used in place of oxytocin used in labor in pregnant females, including humans, cows, sheep, pigs, at or near the end of pregnancy or in pregnant animals whose fetus is about 20 weeks before the

5 parturition has died in the uterus. To do this, the compound is administered intravenously in at a dose of 0.01 to 50 .mu.g / kg body weight per minute infused up to or approximately up to the second stage of the Contractions, d. h- the expulsion of the fetus has ended. These

Compounds are especially effective when the female patient is a week or two past the due date and the natural labor has not yet started or if 12 to 60 hours after the membranes ruptured natural labor has not yet started.

The PGE compounds are designed to increase the reproductive cycle to control ovulating female mammals, including humans and other animals. To this end, will a PGE compound is administered systemically at a dose ranging from 0.01 mg to about 50 mg / kg of body weight advantageously during the period that begins around the time of ovulation and around the time of menstruation or just before menstruation ends. Furthermore, the expulsion of an embryo or fetus by a similar one Administration of the compound effected during the first trimester or the second trimester of normal pregnancy. As a result, they are useful as abortion agents. You can also use it to trigger menstruation while around the first two weeks of a non-occurred mentoring period serve and are therefore used as a contraceptive

30 medium suitable.

For these purposes, these compounds are preferably applied topically at or near the location where the

809841/0791

Cell growth and the keratin bilcujig is sought, preferably in the form of an aerosol liquid or a powder spray, as an isotonic aqueous solution in the case of moist Dressings or as a lotion, cream or ointment in combination with conventional pharmaceutically suitable diluents, used. In certain cases, such as when there is significant fluid loss, as in the case extensive burns or skin losses as a result of other influences, systemic administration is advantageous, for example, by intravenous injection or infusion, separately or in combination with the usual Infusion of blood, plasma, or plasma substitute is performed. Alternative routes of administration are subcutaneous or subcutaneous intramuscular injections near the treatment room or an oral, sublingual, buccal, rectal, or vaginal injection Administration of the active ingredients. The exact dosage used depends on the route of administration, age, weight and the Condition of the patient. To illustrate a moist bandage for topical application on skin burns 2.

and / or 3rd degree one becomes with an area of 5 to 25 cm It is advantageous to use an isotonic aqueous solution containing 1 to SOO ^ ug / ml of the PGB compound or a multiple of this Contains concentration of PGE compound. These prostaglandins are particularly suitable for topical application to be used in combination with antibiotics, for example in combination with gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin and oxytetracycline or in combination with antibacterial agents, for example with mafenide hydrochloride, sulfadiazine, furazolium chloride and nitrofurazone, and in combination with corticoid steroids, for example with hydrocortisone, prednisolone, methylprednisolone and fluprednisolone, with these additional compounds used in the combination in their usual concentration in which they are normally used alone.

0 a 8 41/0791

The PGE compounds of the invention are also useful as bronchodilators suitable for the treatment of asthma and chronic bronchitis and can do this by inhaling aerosol sprays be administered containing the active ingredient in an amount of about 10 .mu.g to about 10 mg / ml of a pharmacologically suitable contain liquid carrier material.

The known PGA and PGB compounds cause a number of strong biologicals even at low dosages Reactions. On the other hand, these known prostaglandins have an unsatisfactorily short duration for many purposes their biological effects. In surprising contrast, the prostaglandin derivatives according to the invention are essential more specific with regard to their property of triggering and / or possessing prostaglandin-like biological reactions

15 a much longer duration of their biological effect.

The prostaglandin derivatives according to the invention are therefore surprising and unexpectedly more effective than the above mentioned known prostaglandins for at least one of the following for these known compounds indicated pharmacological purposes, which is based either on the fact that they are a exercise different or narrower range of biological effects than the known prostaglandins and therefore in their The effects are more specific and have fewer and less harmful side effects than the known prostaglandins,

25 or because they are less frequent due to their longer effects

and must be given in lower doses to produce the desired effect.

Because of their biological responses, the known prostaglandins are capable of causing a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, farm animals, domestic animals, animals of zoos and laboratory animals such as MaUSCn ₇ rats, rabbits and monkeys investigate,

SÖ9841 / 0791

to prevent, combat or alleviate.

The PGA compounds are in mammals, including humans and certain farm animals, such as dogs and pigs, are susceptible to excessive gastric secretion and bring them under control, thereby reducing gastric erosion or the formation of gastrointestinal ulcers or avoided and accelerates the healing of such ulcers already present in the gastrointestinal tract will. For this purpose, the connections are made on intrave-

"0 nasal, subcutaneous or intramuscular routes in one dose from about 0.1 Ug to about 500 µg / kg body weight per minute injected or infused or by injection or infusion daily at a dose of about 0.1 to about 20 mg / kg body weight, the exact dose depending on the age, weight and condition of the patient or the patient Animal and depends on the frequency and route of administration. These compounds can also be used in combination with various non-steroidal anti-inflammatory agents, such as aspirin, phenylbutazone, indomethacin and the like are used to produce the well known ulcerogenic effects to diminish these compounds.

The PGA compounds are useful hypotensive agents for Decrease in blood pressure in mammals, including humans. For this purpose the connections are made by intravenous Infusion at a dose of about 0.01 to about 50 / ug / kg body weight per minute or in a single dose or in several doses totaling about 25 to 2500 , ug / kg body weight given per day.

The PGA compounds and their derivatives and salts increase the flow of blood in the mammalian kidney, which increases the volume and electrolyte content of the urine. For this purpose the PGA compounds can be used to treat

© 09841/0711

2313261

Kidney disorders, especially in the case of severe renal blood flow disorders, for example Hepatorena syndrome and early rejection of transplant recipients Kidneys are inserted. In the case of excessive or unsuitable ADH secretion (3as antidiuretic hormone vasopressin) the diuretic effect of these compounds is even greater. In anephritis, the action is vasopressin these compounds are particularly useful. Because of this, these compounds are useful for healing the skin, which has been damaged by burns, wounds, abrasions, surgical procedures, for example promote and accelerate. These compounds are also suitable for the adhesion and growth of skin's own- Encourage plants, especially small, deep transplants (Davis), which are intended to be used in skinless areas by subsequent waxing outwards instead of directly covering, and are also suitable for the repulsion of Delaying own transplants.

For this purpose, these compounds are preferably applied topically to or near the location where the Growth of the cells and the formation of keratin are aimed at, preferably in the form of a spray liquid or a powder spray, or in the form of an isotonic aqueous solution in the case of moist dressings or in the form of a lotion, cream or ointment in combination with conventional pharmaceutically acceptable diluents begins. In certain cases, for example when there is a significant loss of fluid as a result of excessive There are burns or skin losses due to other causes, systemic administration is advantageous, for example by intravenous injection or infusion, independently of. or in combination with the usual infusion carried out by blood, plasma or such substitutes. Alternative routes of administration are that

809841/0791

subcutaneous or intramuscular administration near the Treatment site and the oral, sublingual, buccal, recta-Ie or vaginal administration of the active ingredients. The exact dose depends on the route of administration and the age, weight and condition of the patient. To illustrate a damp Dressing for the topical treatment of skin burns

2nd and / or 3rd degree one becomes with skin areas from 5 to

25 cm with advantage use an isotonic aqueous solution containing 500 μg / ml of the PGB compound or a multiple this concentration of the PGE compound contains. Especially when used topically, these prostaglandins can be used in Combination with antibiotics, for example gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin and oxytetracycline, with other antibacterial agents, for example mafenide hydrochloride, sulfadiazine, furazolium chloride and Nitrofurazone, and with corticoid steroids, for example Hydrocortisone, prednisolone, methyl prednisolone and fluprednisolone are used, whereby these active ingredients are used in combination in the usual concentration,

20 in which they are normally used alone.

The compounds of the invention cause those described above biological responses associated with their particular type of prostaglandin. The compounds according to the invention are therefore applicable for the purposes described above in the manner indicated above.

The PGA compounds of the invention are also useful Bronchodilators used to treat asthma and chronic Bronchitis and can be used for this by inhalation of aerosol sprays, which one in a concentration from about 10 µg to about 10 mg / ml of a pharmacologically acceptable liquid carrier material.

The well-known PGD compounds unfold even at low levels

09841/0791

Dosages a range of biological responses. On the other hand, these known prostaglandins have the disadvantage an unsatisfactorily short duration of their biological effect. In surprising contrast, those according to the invention are Compounds are much more specific for their ability to cause prostaglandx-like biological responses and / or have a significantly longer duration of their biological effect. Therefore, the prostaglandin derivatives according to the invention are surprisingly and unexpectedly more effective than the above-mentioned known prostaglandins, namely with regard to at least one of the pharmacological points Purposes given below for the known compounds, based on the fact that they are either different and narrower range of biological effects than

15 possess the well-known prostaglandins and therefore in their

Effects are more specific and have weaker and fewer side effects than the well-known prostaglandins cause, or because they are less frequent and due to their longer effects have to be administered in lower doses in order to

20 desired result.

Another advantage of the compounds according to the invention compared to the known prostaglandins is to be seen in that they can be effectively administered to oral, sublingual, intravaginal, can be given buccal or rectal route,

25 in addition to the intravenous, intramuscular or sub-

cutaneous injection or infusion, in which the well-known prostaglandins administered. These properties are beneficial as they make it possible to obtain uniform levels of these Reach active ingredients in the body with fewer, less long and lower dosages and because of the patient can take the active ingredients yourself.

The PGD compounds and their esters and pharmacologically acceptable Salts have an extremely powerful effect on

809841/0791

Causing various biological reactions. It is for this reason that these compounds are used for pharmacological purposes useful. In this regard, reference should be made to Bergstrom et al (Pharmacol. Rev. 20 (1968) 1) and the references cited therein to get expelled. The PGD compounds cause a beneficial decrease in platelet adhesion, which is reflected in shows the adhesion of platelets to glass and inhibits platelet aggregation and thrombus formation, caused by various physical stimulants, such as arterial damage, and by various biological irritants such as ADP, ATP, serotonin, thrombin and collagen.

Because of these biological responses, these known prostaglandins can be used in a wide variety of ways diseases and undesirable physiological conditions in birds and mammals, including humans, farm animals, Pets and animals from zoos and laboratories such as mice, rats, rabbits and monkeys examine, preventively treat, combat or to

20 alleviate.

The PGD compounds are useful for inhibiting platelet aggregation, to reduce the adhesion of platelets and to prevent or prevent their formation of thrombi in mammals including humans, rabbits and rats. For example, these connections to be used for the treatment and preventive treatment of myocardial infarction and postoperative thrombosis «To for this purpose these connections are systemic, i.e. H. intravenous, subcutaneous, intramuscular and in the form of sterile Implants to achieve a longer effect, administered. To achieve a quick response, in particular in emergencies, intravenous administration is preferred, with dosages in the range of about 0.005

S09841 / 07I1

to about 20 mg / kg of body weight per day, the exact dose being dependent on the age, weight and condition of the Patient or animal and depends on the frequency and route of administration.

The PGD compounds are useful hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, the compounds are administered by intravenous infusion at a dose of about 0.01 to about 50 .mu.g / kg body weight per minute or in the form of a single or multiple dosages of about 25-2500 µg / kg body weight given per day.

The PGD connections are also used to control the reproduction cycle by ovulating female mammals including humans and other animals. For this purpose for example, PGD is systemically administered in one dose in the range of 0.01 mg to about 100 mg / kg of body weight and advantageously given for a period of time which is about begins at the time of ovulation and ends around the time of menstruation or just before menstruation.

20 Furthermore, the expulsion of an embryo or fetus by a similar administration of the compound during the first One third or the second third of the normal gestation period. As a result, the connections used as an abortion agent. You can also

management of menstruation can be used for about the first two weeks of a non-occurred menstrual period and therefore are useful contraceptives.

The well-known PGF ^ - and PGF compounds are themselves in small amounts Dosages effective agents that cause a wide variety of biological reactions. On the other hand, show these well-known prostaglandins for many uses an unsatisfactorily short duration of their biological effects.

809841/0791

In surprising contrast, those according to the invention are Prostaglandin derivatives are much more specific with regard to their ability to cause prostaglandin-like biological reactions and / or have a significantly longer duration of their biological effect. Therefore, the prostaglandin derivatives according to the invention are surprisingly and unexpectedly more useful than the prostaglandins mentioned above, in terms of at least one of the pharmacological purposes required for the known compounds are given below, which is based on the fact that they are either a different and narrower They have a spectrum of biological effects than the known prostaglandins and are therefore more specific in their effects and exert weaker and less undesirable side effects than the prostaglandins, or because they are due to them prolonged effects can be given less frequently and in lower dosages to achieve the desired result cause.

The PGE ₀ ^ - and PGF compounds are also selective in that they represent at the most relatively weak stimulants of the smooth muscles.

Another advantage of the compounds according to the invention in Comparison with the known prostaglandins can be seen in the fact that they are in addition to the usual intravenous, intramuscular or subcutaneous injection or infusion, by whatever route the known prostaglandins are administered, also in an effective manner by oral, sublingual, intravaginal, buccal or rectal route can be given. These Properties are beneficial as they help maintain consistent levels of active ingredient in the body with lower, enable less frequent and weaker dosages and allow self-administration by the patient.

0984170791

The PGF ^ and PGF compounds and their esters and their pharmacological acceptable salts are extremely potent agents causing a wide variety of biological reactions, so that they can be used for pharmacological purposes

5 den can. In this regard, Bergstrom et al- (Pharmacol. Rev. 20 (1963) 1} and the references cited therein. Some of these biological responses are a systemic lowering of arterial blood pressure in the fall of the PGF compounds, which can be found, for example, on (with pheno-

10 barbital sodium) anesthetized and pentolinium-treated rats with an indwelling catheter inserted into the aorta and right ventricle; a similarly measured pressor effect of the PGF ₆ J compounds; a stimulation of the smooth muscles, which one can for example by

Investigations on strips of guinea pigs, des

Rabbit duodenum or gerbil colon observed; potentiation of other smooth muscle stimulants; an antilipolytic effect that one goes through the antagonism of the mobility caused by epinephrine

reduction of free fatty acids or by inhibiting the spontaneous release of glycerol from isolated rat fat pads observed.

Because of these biological responses, these known prostaglandins are useful in treating a wide variety of diseases and desired physiological conditions in birds and mammals, including humans, farm animals, Domestic animals and animals living in zoos and laboratories, for example mice, rats, rabbits and monkeys to investigate, prevent, control, or mitigate.

The PGF compounds are useful hypotensive agents and lower blood pressure in mammals, including humans. For this purpose, the connections are made

! 509841/0711

2813281

venous infusion at a dose of about 0.01 to about 50 µg / kg body weight per minute or in a single or multiple dosages of about 25 to 2500, ug / kg body weight per Day given.

The PGF ₆ ^ and PGF compounds can be used in place of oxitocin to ease labor in pregnant females, including humans, cows, sheep, and pigs, at or near the end of pregnancy, or in pregnant animals, such as their fetus For this purpose, the compound is administered intravenously at a dose of 0.01 to 50 / Ug / kg body weight per minute until or until approximately the end of the second stage of labor, ie the expulsion of the Fetus, infused. These compounds are particularly useful when the pregnant woman is a week or two past her due date and has not yet started natural labor, or when natural labor has not started 12 to 60 hours after the membranes have burst.

The PGF ₀ ^ and PGF compounds are useful in regulating the reproductive cycle of ovulating female suckers, including humans and other animals. For example, PGF ^ _{0 is} administered for this purpose. systemically in a dose in the range from 0.01 mg to about 20 mg / kg body weight, which is advantageously carried out during a period of time which begins approximately at the beginning of ovulation and ends approximately at the time of menstruation or immediately before it effecting the expulsion of the embryo or fetus by similar administration of the compound x-r during the first third or the second third of the normal menstrual period. As a result, the compounds can be used as abortion tools. They can also be used to help during menstruation

■ 09841/0711

etwe of the first two weeks of a missed menstrual period trigger and can therefore be used as a contraceptive.

The PGF compounds of the invention are also useful as bronchodilators for the treatment of asthma and chronic Suitable for bronchitis and can be conveniently administered for this purpose by inhalation of aerosol sprays which are shown in a dose ranging from about 10 / ug to about 10 mg / ml of one pharmacologically suitable liquid carrier material are given.

These derivatives described above are also with regard to their biological effect more selective and generally cause a longer effect than the corresponding natural prostaglandins. These preparations are new, in no way expected, and have clear and important advantages.

A number of the new compounds according to the invention can also be used can be used to prepare other novel compounds of the invention.

It is well known that platelet aggregation inhibitors can be used as antithrombotic agents. The inhibition of platelet aggregation can be conveniently measured in vitro by looking at the changes the optical density and / or the light permeability of a platelet-rich plasma after the addition of suitable

25th aggregation agents, such as adenosine diphosphate, epinephrine, Thrombin or collagen monitored. Alternatively, one can measure platelet aggregation in vitro by uses a platelet-rich plasma taken at various time intervals from animals from which one

10 inhibitors administered orally or parenterally Has.

809841/0791

The compounds according to the invention have the property of inhibiting platelet aggregation in vitro when they can be examined using the method below.

The human protein-rich plasma is incubated in a modified Tyrode solution which contains 40 to 50 % of the human protein-rich plasma. The compounds to be examined are used in varying concentrations and, after an incubation time of 5 minutes, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (or light transmittance) is monitored with the eye and the inhibition is recorded as (-) and the non-inhibition as (+). The compounds tested are considered effective if they inhibit aggregation caused by adenosine diphosphate or collagen at a concentration of 25 µg / ml or less over a period of 5 to 10 minutes. The results of testing representative members of the invention are shown in Table A below.

OS S41 / 07

TABLE A

In vitro inhibition of platelet aggregation

link Adenos indijDhqspJiat 25th 2.5 ' 0.25 Collagen 25th 2.5 ⁷ O, 25 Active ingredient concentration , including / ml <-> Active ingredient concentration./ua/ml ( ₊ ) <-> ro
00 250 25O nat (and ent) -IS-Hydroxy-g-oxo-IS, 16-tetra-
methylene-17,18,19,20-tetranor-13-trans ~
prostenic acid
nat (and ent) ~ 15-Hydro2: y-9-oxo-15 _/ 16-tetra-
_C :. _; methylene ~ 17,18,19, 20-tetranor-13 - trans, 5-
o ice, 10 ~ prostatic acid
Q. nat (unä ent) -HoC, IS-dihydroxy-g-oxo-IS, 16-
^. tetramethylene-17,18,19,20-tetranor-5-cis, -
™ * 13 ~ trans-prostadic acid
οnat ~ 15S, 16R (and ent-15R, 16S) -11 «, 15-Dihy ~
^ 4 droxy ~ 9 ~ oxo-15, IG-tri-ethylene-lS-trans-
cö 5-cis-prostadienoic acid and nat-15R, 16S (and
- »ent-lSS, 16R) -IM, ~ 15 ~ dihydroxy-9-oxo-15, -
Lö-triraethylene-lS-trans-S-cis-prostadien-
säui'e
nat (and ent) -IK ^, 15-dihydroxy-9-oxo-15,16-
tetramethylene-17,18,19,20-tetranor-13-
trans-prostenic acid
nat (and ent) ~ 9-oxo-15,16-tetramethylene
17,18,19,2O-tetranor-15,13-trans-prosta-
dienic acid (-) _W.

(") = Inhibition

(+) - No inhibition

CO cn

TABLE A

In vitro inhibition of platelet aggregation

link Adenosine diphosphate 25th 2.5 '0.25 Kollaaen 25th 2.5 ⁷ O, 25 nat (and ent) -9oi / ß-cyano, 15-hydroxy-9-oxo-
15,16-tetramethylene-17,18,19,20-tetranor-
5-cis-13-trans-prostadic acid
nat (and ent) -9tf, 15-dihydroxy-ll-oxo-lS, -
16-tetramethylene-17,18,19,20-tetranor-
13-trans, 5-cis-prostadic acid
ess
onate (and ent) -9CK, 11,15-trihydroxy-15,16-
^ etramethylene-l ?, 18,19, 20-tetranor-13-
^ trans-5-cis-prostadic acid Active ingredient concentration / Ug / ml (-) <-, «♦> Active ingredient concentration, nq / ml <-) "> 250 250

■ »» »(-) = inhibition

o (+) = no inhibition

Recent research has shown that the prostaglandins E "during the caused by various means Platelet aggregation formed from arachidonic acid. It has also been shown that cycioendoperoxides, which during

the conversion of arachidonic acid into PGE "and PGF" . as regulators of platelet aggregation may be more important - PGE, as well as other nonsteroidal anti-inflammatory agents that inhibit prostagiandin synthease, are effective inhibitors of platelet aggregation. Studies in which arachidonate

administered intravenously to rabbits or intraarterially to rats have shown that in vivo administration of arachidonate is also related to platelet aggregation in the microvessels of the lungs and brain "

Thus, the analog prostaglandin derivatives of PGE "

or the cycloendoperoxides and drugs that contain the cyclooxygenase enzyme inhibit. Active ingredients against platelet aggregation and against thrombosis.

The compounds according to the invention inhibit the through Administration of arachidonate to mice caused respiratory depression when treated with the help of the following Procedures examined.

Male albino mice of the Swiss strain, weighing around 20 g, are divided into control groups and groups,

which are treated with the active ingredients, each comprising 4 to 6 mice, which are kept fasted. The one with the mice to be treated with drugs are administered 50, 25, 10 or 1 mg / kg of the compound to be tested as a suspension in 0.5, 0.25 or 0.10 ml of a 2% starch solution. The control animals are only treated with the

Treated starch solution. After 2 hours, all mice are administered intravenously via the tail vein a dose of 50 mg / kg sodium arachidonate in one volume

809841/0791

of 0.2 ml. Then the effect and duration of respiratory depression and recovery or death are observed. The percent inhibition of respiratory depression is calculated from the mean of each drug-treated group and the mean of the control group. Compounds which give an inhibition of 30% or more at a dose of 25 mg / kg or less are referred to as active. The results of this study obtained with representative compounds according to the invention are in the

Table B below summarizes.

09841/0791

TABLE B.

In vivo inhibition of respiratory depression

link

Percent inhibition mg / kg 10 mg / kg 1 mg / kg

nat (and ent) -Ιδ-ΗγαΓΟχγ-θ-οχο-Ιδ, 16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat (and ent) -llc (, 15 - dihydroxy-9-oxo-15,16-tetramethylene ~ 17,18,19,20-tetranor-5-cis, 13-trans-prostadic acid

nat (and ent) -9-oxo-15,16-tetramethylene-17 , 18,19,20-tetranor-15,13-trans-prostadic acid

33

CaJ CD

AH6

The compounds of the invention are also potent hypotensive Means and their prostaglandin-like hypotensive effect is demonstrated by the following research methodThis Method is a modification of the method used by Pike et al. (Prostaglandins, Nobel Symposium 2, Stockholm, June 1966, p. 165) described technique.

Male rats of the Wistar tribe (Royal Har Farms) with an average weight of about are attached 250 g in the supine position with the help of linen vests and elastic bandages on rat boards. The animals are then anesthetized by the intraperitoneal administration of 900 mg / kg urethane. Then the left carotid artery is cannulated with a polyethylene tube (50) to reduce the arterial blood pressure measure while inserting into the left external jugular vein Insert polyethylene tubing (50) to infuse the drug. The animals are left during Balance for 15 to 30 minutes. The compounds to be examined are then infused into 0.5 ml of a saline solution for 1 minute at the specified dose, including an infusion pump (Harvard Model 94O) and a 6 ecm injection syringe used at speed 5. Each dose of active ingredient is flushed in with 0.4 ml of saline solution. then is determined using a Statham Model P23Db Pressure transducer and recorder (Brush Model 260 Recorder) the mean arterial blood pressure before and after drug administration. the percentage decrease in mean arterial blood pressure and the duration of a decrease of at least Io%, the by representative representatives of the compounds according to the invention are listed in Table C below.

809841/0791

TABLE C

Hypotensive effect

link dose
mg / kg Number of d.
animals Percentage min
change d. middle
Arterial blood pressure Duration of a blood
pressure reduction
by at least IO % nat-15S, 16R (and ent-15R, 16S) -lltf, 15-Dihy-
droxy-9-oxo-15,16-trimethylene-13-trans-
5-cis-prostadic acid and nat-15R, 16S-
(and ent-15S, 16R) -IW, 15-dihydroxy ~ 9-oxo-
15,16 ~ trimethylene-13-trans-5-cis-prosta-
dienic acid 1.7 3 - 47 > 10 o nat (and ent) -lltf, 15-dihydroxy-9-oxo-15, -
co 16-tetramethylene-17,18,19,20-tetranor-
⁰⁰ , 13-trans-prostenic acid 2.1 2 - 39 16 - »nat (and ent) -IS-Hydroxy - ^ - oxo-IS, -
"* · 'Lö-tetramethylene-l ?, 18,19, 20-tetranor-
°> 13-trans-prostenic acid 1.8 3 - 9 4th to, nat (and ent) -lltf, 15-dihydroxy-9-oxo-
- »J.5,16-tetramethylene-17,18,19, 20-tetra-
nor-5-cis-13-trans-prostadic acid 2.2 2 - 31 23 nat-15S, 16R (and ent-15R, 16S) -15-hydroxy-
9-OXO-15, lö-trimethylene-lS-trans-prosten-
acid and nat-15R, 16S (and ent-15S, 16R) -
15-hydroxy-9-oxo-15,16-trimethylene-13-
trans-prostenic acid 2.0 2 - 38 4th nat-15S, 16R (and ent-15R, 16S) -15-hydroxy-
9-OXO-15, lö-trimethylene-lS-trans-prosten-
acid ethyl ester and nat-15R, 16S (and
15S, 16R) -15-hydroxy-9-oxo-15,16-trim-
ethylene-13-trans-prostenic acid ethyl ester 1.9 2 - 18th 7 00
Ca)

TABLE C (port setting)

O
CXI
00

link dose
mg / kg Number of d.
animals Percentage min
change d
Arterial blood pressure Duration of a blood
pressure reduction
by at least IO% nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-
9-OXO-15, lö-trimethylene-lS-trans-prosten-
acid ethyl ester 4.0 2 -16 4th nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-
9-OXO-15, Lö-trimethylene-IS-trans-pro-
stenic acid ethyl ester 1.6 2 -43 5 nat-15S, 16R- (and ent-15R, 16S) -9tf, 11 <Χ, 15-
Trihydroxy-15, Lö-trimethylene-IS-trans-S-
cis-prostadic acid and nat-15R, 16S- (and
ent-15S, 16R) -9c (, llo (, 15-trihydroxy-15,16-
trimethylene-lS-trans-B-cis-prostadiene-
acid 2.2 2 -12 4th nat- (and ent) -9o (, 15-dihydroxy-ll-oxo-IS, -
16-tetramethylene-17,18,19,29-tetranor-13-
trans-5-cis-prostadic acid 2.1 4th -29 > 20

CaJ CD

The compounds of the invention are also useful Bronchodilators and can therefore be used effectively to treat asthma.

The bronchodilator effect is determined in guinea pigs, in which one can obtain by intravenous injection of 5-hydroxytryptamine, histamine or acetylcholine according to the Konzett method (see J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung 18 (1968) 995) causes bronchospasm. In Table D below, the bronchodilator effect of representative compounds according to the invention against one or more of the three spasmogenic agents is given as ED ₅₀ , which value is calculated from the results obtained with three logarithmic cumulative intravenous doses.

8098A1 / 0791

TABLE D Bronchodxlative Effect

οσ ο co

link ED, - _n> mg / kg 5-hydroxytryptamine histamine Acetylcholine nat-15S, 16R (and ent-15R, 16S) -HOC, 15-Dihy ~
droxy-9-oxo-15, Lö-trimethylene-IS-trans-S-
cis-prostadic acid and nat-15R, 16S- (and
ent-15S, 16R) -110t, 15-dihydroxy-9-oxo-15, -
le-trimethylene-lS-trans-S-cis-prostadien-
acid
nat- (and ent) -hol / 15-dihydroxy-9-oxo-15, -
16-tetramethylene-17,18,19,20-tetranor-13-
trans-prostanoic acid
nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-
9-OXO-15, lo-trimethylene-lS-trans-prosten-
acid
nat-15R, 16R- (and ent-15S, 16S) -15, hydroxy-
9-OXO-15, lö-trimethylene-lS-trans-prosten-
acid
nat- (and ent) -15-hydroxy-9-oxo-15,16-te-
tramethylene-17,18,19,2Q-tetranor-13-trans-
5-cis, 10-prostatrienoic acid
nat- (and ent) -11, 15-dihydroxy-9-oxo-l, 5-
16-tetramethylene-17,18,19,20-tetranor-5-
cis, 13-trans-prostadic acid 576 χ 1O " ⁹
57 χ 1O ~ ⁶
112 χ 10 " ⁶
18 χ 1O " ⁸
> 3.2 χ 1O ~ ³
58.7 χ 10 ~ ⁶ 648 χ 10 ~ ⁹
7.69 χ 1O ~ ⁶
25.8 χ 10 ~ ⁶
2.07 χ 10 ~ ⁶
632 χ 1O ~ ⁶
32.8 χ 10 " ⁶ 56.6 χ 1O ~ ⁶
413 χ 1O ~ ⁶
43 χ 10 ~ ⁶
> 3.2 χ 10 ~ ³
115 χ 1O ~ ⁶

INJ 00

TABLE D (continued)

link

5-hydroxytryptamine

ED ₁ - _0.0 mg / kg

histamine

Acetylcholine

CD O CO OO

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-13-trans-prostenic acid and nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-IS-trans-prostenic acid

nat-15S, 16R- (and ent-15R, 16S) -11 «*, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadic acid and nat-15R, 16S- (and ent-15S, 16R) -11 *, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadienoic acid

nat- (and ent) -IW, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetra nor-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15, Lö-trimetliylen-lS-tr ans-pros acidic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-13-trans-prostenic acid

320 χ 10

576 χ 10

57 x 10

112 χ 10

18 χ 10

666 χ

-9

648 χ

-9

7.69 χ

-6

25.8 x

-6

2.07 χ

-6

56.2 χ

3.2 χ

56.6 χ

413 χ 10 '

-6

43 χ

-6

TABLE D (continued)

link

5-hydroxytryptamine

ED ₅₀ , mg / kg

histamine

Acetylcholine

O CO OO

nat- (and ent) -9 <X, 15-dihydroxy-11-oxo-15,16-tetramethylene-17,18,19-20-tetranor-13-trans, 5-cis-prostadic acid

Nat- (and ent) -9oc / β-cyano, 15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid

nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans, 5-cis, 10-prostatrienoic acid

253 χ 10

-6

1.8-1 χ 10

-3

> 3.2 χ 10

;> 3.2 χ 10

-3

χ 10

-6

χ 10

-6

> 3.2 x 10 '

2.74 χ 10

> 3.2 χ 10

The invention is explained in more detail below with reference to the following examples.

example 1

trans -1-hydroxy-2- (3-trifluoromethyl) phenoxycyclopentane.

A mixture of 88 g of cyclopentene oxide, 150.7 g is stirred

3-Trifluormethy! Phenol, 5.0 g of sodium hydroxide in 30 ml of water and 4.0 g of methyl tricaprylyl ammonium chloride while 51 hours at 70 to 80 ⁰ C and during 96 hours at 25 ° C. The mixture is then diluted with methylene chloride and poured into

Water. Wash the organic layer with dilute sodium hydroxide and water, the solution dried over magnesium sulfate, the solvent is stripped off to give 221.5 g of a liquid which is distilled (bp ^ _o = 11O-113 ° C)

U, ο

and receives trans-1-hydroxy-2- (3-trifluoromethyl) -phenoxycyclopentane.

Example 2

The procedure described in Example 1 is used to prepare trans-1-hydroxy-2- (4-fluoro) phenoxycyclopentane from 4-fluorophenol and cyclopentane epoxide.

Example 3

The procedure of Example 1 is used to prepare from 3-chlorophenol and cyclopentane epoxide trans-1-hydroxy-2- (3-chloro) phenoxycyclopentane.

Example 4 2- (3-trifluoromethylphenoxy) cyclopentanone.

To a suspension of 327.43 g of pyridinium chlorochromate in

809841/0791

1 liter of methylene chloride is added to 220 g of trans-1-hydroxy-2- (3-trifluoromethylphenoxy) cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours and 15 minutes. A further 50 g of the oxidizing agent are then added and the mixture is stirred for 41/2 hours. The mixture is then diluted with ether and decanted from a black residue, which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is then drawn off, the residue is dissolved in ether, filtered again through silica gel, the solvent is drawn off and the residue is distilled (boiling point _{1 ς} = 113-116 ° C.), with

188 g of 2- (3-trifluoromethylphenoxy) cyclopentanone are obtained. Example 5

Following the procedure of Example 4 is prepared from the Product of Example 2 2- (4-fluorophenoxy) cyclopentanone.

Example 6

Following the procedure of Example 4 is prepared from the Product of Example 3 2- (3-chlorophenoxy) cyclopentanone.

Example 7

IR, 2S- (and IS, 2R) -l-ethynyl-1-hydroxy-2-butyl-cyclopentane and IR, 2R- (and IS, 2S) -l-ethynyl-1-hydroxy-2-butyl-cyclopentane.

Purified acetylene is passed into 150 ml of dry tetrahydrofuran and adds 92 ml of a 2.4m n-butyl magnesium chloride solution dropwise with stirring over the course of 2 hours to. To the resulting solution of acetylene magnesium chloride 21 g of 2-butylcyclopentanone are added dropwise over 15 minutes in 50 ml of tetrahydrofuran. One stirs them

809841/0791

A5 * 4

Mix for 30 minutes and then pour it into an ice-cold, saturated ammonium chloride solution. The mixture is acidified to a pH of 5 and extracted with ether. The ethereal solution is washed with salt solution and dried over Magnesium chloride, removes the ether and distills the

Residue, 14.8 g of a colorless liquid being obtained. The liquid is chromatographed on a dry column filled with silica gel, using a benzene / ethyl acetate mixture (19/1) eluted to separate the isomers-

ne, where IR, 2S (and IS, 2R) -l-ethynyl-1-hydroxy-2-butylcyclopentane and IR, 2R (and IS, 2S) l-ethynyl-l-hydroxy-2-butylcyclopentane receives.

Example 8
l-propargyl-l-hydroxy-cyclohexane.

A stirred suspension of 121.6 g (5.0 mol) is treated

Magnesium in 1 l of anhydrous ether with 0.6 g of mercury (II) chloride and about 100 mg of iodine. After a few minutes, 3 ml of propargyl bromide are added and then, if there is no exothermic reaction it can be determined that a small amount of reactive propargyl bromide and magnesium in ether are added. If the When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at such a rate that the solution refluxes violently. (The propargyl bromide must always be

sem excess must be present, otherwise the reaction will stop. When this happens, about 1 ml of propargyl bromide can be added start the reaction again.) After about half of the propargyl bromide / cyclohexanone mixture has been added, a further 500 to 750 ml are added

: 0 to the reaction mixture in order to dilute it. After expiration

After the addition, the reaction mixture is heated to reflux for at least 1/2 hour, cooled and poured in

809841/0791

A55

vigorous stirring in 4 l of a saturated ammonium chloride solution. Then you separate the ethereal layer, wash it aqueous layer several times with ether, the combined extract was washed twice with saturated sodium chloride solution and dry over anhydrous magnesium sulfate. By evaporation of the ether, 583 g (theory = 630 g) of a dark oil are obtained, which is converted into purified 1-propargyl-1-hydroxycyclohexane distilled.

Examples 9 to 26b

The acetylenic compounds shown in Table I below are prepared in the manner described in Examples 7 and 8 Alcohols based on the acetylene Grignard reagent and the ketone, which are also given in the table «

80 9841/0791

TABLE I.

example Grignard reagent Ketone Acetylenic alcohol 9 Acetylene magnesium chloride Cyclohexanone 1-ethynyl-1-hydroxycyclohexane 10 Acetylene magnesium chloride Cyclopentanone 1-ethynyl-1-hydroxycyclopentane 11 Acetylene magnesium chloride Cycloheptanone 1-ethynyl-1-hydroxycycloheptane 12th Acetylene magnesium chloride 3-propylcyclopenta-
non IR, 3S- (and IS, 3R) -1-ethynyl-l-
hydroxy-3-propycyclopentane 13th Acetylene magnesium chloride 3-propylcyclopenta-
non IR, 3R- (and IS, 3S) -lethynyl-1-
hydroxy-3-propylene cyclopentane 14th Acetylene magnesium chloride 2-butylcyclohexanone IR, 2S- (and IS, 2R) -1-ethynyl-l-
hydroxy-2-butycyclohexane 15th Acetylene magnesium chloride 2-butylcyclohexanone IR, 2R- (and lS, 2S) -l-ethynyl-l-
hydroxy-2-butylcyclohexane 16 Acetylene magnesium chloride 2- (3-trifluoromethyl-
phenoxy) cyclopenta
non IR, 2S- (and 1S, 2R) -1-ethynyl-1-
hydroxy-2- (3-trifluoromethylphene
oxy) cyclopentane 17th Acetylene magnesium chloride 2- (3-trifluoromethyl-
phenoxy) cyclopenta
non IR, 2R- (and lS, 2S) -l-ethynyl-l-
hydroxy-2- (3-trifluoromethylphene
oxy) cyclopentane 18th Acetylenemagnesium chloride 2- (4-trifluorophen
oxy) cyclopentanone IR, 2S- (and IS, 2R) -1-ethynyl-l-
hydroxy-2- (4-fluorophenoxy) cyclo
pentane 19th Acetylene magnesium chloride 2- (4-fluorophenoxy) -
cyclopentanone IR, 2R- (and IS, 2S) -1-ethynyl-l-hy-
hydroxy-2- (4-fluorophenoxy) cyclopentane 20th Acetylene magnesium chloride 2- (3-chlorophenoxy) -
cyclopentanone IR, 2S- (and IS, 2R) -1-ethynyl-l-hy-
hydroxy-2- (3-chlorophenoxy) cyclopentane 21st Acetylene magnesium chloride 2- (3-chlorophenoxy) -
cyclopentanone IR, 2R- (and IS, 2S) -1-ethynyl-l-hy-
hydroxy-2- (3-chlorophenoxy) cyclopentane

TABLE I (port setting)

example Grignard reagent Ketone Acetylene, like alcohol 22nd Ethylene Magnesium Chloride 3-methylcyclohexanone IR ₇ 3S- (and IS, 3R) -1-ethynyl-1-hy-
hydroxy-3-methylcyclohexane '23 Acetylene magnesium chloride 3-methylcyclohexanone IR, 3R- (and IS, 3S) -! - ethynyl-1-hy-
hydroxy-3-methylcyclohexane 24 Propargyl magnesium bromide 2-butylcyclopentanone IR, 2S- (and IS, 2R) -1-propargyl-l-
hydroxy-2-butylcyclopentane 25th Propargyl magnesium bromide 2-buty / cyclopentanone IR, 2R- (and lS, 2S) -l-propargyl-l-
hydroxy-2-butylcyelopentane 26th Propargylmagne s i umbromi d 2- (3-trifluoromethyl-
phenoxy) cyclopentanone IR, 2S- (and IS, 2R) -1-propargyl-1-
hydroxy-2- (3-trifluoromethylphenoxy) -
cyelopentan 26 b Propargyl magnesium bromide 2- (3-trifluoromethyl-
phenoxy) cyclopentanone IR, 2R- (and lS, 2S) -l-propargyl-l-
hydroxy-2- (3-trifluoromethylphenoxy) -
cyelopentan

OO IN) CD

/ 158

Example 28 a

1R, 2S (and IS, 2R) -l-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

^{24.1 g are added at 0} ° C. with stirring to a solution of 29.4 g of IR, 2S- (and IS, 2R) -1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazole in 180 ml of dimethylformamide Trimethylsilyl chloride. The mixture is stirred for 3 hours, then poured into 700 ml of hexane and washed twice with water and once with salt solution. The ethereal solution is then dried over magnesium sulfate, the solvent is drawn off and the residue is distilled (bp _A = 64-72 ° C ), 35.8 g of IR, 2S (and IS, 2R) -1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane being obtained.

Example 28 b

IR, 2R- (and IS, 2S) -l-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

36.9 g of trimethylsilyl chloride are added to a mixture of 45, Og IR, 2R- (and IS, 2S) -1-ethynyl-1-hydroxy-2-butylcyclopentane and 46.2 g of imidazole in 255 ml of dimethylformamide under nitrogen at ^{0 ° C.} . The mixture is stirred for 3 hours at room temperature, then poured into 700 ml of hexane, water is added, the organic layer is separated off, the aqueous layer is extracted with hexane, the combined hexane solutions are washed twice with water, dried over magnesium sulphate, and then extracted The solvent is removed and the residue is distilled to give 53 g of the product in the form of a colorless oil.

809841/0791

Example 28 c 1-Ethynyl-1-trimethylsilyloxy-cyclohexane.

194 g of imidazole and 158.2 g of 1-ethynylcyclohexanl-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath.

Then, while cooling and stirring, 152 g of methylchlorosilane are added in the course of about a minute, and the mixture is stirred during 1 hour and then let it stand overnight. Then 1 l of hexane is added, the lower layer is separated off and diluted with Water and extracted with hexane. The hexane layers are washed several times with water, combined and dried over Magnesium sulphate, filtered, the hexane evaporated to give 198.5 g of a product which is distilled to yield 168 g of the desired product.

Example 28 d 15 1-propargyl-1-trxmethylsilyloxy-cyclohexane.

To a stirred solution of 55.4 g of 1- (2-propyn-l-yl) cyclohexanol (H. Gutmann et al. HeIv. Chim. Acta 42 (1959) 719) and 79 g of imidazole in 240 ml of dimethylformamide are added 10 ° C in the course of 10 minutes 56 ml of chlorodimethylsilane.

The cloudy yellow solution is stirred for 26 hours at room temperature and the mixture obtained is partitioned between 1000 ml of hexane and 400 ml of water at 0 to 5 ° C, the hexane phase washes successively with 6 χ 200 ml of cold water and 200 ml of saline solution, dry the extract over magnesium sulfate, filter, evaporate and obtain 85 g of a colorless Liquid. IR spectrum (film): 1240 and 830 cm (trimethylsilyloxy group).

809841/0791

/ toO

Example 29 a

IR, 2S- (and IS, 2R) -1- (trans-2-iodovinyl) -1-trimethylsilyloxy-2-butyl-cyclopentane.

To a mixture of 9.2 g of sodium borohydride and 45.8 g of 2-methyl

5 2-butene in 350 ml of dry tetrahydrofuran is added with stirring and under nitrogen at ⁰ ° C. in the course of 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, the resulting solution of diisoamylborane is added over the course of 20 minutes with 38.8 g of IR, 2S- (and IS, 2R) -1-ethynyl-l-trimethylsilyl-

10 oxy-2-butylcyclopentane and 40 ml of tetrahydrofuran. The mixture is stirred for 2 hours and then kept overnight
at -20 ⁰ C, then allowed to warm ⁰ ° C, and are at ⁰ ° C 85 g of dry trimethylamine oxide in portions in the course of 20 minutes. After stirring for 1 hour

at 25 ° C., the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g ■ Iodine in 250 ml of tetrahydrofuran in a stirred cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the organic layer is separated, ex-

20 extracts the aqueous layer with ether, washes the combined organic solutions twice with a saturated sodium thiosulphate solution, once with a saline solution, dry the solution over magnesium sulfate, strip off the solvent and dissolves the residue in hexane. The hexane solution is filtered

over diatomaceous earth and silica gel, the hexane is drawn off and the residue is purified by dry column chromatography over silica gel, eluting with hexane, giving 45.35 g of IR, 2S- (and IS, 2R) -1- (trans-2-iodovinyl) -1-trimethylsilyloxy-2-butyl-cyclopentane receives.

809841/0791

Example 29 b

IR, 2R- (and IS, 2S) -1- (trans-2-iodovinyl) -1-trimethylsilyloxy-2-butylcyclopentane.

To a mixture of 12.22 g of sodium borohydride and 60.82 g of 2-methyl-2-butene in 450 ml of tetrahydrofuran is added dropwise 54.6 ml of boron trifluoride etherate over 20 minutes at 0 ° C. under nitrogen. The solution is stirred for 2 hours at ⁰ ° C. and then for 30 minutes at room temperature. The solution is cooled to 0 ° C. and 55.5 g of IR, 2R- (and IS, 2S) -l-ethynyl-1-trimethylsilyloxy-2-butyl-cyclopentane in 50 ml of tetrahydrofuran are added. The mixture is left to stand overnight in a cold room, ^{112.8 g of trimethylamine oxide are then added to it at 0} ° C. with stirring over the course of 20 minutes, the mixture is stirred for 90 minutes at room temperature and filtered. A solution of 565 g of sodium hydroxide in 2000 ml of water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran are added to the filtrate at the same time. The mixture is stirred for 30 minutes, the organic layer is separated off and the aqueous layer is extracted with ether.

The combined organic solutions are washed with saturated sodium thiosulphate solution and with saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered through a layer of silica gel. One draws the solvent and an orange-colored liquid is obtained, which is chromatographed over a dry silica gel column, with 59.5 g of product are obtained in the form of a yellow liquid.

Example 3O

1- (3-tri-n-butylstannyl-2-trans-propenyl) -l-trimethylsilyloxycyclohexane.

To a stirred mixture of 31.5 g of 1-propargyl-l-trimethyl-

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ActL

silyloxy-cyclohexane and 150 mg of azobisisobutyronitrile are added to 41 ml of tri-n-butyltin hydride. Heat the stirred mixture to about 80 ⁰ C. The initial exothermic reaction is slowing down, whereupon then the temperature is maintained for 1 hour at 130 to 135 ° C. The product is distilled and 56 g of a colorless liquid are obtained (bp _1E -., = 150-16O ⁰ C), NMR spectrum (CDCl _J: £ 6.0 (multiplet, vinyl proton).

Examples 31 to 50

Using the methods described in Examples 28a, b, c and d above The procedures given are converted to the acetylenic alcohols given in Table II below into their corresponding acetylenic trimethylsilyloxy derivatives, which in turn are converted using those in the above Examples 29a and 29b in the procedures given corresponding trans-2-iodovinyl derivatives or using the method given in Example 3 in their corresponding trans-2-tri-n-butylstannyl derivatives are converted (Table II).

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TABLE II

example Acetylene derivative
of example Procedure according to
example Iodine vinyl compound or vinyl tin compound 31 9 29 1- (trans-2-iodovinyl) -l-trimethylsilyloxy-cyclo-
hexane 32 10 29 1- (trans-2-iodoviny1) -l-trimethylsilyloxy-cyclo-
pentane 33 11 30th 1- (trans-2-tri-n-butylstannylvinyl) -1-trimethyl-
silyloxy-cycloheptane OO 34 12th 29 IR, 3S- (and IS, 3R) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-3-propylcyclopentane O
(O
09 35 13th 29 IR, 3R- (and IS, 3S) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-3-propylcyclopentane - » 36 7th 29 IR, 2R- (and IS, 2S) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-2-butylcyclopentane O
^ J
<o 37 14th 29 IR, 2S- (and IS, 2R) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-2-butylcyclohexane ~ * 38 15th 29 IR, 2R- (and IS, 2S) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-2-butylcyclohexane 39 16 30th IR, 2S- (and IS, 2R) -I- (trans-2-tri-n-butylstannyl-
vinyl) -l-trimethylsilyloxy-2- (3-tri ^ fluoromethyl-
phenoxy) cyclopentane 40 17th 30th IR, 2R- (and IS, 2S) -1- (trans-2-tri-n-butylstannyl-
vinyl) -l-trimethylsilyloxy-2- (3-trifluoromethyl-
phenoxy) cyclopentane 41 18th 29 IR, 2S- (and IS, 2R) -1- (trans-2-iodovinyl) -1-trimethyl- ^
silyloxy-2- (4-fluorophenoxy) cyclopentane ^ j 42 19th 29 IR, 2R- (and IS, 2S) -1- (trans-2-iodovinyl) -1-trimethyl- CO
silyloxy-2- (4-fluorophenoxy) cyclopentane ¹ ^
CD

TABLE II (Porting)

example 43 Acetylene derivative
of example Procedure according to
example Iodine vinyl compound or vinyl tin compound 44 20th 30th IR, 2S- (and IS, 2R) -I- (trans-2-tri-n-butylstannyl-
vinyl) -l-trimethylsilyloxy-2- (3-chlorophenoxy) -
cyclopentane 45 21st 30th IR, 2R- (and IS, 2S) -1- (trans-2-tri-n-butylstannyl-
vinyl) -l-trimethylsilyloxy-2- (3-chlorophenoxy) -
cyclopentane 46 22nd 29 IR, 3S- (and IS, 3R) -1 (trans-2-iodovinyl) -1-trimethyl-
silyloxy-3-methylcyclohexane OO
O
CO 47 23 29 IR, 3R- (and IS, 3S) -1- (trans-2-iodovinyl) -1-trimethyl-
silyloxy-3-methylcyclohexane OO
* · »
_ * 48 24 30th IR, 2S- (and IS, 2R) -1- (3-tri-n-butylstannyl-2-trans-
propenyl) -1-trimethylsilyloxy-2-butylcyclopentane O 49 25th 30th IR, 2R- (and IS, 2S) -1- (3-tri-n-butylstannyl-2-trans-
propenyl) -1-trimethylsilyloxy-2-butylcyclopentane (O
_ » 50 26th 30th IR, 2S- (and IS, 2R) -1- (3-tri-n ~ butylstannyl-2-trans-
propenyl) -l-trimethylsilyloxy-2- (3-trifluoromethyl-
phenoxy) cyclopentane 27 30th IR, 2R- (and IS, 2S) -1- (3-tri-n-butylstannyl-2-trans-
propenyl) -l-trimethylsilyloxy-2- (3-trifluoromethyl-
phenoxy) cyclopentane

Example 51

2- (6-Carbotrimethylsilyloxy-hex-2-cis-enyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1 g of 2- (6-carboxy-hex-2-cis-enyl) -4-hydroxy-cyclopent-2-en-one 3.3 ml of hexamethyldisilazane are added to 12.5 ml of dry pyridine under argon at 15 ° C. and with stirring (HMDS) followed by the dropwise addition of 1.6 ml trimethylchlorosilane (TMCS). One stirs the formed Mixture for 1 hour at room temperature and then evaporate to dryness (vacuum pump). You take the residue with hexanes and filter through a filter aid (Celite). Evaporation of the mother liquor followed by evaporation twice with toluene gives 1.5 g (96%) pure 2- (δ-Carbotrimethylsilyloxy-hex-1-cis-enyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

Example 52

2- (δ-carbotrimethylsilyloxy-hexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1 g of 2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-l-one 3.3 ml of hexamethyldisilazane are added to 12.5 ml of dry pyridine at 15 ° C. under argon and with stirring followed by the dropwise addition of 1.6 ml of trimethylchlorosilane. The mixture obtained is stirred for 1 hour at room temperature and then concentrated to dryness the residue with hexane, filtered through diatomaceous earth, evaporated the mother liquor and obtained after evaporation twice with toluene the pure product.

8098A1 / 0791

Example 53

2- (6-Carbomethoxy-hexyl) -4- (R) -trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1.0 g of 2- (6-carbomethyl-hexyl) -4- (R) -hydroxy-cyclopent-2-en-1-one (R. Pappo et al., Tetrahedron Letters (1973) 943) in 12.5 ml of dry pyridine is added at 15 ° C under argon and with stirring 3.3 ml (24 mmol) of hexamethyldisilazane (HMDS), followed by the dropwise addition of 1.6 ml (2O.5 mmol) of trimethylchlorosilane (TMCS). Man

LO stirs the mixture obtained for 1 hour at room temperature and then concentrated to dryness (vacuum pump). The residue is taken up in hexane and filtered through a filter aid (Celite). Evaporation of the mother liquor followed by evaporation twice with toluene gives 2- (6-carbo-

.5 methoxy-hexyl) -4- (R) -trimethylsilyloxy-cyclopent-2-en-1-one.

Example 54

2- (6-Carbomethoxyhexyl) -4- (S) -trimethylsilyloxy-cyclopent-2-en-1-one.

Following the procedure of Example 239, the title compound is obtained by treating 2- (6-carbomethoxyhexyl) -4- (S) -hydroxycyclopent-2-en-1-one (R. Pappo et al., Tetrahedron Letters (1973) 943) with hexamethyldisilazane and trimethylsilyl chloride.

Example 55
5-chloro-1- (2-furyl) -1-pentanol.

To a stirred suspension of 2-furyllithium (which can be obtained from 0.53 mol of n-butyllithium and 39.5 g of furan according to the process

as described in J. Org. Chem. 27 (196 2) 1216) in 350 ml of ether and approx. 200 ml of hexane are added at -78 ° C. in the course of 25 minutes to a solution of 57.9 g 5-chloropentanol (Chemical Abstracts 59 (1963) 7579 f) in 80 ml of ether. The mixture is warmed to OC for 20 minutes, stirred for 15 minutes at OC and then treated with 140 ml of a saturated ammonium chloride solution. The ether phase is washed with water and salt solution, dried over a magnesium sulfate-potassium carbonate mixture and concentrated to a liquid. Nuclear Magnetic Resonance Spectrum (CDCl3,): 6 "3.59 (triplet, CH ₂ Cl ₂ ) and 4.70 (triplet, CH ₂ CHOH).

Example 56

5- (carbathoxymethylthio) -1- (2-furyl) -1-pentanol.

To a stirred, refluxed mixture of 76 g of mercaptoessoxylate ethyl ester, 79.5 g of 5-chloro-1- (2-furyl) -1-pentanol (Example 55) and 10 ml of a 1.5 M sodium ethylate solution in ethanol are added over the course of 15 minutes 3OO ml of the 1.5m sodium ethylate solution. The mixture obtained is stirred under reflux for 3 hours and cooled and narrow to withdraw most of the ethanol.

The residue is then distributed between ether and water, the ether phase is washed with salt solution, dried over potassium carbonate, the solution is concentrated, diluted with xylene and concentrated again, an oil being obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): <f 3.24 (singlet, -S-CH ₂ CO ₂ C ₂ H ₅ ) and 4.7O (triplet, CH ₂ CHOH).

Example 57

2- (6-Carboxy-5-thia-hexyl) - ^ - hydroxy-cyclopent ^ -en-l-one.

A solution of 125 g of 5- (carbathoxymethylthio) - is heated

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1- (2-furyl) -1-pentanol (Example 56), 22.4 g of sodium formate, Boil 250 ml of formic acid and 400 mg of hydroquinone in 2000 ml of dioxane and 1330 ml of water while stirring for 20 hours at reflux.

5 The solution, which contains crude 3-hydroxy-2- / I- (carbäthoxymethylthio) -butyl7-cyclopent-4-en-l-one, is cooled and treated for 10 minutes with 75 ml of sulfuric acid (d = 1.84). The solution is heated with stirring
reflux for 16 hours, cools, saturates

■ jQ with sodium chloride and extracted with ethyl acetate.
The extract is washed with brine, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel using chloroform, which is progressively enriched with ether, with ether and with ether, the

it is progressively enriched with acetone to give the title compound in the form of an oil. Nuclear Magnetic Resonance Spectrum (CDCl3-): £ 3.24 (singlet, -S-CH ₂ -CO ₂ C ₂ H ₅ ), 5.0 (broad singlet -CHOH-).

Example 58

2- (o-Carbotrimethylsilyloxy-S-thia-hexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a stirred solution of 28.4 g of 4-hydroxy-2- / 4 * -carboxy-

methylthio) butyl7-cyclopent-2-en-l-one (example) and

76 ml of hexamethyldisilazane in 330 ml of pyridine are added in the

run for 5 minutes at 5 ° C. 38 ml of chlorotrimethylsilane. The mixture is stirred for 3.5 hours at room temperature, then for 5 minutes at 45 ° C. and then evaporated to remove the solvent. The residue is stirred with 1000 ml of petroleum ether and filtered. The filtrate is treated with activated charcoal, filtered, the filtrate is concentrated with the aid of toluene and a liquid is obtained. NMR spectrum (CDCl ₃ ): <fo, 18 (singlet, trimethylsilyloxy group) and

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0.28 (singlet, trimethylsilyloxycarbonyl group).

Example 59

4-chloro-1- (2-furyl) -1-butanol.

To a stirred suspension of 2-furyllithium (which has been prepared from 0.53 mol of n-butyllithium and 39.5 g of furan by the procedure described in J. Org. Chem. 27 (1962) 1216) in 35Ο ml Ether and about 200 ml of hexane. a solution of 57.9 g of 4-chlorobutanol (Chemical Abtracts 59 (1963) 7579 f) in 80 ml of ether is obtained at -78 ° C. in the course of 25 minutes. The mixture is warmed to ⁰ ° C. for 20 minutes, stirred at 0 ° C. for 15 minutes and then treated with 140 ml of saturated ammonium chloride solution. The ether phase is washed with water and salt solution, dried over a magnesium sulfate / potassium carbonate mixture and concentrated to a liquid. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): <$ "3.59 (triplet, CH ₂ Cl) and 4.70 (triplet, CH ₂ CHOH).

Example 6O

4- (carbethoxymethylthio) -1- (2-furyl) -1-butanol.

To a mixture of 76 g of ethyl mercaptoessxgate, 79.5 g of 4-chloro-1- (2-furyl) -1-butanol (Example 59) and 10 ml of 1.5M sodium ethylate, boiling under reflux with stirring. solution in ethanol is added in the course of 15 minutes a further 300 ml of the 1.5m sodium ethylate solution. The mixture obtained is stirred under reflux for 3 hours, cooled and concentrated in order to remove most of the ethanol. The residue is partitioned between ether and water, the ether phase is washed with salt solution and dried over potassium carbonate. The solution is concentrated, diluted with xylene, concentrated again and an oil is obtained. NMR spectrum (CDCl ₃ ): 6 * 3.24 (singlet,

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AlO

-S-CH ₂ -CO ₂ C ₂ H ₅ ) and 4.70 (triplet, CH ₂ CHOH).

Example 61

2- (5-Carboxy-4-thia-pentyl) ^ -hydroxy-cyclopent ^ -en-l-one.

A solution of 125 g of 4- (carbethoxymethylthio) -l- (2-furyl) -l-butanol is heated (Example 60), 22.4 g sodium formate, 250 ml of formic acid and 400 mg of hydroquinone in 2OOO ml of dioxane and 1330 ml of water for 20 hours with stirring to the boil at reflux.

The solution, the crude 3-hydroxy-2- / 3- (carbäthoxymethylthio) propyl7-cyclopent-4-en-l-one, is cooled contains, and treats it in the course of 10 minutes while stirring with 75 ml Sulfuric acid (d = 1.84). The solution is heated to reflux with stirring for 16 hours, cooled and saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate and constricts. The residue is chromatographed on silica gel using chloroform, which is progressively obtained enriched with ether, of ether and of ether, which one enriches progressively with acetone, as eluent, whereby one ι the title compound behaves in the form of an oil.

Example 62

2- (5-Carbotrimethylsilyloxy-4-thia-pentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a stirred solution of 28.4. g of 4-hydroxy-2- / 4- (carboxymethylthio) butyl7-cyclopent-2-en-1-one (example) and 76 ml of hexamethyldisilazane in 330 ml of pyridine are added in the course of time
of 5 minutes at 5 ° C. 38 ml of chlorotrimethylsilane. The mixture is stirred for 3.5 hours at room temperature while

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5 minutes at 45 ° C and then concentrated to remove the solvent. The residue is slurried with 1000 ml of petroleum ether and filtered. The filtrate is treated with
Activated charcoal, filtered, the filtrate concentrated with the help of toluene and obtained a liquid. NMR spectrum (CDCI-): c5 "0.18 (singlet, trimethylsilyloxy group) and 0.28 (singlet, trimethylsilyloxycarbonyl group).

Example 63

nat- (and ent) -lld, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-prostanoic acid.

A solution of nat- (and ent) -lic *, 15-dihydroxy-9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-13-transprostic acid is hydrogenated (800 mg) in 50 ml of ethyl acetate in a Parr apparatus using 500 mg of 5% rhodium-on-carbon. The catalyst is filtered off, the filtrate is evaporated to dryness and the title compound is obtained.

Examples 64 to 66

By hydrogenating the prostate acids given in Table III below in ethyl acetate using
of rhodium-on-carbon as a catalyst following the procedure of Example 63 gives those in Table III
indicated prostanoic acids.

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TABLE III

example 13-trans prostatic acid
of example Prostanoic acid 64 72 nat-15S, 16R- (and ent-15R, 16S) -Hof, 15-dihydroxy-9-oxo-
15,16-trimethylene prostanoic acid 65 73 nat-15S, 16S- (and ent-15R, 16R) -lltf, 15-dihydroxy-9-oxo-
15,16-trimethylene prostanoic acid 66 · 83 nat- (and ent) -llo (, 16-dihydroxy-9-oxo-16,17-tetramethylene-
18,19,20-trinor-prostanoic acid

Example 67

nat- (and ent) -llo (, 15-dihydroxy-9-oxo-15, 16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadic acid.

A solution of 1.64 g of thiophenol in 45 ml of ether is added to 6.48 ml of a 2.3m n-butyllithium solution in hexane at 0 ° C. under nitrogen. After 1 hour at ⁰ ° C., a solution of 5.85 g of tri-n-butylphosphine-copper complex in 140 ml of ether is added and the mixture is kept in the refrigerator overnight. 35 ml of a solution of tert-butyllithium are then added to a solution of 4.54 g of 1- (trans-2-iodo-vinyl) -l-trimethylsilyloxy-cyclohexane in 8 ml of toluene under nitrogen at -40 ° C. with stirring . After 90 minutes, a few ml of ether are added, the mixture is stirred for 15 minutes at room temperature, the solution is cooled again to -78 ° C., the copper solution is cooled to -78 ° C. and transferred in the form of a uniform jet into the vinyl lithium solution . The solution is stirred for 35 minutes at -78 ° C and then a solution of 5.0 g of 2- (δ-carbotrimethylsilyloxy-hex ^ -cis-enyl) 4-trimethylsilyloxy-cyclopent-2-en-1-one ( Example 51) in 10 ml of ether. The mixture is brought into a cooling bath having a temperature of -45 ° C, stirred for 3 hours and then leaves them in the course of 15 minutes, at -20 ⁰ C heat. After cooling again to -4O C, a solution of 2.0 g of acetic acid and 5 ml of ether is added. A saturated ammonium chloride solution is added followed by a small amount of dilute hydrochloric acid. The mixture is poured into ether, the aqueous layer is extracted with ether, the combined ether layers are washed with dilute hydrochloric acid, twice with water and then with saturated sodium chloride solution, the ether is dried over magnesium sulphate and the solvent is removed leaving a yellow oil. The oil is stirred for 45 minutes in 5O ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1) and

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then pour in water. The solution is extracted with ether, the ether solution is washed twice with water and once with salt solution, the solution is dried over magnesium sulfate and the solvent is stripped off. The residue is chromatographed on a dry silica gel column using ethyl acetate, which contains 1 % acetic acid, as eluent, and 2.15 g of nat- (and ent) -lltf, 15-dihydroxy-9-oxo-15,16-tetramethylene 17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid.

"0 example 68

nat- (and ent) -HO ^, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenoic acid.

To a solution of 1.01 g of thiophenol in 30 ml of ether, 4.0 ml of a 2.3M n-butyllithium ^{solution are added under nitrogen at 0 ° C. and with stirring.} The mixture is stirred for 1 hour and then a solution of 3.61 g of the copper-tri-n-butyl-phosphine complex in 85 ml of ether is added.

23 ml of 0.8m tert-butyllithium solution are added to 2.98 g of 1- (2-trans-iodovinyl) -1-trimethylsilyloxy-cyclohexane in 8 ml of toluene at -45 ° C. under nitrogen and with stirring. The mixture is stirred and cooled for a further 75 minutes. The cooling bath is then removed and the solution is stirred for 10 minutes, 5 ml of ether are added and the solution is cooled to -78 ° C. The copper solution is then cooled to -78 ° C. and added to the vinyl lithium solution via a double needle. After 30 minutes, a solution of 3.4 g of 1- (6-carbotrimethylsilyloxy-hexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one in ether is added. Transfer the solution then placed in a dry ice / acetonitrile bath with a temperature of -45 to -50 ⁰ C and stirred for 3 hours. The solution is allowed during the course of 2o minutes at -2O ° C to warm, and then stirred for 10 minutes at -20 ⁰ C. To this solution

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are 5 ml of acetic acid in 5 ml of ether and then mixed with 0.5m hydrochloric acid solution. The solution is poured into Water and extracted with ether. The ethereal solution is washed with water and dried over magnesium sulfate. Then pulls the solvent is removed and most of the thiophenol is removed. The residue is dissolved in 100 ml of an acetic acid / tetrahydrofuran / water mixture and stir for 1 hour. The mixture is poured into water and extracted with ether. The ether extract is washed several times with water and dried it over magnesium sulfate, pulls off the ether and gets a yellow oil. The oil is chromatographed on a dry one Silica gel column, being treated with an ether / ethyl acetate mixture (1/1) eluted. The product is isolated in the form of a light green-yellow oil, which decomposes on drying

15 sets and makes a dirty-white pest.

Example 69

nat- (and ent) -11O (, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-trans-prostadic acid.

A solution of 10.3 g of 1- (3-tri-n-butylstannyl-2-trans-propenyl) -1-trimethylsilyloxy-cyclohexane (Example 3O) in 7 ml of tetrahydrofuran is cooled in a dry ice / acetone bath under nitrogen and then treated in the course of 10 minutes with 8.6 ml of a 2.5M n-butyllithium solution in hexane. The resulting solution is stirred for 1 hour at -40 ° C, then for another hour at -20 to -30 ⁰ C, cooled again to -78 ° C and treated over 10 minutes with a solution of 2.68 g of copper pentine, 7.87 ml of hexamethylphosphoric triamide and 19 ml of tetrahydrofuran. The resulting solution is stirred for 1 hour at -70 to -50 ⁰ C and re-cooled to -78 ° C and treated with a solution of 5.8 g of 2- (6-Carbotrimethylsilyloxy-hex-2-cis-enyl) -4-trimethylsilyloxycyclopent-2-en-l-one (Example 51) in 12 ml of tetrahydrofuran,

809841/0791

which treatment is carried out for 10 minutes. The mixture is then stirred for 40 minutes at -4O to -5O ° C, then for 25 minutes at -2O to -25 ° C, then cools to -4O ° C and pour into 500 ml of a cold, saturated ammonium chloride solution and 300 ml of ether. To the educated Mixture is added 8 ml of glacial acetic acid and extracted with ether. The combined ether extract is washed with water, with diluted Hydrochloric acid, filter through filter aid (Celite) and wash again with water and a saturated one Sodium chloride solution. Evaporation of the solvents under reduced pressure gives 15.2 g of an oil. One stirs a solution of this crude oil in 175 ml of a glacial acetic acid / tetrahydrofuran / water mixture (4/2/1) for 50 minutes under nitrogen at room temperature. Then you move them Mixture with 15Ο ml of toluene and concentrated under reduced pressure. The crude product obtained is chromatographed over Purified silica gel and gives nat- (and ent) -llo (, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostadic acid.

20 Example 70

nat-15S, 16R (and ent-15R, 16S) - and nat-15R, 16S- (and ent-15S, 16R) -llo (, 16-dihydroxy-9-oxo-15, lo-trimethylene-IS-trans-S-cisprostadienoic acid.

To a solution of 1.44 g of thiophenol in 40 ml of ether are added under nitrogen and with stirring at 0 ⁰ C 5.65 ml of a 2.3 m n-butyllithium solution. After stirring for one hour at ⁰ ° C., a solution of the bis-tri-n-butylphosphine-copper iodide complex in 100 ml of ether is added and the solution is kept in a refrigerator overnight.

To 4.76 g of IR, 2S- (and IS, 2R) -I- (trans-2-iodovinyl) -1-trimethylsilyloxy-2-butyl-cyclopentone 32.5 ml of an O, 8m tert, - are added to 10 ml of toluene under nitrogen at -45 ° C with stirring

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Butyllithium solution. After stirring for 90 minutes at -45 ° C., the solution is removed from the cooling bath and stirred for 15 minutes. The solution is then cooled to -78 ° C., the copper solution is cooled to -78 ° C. and then added to the vinyl lithium solution. After 30 minutes, a solution of 4.4 g of 1- (6-carbotrimethylsilyloxy-hex-2-cis-enyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one in 20 ml of ether is added. The solution is stirred for 3 hours at -45 ° C and then leaves them in the course of 3 minutes to warm to -20 ⁰ C.

The solution is stirred for 15 minutes at -20 ° C. and then a solution of 2.5 ml of acetic acid in 15 ml of ether is added of a dilute hydrochloric acid solution. The mixture is extracted with ether, the ether extract is washed with a saturated sodium chloride solution and dried over - magnesium sulfate. The solvent is drawn off and a yellow oil is obtained. This oil is stirred for 1 hour in 7O ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1), pour into water and extracted with ether. The extract is dried over magnesium sulfate and the ether is removed. The The residue is chromatographed on a dry silica gel column, isolating the ether and obtaining the separated isomers.

Examples 78 to 153

In the manner described in Examples 67 to 70 above, those indicated in Table IV below are prepared 9-OxD-prostaglandins from the specified iodovinyl compounds or vinyl tin compounds and the specified cyclopent-2-en-l-ones. In the reactions in which 4-hydroxy-cyclopent-2-en-l-one are used, these are first converted into their corresponding bis-trimethylsilyloxy- ^ derivatives converted as indicated in Examples 51 and above. Only the acids are shown in Table IV indicated, it being understood, however, that fiction

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according to both the acids and the esters are claimed. In those cases where there are two diastereoisomers the conjugate addition, only one of the diastereoisomers is given in Table IV.

It goes without saying, however, that the other diastereoisomer is also formed, which in its natural and ent forms the opposite (mirror image) configuration on the asymmetric carbon atoms of the / 2> Chain (i.e. the chain having the C -C residue, etc.) as the corresponding ones Nat and ent forms of the diastereoisomers given in the table. Both diastereoisomers are according to the invention claimed, as well as their corresponding enantiomers.

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example

Iodovinyl compound or vinyl tin compound of Example

TABLE IV
Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

ο
ta co

72 73 74

76 77 78 79 80

29a

36

31

32

33

34

35

37

38

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhexyl) -4-hydroxyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 16R- (and ent-15R, 16S) -11 «, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -IKK, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-prostenic acid

nat- (and ent) -llc <, 15-dihydroxy-9-oxo-15,16-tetraraethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -lltf, 15-dihydroxy-9-oxo-15,16-trimethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -lic *, 15-dihydroxy-15,16-pentamethylene-17,18,19,20-tetranor-13 ~ trans-prostenic acid

nat-15S, 17R- (and ent-15R, 17S) -110 (, 15-dihydroxy-9-oxo-15,17-dimethylene-13-trans-prostenic acid

nat-15S, 17S- (and ent-15R, 17R) -lia, 15 Dihydroxy-9-oxo-15,17-dimethylene-13-trans-prostenoic acid

nat-15S, 16R- (and ent-15R, 16S) -110 (, 15 dihydroxy-9-oxo-15,16-tetramethylene-13-trans-prostenoic acid

nat-15S, 16S- (and ent-15R, 16R) -Ιΐοί, 15 Dihydroxy-9-oxo-15,16-tetramethylene-13-trans-prostenic acid

TABLE IV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its diastereoisomer and its ethyl ester (see above)

81

82

83

_Γ 84

_ »85

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhexyl) -4 ~ hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

nat-15R, 16S- (and ent-15S, 16R) -lltf, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20 tetranor-13-trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20 tetranor-13-trans-prostenic acid

nat- (and ent) -llo (, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) -11σ (, 15-dihydroxy-9-oxo-15, lo-trimethylene-lo- (4-fluorophenoxy) -17,18,19,20-tetranor 13-trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor 13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) -lltf, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13 -trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -11 «*, 15- NJ

Dihydroxy-9-oxo-15,16-trimethylene-lo-OO

(3-chlorophenoxy) -17,18,19,20-tetranor- - ^Δ

13-trans-prostenic acid · ^ω

nat-15S, 17R- (and ent-15R, 17S) -110 (, 15-dihydroxy-9-oxo-15,17-trimethylene-19-20-dinor-13-trans-prostenic acid

TABLE IV (continued)

Example iodovinyl compound or vinyl tin compound of example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its diastereoisomer and its ethyl ester (see above)

O
OO
CD

90

92

93

94 95 96

46

47

48

49

50

29a

"36

31

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhexyl) -4-hydroxycaclopent- = 2-en-1-one

2- (6-carboxyhexyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 17S- (and ent-15R, 17R) -lltf, 15-dihydroxy-9-oxo-15,17-trimethylene-19-20-dinor-13-trans-prostenic acid

nat-16R, 17S- (and ent-16S, 17R) -llc {, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-13-trans-prostenoic acid

nat-16R, 17R- (and ent-16S, 17S) -llo (, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-13-trans-prostenoic acid

nat-16R, 17S- (and ent-16S, 17R) -11θ (, 16-dihydroxy-9-oxo-16,17-trimethylene-16- (3-trifluoromethylphenoxy) -18,19,20-trinor-13- trans-prostenic acid

nat-16R, 17R- (and ent-16S, 17S) -11 <*, 16-dihydroxy-9-oxo-16,17-trimethylene-16- (3-trilofluoromethylphenoxy) -18,19,20-trinor-13 -trans-prostenic acid ■

nat-15S, 16R- (and ent-15R, 16S) -lic *, 15-dihydroxy-9-oxo-15,16-r-trimethylene-7-nor-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -11 <^, 15-dihydroxy-9-oxo-15 _/ .16-trimethylene-2-nor-13-trans-prostenic acid

nat- (and ent) -llo (, 15-dihydroxy-9-oxo-15,16-tetramethylene-2,17,18,19,20-pentanor-13-trans-prostenoic acid

TABLE IV (continued)

example

Iodovinyl compound or vinyl tin compound of example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

O
CD
CO

97 98 99

100 101

102

103 104 105

32

33

34

35

39

40

29a

36

31

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-Carbxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (5-carboxypentyl) -4-hydroxycyclopent-2-en-1-one

2- (7-Carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

2- (7-carboxyheptyl) - ^ - hydroxy cyclopent-2-en-l-one

2- (7-carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

nat- (and ent) -HoC, 15-dihydroxy-9-oxo-15,16-trimethylene-2,17,18,19,20-pentanor-13-trans-prostenoic acid

nat- (and ent) -ll ** ,, 15-dihydroxy-9-oxo-15,16-pentamethylene-2,17,18,19,20-pentanor-13-trans-prostenoic acid

nat-15S, 17R- (and ent-15R, 17S) -IIoC, 15-dihydroxy-9-oxo-15,17-dimethylene-2-nor-13-trans-prostenic acid

nat-15S, 17S- (and ent-15R, 17R) -llö (,, 15-dihydroxy-9-oxo-15,17-dimethylene-2-nor-13-trans-prostenoic acid

nat-15R, 16S- (and ent-15S, 16R) -llöC, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -2,17,18,19, -20- pentanor-l3-trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -11 <X, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -2,17,18,19,20 -pentanor-13-trans-prostenic acid

nat-15S, 16R- (and ent-15R, 16S) -lloi, 15-dihydroxy-9-oxo-15,16-trimethylene-lhomo-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -Hot, 15-dihydroxy-9-oxo-15,16-trimethylene-lhomo-13-trans-prostenoic acid

nat- (and ent) -lia, 15-dihydroxy-9-oxo-

15,16-tetramethylene-17,18,19,20-tetra-CD

nor-1-homo-l 3-trans-prostenic acid "" "*

TABLE IV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its diastereoisomer and its ethyl ester (see above)

IF
O
CO

106

107

108

109

111

112

113

37

38

41

42

46

47

48

2- (7-Carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

2- (7-Carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

2- (7-Carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

2- (7-Carboxyheptyl) -4-hydroxycyclopent-2-en-1-one

2- (8-carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

2- (8-carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

2- (8-carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 16R- (and ent-15R, 16S) -IIICC, 15-dihydroxy-9-0X0-15,16-tetramethylene-lhomo-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -II06,15-dihydroxy-9-oxo-15,16-tetramethylene1-homo-13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) -Hoc, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -l-homo-17,18,19,20 -tetranor-13-trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -II06,15-dihydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -l-homo-17,18,19,20 -tetranor-13-trans-prostenic acid

nat-15S, 17R- (and ent-15R, 17S) -llo (, 15-dihydroxy-9-oxo-15,17-trimethylene-19, -20-dinor-la, lb-dihomo-13-trans-prostenic acid

nat-15S, 17S- (and ent-15R, 17R) -llo (, 15-dihydroxy-9-oxo-15,17-trimethylene-19,20-dinor-la, lb-dihomo-13-trans-prostenic acid

nat-16R, 17S- (and ent-16S, 17R) -Hoc, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-la, lb-dihomo-13-trans-prostenis acid

nat-16R, 17R- (and ent-16S, 17S) -litt, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-la, lb-dihomo-13-trans-prostenoic acid

TABLE IV (continued)

example

Iodine vinyl compound or
Vinyl tin compound of
example

Cyclopent-2-en-1-one

2- (8-carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

2- (8-carboxyoctyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopenten-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

nat-16R, 17S- (and ent-16S, 17R) -IKX, 16-dihydroxy-9-oxo-16,17-trimethylene-16- (3-trifluoromethylphenoxy) -18,19,20-trinor-la, lb -dihomo-13-trans-prostenic acid

nat-16R, 17R- (and ent-16S, 17S) -llo <, 16-dihydroxy-9-oxo-16,17-trimethylene-16- (3-trifluoromethylphenoxy) -18,19,20-trinor-la, lb-dihomo-13-trans-prostenic acid

nat-15S, 16R- (and ent-15R, 16S) -11σ (, 15-dihydroxy-9-oxo-15,16-trimethylene-13 ~ trans-5-cis-prostadic acid

nat-15S, 16S- (and ent-15R, 16R) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadic acid

nat- (and ent) -lltf, 15-dihydroxy-9-oxo-15,16-trimethylene-17,18 _/ 19-2O-tetra-

nor-13-trans-5-cis-prostadic acid

nat- (and ent) -11 <K, 15-dihydroxy-9-oxo-15,16-pentamethylene-17,18,19,20-tetranor-13-trans-5-cis-prostadic acid

nat-15S, 17R- (and ent-15R, 17S) -llo (, 15-dihydroxy-9-oxo-15,17-dimethylene-13-trans-5-cis-prostadic acid

nat-15S, 17S- (and ent-15R, 17R) -llc < , 15-dihydroxy-9-oxo-15,17-dimethylene-13-trans-5-cis-prostadienoic acid

TABLE IV (continued)

Example iodovinyl compound or vinyl tin compound of example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

122

123

124

37

38

39

125

40

126

127

128

41

42

43

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 16R- (and ent-15R, 16S) -HfK ₁ 15 dihydroxy-9-oxo-15,16-tetramethylene-13-trans-5-cis-prostadic acid

nat-15S, 16S- (and ent-15R,
Dihydroxy-9-oxo-15,16-tetramethylene-13-trans-5-cis-prostadic acid

nat-15R, 16S- (and ent-15S, 16R) -IKK, 15-dihydroxy-9-oxo-15, lo-trimethylene-lo- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-IS -trans-S-cis-prostadic acid

nat-15R, 16R- (and ent-15S, 16S) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20 tetranor-IS-trans-S-cis-prostadienoic acid

nat-15'R, 16S- (and ent-15S, 16R) -llc (, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -17,18,19,20- tetranor-13-trans-5-cis-prostadienoic acid

nat-15R, 16R- (and ent-15S, 16S) -11 «, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor- 13-trans-5-cis-prostadic acid

nat-15R, 16S- (and ent-15S, 16R) -IKK, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13 -trans-5-cis-prostadic acid

TABLE IV (continued)

example

Iodovinyl compound or vinyl tin compound of example

Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

129 130 131 132 133

134 135

2- (6-carboxyhex-2-cis-enyD-4-hydroxycyclopent-2-en-l-

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cis ~ enyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

nat-15R, 16R- (and ent-15S, 16S) -llrf, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13 -trans-5-cis-prostadic acid

nat-15S, 17R- (and ent-15R, 17S) -llo (, 15-dihydroxy-9-oxo-15,17-trimethylene-19, 20-dinor-13-trans-5-cis-prostadic acid

nat-15S, 17S (and ent-15R, 17R) hoof,
15-dihydroxy-9-oxo-15,17-trimethylene-19,20-dinor-13-trans-5-cis-prostadic acid

nat-16R, 17S- (and ent-16S, 17R) -11 «, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-IS-trans-S-cis-prostadic acid

nat-16R, 17R- (and ent-16S, 17S) -llo <, 16-dihydroxy-9-oxo-16,17-trimethylene-2O-methyl-l-3-trans-5-cis-prostadic acid

nat-16R, 17S- (and ent-16S, 17R) ~ llc (, 16-dihydroxy-9-oxo-16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-13- trans-5-cis-prostatic acid

nat-16R, 17R- (and ent-16S, 17S) -llo <, 16- cxj Dihydroxy-9-oxo-16,17-trimethylene-17- -> (3-trifluoromethylphenoxy) -18,19,20- co trinor-IS-trans-S-cis-prostadienoic acid NJ

TABLE IV (Porting)

example

Iodovinyl compound or
Vinyl tin compound of
example

Cyclopent-2-en-1-one 9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

29a

36

31

37

38

39

40

2- (8-Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (8 ~ Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) ^ -4-hydroxycyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 16R- (and ent-15R, 16S) -llfl (, 15-dihydroxy-9-oxo-15,16-trimethylene-la, -lb-dihomo-IS-trans-S-cis-prostadienoic acid

nat-15S, 16S- (and ent-15R, 16R) -llo (, 15-dihydroxy-9-oxo-IS, 16-trimethylene-la, -lb-dihomo-IS-trans-S-cis-prostadienoic acid

nat- (and ent) -llö (, 15-dihydroxy-9-oxo-15,16-tetramethylene-la, lb-dihomo-17, -18,19,20-tetranor-13-trans-5-cisprostadienoic acid

nat-15S, 16R- (and ent-15R, 16S) -11 <X, 15-dihydroxy-9-oxo-15,16-tetramethylene-la, -lb-dihomo-IS-trans-S-cis-prostadienoic acid

nat-15S, 16S- (and ent-15R, 16R) -11ο (, 15-kydroxy-9-oxo-15,16-tetramethylene-la, -lb-dihomo-IS-trans-S-cis-prostadienoic acid

nat-15R, 16S- (and ent-15S, 16R) -lK, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -la, lb-dihomo-17,18,19 , 20-tetranor-13-trans-5- ^ 0 cis-prostadic acid QO

nat-15R, 16R- (and ent-15S, 16S) -llöf, 15- ^ Dihydroxy-9-oxo-15, lo-triemethylene-16-psj (3-trifluoromethylphenoxy) -la, lb-dihomo-cn 17,18,19.20-tetranor-13-trans-5-cis- - * prostadic acid

TABLE IV (continued)

CD CO OO

example Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-oxo-prostaglandin product and its
Diastereoisomer and its ethyl
ester (see above) 143 29a 2- (6-carboxy-S-oxa-hex-
yl) ^ -hydroxycyclopent - ^ -
en-l-on nat-15S, 16R- (and ent-15R, 16S) -IIoC, 15-
Dihydroxy-3-oxa-9-oxo-15,16-trimethylene
13-trans-prostenic acid 144 36 2- (6-carboxy-5-oxa-hex-
yl) -4-hydroxycyclopent-
2-en-l-on nat-15S, 16S- (and ent-15R, 16R) -11ö <, 15-
Dihydroxy-3-oxa-9-oxo-15,16-trim
ethylene-13-trans-prostenic acid 145 31 2- (6-carboxy-5-oxa-hex-
yl) -4-hydroxycyclopent-
2-en-l-on nat- (and ent) -Ho /, 15-dihydroxy-3-oxa-
9-OXO-15,16-tetramethylene-17,18,19,20-
tetranor-13-trans-prostenic acid 146 43 2- (6-carboxy-4-methyl-
hex-2-cis-enyl) -4-hy-
droxycyclopent-2-en-1-one nat-15R, 16S- (and ent-15S, 16R) -llo (, 15-
Dihydroxy-4-methyl-9-oxo-15,16-tri-
methylene-16- (3-chlorophenoxy) -17,18,19, -
20-tetranor-13-trans-prostenic acid 147 44 2- (6-carboxy-4-methyl-
hex-2-cis-enyl) -4-hy-
droxycyclopent-2-en-1-one nat-15R, 16R- (and ent-15S, 16S) ~ llo [, 15-
Dihydroxy-4-methyl-9-oxo-15,16-tri-
methylene-16- (3-chlorophenoxy) -17,18,19, -
20-tetranor-13-trans-prostenic acid 148 45 2- (6-carbxy-4-methyl-
hex-2-cis-enyl) -4-hy-,
droxycyclopent-2-en-1-one nat-15S, 17R- (and ent-15R, 17S) ~ llo {, 15-
Dihydroxy-4-methyl-9-oxo-15,17-tri-
methylene-19,20-dinor-13-trans-prosten-
acid 149 46 2- (6-carboxy-4-methyl-
hex-2-cis-enyl) -4-hy-
droxycyclopent-2-en-1-one nat-15S, 17S- (and ent-15R, 17R) -11C (, 15-
Dihydroxy-4-methyl-9-oxo-15,17-trim-
ethylene-19,20-dinor-13-trans-prosten-
acid 150 47 2- (6-carboxy-4-methyl-
hex-2-cis-enyl) -4-hy-
droxycyclopent-2-en-1-one nat-16R, 17S- (and ent-16S, 17R) -11 «, 16-
Dihydroxy-4-methyl-9-oxo-16,17-trim-
ethylene-20-methyl-13-trans-prosten
acid

CO fsj CT)

example

Iodovinyl compound or vinyl tin compound of Example

TABLE IV (continued) Cyclopent-2-en-1-one

9-oxo-prostaglandin product and its Diastereoisomer and its ethyl ester (see above)

151 152

oo

48

49

50

2- (6-Carboxy-4-ethylhex-2-cis-enyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxy-4-ethylhex-2-cis-enyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxy-4-ethylhex-2-cis-enyl) -4-hydroxyeyelopent-2-en-1-one

nat-16R, 17R- (and ent-16S, 17S) -llo (, 16-dihydroxy-4-ethyl-9-oxo-16,17-trimethylene-2O-methyl-13-trans-prostenic acid

nat-16R, 17S- (and ent-16S, 17R) -lic *, 16-dihydroxy-4-ethyl-9-oxo-15,17-tri-. methylene-17- (3-trifluororaethylphenoxy) -18,19,20-trinor-13-trans-prostenic acid

nat-16R, 17R- (and ent-16S, 17S) -HoC, 16-dihydroxy-4-ethyl-9-oxo-15,17-trimethylene-1- (3-trifluoromethylphenoxy) -18,19,20-trinor -13-trans-prostenic acid

OJ IV) CT)

Examples 154 to 183

Following the procedure of Examples 67 to 70, the 9-Oxo-110 (-hydroxyprostaglandin methyl ester given in Table V below from the specified cyclopent-2-en-1-ones and the specified iodovinyl compounds or vinyltin compounds manufactured.

In those cases in which two diastereoisomers are formed in the conjugate addition, both are obtained in optically active form, although only one of the diastereoisomers is given in Table V. It goes without saying, however, that the other diastereoisomer is also formed, which in its nat or ent form has the opposite (mirror image) configuration at the asymmetric carbon atom in the β chain (the chain having _{the C 13} -C _{14 radical)} contains, with respect to the corresponding nat or ent form of the specified diastereoisomer, but both diastereoisomers are claimed according to the invention.

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TABLE V

example 154 Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one Optically active 9-oxo prostaglandin
product and its optically active
Diastereoisomer 155 29a 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
cyclopent-2-en-l-one nat-15S, 16R-IIoC, 15-dihydroxy-9-oxo-
15, lo-trimethylene-LS-trans-prosten-
acid methyl ester 156 36 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
cyclopent-2-en-l-one nat-15S, 16S-1KX, 15-dihydroxy-9-oxo-
15, Lö-trimethylene-LS-trans-prosten-
acid methyl ester 8098 157 31 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
caclopent-2-en-l-one nat-lloC, 15-dihydroxy-9-oxo-15, sol
tet ramethylene-17,18,19,20-tetranor-
13-trans-prostenic acid methyl ester ! 41/0 158 30th 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
cyclopent-2-en-l-one nat-llci, 16-dihydroxy-9-oxo-16,17-
tetramethylene-18,19,20-trinor-13-
trans-prostenic acid methyl ester 791 159 39 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
cyclopent-2-en-l-one nat-15R, 16S-IIOC, 15-dihydroxy-9-oxo-
15,16-trimethylene-16- (3-trifluoro-
methylphenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid methyl ester 160 40 2- (6-carbomethoxyhexyl) -
4 (S) -trimethylsilyloxy-
cyclopent-2-en-l-one nat-15R, 16R-IlUf, 15-dihydroxy-9-oxo-
15,16-trimethylene-16- (3-trifluoro-
methylphenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid methyl ester 161 29a 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-1-one ent-lSR ^ öS-HOMS-dihydroxy-g-oxo-
15, Lö-trimethylene-LS-trans-prosten-
acid methyl ester 36 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-l-one ent-lSR ^ öR-lloMS-dihydroxy-g-oxo-
15, lo-trimethylene-LS-trans-prosten-
acid methyl ester

OO N) CD

TABLE V (continued)

O CO OO

example Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one Optically active 9-0xo prostaglandin
product and its optically active
Diastereoisomer 162 31 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-l-one ent-llof, 15-dihydroxy-9-oxo-15,16-
tetramethylene-17,18,19,20-tetranor-
13-trans-prostenic acid methyl ester 163 30th 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-l-one ent-llö (, 16-dihydroxy-9-oxo-16 _y 17-
tetramethylene-18,19,20-trinor-13-
trans-prostenic acid methyl ester 164 39 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-l-one ent-15S, 16R ₁ -IlOL, 15-dihydroxy-9-oxo-
15, Lö-trimethylene-Lö- (3-trifluoro-
methylphenoxy) -17,18,19-20-tetra-
methyl nor-13-trans-prostenoate 165 40 2- (6-carbomethoxyhexyl) -
4 (R) -trimethylsilyloxy-
cyclopent-2-en-l-one ent-15S, 16S-llo (, 15-dihydroxy-9-oxo-
15,16-trimethylene-16- (3-trifluoro-
methylphenoxy) -17.18 _/ 19.20-tetra-
methyl nor-13-trans-prostenoate 166 29a 2- (6-carbomethoxyhex-2-
cis-enyl) -1 (S) -trimethyl-
silyloxy-cyclopent-2-en-
1-on nat-15S, 16R-11C (, 15-dihydroxy-9-oxo-
15, lo-trimethylene-lS-trans-S-cis-
methyl prostenate 167 36 2- (6-carbomethoxyhex-2-
cis-enyl) -4 (S) -trimethyl-
silyloxy-cyclopent-2-en-
1-on nat-15S, 16S-11O (, 15-dihydroxy-9-oxo-
15,16-trimethylene-13 ~ trans-5-cis-
methyl prostadiac acid 168 31 2 "(6-carbomethoxyhex-2-
cis-enyl) -4 (S) -trimethyl-
silyloxy-cyclopent-2-en-
1-on nat-llo (, 15-dihydroxy-9-oxo-15,16-
tetramethylene-17,18,19,20-tetranor-
13-trans-5-cis-prostadic acid
methyl ester

TABLE V (continued)

example

Iodoviny! Compound or vinyl tin compound of example

Cyclopent-2-e n-1-one

Optically active 9-0xo prostaglandin product and its optically active Diastereoisomer

169 170

30th

39

O
CO
CD

171

40

cd 172 173 174 175

31

29a

36

30th

2- (6-Carbomethoxyhex-2-cisenyl) -4 (S) -trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbomethoxyhex-2-cisenyl) -4 (S) -trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbomethoxyhex-2-cisenyl) -4 (S) -trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

nat-lld, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-13-trans-5-cis-prostadienoic acid methyl ester

nat-15R, 16S-IIoC, 15-dihydroxy-9-oxo-

methylphenoxy) -!?, 18,19,20-tetranorlS-trans-S-cis-prostadienoic acid methyl- ester

nat-15R, 16R-IIoC, 15-dihydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-IS-trans-S-cis-prostadienoic acid methyl ester

Nat- (and ent) -11 oil 15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-17,18, -19,20-tetranor-13-trans-prostenic acid.

nat-15S, 16R- (and ent-15R, 16S) -lloi, 15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -Hd, -15 -dihydroxy-3-thia-9-oxo-15,16-trimethylene-13-trans-prostenoic acid

nat- (and ent) -llri, 16-dihydroxy-3-thia-9-oxo-16,17-tetramethylene-18,19,20-trinor-13-trans-prostenic acid

TABLE V (continuation)

example

Iodovinyl compound or
Vinyl tin compound of
example

Cyclopent-2-en-l-one Optically active 9-oxo-pizstaglandin product and its optically active diastereoisomer

39

40

31

29a

36

30th

39

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (6-Carbotrimethylsilyloxy-5-thiahexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-l-one nat-15R, 16S- (and ent-15S, 16R) -Hot, -

-Dihydroxy-3-thia-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-transprostic acid

nat-15R, 16R- (and ent-15S, 16S) -11 *, 15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19, 20-tetranor-13-trans-prostenic acid

nat- (and ent) -lloC, 15-dihydroxy-3-thia-9-oxo-15,16-tetramethylene-4-17,18,19,2O-pentanor-13-transprostic acid

nat-15S, 16R- (and ent-15R, 16S) -11Q (, 15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-4-nor-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -llQl, -

methylene-4-nor-13-trans-prostenic acid

nat- (and ent) -lloC 16-dihydroxy-3-thia-9-OXO-16,17-tetramethylene-4-18,19,20-tetranor-13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) 15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) 4,17,18,19,20-pentanor-13-trans-prostenic acid

γ> ο cn

example

Jodviny! .Compound or Vinyl tin compound of example

TABLE V (continued) Cyclopent-2-en-l-one Optically active 9-0xo-prostaglandin product and its optically active
Diastereoisomer

40

2- (5-Carbotrimethylsilyloxy-4-thiapentyl) -4-trimethylsilyloxy-cyclopent-2-en-l-one nat-15R, 16R- (and ent-15S,
15-dihydroxy-3-thia-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) 4,17,18,19,20-pentanor-13-trans-prostenoic acid

OO CT)

Example 184

nat- (and ent) -llo (, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid methyl ester.

To a solution of 0.1 g of nat- (and ent) -llo (, 15-dihydroxy-9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans- prostadic acid one gives an excess of a solution of diazomethane in ether. After 5 minutes you drive away the excess diazomethane and the solvent with the aid of a stream of nitrogen and obtain the title methyl ester.

Examples 185-190

Following the procedure of Example 184, the prostaglandins given in Table VI below are mixed with the specified diazoalkanes esterified to the specified compounds.

809841/0791

TABLE VI

example 185 Prostaglandin
of example Diazoalkane Esterified prostaglandin product 186 69 Diazomethane η a t- (and ent) -HoC, 16-dihydroxy-9-oxo-16,17-tetramethylene-
18,19, ZO-trinor-S-cis-IS-trans-prostadienoic acid methyl ester 187 72 Diazomethane nat-15S, 16R- (and ent-15R, 16S) -Hoc, 15-dihydroxy-9-oxo-15, 16-
trimethylene-13-trans-prostenic acid ethyl ester 188 73 1-diazopropane nat-15S, 16S- (and ent-15R, 16S) -lloU 15-dihydroxy-9-oxo-15,16-
trimethylene-13-trans-prostenic acid-n-propyl ester 09
O
CO 189 74 Diazomethane nat- (and ent) -HoC, 15-dihydroxy-9-oxo-15, 16-tetramethylene
17,18,19,20-tetranor-13-trans-prostenoic acid methyl ester QO
-Ο · 190 86 1-diazohexane nat-15S, 16R- (and ent-15R, 16S) -Hd ,, lS-dihydroxy-g-oxo-lS, 16-
trimethylene ~ 5-cis-13-trans-prostadienoic acid-n-hexyl ester / 079 191 Diazomethane nat- (and ent) -hol, 15-dihydroxy-9-oxo-15,16-tetramethylene
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid methyl
ester

Example 191

nat- (and ent) -9 (X, 11 <X, 15-trihydroxy-15,16-tetramethylene-17, -18,19,20-tetranor-13-trans, 5-cis-prostadic acid.

To a solution of 1.25 g of nat- (and ent) -lloi, 15-dihydroxy-9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-13-trans, 5-cis-prostadic acid in 20 ml of tetrahydrofuran are added under nitrogen and with stirring at -78 ° C. 21.4 ml of a 0.5 M solution of lithium perhydro-9b-borophenalyl hydride in tetrahydrofuran. After stirring for 30 minutes at -78 ° C., the solution is allowed to ^{warm to 0} ° C. over the course of 1 hour and then poured into a dilute sodium carbonate solution. The aqueous mixture is extracted three times with ether, the aqueous layer is separated off and 1 ml of 30% hydrogen peroxide is added. After 10 minutes, the aqueous solution is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried over magnesium sulphate, the solvent is evaporated and 1.14 g of the desired product is obtained in the form of a yellow oil.

^ O Example 192

nat-15S, 16R- (and ent-15R, 16S) - and nat-15R, 16S- (and ent-15S, 16R) -9 «, 11 <*, 15-trihydroxy-15, lo-trimethylene-IS-transprostadienoic acid.

To a solution of 1.12 g of a mixture of the analogous 9-oxo derivatives of the above compounds in 20 ml of tetrahydrofuran is added under nitrogen and with stirring at -78 ° C. 2O ml of a 0.5 m solution of lithium perhydro-gb-boraphenalyl hydride in Tetrahydrofuran. After stirring for 30 minutes at -78 ° C the solution is allowed during the course of 1 hour at 0 ⁰ C heat. The mixture is poured into a dilute

809841/0791

Sodium carbonate solution and washes this mixture several times with ether. The aqueous solution is mixed with 3 ml of 30% strength Hydrogen peroxide. After 10 minutes, the solution is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is dried with magnesium sulfate and activated charcoal and the solvent is drawn off / with pale yellow oil remains. This oil is chromatographed on a column loaded with dry silica gel, wherein it is eluted with ethyl acetate and the desired D mixed isomers are obtained as oils.

Example 193

nat- (and ent) -9o (, llo (, 16-trihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostadic acid.

1.9 g of nat- (and ent) -lief, 16-dihydroxy-9-oxo-16, 17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostadiene are purified acid chromatographically by eluting with an increasing gradient of initially 30% ethyl acetate in Hexane, using a total of 3.5 liters of the eluent. 51O mg of the purified material are obtained.

Dissolve 400 mg of this purified material in 5 ml of freshly distilled tetrahydrofuran and cool in under nitrogen a dry ice / acetone mixture. Then, in the course of 10 minutes, 5 ml of lithium electride (Im in a 1/1 pentane / Tetrahydrofuran mixture). After stirring for 1 hour, 5 ml of water are added and the cooling bath is removed. One stirs the mixture for a further hour, acidified with 4N hydrochloric acid solution and extracted with ether. The ether extracts are combined, washed with water and brine, whereupon the solvent is left to dryness evaporates. The residue is dissolved in 3 ml of tetrahydrofuran and cooled in an ice bath. Then one treats one after the other

809841/0791

with 1 ml of a 2.5N sodium hydroxide solution and 0.8 ml of 30 % strength hydrogen peroxide, whereupon the mixture is stirred in an ice bath under nitrogen for 25 minutes. The mixture is diluted with water, acidified with a 4N hydrochloric acid solution and extracted with an ether / ethyl acetate mixture. The combined organic extracts are washed with water and brine. Evaporate the solvent to dryness on a rotary evaporator. The residue is applied to a thin-layer chromatography plate coated with silica gel 2 × 2000λ and developed with a 1% strength solution of acetic acid in ethyl acetate. The product is detected with iodine vapors and the silica gel is washed off using 100 ml of ethyl acetate and 200 ml of a 20% solution of methanol in chloroform. The solvents are evaporated in the presence of toluene using a rotary evaporator and then in vacuo. The desired product is recrystallized from chloroform.

Examples 194-223

in the manner described with respect to Examples 191-193 the 9-oxo-prostaglandins given in Table VII below are reduced with lithium-perhydro-9b-borophenalyl hydride or lithium electrid with formation of the specified 9fl (-hydroxy compounds.

809841/0791

TABLE VII

example 9-oxo-prostaglandin
of example 9U- hydroxy prostaglandin product 194 72 nat-15S, 16R- (and ent-15R, 16S) -9d, lld, 15-trihydroxy-15,16-
trimethylene-13-trans-prostenic acid 195 73 nat-15S, 16S- (and ent-15R, 16R) -9o (, lies /, 15-trihydroxy-15,16-
trimethylene-13-trans-plastic acid 196 74 nat- (and ent) -9o (, 11 <<, 15-trihydroxy-15,16-tetramethylene-
17,18,19,20-tetranor-13-trans-prostenoic acid OO
O
ίο 197 69 nat- (and ent) -9 *, lld, 16-trihydroxy-16,17-tetramethylene-
18,19,20-trinor-13-trans-5-cis-prostadic acid OO 198 81 nat-15R, 16S- (and ent-15S, 16R) -9 <&, llo <, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans-prostenic acid 0791 199 82 nat-15R, 16R- (and ent-15S, 16S) -9o (, H ^, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans-prostenic acid 200 ' 83 nat- (and ent) -9 (£, Hot, 16-trihydroxy-16,17-tetramethylene-
18,19,20-trinor-13-trans-prostenic acid 201 84. nat-15R, 16R- (and ent-15S, 16S) -9U, lld, 15-trihydroxy-15,16-
trimethylene-16- (4-fluorophenoxy) -7-homo-17,18,19,20-tetra-
nor-13-trans-prostenic acid 202 86 nat-15S, 16R- (and ent-15R, 16S) - 90 (, H ^ 15-trihydroxy-
15,16-trimethylene-13-trans-5-cis-prostadic acid 203 87 nat-15S, 16S- (and ent-15R, 16R) -9ώί, llo (, 15-trihydroxy-15, 16-
trimethylene-13-trans-5-cis-prostadienoic acid 204 124 nat-15R, 16S- (and ent-15S, 16R) -9 <X, ll <a (, 15-trihydroxy-15, 16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid

TABLE VII (continued)

example 9-oxo-prostaglandin
of example 9c (-hydroxy prostaglandin product 205 125 nat-15R, 16R- (and ent-15S, 16S) -9o (, lic *, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid 206 126 nat-15R, 16S- (and ent-15S, 16R) -9o (, lld ,, 15-trihydroxy-15,16-
trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid 207
OO 127 nat-15R, 16R- (and ent-15S, 16S) -9e (, 114, 15-trihydroxy-15,16-
trimethylene-16- (4-fluorophenoxy) -17,18,19,20 ~ tetranor-13-
trans-5-cis-prostadic acid (JD 208
CO 128 nat-15R, 16S- (and ent-15S, 16R) -9Oi, 11 «, 15-trihydroxy-15,16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-
trans-cis-S-prostad.iensaure """■ 209
O
^ J
(O 129 nat-15R, 16R- (and ent-15S, 16S) -9 <K, He /, 15-trihydroxy ~ 15,16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid - * 210 134 nat-16R, 17S- (and ent-16S, 17R) -9 <x, IKX, 16-trihydroxy-16,17-
trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-
13-trans-5-cis-prostadic acid 211 135 nat-16R, 17R- (and ent-16S, 17S) -9 *, H ^, 16-trihydroxy-16,17-
trimethylene-rl7- (3-trifluoromethy Iphenoxy) -18,19, 20-trinor-
13-trans-5-cis-prostadic acid 212 136 nat-15R, 16R- (and ent-15R, 16S) -9o (, IKX, 15-trihydroxy-15,16-
trimethylene-la, ib-dihomo-IS-trans-S-cis-prostadienoic acid 213 138 nat- (and ent) -90 <, llo (, 15-trihydroxy-15,16-tetramethylene-
Ia, lb-dihomo-17,18,19,20-tetranor-13-trans-5-cis-prosta-
dienic acid 214 144 nat-15S, 16S- (and ent-15R, 16R) -9U, llo <, 15-trihydroxy-3-oxa-
15, lo-trimethylene-13-trans-prostenic acid

9-oxo-prostaglandin
of example TABLE VII (continued) example 145 9o (-Hydroxy prostaglandin product 215 149 nat- and (ent) -9o (, 11 ^, 15-trihydroxy-3-oxa-15, 16-tetramethylene
17,18,19,20-tetranor-13-trans-prostenoic acid 216 154 nat-15S, 17S- (and en t-15R, 17R) -9 <X, 11 <*, 15-trihydroxy-4-methyl-
15,17-trimethylene-19 ', 20-dinor-13-trans-prostenic acid 217 156 nat-15S, 16R-9o (, llo (, 15-trihydroxy-15, lo-trimethylene-lS-trans-
methyl prostenate 218 157 nat-9o (, Hot, 15-trihydroxy-15, 16-tetramethylene-17,18,19, 20-tetra-
methyl nor-13-trans-prostenoate ⁰⁹ 219
ο
CO 161 nat-901., HoC, 16-trihydroxy-16,17-tetramethylene-18,19, 20-trinor-
13-trans- ^ prostenic acid methyl ester ⁰⁰ 220
_Λ ■ 166 ent-15R, 16R-9 <k, 1 Ic ^, 15-trihydroxy-15, le-trimethylene-lS-trans-
methyl prostenate ^ - 221
ο 170 nat-15S, 16R-9oQ, llc ^ _t 15-trihydroxy-15, lö-trimethylene-lS-trans-
5-cis-prostadienoic acid methyl ester <ö 222 171 nat-15R, 16S-9 <, llcO 15-Trihydroxy-15, Lö-trimethylene-Lö- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans-5-cis
methyl prostadiac acid 223 nat-15R, 16R-9 <K "11 <^, 15-trihydroxy-15, lö-trimethylene-lo- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans-5-cis-
Prostadic acid methyl ester

Example 224

nat- (and ent) -9β, llo (, 15-trihydroxy-15, 16-tetramethylene-17, 18,19,20-tetranor-13-trans, 5-cis-prostadic acid.

To a stirred, ice-cold solution of 1.1 g of nat- (and ent) -HoC, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19, 20-tetranor-13-trans, 5- cis-prostadienoic acid in 100 ml of ethanol is added to 1 g of sodium borohydride in portions over the course of 1 minute. The mixture is then stirred for 5 minutes at 0 C and finally for 1.5 hours at room temperature. .0 The bulk of the ethanol is evaporated off at room temperature and the residue is treated, while cooling in an ice bath, with ether and then with dilute hydrochloric acid. The organic phase is separated off and washed with water and a saturated sodium chloride solution. The solution is dried over anhydrous magnesium sulfate and evaporated to dryness. The material is chromatographed on silica gel and the title compound and the o (-Ep ± mers are obtained.

Examples 225-254

By treating the 9-oxo derivatives given in Table VIII below with sodium borohydride according to the procedure Example 224 gives the 9β-hydroxy derivatives given in the same table. One also obtains the corresponding 9fl (-epiners.

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TABLE VIII

example 9-oxo-prostaglandin
of example 9β-hydroxy prostaglandin product 225 72 nat-15S, 16R- (and ent-15R, 16S) -9β, llo (, 15-trihydroxy-15, 16-
trimethylene-13-trans-prostenic acid 226 73 nat-15S, 16S- (and ent-15R, 16R) -9β, HoC, 15-trihydroxy-15,16-
trimethylene-13-trans-prostenic acid 227 74 nat- (and ent) -9β, H ₀ ^, 15-trihydroxy-15,16-tetramethylene
17, 18, 19, 20-tetranor-13-trans-prostenoic acid 228
ex" 69 nat- (and ent) -9ß, Ιΐοζ, 16-trihydroxy-16,17-tetramethylene-
18,19,20-trinor-13-trans-5-cis-prostadic acid S 229
OO
** - 81 nat-15R, 16S- (and ent-15S, 16R) -9β, llo (, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-prostenic acid ^ 230
O
-j 82 nat-15R, 16R- (and ent-15S, 16S) -9β, 11 <, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid CO
_ * 231 83 nat- (and ent) -9ß, llo (, 16-trihydroxy-16,17-tetramethylene-
18,19,20-trinor-13-trans-prostenic acid 232 84 nat-15R, 16R- (and ent-15S, 16S) -9ß, 11ος, 15-trihydroxy-15,16-
trimethylene-16- (4-fluorophenoxy) -7-homo-17,18,19,20-tetranor-
13-trans-prostenic acid 233 86 nat-15S, 16R- (and ent-15R, 16S) -9β, 11 ";, 15-trihydroxy-15, 16-
trimethylene-13-trans-5-cis-prostadienoic acid 234 87 nat-15S, 16S- (and ent-15R, 16R) -9ß, 11ο (, 15-trihydroxy-15, 16-
trimethylene-13-trans-5-cis-prostadienoic acid 235 124 nat-15R, 16S- (and ent-15S, 16R) -9ß, Hof ,, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid 236 125 nat-15R, 16R- (and ent-15S, 16S) -9ß, llok, 15-trihydroxy-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid

TABLE VIII (continued)

3example 9-oxo-prostaglandin
of example 9β-hydroxy prostaglandin product 237 126 nat-15R, 16S- (and ent-15S, 16R) -9β, Uo ^, 15-trihydroxy-lS, 16-
trimethylene-16 (4-fluorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid 238 127 nat-15R, 16R- (and ent-15S, 16S) -9ß, llo <, 15-trihydroxy-15,16-
trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid 239
GD
O 128 nat-15R, 16S- (and ent-15S, 16R) -9β, 11 <<, 15-trihydroxy-15,16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid oo240
__ » 129 nat-15R, 16R- (and ent-15S, 16S) -9β, HoC, 15-trihydroxy-15,16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid o241
CO 134 nat-16R, 17S- (and ent-16S, 17R) -9β, llo (, 16-trihydroxy-16,17-
trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-
13-trans-5-cis-prostadic acid 242 135 nat ~ 16R, 17R- (and ent-16S, 17S) -9ß, llc <, 16-trihydroxy-16,17-
trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-
13-trans-5-cis-prostadic acid 243 136 nat-15R, 16R- (and ent-15R, 16S) -9ß, llo (, 15-trihydroxy-15,16-
trimethylene-la, lb-dihomo-IS-trans-S-cis-prostadienoic acid 244 138 nat- (and ent) -9ß, llo (/ 15-trihydroxy-15,16-tetramethylene-
Ia, lb-dihomo, 17,18,19,2Q-tetranor-13-trans-5-cis-prosta-
dienic acid 245 144 nat-15S, 16S- (and ent-15R, 16R) -9ß, llö <, 15-trihydroxy-3-oxa-
15,16-trimethylene-13-trans-prostenic acid 246 145 nat- (and ent) -9ß, lld., 15 ~ trihydroxy-3-oxa-15,16-tetramethylene-
17,18,19,20-tetranor-13-trans-prostenoic acid

9-oxo-prostaglandin
of example TABLE VIII (continued) example 149 9β-hydroxy prostaglandin product 247 154 nat-15S, 17S- (and ent-15R, 17R) -9ß, llo (, 15-trihydroxy-4-methyl-
15,17-trimethylene-19,20-dinor-13-trans-prostenic acid 248 156 nat-15S, 16R-9β, lle4,15-trihydroxy-15,16-trimethylene-13-trans-
methyl prostenate 249 157 nat-gß ^ lo ^ lS-trihydroxy-lS, 16-tetramethylene-17,18,19, 20-
tetranor-13-trans-prostenic acid methyl ester 250 161 nat-9ß, Hai., 16-trihydroxy-16,17-tetramethylene-18,19, 20-trinor-
13-trans-prostenic acid methyl ester g251
co 166 ent-15R, 16R-9ß, llc <, 15-trihydroxy-IS, 16-trimethylene-13-trans-
methyl prostenate -252 170 nat-15S, 16R-9ß, lloC, 15-trihydroxy-lS, 16-trimethylene-13-trans-
5-cis-prostadienoic acid methyl ester ^ 253
-α
(O 171 nat-15R, 16S-9ß, Hot ,, 15-trihydroxy-15,16-trimethylene-ie- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans-5-cis-
methyl prostadiac acid -254 nat-15R, 16R-9ß, lick, iS-trihydroxy-lS, lo-trimethylene-lo- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans-5-cis-
methyl prostadiac acid

Example 255

nat- (and ent) -9o (, 15-dihydroxy-II-oxo-IS, 16-tetramethylene-17,18,19,20-tetranor-5-cis, 13-trans-prostadic acid

To a solution of 0.5 g of nat- (and ent) -9o (, llo (, 15-trihydroxy-5 15,16-tetramethylene-17,18,19,20-tetranor-5-cis, 13-trans- Prostadic acid in 25 ml of acetone is added at -35 ° C. with stirring
dropwise 0.67 ml Jones reagent (2.67 g CrO ₃ + 2.3 ml H ₂ SO., which mixture is made up to 10 ml with water). After 13
Minutes are added 0.4 ml of isopropyl alcohol and then 2 ml

LO water to. The mixture is poured into water and then saturated with sodium chloride and extracted into ethyl acetate. The solution is dried over magnesium sulfate, the solvent is drawn off and a yellow oil is obtained. This oil
is chromatographed on a dry silica gel gel

L5 filled column, eluting with ether and 1% acetic acid. The main band is isolated and extracted with ethyl acetate and acetone, and the title compound is obtained.

Example 256

nat- (and ent) -9o <, 16-dihydroxy-II-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostadic acid.

130 mg of nat- (and ent) -9oC, HoC, 16-trihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostadic acid are dissolved in 7 ml of acetone and 2 ml of glacial acetic acid and cool under nitrogen in a dry ice / acetonitrile bath. Then there

0.15 ml of Jones reagent is added and the mixture is stirred during 2 hours in the same cooling bath. Then the temperature of the bath is slowly increased to -20 ° C until the mixture is mixed discolored green. Then a few drops of isopropyl alcohol are added, the mixture is diluted with water and extracted three times with 30 ml of ether. The ether extracts are combined and washed

809841/0791

them with water and saline. The solvents are then evaporated to dryness in the presence of toluene. The residue is passed through a column filled with silica gel which has been packed with 40% ethyl acetate in hexane. Eluting a 40 to 50% solution of ethyl acetate in hexane gives 46 mg of the pure product.

Examples 257-283

In the manner indicated in Examples 224 and 225 above, the 9o (, llo (, - hydroxy-prostaglandins indicated in Table IX below are oxidized with the Jones reagent to form the 9ΰ (- hydroxy-11 -oxo- prostaglandine ..

809841/0 791

TABLE IX

example 257 9 <<, llate-dihydroxy-prosta-
glandin by example 9 <ä-Hydroxy-11-oxo-pros taglandin-prodokt 258 197 nat- (and ent) -9o <, 16-dihydroxy-ll-oxo-16,17-tetramethylene-
18,19,20-trinor-13-trans-5-cis-prostadic acid 259 198 nat-15R, 16S- (and ent-15S, 16R) -9o (, 15-dihydroxy-ll-oxo-15,16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-prostenic acid CD 260 199 nat-15R, 16R- (and ent-15S, 16S) -9 ^, 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-prostenic acid O
CO
00 261 200 nat- (and ent) -9c <, 16-dihydroxy-ll-oxo-16, 17-tetramethylene-
18,19,20-trinor-13-trans-prostenic acid "·>.
O 262 201 nat-15R, 16R- (and ent-15S, 16S) -9ος, 15-dihydroxy-ll-oxo-lS, -
16-trimethylene-16- (4-fluorophenoxy) -7-homo-17,18,19,20-
tetranor-13-trans-prostenic acid -J
CO 263 202 nat-15S, 16R- (and ent-15R, 16S) -9o (, 15-dihydroxy-ll-oxo-lS, 16-
tri-ethylene-13-trans-5-cis-prostadienoic acid 264 203 nat-15S, 16S- (and ent-15R, 16R) -9 <K, lS-dihydroxy-ll-oxo-15,16-
trimethylene-13-trans-5-cis-prostadienoic acid 265 204 nat-15R, 16S- (and ent-15S, 16R) ~ 9 <K, 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid 266 205 nat-15R, 16R- (and ent-15S, 16S) -9q (, 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetra-
nor-13-trans-5-cis-prostadic acid 206 nat-15R, 16S- (and ent-15S, 16R) -9ci., 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid

TABLE IX (continued)

example 267 9o (, llo ^ -dihydroxy-prosta-
glandin by example 9 ^ -Hydroxy-ll-oxo-prostaglandin product 268 207 nat-15R, 16R- (and ent-15S, 16S) -9 *, 15-dihydroxy-ll-oxo-15,16-
trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid 269 208 nat-15R, 16S- (and ent-15S, 16R) -9o (, 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid OO
O 270 209 nat-15R, 16R- (and ent-15S, 16S) -9o <, 15-dihydroxy-ll-oxo-15,16-
trimethylene-16 (3-chlorophenoxy), 17,18,19,20-tetranor-13-trans-
5-cis-prostadic acid CO
OO
-t- 271 210 nat-16R, 17S- (and ent-16S, 17R) -9e <, lo-dihydroxy-H-oxo-lo, 17-
trimethylene-1- (3-trifluoromethylphenoxy) -18,19,20-trinor-13-
trans-5-cis-prostadic acid / 079 272 211 ■ nat-16R, 17R- (and ent-16S, 17S) -9o <, le-dihydroxy-ll-oxo-lö, 17-
trimethylene-l- (3-trifluoromethylphenoxy) -18,19,20-trinor-13-
trans-5-cis-prostadic acid 273 212 nat-15R, 16R- (and ent-15R, 16S) -9o (, 15-dihydroxy-ll-oxo-lS, 16-
trimethylene-la, lb-dihomo-IS-trans-S-cis-prostadienoic acid 274 213 nat- (and ent) -9, lS-dihydroxy-ll-oxo-lS .. 16-tetramethylene-
Ia, lb-dihomo-17,18,19,20-tetranor-13-trans-5-cis-prostadiene-
acid 275 214 nat-15S, 16S- (and ent-15R, 16R) -9 <^, lS-dihydroxy-ll-oxo-S-oxa-
15, lo-trimethylene-IS-trans-prostenic acid 276 215 nat- (and ent) -9o <, 15-dihydroxy-11-oxo-3-oxa-15, 16-tetramethylene
17,18,19,20-tetranor-13-trans-prostenoic acid 216 nat-15S, 17S- (and ent-15R, 17R) -9 (X, lS-dihydroxy-ll-oxo ^ -methyl-
15,17-trimethylene-19,20-dinor-13-trans-prostenic acid

TABLE IX (continued)

CO O CO OO

-J (O

example 9o (, llo (-dihydroxy-prosta-
glandin by example 9o (-Hydroxy-ll-oxo-prostaglandin product 277 217 nat-15S, 16R-94,15-dihydroxy-ll-oxo-15,16-trimethylene
13-trans-prostenic acid methyl ester 278 218 nat-9 <^, lS-dihydroxy-ll-oxo-lS, 16-tetramethylene-17,18,19, 20-
tetranor - 13-trans-prostenic acid methyl ester 279 219 nat-9of, 15-dihydroxy-ll-oxo-16,17-tetramethylene-18,19,20-
trinor-13-trans-prostenic acid methyl ester 280 220 ent-15R, 16R-9o (, 15-dihydroxy-ll-oxo-IS, 16-trimethylene
13-trans-prostenic acid methyl ester 281 221 nat-15S, 16R-9o (, 15-dihydroxy-ll-oxo-lS, 16-trimethylene
13-trans-5-cis-prostadienoic acid methyl ester 282 222 nat-15R, 16S-9 <X, 15-dihydroxy-ll-oxo-lS, 16-trimethylene
16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-
trans-5-cis-prostadienoic acid methyl ester 283 223 nat-l5R, l6R-9o <, 11i><, dihydroxy-ll-oxo-l5,16-trimethylene-16-
(3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans-
5-cis-prostadienoic acid methyl ester

rs)

co (J)

YES

Example 284

nat- (and ent) -IS-hydroxy-Q-oxo-IS, 16-tetramethylene-17,18,19, -20-tetranor-5-cis, 10,13-trans-prostatrienoic acid.

To 2.07 g (6.38 mmol) of 1- (2-iodovinyl) -l-trimethylsilyloxy-cyclohexane in 3 ml of toluene is added with stirring and under nitrogen. at -4o ° C 16.1 ml of a 0.8m tert-butyllithium solution in pentane. After 1 hour, 6 ml of ether are added and the mixture is stirred at 25 ° C. for 25 minutes. The solution is then cooled to -78 ° C. and a solution of 0.842 g (6.45 mmol) of copper pentine and 2.58 ml of hexamethylphosphoric triamide in 35 ml of ether is added. After 1 hour and 45 minutes, a solution of 2.35 g (6.38 mmol) of 2- (6-carbotrimethylsilyloxy-hex-2-cisenyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one in 35 ml of ether too. After stirring for 1 hour at -78 ° C. and for 1 hour at 0 ° C., the mixture is poured into a dilute hydrochloric acid solution. The mixture is extracted with ether, the ether is drawn off and the residue is dissolved in 14 ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1). After 1 hour, the mixture is poured into water and extracted with ether. The ether is stripped off, the residue is purified by dry column chromatography over silica gel, eluting with ether containing 0.75% acetic acid, and 1.1 g of the title compound is obtained.

Examples 285-298

If the mixtures of conjugate addition are allowed to ^{warm to 0} ° C. according to the procedure of Example 284, then from the iodovinyl compounds or vinyl tin compounds indicated in Table X below and the indicated cyclopent-2-ene-l- ons that are also in the

30 Table X specified products.

809841/0791

In the cases where two diastereoisomers are formed in the conjugate addition reaction, only one of the diastereoisomers is shown in Table X. It goes without saying, however, that the other diastereoisomer is also formed which, in its nat and ent forms, has the opposite (mirror image) configuration on the asymmetric carbon atoms of the β chain (the chain which the C _1. , -C ₁ . -Rest etc.) with respect to the nat and ent forms of the specified diastereoisomer. These two diastereo-

However, the invention also relates to isomers as well as their corresponding enantiomers.

809841/0791

TABLE X

example 285 Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-oxo-10, 13-trans-prostadienoic acid pro-
duct and its diastereoisomer
(if there is one, see above) 286 29a 2- (6-carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-
9-oxo-15,16-trimethylene-13-trans, 10-
prostadic acid 287 36 2- (6-carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat-15S, 16S- (and ent-15R, 16R) -15-Hy-
droxy-9-oxo-15,16-trimethylene-13-trans-
10-prostadic acid αο
ο
Γ « 288 31 2- (6-carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat- (and ent) -15-hydroxy-9-oxo-15,16-
tetramethylene-17,18,19,20-tetranor-
13-trans, 10-prostadic acid 1841/0 289 39 2- (6 - carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat-15R, 16S- (and ent-15S, 16R) -15-Hy-
droxy-9-oxo-15, lö-trimethylene-lo- (3-
trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans, 10-prostadic acid 791 290 40 2- (6-carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15,16-trimethylene-16- (3 -
trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans, 10-prostadic acid 291 30th 2- (6-carboxyhexyl) -4-hy-
droxy-cyclopent-2-en-l-one nat- (and ent) -16-hydroxy-9-oxo-16,17-
tetramethylene-18,19,20-trinor-13-
trans, 10-prostadic acid 292 42 2- (5-carboxypentyl) -cyclo-
pen-2-en-l-on nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15, lö-trimethylene-lo- (4-
fluorophenoxy) -17,18,19,20-21-pentanor- ro
13-trans, 10-prostadic acid 00 29a 2- (6-carboxyhex-2-cis-
enyl) -4-hydroxycyclopent-
2-en-l-on nat-15S, 16R- (and ent-15R, 16S) -15-Hy- ^ ₀
droxy-9-oxo-15, lo-trimethylene-IS-trans-fsj
5-cis, 10-prostadienoic acid <j>

TABLE X (continued)

example

Iodovinyl compound or
Vinylζinn connection of
example

Cyclopent-2-en-1-one 9-oxo-10,13-trans-prostadic acid product and its diastereoisomer (if there is one, see above)

293

294

36

39

295

40

296

297

298

41

43

30th

2- (6-carboxyhe; c-2-cisenyl) -4-hydroxycylcopent-2-en-1-one

2r- (6-carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -4-hydroxycyclopent-2-en-1-one

2- (6-Carboxyhex ~ 2-cisenyl) -4-hydroxycyclopent-2-en-1-one

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16 ~ trimethylene-13-trans-5-cis, 10-prostatrienoic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-lo- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans -5-cis, 10-prostatrienoic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans -5-cis, 10-prostatrienoic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-lo- (4-fluorophenoxy) -17,18,19,20-tetranor-13-trans -5-cis, 10-prostatrienoic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-lo- (3-chlorophenoxy) -17,18,19,20-tetranor-13-trans -5-cis, 10-prostatrienoic acid

nat- (and ent) -lo-hydroxy-g-oxo-lo, 17-tetramethylene-18,19,20-trinor-13-trans-5-cis, 10-prostatrienoic acid

CO NJ (J)

Example 299

Nat- (and ent) -IS-hydroxy-g-oxo-IS, 16-tetramethylene-17,18,19, -20-tetranor-10, 13-trans-prostadic acid.

A solution of 1.5 g of nat- (and ent) -llo (, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenic acid is left and 80 ml of 0.5N hydrochloric acid in a tetranhydrofuran / water mixture (1/1) for 72 hours under argon at room temperature. You treat them Then solution with brine and extract with ether. Wash the extract with saline and dry with anhydrous Magnesium sulfate. The residue that remains after the solvent has evaporated is purified by dry column chromatography over silica gel, the product being obtained in the form of an oil.

15 Example 300

nat- (and ent) -16, hydroxy-9-oxo-16,17-tetramethylene-18,19, 20-trinor-5-cis, 10,13-trans-prostatrienoic acid.

40 mg of nat- (and ent) -lltf, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis, 13-trans-prostatic acid are dissolved with stirring and under Nitrogen at room temperature for 3 days in 5 ml of a 0.5N hydrochloric acid solution in a tetrahydrofuran / water mixture (which is obtained by making up to 10 ml of 5 ml of hydrochloric acid solution with tetrahydrofuran). The mixture is then poured into a saturated sodium chloride solution and extracted with ether. The ether extract is washed with water and brine, after which the solvent is evaporated. The dried residue is applied to a thin-layer chromatography plate and developed twice with a solution of 40 % ethyl acetate and 0.5% acetic acid in hexane. The product is recovered in ethyl acetate.

8098 4 1/0791

Examples 30 to 315

By treating the IV-hydroxy-9-oxo-prostenoic acids given in Table XI below according to the procedure of Examples 299 and 300, the products likewise given in this table are obtained.

809841/0791

TABLE XI

example llc ^ -hydroxy-9-oxo-prosta-
glandin by example 9-Oxo-10, 13-trans-prostaglandin product 301 131 nat-15R, 16R- (and ent-15S, 16S) -Ιδ-Ηγάι-οχγ-θ-οχο-Ιδ, 16-
trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-
10.13-trans-5-cis-prostatic acid 302 136 nat-16R, 17S- (and ent-16S, 17R) -lö-Hydroxy-g-oxo-lö, 17-
trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-
trinor-10,13-trans-5-cis-prostadic acid CO 303 137 nat-16R, 17R- (and ent-16S, 17S) -16-hydroxy-9-oxo-16,17-
trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-
trinor-10,13-trans-5-cis-prostadic acid O
co
CD 304 138 nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-
trimethylene-la, lb-dihomo-10, lS-trans-S-cis-prostadiene-
acid 1/07 « 305 140 nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene
Ia, lb-dihomo-17,18,19,20-tetranor-lO.13 - trans-5-cis-
prostadic acid % v 306 146 nat-15S <16S- (and ent-15R, 16R) -IS-Hydroxy-g-oxo-S-oxa-
15,16-trimethylene-10,13-trans-prostenic acid 307 147 nat- (and ent) -15-hydroxy-9-oxo-3-oxa-15,16-tetramethylene
17,18,19,20-tetranor-l0,13-trans-prostenic acid 308 151 nat-15S, 17S- (and ent-15R, 17R) -lS-hydroxy ^ -oxo ^ -methyl-
15,17-trimethylene-19,20-dinor-10,13-trans-prostenic acid 309 156 nat-15S, 16R-15-hydroxy-9-oxo-15,16-trimethylene-10,13-
trans-prostate methyl ester

GO K) CD

TABLE XI (continued)

example llo (-hydroxy-9-oxo-prosta-
glandin by example 9-Oxo-10, 13-trans-prostaglandin product 310 158 nat-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-
tetranor-10,13-trans-prostenoic acid methyl ester 311 159 nat-16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-
trinor-10,13-trans-prostenic acid methyl ester . 312 '163 nat-15R, 16R-15-hydroxy-9-oxo-15,16-trimethylene-10, 13-
trans -prostenic acid methyl ester 313 168 nat-15S, 16R-15-hydroxy-9-oxo-15,16-trimethylene-10, 13-
trans -5-cis-prostadienoic acid methyl ester S ³ I ⁴
CO
00 172 nat-15R, 16S-15-hydroxy-9-oxo-15,16-trimethylene-16- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-10, 13-
trans -5-cis-prosadienoic acid methyl ester Ξ315
-v,
0
CO 173 nat-15R, 16R-15-hydroxy-9-oxo-15,16-trimethylene-16- (3-
trifluoromethylphenoxy) -17,18,19,20-tetranor-10, 13-
trans -5 -eis -pros tadienoic acid methyl ester

00 co cn

Example 316

nat- (and ent) -lo-hydroxy ^ -oxo-lo, 16-tetramethylene-17,18, -19,20-tetranor-5-cis, 8,13-trans-prostatrienoic acid.

A solution of 0.70 g of potassium carbonate and 0.40 g of nat- (and ent) -HcC, lo-dihydroxy-g-oxo-IS, 16-tetramethylene-17,18,19,20-tetranor-5- cis, 13-trans-prostadic acid in 200 ml of a methanol / water mixture (5/5) for 24 hours Stand room temperature. The solution is then diluted with water and acidified with hydrochloric acid. One extracts the solution with ether, the ether layer dries over magnesium sulfate, the solvent is drawn off and the title compound is obtained in the form of an oil.

Examples 317 to 322

Following the procedure given in Example 316 above, those given in Table XII below are treated llot hydroxy compounds with potassium carbonate and

8 (12)

receives the A derivatives given in the same table.

Example 323

nat- (and ent) -llo (/ β-cyano-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis, 13-trans-prostadic acid.

A mixture of 0.45 g of nat- (and ent) -15-hydroxy-9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-13-trans, 5-cis, 10- prostatric acid, 0.68 g of acetone cyanohydrin and 0.143 g of sodium carbonate in 1 ml of ethanol and 1 ml of water under nitrogen for 2 hours at reflux. Then stir the solution is diluted overnight, the dark solution obtained is diluted with water, acidified with hydrochloric acid and

80984 1/0791

extracted with ether. The ether solution is dried with magnesium sulfate and activated charcoal, filter through a layer of silica gel and draw off the solvent, leaving 0.37 g of the desired product.

Examples 324 to 332

Following the procedure of Example 323, the Δ derivatives given in Table XIII below are formed the 11of / β-cyano derivatives also indicated there.

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TABLE XII

example 1 lo (-hydroxy prostaglandin
of example Δ ^{8 (12} -prostaglandin 317 71 nat- (and ent) -16-hydroxy-9-oxo-16,17-tetramethylene
18,19,20-trinor-8,13-trans, 5-cis-prostatrienoic acid 318 74 nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-
trimethylene-8,13-trans-prostadic acid 319 75 nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-
trimethylene-8,13-trans-prostadic acid O 320 76 nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene
17,18,19,20-tetranor-8,13-trans-prostadic acid CU
OO
-fr *. 321 118 nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-
trimethylene-8,13-trans, 5-cis-prostatrienoic acid ~ ^.
O 322 119 nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-
trimethylene-8,13-trans, 5-cis-prostatrienoic acid

example A ^l0 derivative
example from TABLE XIII 324 195 llo (/ ß-cyano-prostaglandin 325 196 nat-15S, 16R- (and ent-15R, 16S) -llo '/ ß-cyano-lS-hydroxy-g-oxo-
15,16-trimethylene-13 - trans-prostenic acid 326 197 nat-15S, 16S- (and ent-15R, 16R) -llX / ß-cyano-lS-hydroxy-g-oxo-
15,16-trimethylene-13-trans-prostenic acid 327 198 nat- (and ent) -Hai / ß-cyano-lS-hydroxy-g-oxo-lS, 16-tetramethylene-
17,18,19,20-tetranor-13-trans-prostenoic acid 09 328 199 nat-15R, 16S- (and ent-15S, 16R) -lltf / ß-cyano-lS-hydroxy ^ -oxo-
15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans-prostadic acid W.
<O
CO 329 200 nat-15R, 16R- (and ent-15S, 16S) -lltf / ß-cyano-lS-hydroxy-g-oxo-
15, Lö-trimethylene-ie- (3-trifluoromethylphenoxy) -17,18,19,20-
tetranor-13-trans-prostenic acid O 330 210 nat- (and ent) -lltf / ß-Cyano-lö-hydroxy ^ -oxo-lö, 17-tetramethylene-
18,19,20-trinor-13-trans-prostenic acid co 331 209 nat- (and ent) -1 Ιοί / ß-cyano-16-hydroxy-9-oxo-16,17-tetramethylene
18,19,20-trinor-13-trans, 5-cis-prostadic acid 332 213 nat- (and ent) -llO (/ ß-cyano-15-hydroxy-9-oco ~ 15,16-tetramethylene-
17,18,19,20-tetranor-13-trans-prostenoic acid nat-16R, 17R- (and ent-16S, 17S) -lltf / ß-cyano-ie-hydroxy-g-oxo-
16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-
13-trans-5-cis-prostenic acid

Example 333

2- (6-Carbotrimethylsilyloxy-hex-2-cis-enyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1 g of 2- (6-carboxy-hex-2-cis-enyl) -4-hydroxy-cyclopent-2-en-1-one 3.3 ml of hexamethyldisilazane are added to 12.5 ml of dry pyridine at 15 ° C. under argon and with stirring (HMDS) followed by the dropwise addition of 1.6 ml of trimethylchlorosilane (TMCS) - stir the formed Mixture for 1 hour at room temperature and then evaporate to dryness (vacuum pump). Take the residue in hexanes and filtered through a filter aid (Celite). Evaporation of the mother liquor followed by evaporation twice with toluene gives 1.5 g (96%) pure 2- (6-Carbotrimethylsilyloxy-hex-2-cis-enyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

Example 334

2- (6-Carbotrimethylsilyloxy-hexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1 g of 2- (6-carboxy-hexyl) -4-hydroxy-cyclopent-2-en-1-one in 12.5 ml of dry pyridine is added at 15 ° C under argon and with stirring 3.3 ml of hexamethyldisilazane, after which 1.6 ml of trimethylchlorosilane are added dropwise. The mixture formed is stirred for 1 hour at room temperature and then concentrated to dryness. The residue is taken up in hexane, filtered through diatomaceous earth, the mother liquor evaporates and the pure product is obtained by evaporating twice with toluene.

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Example 335

2- (6-Carbomethoxy-hexyl) -4 (R) -trimethylsilyloxy-cyclopent-2-en-1-one.

To a solution of 1.0 g of 2- (6-carbomethyl-hexyl) -4 (R) -hy-5 droxy-cyclopent-2-en-l-one (R. Pappo et al., Tetrahedron Letters (1973) 943) in 12.5 ml of dry pyridine is added at 15 ° C. under argon and with stirring, 3.3 ml (24 mmol) of hexamethyldisilazane (HMDS) and then 1.6 ml (20.5 mmol) of Trxmethylchlorosxlan (TMCS) are added dropwise. The mixture formed is stirred 10 for 1 hour at room temperature and then concentrated

Dry off (vacuum pump). The residue is then taken up in hexanes and filtered through a filter aid (CeIite). Evaporation of the mother liquor, followed by evaporation twice with toluene, gives 2- (6-carbomethoxy-hexyl) -15 4 (R) -trimethylsilyloxy-cyclopent-2-en-1-one.

Example 336

2- (6-Carbomethoxy-hexyl) -4 (S) -trimethylsilyloxy-cyclopent-2-en-1-one.

Following the procedure of Example 239, treatment of 2- (6-carbomethoxy-hexyl) -4 (S) -hydroxy-cyclopent-2-en-1-one is obtained (R. Pappo et al., Tetrahedron Letter (1973) ^ 943) with hexamethyldisilazane and trimethylsilyl chloride die Title compound.

Example 337
5-chloro-1- (2-furyl) -1-pentanol.

To a stirred suspension of 2-puryllithium (which one from 0.53 mol of n-butyllithium and 39.5 g of furan according to the in

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J. Org. Chem. 27 (1962) 1216) in 350 ml of ether and approx. 200 ml of hexane, a solution of 57.9 g of 5-chloropentanol (Chemical Abstracts 59 (1963) 7579 f) in 80 ml of ether. The mixture is heated for 20 minutes at 0 ⁰ C, stirred for 15 minutes at O ⁰ C and then treated with 140 ml of a saturated ammonium chloride solution. The ether phase is washed with water and with salt solution, dried over a magnesium sulfate / potassium carbonate mixture and concentrated to dryness, a liquid being obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): <$ "3.59 (triplet, CH ₂ Cl ₂ ) and 4.70 (triplet, CH ₂ CHOH).

Example 338

5- (Carbethoxymethylethyl) -1- (2-furyl) -1-pentanol.

To a mixture of 76 g of ethyl mercaptoacetate, stirred at reflux, 79.5 g of 5-chloro-l- (2-furyl) -1-pentanol (Example 337) and 10 ml of a 1.5 M sodium ethylate solution in Ethanol is added in the course of 15 minutes a further 300 ml of the 1.5m sodium ethylate solution. The mixture formed is stirred reflux for 3 hours, cool and concentrate in order to remove most of the ethanol. The residue is distributed between ether and water. The ether phase is washed with salt solution and dried over potassium carbonate. The solution is then concentrated, diluted with xylene, concentrated again and an oil is obtained. NMR spectrum (CDCl-):

<f 3.24 (singlet, -S-CH ₂ CO ₂ C ₂ H ₅ ) and 4.70 (triplet, - CH ₂ CHOH).

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MS 2813281

Example 339

2- (e-Carboxy-5-thia-hexyl) ^ - hydroxy-cyclopent ^ -en-l-one.

A solution of 125 g of 5- (carbethoxymethylthio) -l- (2-furyl) -l-pentanol is heated (Example 338), 22.4 g of sodium formate, 250 ml of formic acid and 400 mg of hydroquinone in 2000 ml of dioxane and 1330 ml of water for 20 hours with stirring to reflux.

The solution, the crude 3-hydroxy-2- / 3- (carbäthoxyäthylthio) -butyl7-cyclopent-4-en-l-one, is then cooled contains, from and

10 treated them for 10 minutes while stirring with 75 ml

Sulfuric acid (d = 1.84). The stirred solution is then refluxed for 16 hours and cooled then it saturates with sodium chloride and extracted with ethyl acetate. The extract is washed with saline solution,

15 dries it over magnesium sulphate and constricts it. The

The residue is chromatographed on silica gel using of chloroform, which is progressively enriched with ether, ether and ether, which is progressively enriched with acetone is, as the eluent, the title compound in

^ O takes the form of an oil. NMR spectrum CDCl ₃ ): £ * 3.24 (singlet, -S-CH ₂ -CO ₂ C ₂ H ₅ ) and 5.0 (broad singlet, -CHOH-).

Example 340

Preparation of 2- (δ-carbotrimethylsilyloxy-S-thia-hexyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a stirred solution of 28.4 g of 4-hydroxy-2- / 3- (carboxymethylthio) -butyl7-cyclopent-2-en-1-one (Example) and 76 ml of hexamethyldisilazane in 330 ml of pyridine are added at 5 ° C in the course of 5 minutes 38 ml of chlorotrimethylsilane. The mixture is stirred for 3.5 hours at room temperature

809841/0791

door, for 5 minutes at 45 ° C and then steam it to remove of the solvent. The residue is then stirred with 100 ml of petroleum ether and filtered. Treated the filtrate it is filtered with activated charcoal, the filtrate is concentrated with toluene and a liquid is obtained. NMR spectrum (CDCl.,):

& 0.18 (singlet, trimethylsilyloxy group) and 0.28 (singlet, trimethylsilyloxy-carbonyl group).

Example 341

4-chloro-1- (2-furyl) -1-butanol.

To a stirred suspension of 2-furyllithium (which has been prepared from 0.53 mol of n-butyllithium and 39.5 g of furan according to the procedure described in J. Org. Chem. 27 (1962) 1216) in 350 ml of ether and approx A solution of 57.9 g of 4-chlorobutanol (Chemical Abstracts 59 (1963) 7579 f) in 80 ml of ether is added at -78 ° C. in the course of 25 minutes. The mixture is heated over 20 minutes to ⁰ ° C, stirred for 15 minutes at 0 ⁰ C and then treated with 140 ml of a saturated Amrnoniumchloridlösung. The ether phase is washed with water and salt solution, dried over a magnesium sulfate / potassium carbonate mixture and evaporated to dryness, a liquid being obtained. NMR spectrum (CDCl-.): If 3.59 (triplet, CH ₂ Cl) and 4.70 (triplet, CH ₂ CHOH).

Example 342

4- (carbethoxymethylthio) -1- (2-furyl) -1-butariol.

To a mixture of 76 g of ethyl mercaptoacetate, stirred at reflux, 79.5 g of 4-chloro-1- (2-furyl) -1-butanol (Example 341) and 10 ml of a 1.5 M sodium ethylate solution in ethanol are added in the course of 15 minutes a further 300 ml of a 1.5 M sodium ethylate solution. The mixture formed is stirred

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Schung for 3 hours under reflux, cools and concentrates Removal of the bulk of the ethanol. The residue is distributed between ether and water. The ether phase is washed with saline and dry over potassium carbonate. The solution is then concentrated, diluted with xylene, and again concentrated

one and get an oil. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): <f 3.24 (singlet, -S-CH ₂ -CO ₂ C ₂ H ₅ ) and 4.70 (triplet, CH ₂ CHOH).

Example 343

2- (5-Carboxy-4-thia-pentyl) ^ -hydroxy-cyclopent ^ -en-l-one.

A solution of 125 g of 4- (carbethoxymethylthio) -l- (2-furyl) -l-butanol is heated (Example 342), 22.4 g of sodium formate, 250 ml of formic acid and 400 mg of hydroquinone in 20OO ml of dioxane and 1330 ml of water for 20 hours with stirring to the boil at reflux.

The solution containing the crude 3-hydroxy-2 ~ / 3- (carbäthoxymethylthio) propyl7-cyclopent-4-en-1-one is then cooled and treats it for 10 minutes while stirring with 75 ml of sulfuric acid (d = 1.84). The stirred solution is heated reflux for 16 hours, cools, saturates

20 with sodium chloride, extracted with ethyl acetate,

washes the extract with saline solution, dries it over magnesium sulfate and constricts it. The residue is chromatographed on silica gel using chloroform, the progressive is enriched with ether, ether and ether progressively enriched with acetone as eluents, whereby the title compound is obtained in the form of an oil.

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Example 344

2- (S-Carbotrimethylsilyloxy ^ -thia-pentyl) -4-trimethylsilyloxy-cyclopent-2-en-1-one.

To a stirred solution of 28.4 g of 4-hydroxy-2- / 4- (carboxy methylthio) butyl7-cyclopent-2-en-l-one (example) and 76 ml of hexamethyldisilazane in 330 ml of pyridine are added in the course of 5 minutes at 5 ° C 38 ml of chlorotrimethylsilane. The mixture is stirred for 3.5 hours at room temperature, for 5 minutes at 45 ° C. and then evaporated to remove the solvent. The residue is slurried with 100 ml of petroleum ether and filtered. The filtrate is treated with activated charcoal, filtered, the filtrate is concentrated with the aid of toluene and a liquid is obtained. NMR spectrum (CDCI): So, 18 (singlet, trimethylsilyloxy group) and O, 28 (singlet, trimethylsilyloxycarbonyl group).

Example 345

nat- (and ent) -110 (, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-prostanoic acid.

A solution of nat- (and ent) -11 <¥, 15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans- Prostenic acid (800 mg) in 50 ml of ethyl acetate in a Parr apparatus using 500 mg of 5% rhodium on carbon as a catalyst. The catalyst is then filtered off, the filtrate is concentrated to dryness and the Title compound.

Examples 346 to 348

By hydrogenating the prostate acids given in Table XIV below in ethyl acetate using

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generation of a rhodium-on-carbon catalyst according to the The procedure of Example 63 gives the prostanoic acids given in the same table.

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TABLE XIV

Example 13-trans-prostatic acid of Example

O CO OO

346

347 348

72

73 83 Postanoic acid

nat-15S, 16R- (and ent-15R, 16S) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene prostanoic acid

nat-15S, 16S- (and en t-15R, 16R) -llo (, 15-dihydroxy-9-oxo-15,16-trimethylene prostanoic acid

nat- (and ent) -llo (,, 16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-prostanoic acid

Example 349

nat-15S, 16S- (and ent-15R, 16R) -lS-hydroxy-g-oxo-lS, 16-trimethylene-13-trans-prostenic acid ethyl ester and nat ~ 15R, 16R- (and ent-15S, 16S) - 15-Hydroxy-9-oxo-15, lo-trimethylene - ^ -
trans-prostenic acid ethyl ester.

9.56 ml of a 2.3m solution of n-butyllithium are added to a solution of 2.42 g of thiophenol in 60 ml of ether under nitrogen at ^{0 ° C.} The mixture is stirred for 1 hour and then a solution of 8.64 g of tri-n-butyl copper iodide

IO phosphine complex in 120 ml of ether too. To 7.69 g of IR, 2R (and IS, 2S) -1- (trans-2-iodovinyl) -1-trimethylsilyloxy-2-butylcyclopentane 53.75 ml of a 0.8m tert-butyllithium solution are added to 15 ml of toluene at -45 ° C. After stirring under nitrogen The solution is removed from the for 90 minutes

15 cooling bath and stir it for 10 minutes. The solution is cooled again to -78 ° C and 10 ml of ether are added. then The copper solution is cooled to -78 ° C and added to the vinyl solution via a double needle. After 20 minutes, 5.0 g are added 2- (6-Carbethoxy-hexyl) -cyclopent-2-en-l-one in 20 ml of ether

to. One then the mixture is stirred 9O minutes at -5o to -40 ⁰ C and then for 30 minutes at O ⁰ C. It is a saturated ammonium chloride solution to the mixture, which was then stirred for 10 minutes. Separate the organic layer and extract the aqueous layer

25 with ether. The combined ethereal solutions are washed with dilute Hydrochloric acid solution and then with a saturated aqueous sodium bicarbonate solution. You dry them Solution with magnesium sulfate and uses a furan / acetic acid / water mixture (2/4/1) as solvent. Then you give

three drops of concentrated hydrochloric acid to and

The mixture is stirred for 2 hours at 45 ° C., after which it is stored ^{at 0 ° C. overnight.} The mixture is then poured into water and extracted with ether. The ethereal solution

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it is washed with water and a saturated aqueous sodium bicarbonate solution, followed by drying with magnesium sulfate. The ether is removed and a yellow oil is obtained. This oil is chromatographed on a dry silica gel column, eluting with an ether / hexane mixture (1/1) and adding 1.22 g of nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9- oxo-15, -16-trimethylene-13-trans - prostenic acid ethyl ester (lower R _f value) and 0.51 g of nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo- 15, Lö-trimethylene-IS-trans-prostenic acid ethyl ester (higher R _f value) and 0.83 g of a mixture of the two isomers is obtained.

Example 350

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15, 16-trimethylene-13-trans-prostenoic acid ethyl ester and nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-13-trans-prostenoic acid ethyl ester.

To a solution of 2.42 g of thiophenol in 60 ml of ether are added under nitrogen at 0 ⁰ C, 9.56 ml of a 2.3 m n-butyllithium solution. The mixture is stirred for 1 hour and then 3.64 g of the copper-tri-n-butyl-phosphine complex in 120 ml of ether are added. The solution is kept in a refrigerator. To 7.69 g of IR, 2S- (and IS, 2R) -1- (trans-2-iodovinyl) -l-trimethylsilyloxy-2-butylcyclopentane and 15 ml of toluene are added at -45 ° C. 53.75 ml of tert. -Butyllithium. After stirring for 90 minutes, the solution is removed from the cooling bath, stirred for 15 minutes and then cooled again to -78 ° C. The copper solution is cooled to -78 ° C. and added to the vinyl lithium solution. After 35 minutes, 5.0 g of 2- (6-carbethoxy-hexyl) -cyclopent-2-en-l-one in 35 ml of ether are added, whereupon 35 ml of ether are added. The mixture is then stirred for 90 minutes at -45 ° C. and finally for 30 minutes at ⁰ ° C. Then a saturated ammonium chloride solution is added

8098A1 / 0791

solution, separates the ethereal layer, washes it with dilute hydrochloric acid and concentrated sodium bicarbonate solution, if the solution dries over magnesium sulfate, the solvent is stripped off and a yellow liquid is obtained.

5 This liquid is dissolved in 150 ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1). One drop of concentrated hydrochloric acid solution is added and the mixture is stirred Mix for 30 minutes at room temperature and then for 3.5 hours at 40 ° C. One draws the solvent

and a mixture of the two racemic title compounds is obtained. The diastereoisomers can be separated by chromatography.

Example 351

nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene-17,18, -15 19,20-tetranor-13-trans-prostenic acid ethyl ester.

To a solution of 0.735 g of 1- (trans-2-iodovinyl) -1-trimethylsilyloxy-cyclohexane 1.14 ml of a 2.04M n-butyllithium solution are added to 1 ml of toluene, which has been cooled to -40 ° C. under argon in hexane. The mixture is stirred for 2 hours, 2 ml of ether are added and the mixture is allowed to dissolve Warm up to room temperature, a clear, colorless solution being obtained. This solution is cooled to -40 ° C. and treated then with O.90 ml of a 2.44m trimethylaluminum solution in heptane. The mixture is allowed to warm to room temperature and then treated with 2 ml of ether. By Cooling to -40 ° C gives a precipitate. The reaction mixture is then treated with 0.620 g of 2- (6-carbethoxyhexyl) cyclopent-2-en-1-one. The cooling bath is removed, the mixture is allowed to warm to room temperature and is stirred over night. The mixture is then poured onto ice and diluted hydrochloric acid, extracted with ether and washed organic phase with water and a saturated salt solution,

809841/0791

dry with magnesium sulfate and evaporate to give 1.042 g of an almost colorless oil. You submit the whole crude oil of a dry column chromatography over 100 g of silica gel, which is in a column with dimensions of 50.8 3.18 cm (20 χ 1 1/4 inch) packed and equilibrated with 10% by weight of a benzene / ethyl acetate mixture (9/1). The column is eluted with a benzene / ethyl acetate mixture (9/1) and then cut into sections 1 inch (2.54 cm) lengths. The product can be found in the

"" ι column at an R, - value of 0.60 to 0.75 and gives 0.460 g of an oil. This oil is dissolved in 10 ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1) and stir the for 3 minutes at room temperature. Then you vaporize that Solvent in vacuo on a water bath at 37 ° C. 10 ml of xylene are added, the mixture is evaporated and 0.406 g of nat- (and ent -) - 15-Hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenic acid ethyl ester.

Example 352

ant-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15 _; 16-trimethylene-13-trans-prostenic acid.

A mixture of 0.9 g of nat-15S, 16S- (and ent-15R, -16R) -15-hydroxy-9-oxo-15, lo-trimethylene-IS-trans-prostenic acid ethyl ester is stirred and 0.32 g of sodium hydroxide in 1 ml of water and 12 ml of methanol for 3.5 hours at room temperature. Then pour dissolve the solution in water and wash with ether. The solution is acidified with hydrochloric acid and extracted with Ether. The ether is drawn off and 0.83 g of nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-13-transpros are obtained tens acid.

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Example 353

nat-15R, 16R- (and ent-15S, 16S) -IS-Hydroxy - ^ - oxo-lS, 16-trimethylene-13-trans-prostenic acid-

A mixture of 0.38 g of nat-15R, 16R- (and ent-15S, 16S) -IS / hydroxy - ^ - oxo-IS, lo-trimethylene-IS-trans-prostenic acid ethyl ester and 0.14 g is stirred Sodium hydroxide in 6 ml of methanol
for 3.5 hours. Then the solution is poured into water and washed with ether. The solution is acidified with hydrochloric acid and extracted with ether. One withdraws the ether
and receives 0.35 g of the product in the form of a yellow oil.

Example 354

nat-15S, 16R- (and ent-15R, 16S) - and nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-IS-trans-prostenoic acid .

To 3.5 g of a mixture of the ethyl esters of the title compound are added 1.26 g of sodium hydroxide in 2.5 ml of water and
50 ml of methanol. The mixture is stirred for 4 hours at room temperature under nitrogen and then poured into water. The solution is washed with ether, acidified with hydrochloric acid and extracted with ether. The ether layer is dried with magnesium sulfate and activated charcoal and filtered
through a layer of silica gel, the solvent is drawn off
and receives a yellow oil. The product is cleaned thoroughly
dry column chromatography, using an acetic acid

25 ethyl ester / hexane mixture (2/3) eluted and 2.41 g of the

desired mixed isomer is obtained in the form of an almost colorless oil.

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Example 355

Nat- (and ent) -IS-Hydroxy-Q-oxo-IS, 16-tetramethylene-17,18, -19,20 ~ tetranor-13-trans-prostenic acid.

A mixture of 5.54 g of the ethyl ester of the title compound is stirred and 2.58 g of potassium hydroxide in 100 ml of a water / methanol mixture (1/1) under argon for 22 hours Room temperature. The solvent is then partially evaporated in vacuo, the residue is diluted with water and acidified with hydrochloric acid. The aqueous phase is extracted with ether, the organic phase is washed with water and saturated Saline, dry them with magnesium sulfate and evaporates them to dryness. The oil obtained is concentrated in vacuo overnight and 4.826 g of the desired product are obtained in the form of an almost colorless oil.

15 Examples 356 to 452

Following the procedure described in Examples 349, 350 and 351 above, those in the following are prepared Table XV indicated 9-oxo-prostaglandins from the indicated Iodovinyl compounds or vinyl tin compounds and the specified cyclopent-2-en-l-one. The in Table XV specified cyclopent-2-en-l-ones are in the form of their ethyl esters used. The products of the conjugate addition are ethyl esters which, according to the procedure of the examples 352, 353 and 354 are hydrolyzed. In Table XV below, only the acids are given, with it it is understood, however, that according to the invention both the acids as well as the esters are claimed. In cases where two diastereoisomers are formed during conjugate addition only one of the diastereoisomers is given in Table XV. However, it can also be seen here that the other diastereoisomer is also formed, the

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in its nat and ent forms has the opposite (mirror image) configuration on the asymmetric carbon atoms of the β chain (the chain which has the C ₁ ^ -C ₁₄ residue) compared to the corresponding nat and ent forms of the diastereoisomer given in the table. However, these two diastereoisomers are also a subject of the invention, as are their corresponding enantiomers.

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TABLE XV example

Iodovinyl compound or vinyl tin compound of example

Cyclopent-2-en-l-one 9-oxo-prostaglandin derivative and its Diastereoisomer or its ethyl ester, if such is possible (see above)

32

33

34

35

37

38

39

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one

2- (6-carboxyhexyl) cyclopent-2-en-1-one Nat- (and ent) -IS-hydroxy-g-oxo-IS, 16-trimethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -15-hydroxy-9-oxo-15,16-pentamethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat-15S, 17R- (and ent-15R, 17S) -15-hydroxy-9-oxo-15 _/ 17-dimethylene-13-trans-prostenoic acid

nat-15S, 17S- (and ent-15R, 17R) -15-hydroxy-9-oxo-15,17-dimethylene-13-trans-prostenic acid

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-tetramethylene-13-trans-prostenoic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-tetramethylene-13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans -prostenic acid

TABLE XV (continued)

example 363 Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-oxo-prostaglandin derivative and its
Diastereoisomer or its ethyl
ester, if such is possible
(see above) 364 40 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15,16-trimethylene-16- (3-
trifluoromethylphenoxy) ~ 17,18,19,20-
tetranor-13-trans-prostenic acid 00
O 365 30th 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat- (and ent) -16-hydroxy-9-oxo-16,17-
tetramethylene-18,19,20-trinor-13-
trans-prostenic acid CO
OO
4> -
-v. 366 41 2- (6-carboxyhexyl) -cyclo-
pent-k2-en-l-on nat-15R, 16S- (and ent-15S, 16R) -15-Hy-
droxy-9-oxo-15,16-trimethylene-16- (4-
fluorophenoxy), 17,18,19,20-tetranor-
13-trans-prostenic acid 0791 367 42 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15, le-trimethylene-lo- (4-
fluorophenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid 368 43 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15R, 16S- (and ent-15S, 16R) -15-Hy-
droxy-9-oxo-15, lö-trimethylene-lo- (3-
chlorophenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid 369 44 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15,16-trimethylene-16- (3-
chlorophenoxy) -17,18,19,20-tetranor-
13-trans-prostenic acid 45 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15S, 17R- (and ent-15R-17S) -15-Hy-
droxy-9-oxo-15.17-trimethylene-19.20-
dinor-13-trans-prostenic acid

TO CX)

TABLE XV (continued)

example 370 Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-oxo-prostaglandin derivative and its
Diastereoisoraeres or its ethyl
ester, if such is possible
(see above) 371 46 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-15S, 17S- (and ent-15R, 17R) -15-Hy-
droxy-9-oxo-15.17-trimethylene-19.20-
dinor-13-trans-prostenic acid 09 372 47 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-16R, 17S- (and ent-16S, 17R) -16-Hy-
droxy-9-oxo-16,17-trimethylene-2O-me-
ethyl-13-trans-prostenic acid C £>
CO
». 373 48 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-16R, 17R- (and ent-16R, 17S) -16-Hy-
droxy-9-oxo-16,17-trimethylene-2O-
methyl-13-trans-prostenic acid 1/0791 374 49 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-16R, 17S- (and ent-16S, 17R) -16-Hy-
droxy-9-οχο-Ιδ, 17-trimethylene-17- (3-
trifluoromethylphenoxy) -18,19,20-tri-
nor-13-trans-prostenic acid 375 50 2- (6-carboxyhexyl) -cyclo-
pent-2-en-l-on nat-16R, 17R- (and ent-16S, 17S) -16-Hy-
droxy-9-oxo-16,17-trimethylene-17- (3-
trifluoromethylphenoxy) -18,19,20-tri-
nor-13-trans-prostenic acid 376 29a 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15S, 16R- (and ent-15R, 16S) -15-Hy-
droxy-9-oxo-15,16-trimethylene-2-nor-
13-trans-prostenic acid 36 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15S, 16S- (and ent-15R-16R) -15-Hy-
droxy-9-oxo-15,16-trimethylene-2-nor-
13-trans-prostenic acid

TABLE XV (continued)

example Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-oxo-prostaglandin derivative and its
Diastereoisomer or its Äthal-
ester, if such is possible
(see above) 377 31 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat- (and ent) -IS-hydroxy-g-oxo-IS, 16-
tetramethylene-2,17,18,19,20-pentanor-
13-trans-prostenic acid 378 32 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat- (and ent) -15-hydroxy-9-oxo-15,16-
trimethylene-2,17,18,19,20-pentanor-
13-trans-prostenic acid GO 379
σ
OO 33 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat- (and ent) -15-hydroxy-9-oxo-15,16-
pentamethylene-2,17,18,19,20-pentanor-
13-trans-prostenic acid * - 380
"*>
O 34 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15S, 17R- (and ent-15R, 17S) -15-Hy-
droxy-9-oxo-15,17-dimethylene-2-nor-
13-trans-prostenic acid - * 381
<£> 35 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15S, 17S- (and ent-15R, 17R) -15-Hy-
droxy-9-oxo-15,17-dimethylene-2-nor-
13-trans-prostenic acid 382 39 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15R, 16S- (and ent-15S, 16R) -15-Hy-
droxy-9-oxo-15,16-trimethylene-16- (3-
trifluoromethylphenoxy) -2,17,18,19,20-
pentanor-13-trans-prostenic acid 383 40 2- (5-carboxypentyl) -cyclo-
pent-2-en-l-on nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-9-oxo-15, lö-trimethylene-lo- (3-
trifluorraethylphenoxy) -2,17,18,19,20-
pentanor-13-trans-prostenic acid

TABLE XV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin derivative and its Diastereoxsomeres or its ethyl ester, if such is possible (see above)

O
CO
OO

384 385 386

387 388 389

390

29a

36

31

37

38

41

42

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

2- (7-Carboxyheptyl) -cyclopent-2-en-1-one

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-1-homo-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-lhomo-13-trans-prostenic acid

nat- (and ent) -IS-hydroxy-g-oxo-15,16-tetramethylene-1-homo-17,18, -19,20-tetranor-13-trans-prostenic acid

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-tetramethylene-1-homo-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-tetramethylene-lhomo-13-trans-prostenic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15, lo-trimethylene-lo- (4-fluorophenoxy) -l-homo-17,18,19,20-tetranor -13-trans-prostenic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -l-homo-17,18,19,20-tetranor -13-trans-prostenic acid

TABLE XV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin derivative and its Diasteresoisoraeres or its ethyl ester, if such is possible (see above)

391

392 oo

oo 393

394 395

45

46

47

48

49

396

50

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

2- (8-Carboxyoctyl) -cyclopent-2-en-1-one

nat-15S, 17R- (and ent-15R, 17S) -15-hydroxy-oxo-15,17-trimethylene-19,20-dinor-la, lb-dihomo-13-trans-prostenic acid

nat-15S, 17S- (and ent-löR, 17R) -15-hydroxy-oxo-15,17-trimethylene-19,2o-dinor-la, lb-dihomo-13-transprostic acid

nat-16R, 17S- (and ent-16S, 17R) -16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-la, lb-dihomo-13-transprostic acid

nat-16R, 17R- (and ent-16S, 17S) -16-hydroxy-9-oxo-16 , 17-trimethylene-20-methyl-la / lb-dihomo-13-transprostic acid

nat-16R, 17S- (and ent-16S, 17R) -16-hydroxy-9-oxo-16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18, -19,20-trinor-la, lb- dihomo-13-transprostic acid

nat-16R, 17R- (and ent-16S, 17S) -16-hydroxy-9-oxo-16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-la, lb-dihomo -13-trans-prostenic acid

TABLE XV (continued)

example Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-0xo-prostaglandin derivative and its
Dxastereoisomeres or its ethyl
ester, if such is possible
(see above) 397 29a 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat-15S, 16R- (and ent-15R, 16S) -15-Hy-
droxy-9-oxo-15,16-trimethylene-13-
trans ~ 5-cis-prostadic acid 398 36 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat-15S, 16S- (and ent-15R, 16R) -15-Hy-
droxy-9-oxo-15,16-trimethylene-13-
trans-5-cis-prostadic acid CO
O
CO
OO 399 31 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat- (and ent) -15-hydroxy-9-oxo-15,16-
tetramethylene-17,18,19,20-tetranor-
13-trans-5-cis-prostadic acid ■ is ·
- «>.
σ 400 32 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat- (and ent) -15-hydroxy-9-oxo-15,16-
trimethylene-17,18,19,20-tetranor-13-
trans-5-cis-prostadic acid -j
to 401 33 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat- (and ent) -15-hydroxy-9-oxo-15,16-
pentamethylene-17,18,19,20-tetranor-
13-trans-5-cis-prostadic acid 402 34 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat-15S, 17R- (and ent-15R, 17s) -15-Hy-
droxy-9-oxo-15,17-diemethylene-13-
trans-5-cis-prostadic acid 403 35 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat-15S, 17S- (and ent-15R, 17R) -15-Hy-
droxy-9-oxo-15,17-dimethylene-13-
trans-5-cis-prostadic acid 404 37 2- (6-carboxyhex-2-cis-
enyl) cyclopent-2-en-1-one nat-15S, 16R- (and ent-15R, 16S) -15-Hy-
droxy-9-oxo-15,16-tetramethylene-13-
trans-5-cis-prostadic acid

TABLE XV (port setting)

example

Jodviny! .Compound or Vinyl tin compound of example

Cyclopent-2-en-l-one 9-oxo-prostaglandin derivative and its Diastereoisomer or its ethyl ester, if such is possible (see above)

38

39

O CO OO

40

410

30th

41

42

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) ^ cyclopent-2-en-1-one nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-tetramethylene-13-trans-5-cis-prostadic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19, -20-tetranor-13- trans-5-cis-prostadic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-trans -5-cis-prostadic acid

nat- (and ent) -16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-13-trans-5-cis-prostadic acid

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-16- (4-luophenoxy) -17,18,19,20-tetranor-13- trans-5-cis-prostadic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (4-fluorophenoxy) -17,18,19,20-tetranor-IS-trans -S-cis-prostadic acid

TABLE XV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin derivative and its Diastereoisomer or its ethyl ester / if such is possible (see above)

σ
-α
co

411 412 413 414 415 416 417

43

44

45

46

47

48

49

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cis- · enyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carbpxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-trans -5-cis-prostadic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-chlorophenoxy) -17,18,19,20-tetranor-13-trans -5-cis-prostadic acid

nat-15S, 17R- (and ent-15R, 17S) -15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-13-trans-5-cis-prostadic acid

nat-15S, 17S- (and ent-15R, 17R) -15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-13-trans-5-cis-prostadic acid

nat-16R, 17S- (and ent-16S, 17R) -16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-13-trans-5-cis-prostadic acid

nat-16R, 17R- (and ent-16S, 17S) -16-hydroxy-9-oxo-16,17-trimethylene-2O-methyl-IS-trans-S-cis-prostadic acid

nat-16R, 17S- (and ent-16S, 17R) -16-hydroxy-9-oxo-16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-IS-trans-S -cis-prostadic acid

TABLE XV (port setting)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-1-one

9-oxo-prostaglandin derivative and its Diastereoisomer or its ethyl ester, if such is possible (see above)

418

50

O
CO
OO

419 420 421 422 423

29a

36

31

37

38

2- (6-Carboxyhex-2-cisenyl) -cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cisenyl) -cyclopent-2-en-1-one

nat ~ 16R, 17R- (and ent -lös, 17S) -16-hydroxy-9-oxo-16,17-trimethylene-17- (3-trifluoromethylphenoxy) -18,19,20-trinor-13-trans-5 -cis-prostadia ~ acid

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-Ia, lb-dihomo-13-trans-5-cis-prostadienoic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-Ia, lb-dihomo-IS-trans-S-cis-prostadic acid

nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene-la, lb-dihomo-17,18,19,20-tetranor-13-trans-5-cis-prostadienoic acid

nat-15S, 16R- (and ent-15R, 16S) -15-hydroxy-9-oxo-15,16-tetramethylenla, lb-dihomo-13-trans-5-cis-prostadic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-9-oxo-15,16-tetramethylene-Ia, lb-dihomo-IS-trans-S-cis-prostadic acid

TABLE XV (continued)

example

Iodovinyl compound or vinyl tin compound of Example

Cyclopent-2-en-l-one 9-oxo-prostaglandin derivative and its Diastereoisomer or its ethyl ester, if such is possible (see above)

39

40

29a

36

31

32

33

2- (8-Carboxyoct-2-cis-enyl) cyclopent-2-en-1-one

2- (8-Carboxyoct-2-cis-enyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl). Cyclopent-2-en-1-one

2- (ö-Carboxy-S-oxa-hexyl) cyclopent-2-en-l-one nat-15R, 16S- (and ent-15S, 16R) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -la, lb- dihomo-17,18,19,20-tetranor-13-trans-5-cis-prostadic acid

nat-15R, 16R- (and ent-15S, 16S) -15-hydroxy-9-oxo-15,16-trimethylene-16- (3-trifluoromethylphenoxy) -la, lb-dihomo-17,18,19,20 -tetranor-13-trans-5-cis-prostadienoic acid

nat-15S, 16R- (and ent-15R, 16W) -15-hydroxy-3-oxa-9-oxo-15,16-trimethylene-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-3-oxa-9-oxo-15,16-trimethylene-13-trans-prostenic acid

nat- (and ent) -15-hydroxy-3-oxa-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -15-hydroxy-3-oxa-9-oxo-15,16-trimethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -15-hydroxy-3-oxa-9-oxo-15,16-pentamethylene-17,18,19,20-tetranor-13-trans-prostenic acid

TABLE XV (port setting)

example OO Iodovinyl compound or Cyclopent-2-en-1-one 9-oxo-prostaglandin derivative and its σ 433 Vinyl tin compound of Diastereoisomer or its ethyl CO example ester, if such is possible OO
* «· (see above) 431 - * 434 34 2- (6-carboxy-5-oxa-hexyl) - nat-15S, 17R- (and ent-15R, 17S) -15- * -% cyclopent-2-en-l-one Hydroxy-3-oxa-9-oxo-15,17-dimethylene 13-trans-prostenic acid 432 CO 35 2- (6-carboxy-5-oxa-hexyl) - nat-15S, 17S- (and ent-15R, 17R) -15- ■ ** 435 cyclopent-2-en-l-one Hydroxy-3-oxa-9-oxo-15,17-dimethylene 13-trans-prostenic acid 30th 2- (6 ~ carboxy-5-oxa-hexyl) - nat- (and ent) -16-hydroxy-3-oxa-9-oxo- cyclopent-2-en-l-one 16,17-tetramethylene-18,19,20-trinor- 436 13-trans-prostenic acid 41 2- (6-carboxy-5-oxa-hexyl) - nat-15R, 16S- (and ent-15S, 16R) -15- cyclopent-2-en-l-one Hydroxy-3-oxa-9-oxo-15,16-trimethylene 16- (4-fluorophenoxy) -17,18,19,20-te- tranor-13-trans-prostenic acid 42 2- (6-carboxy ~ 5-oxa-hexyl) - nat-15R, 16R- (and ent-15S, 16S) -15-Hy- cyclopent-2-en-l-one droxy-3-oxa-9-oxo-15,16-trimethy.len- 16- (4-fluorophenoxy) -17,18,19,20-te- tranor-13-trans-prostenic acid 43 2- (6-carboxy-5-thia-hexyl) - nat-15R, 16S- (and ent-15S, 16R) -15- cyclopent-2-en-l-one Hydroxy-3-thia-9-oxo-15,16-trimethylene 16- (3-chlorophenoxy) -17,18,19,20-tetra- nor-13-trans-prostenic acid

TABLE XV (continued)

example 437 Iodovinyl compound or
Vinyl tin compound of
example Cyclopent-2-en-1-one 9-0xo-prostaglandin derivative and its
Diastereoisomer or its ethyl
ester, if such is possible.
(see above) 438 44 2- (6-Carboxy-5-thia ~ hexyl) - ·
cyclopent-2-en-l-one nat-15R, 16R- (and ent-15S, 16S) -15-Hy-
droxy-3-thia-9-oxo-15,16-trimethylene
16- (3-chlorophenoxy) -17,18,19,20-te-
tranor-13-trans-prostenic acid 439 45 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-15S, 17R- (and ent-15R, 17S) -15-Hy-
droxy-3-thia-9-oxo-15,17-trimethylene
19,20-dinor-13-trans-prostenic acid 09
O
CO
OO 440 46 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-15S, 17S- (and ent-15R, 17R) -15-Hy-
droxy-3-thia-9-oxo-15,17-trimethy-
len-19,20-dinor-13-trans-prosten-
acid 1/071 441 47 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-16R, 17S- (and ent-16S, 17R) -16-Hy-
droxy-3-thia-9-oxo-16,17-trimethylene
20-methy1-13-trans-prostenoic acid to 442 48 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-16R, 17R- (and ent-16S, 17S) -16-Hy-
droxy-3-thia-9-oxo-16,17-trimethylene
20-methyl-13-trans-prostenic acid 443 49 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-16R, 17S- (and ent-16S, 17R) -16 - Hy-
droxy-3-thia-9-oxo-16,17-trimethylene
17- (3-trifluoromethylphenoxy) -18,19,20-
trinor-13-trans-prostenic acid 50 2- (6-carboxy-5-thia-hexyl) -
cyclopent-2-en-l-one nat-16R, 17R- (and ent-16S, 17S) -16-Hy-
droxy-3-thia-9-oxo-16,17-trimethylene
17- (3-trifluoromethylphenoxy) -18,19,20-
trinor-13-trans-prostenic acid

TABLE XV (continued)

example

Iodovinyl compound or
Vinyl tin compound of
example

Cyclopent-2-en-l-one 9-oxo-prostaglandin derivatives and its diastereoisomer or its ethyl ester, if such is possible (see above)

2- (ö-carboxy-S-thia-hexyl) cyclopent-2-en-l-one

2- (6-Carboxy-5-thia-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-thia-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1-one

2- (6-carboxy-5-oxa-hexyl) cyclopent ~ 2-en-l-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1-one

2- (6-Carboxy-5-oxa-hexyl) cyclopent-2-en-1 - one nat-15S, 16R- (and ent-15R _; 16S-15-hydroxy-3-thia-9-oxo-15 , 16-trimethylene-13-trans-prostenic acid

nat-15S, 16S- (and ent-15R, 16R) -15-hydroxy-3-thia-9-OXO-15,16-trimethylene-13-trans-prostenic acid

nat- (and ent) -15-hydroxy-3-thia-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat- (and ent) -lS-

oxo-15,16-pentamethylene-17,18,19,20-tetranor-13-trans-prostenic acid

nat-15S, 17R- (and ent-15R, 17s) -15-hydroxy-3-oxa-9-oxo-15,17-dimethylene-13-trans-prostenic acid ·

nat-15S, 17S- (and ent-15R, 17R) -15-hydroxy-3-oxa-9-oxo-15,17-dimethylene-13-trans-prostenic acid

nat- (and ent) -lo-hydroxy-S-oxa-9-OXO-16,17-tetramethylene-18,19,20-trinor-13-trans-prostenic acid

TABLE XV (continued)

example OO Iodovinyl compound or Cyclopent-2-en-1-one 9-oxo-prostaglandin derivative and its O Vinyl tin compound of Diastereoisomer or its ethyl CIJ
OO example ester, if such is possible (see above) 451 41 2- (6-carboxy-5-oxa-hexyl) - nat-15R, 16S- (and ent-15S, 16R) -15- cyclopent-2-en-l-one Hydroxy-3-oxa-9-oxo-15,16-trim- ethylene-16- (4-fluorophenoxy) -17.18, - 19.20-tetranor-13-trans-prosten- acid 452 42 2- (6-carboxy-5-oxa-hexyl) - nat-15R, 16R- (and ent-15S, 16S) -15- cyclopent-2r-en-l-one Hydroxy-3-oxa-9-oxo-15,16-trim- ethylene-16- (4-fluorophenoxy) -17.18, - - ^ 19,20-tetranor-13-trans-prosten- ^ acid ^ j.

Example 453

nat- (and ent) -9-0x0-15,16-tetramethylene-17,18,19,2O-tetranor-15,13-trans-prostadienoic acid ethyl ester.

To a solution of 23.211 g of 1- (2-iodovinyl) -1-trimethylsilyl-

5 oxy-cyclohexane in 23 ml of dry toluene, which one under argon has cooled to -40 C, give it in the course of 10 minutes 35.1 ml of a 2.04M n-butyllithium solution in hexane. One stirs the resulting solution for 2 hours at -40 ° C, during which time a white precipitate forms. To this

60 ml of dry ether are added to the mixture, the mixture is heated to 10 ^° C. for 20 minutes and a clear, colorless solution is obtained. This solution is cooled to -40 ⁰ C and mixed them in the course of 5 minutes 34.8 ml of a 2,057m trimethylaluminum in heptane. The cooling bath is removed and left

^{the solution heats up to 0} ° C. over the course of 20 minutes, a white precipitate forming. The mixture is cooled to -78 ° C. and 17.653 g of 2- (6-carboethoxy-hexyl) -cyclopent-2-en-1-one are added to the mixture over the course of 5 minutes. The cooling bath is removed and allowed to warm slowly to room temperature, stirring first by hand and then mechanically after the mixture has become more agile. The mixture is stirred overnight and a clear, pale reddish-orange single-phase solution is obtained. This solution is poured into 22 ml of concentrated hydrochloric acid and 400 g of ice, stirred for 20 minutes and extracted with ether. The organic phase is washed with water and saturated salt solution, dried with magnesium sulfate and evaporated, and 38.04 g of a pale yellowish oil are obtained. This oil is distilled to remove impurities. The flask residue (26.51 g) is then purified by dry column chromatography (column I) on 800 g of silica gel which has been equilibrated with 80 g of a benzene / ethyl acetate mixture (9/1). Elute the column (157.5 χ 5.1 cm

809841/0791

(62 χ 2 inch)) with a benzene / ethyl acetate mixture (9/1), after which 60 ml of the solvent is passed through the column. The column is cut into segments 2.54 cm (1 inch) long. The product of cuts 41 bis (R _f value 0.65 to 0.81, 7.55 g) is kept for further use. Sections 24 to 40 (R value 0.37 to 0.65, 15.86 g) are dry column chromatography (column II) over 800 g of silica gel, which is mixed with 10% by weight of a benzene / ethyl acetate mixture (9 / 1) equilibrated in a column 0 (147.3 χ 5.1 cm (58 χ 2 inches)). The column is eluted with the same solvent and then another 100 ml of the solvent is passed through the column. The column is cut into sections 2.54 cm (1 inch) long. The products of cuts 41 to 54 (R value 0.69 to 0.93, 8.46 g) are saved for later use. The material from sections 33 to 40 is purified by dry column chromatography (column III) over 440 g of silica gel, which is mixed with 10% by weight of a benzene / ethyl acetate mixture (9/1) in a column (132.1 χ 3.8 cm (52 χ 1 1/2 inch)) has equilibrated. The column is eluted with the same solvent and then another 15Ο ml of the solvent is passed through the column. “The product is found in sections 35 to 49 (R value 0.65 to 0.94, 3.38 g). The following products are combined: column I, sections 41 to 50 (R _f value 0.65 to 0.81, 7.55 g); Column II, sections • 41 to 54 (R _£ value 0.69 to 0.93, 8.46 g) and column III, sections 35 to 49 (R _f value 0.65 to 0.94, 3.38 g) so that a total of 19.39 g is obtained. The material is dissolved in 450 ml of an acetic acid / tetrahydrofuran / water mixture (4/2/1) and the solution is allowed to stand for 30 minutes at room temperature. The mixture is then evaporated in vacuo on a water bath at 40 ° C. using of 200 ml of xylene and 13.61 g of an oil are obtained. This oil is purified by dry column chromatography over 830 g of silica gel which is treated with 10% by weight of a hexane / ethyl acetate mixture

809841/0791

(9/1) equilibrated in a column (150 χ 5.1 cm (59 χ 2 inches)) Has. The column is eluted with the same solvent and a further 600 ml of the solvent are then passed through through the pillar. The column is examined for the ultraviolet bands. The material from sections 37 to 45 (R value 0.61 to 0.76, 3.65 g) is distilled (K. 175 to 180 ° C) and gives 3.609 g of nat- (and ent) -9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-15,13-trans-prostadienoic acid ethyl ester.

Example 454

10 nat- (and ent) -9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-15,13-trans-prostadic acid.

A mixture of 2.800 g of nat- (and ent) -9-0xo-15,16-tetramethylene-17,18,19,20-tetranor-15,13-trans-prostadienoic acid ethyl ester is stirred and 1.40 g of potassium hydroxide in 40 ml of a water / methanol mixture (1/1) over Ne.cht under nitrogen at room temperature. Then the mixture is partially evaporated in vacuo, distributed between ether and hydrochloric acid solution, wash the organic phase well with water and saturated salt solution, dry with magnesium sulfate

10 and evaporated to give 2.52 g of a yellowish oil. This oil is distilled at 200 ⁰ C in vacuum to give 2.460 g of the desired product in the form of an almost colorless oil.

809841/0791

Claims (2)

- J *. 28132Q1 PATENT CLAIMS 1 ... Optically active prostanoic acid derivatives of the general formula ^C 13 " ^C 14- in the 5 W a group of the general formulas wherein R _{1 is} a hydroxyl group, a tri- or a C.-Cg alkoxy group; -C.) - alkylsilyloxy group 809841/0791 R "represents a hydrogen atom, a hydroxyl group, a TrI- (C _1- C.) alkylsilyloxy group or a C 1 -C 4 alkanoyloxy group; Y is a trivalent group of the general formulas R ₃ O CH ₂ - wherein R _{3 is} a hydrogen atom, a tri- (C _1- C.) - alkylsilyloxy group or a C ₂ -C, - alkanoyl group, with the proviso that when W contains a / v ^ CN group, R_ is a hydrogen atom; X is a divalent group of the general formulas una wherein R. represents a C ₃ -C alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; η 0 or an integer with a value from 1 to 4; m O or an integer with a value from 1 to 4, with provided that the sum of η and m has a value from 2 to 4; the C- ₃ _C .. radical is an ethylene group or a trans-vinylene group; w 0 or 1 and Z is a divalent group of the general formulas - (CH ₂ ) -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) -, - (CH ₃ ) ^ O-CH ₃ - and 809841/0791 - 2 «7 - wherein ρ is an integer with a value from 5 to 7; q is an integer with a value from 1 to 3 and t represent an integer from 3 to 5; with the proviso that when Z is a double bond
has, the C __c. .-Radical represents a trans-vinylene group;
as well as the racemic mixture of these compounds, the mirror isomers of these compounds and the pharmacologically acceptable cationic salts of the compounds in which R- is a hydrogen atom. 2. Process for the production of optically active prostanoic acid derivatives the general formula wherein R _{1 is} a hydroxyl group or a C. to C. alkoxy group;
R_ is a hydrogen atom, a hydroxyl group or a
C 1-4 alkanoyloxy group;
Y is a trivalent group of the general formulas HO CH ₂ - and HO CH ₂ - 809841/0791 X is a divalent group of the general formulas and worxn R. a C ₁ -C ₇ -Al] CyI group, a hydrogen atom, a phen-5 oxy group or one with halogen atoms, trifluoromethyl group phenoxy group substituted by pen and / or methoxy groups; η 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4 be-10 sits; the C ₁ ^ -C _1. radical is an ethylene group or a trans-vinylene group; w 0 or 1; and Z is a divalent group of the general formulas ice cream
- (CH,) -, -CH ₉ -CH = CH-CH ₉ - (CH) 1-, - (CH ₉ KO-CH ₉ - and wherein ρ represents an integer with a value of 5 to 7, q represents an integer with a value of 3 to 5; with the proviso that when Z contains a double bond, the C ₁₃ -C ₁₄ radical represents a trans-vinylene group, characterized in that a cyclopentenone of the general formula is used 309841/0791 worm R 'is a C, -C ^ -alkoxy group or a protective group, such as 1 JD a tri- (C ₁ -C ₄ ) alkylsilyloxy group; R ^{1 is} a hydrogen atom, a C ₂ -Cj - alkanoyloxy group or a protective group, such as a tri- (C -C) -alkylsilyloxy group, with a connection of the general formulas L H \ / and / ^{C = C} \ HR ₉ . worxn
L is a group of general formulas -Ca-C = CR ₇ , -Cu-S- ^ \ , R ₇ wherein R "represents a C -C alkyl group, and Rg is a group of the general formula mean in which P is a protective group, such as a group of the general formula -Si-R ₁₁ , in which R _{11 is} a tri-lower (C ₂ -C ₅ ) -alkyl group and m, n, w and X have the meanings given above 809841/0791 (β - 2 OK - to a compound of the general formula (CH ₂ ) _W -C wherein R'j, / ^R ' ₂ ' ^w / ^p / ⁿ > ^m ' ^{z and x have the} meanings given above, is reacted, followed by the removal of the protective groups to form a compound of the general formula wherein R, R, w, Y, n, m, X and Z have the meanings given above own; whose Δ. -Binding one to form a compound of the general formula - (CH ₂ ) _W -Y can reduce, in which R-, R ₃₇ w, n, m, Y, X and Z have the meanings given above. 809841/0791 - 2 * 1 - 3. Process for the production of optically active prostanoic acid derivatives the general formula ^C 13-Cl4-KH ₂ ) _W -Y χ wherein R _{1 is} a hydroxyl group or a CL-C.alkoxy group; Y is a trivalent group of the general formulas - ^c and ^{H0 CH} 2 "HO X is a divalent group of the general formulas in the R. a C.-C-alkyl group, a hydrogen atom, a phenoxy group or one substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups Represents phenoxy group; η O or an integer from 1 to 4; m O or an integer with a value from 1 to 4 with the proviso that the sum of η and m has a value from 2 to 4 owns; the CL3-C radical is an ethylene group or a trans-vinylen group; 809841/0701 w O or 1; and Z is a divalent group of the general formulas ice cream - (CH ₂ ) -, -CH ₂ -CH = CK-CH ₂ - (CH ₃ ) -, - (CH) _t -O-CH ₂ - and - (CH ₂ ) _t -S-CH ₂ -wherein ρ is an integer with a value of 5 to 7, q is an integer with a value of 1 to 3, and t is an integer with a value of 3 to 5; with the proviso that when Z contains a double bond, the C -C ₁₄ radical represents a trans-vinylene group, characterized in that a cyclopentenone of the general formula in the R ¹ , a C.-Cg -alkoxy group or a protective group, such as a tri- (C -C ₄ ) -alkylsilyloxy group, R 'denotes a protective group such as a tri- (C ₁ -C ₄ ) -alkylsilyloxy group and
Z has the meanings given above; with a connection of the general formulas L H and \ / C = C 809841/0791 - 2-T3 - where L is a group of the general formulas -R ₇ , -CU-S- / "Λ, wherein R "represents a C.-C ₇ -alkyl group, and a group of the general formula X ^; where P is a protective group, such as a group of the general formula -Si-R ₁₁ , in which R _{11 is} a tri-lower (C -C.) - alkyl group, and m, n, w and X have the meanings given above own; to a compound of the general formula _(CH2 , "- C Pc / V ( in which R'- ,, ^RI 9 ' ^{W / P} ' ⁿ ' ^m ' ^{z and x have the meanings} given ofc) en, followed by a) the cleavage of the protective groups and the dehydratation with formation of a compound of the general formula 809841/0791 Aft - 2 * 4 (CH ₂ ) _W -Y χ in which Z, R, w, m, n, Y and X have the meanings given above possess genes; or b) the splitting off of the protective groups, the reduction of the Δ bond and dehydration to form a compound of the general formula fi , ^ ZCR ₁ CH ₂ -CH ₂ - (CH ₂ ) _W -YX in which Z, R-, w, Y, m, η and X have the meanings given above, and
followed by c) the treatment of the products of steps a) and b) with acetone cyanohydrin and a basic catalyst such as sodium carbonate. 4. Process for the production of optically active prostanoic acid derivatives the general formula 809841/0791 A4 215 - in the R _{1 is} a hydroxyl group or a straight-chain or branched one C ₁ -C ₆ alkoxy group; Rj. A hydrogen atom or a C "-C _r -alkanoyloxy group; Y is a trivalent group of the general formulas C ¹ J ^ d C: HO CH ₂ - HO CH ₂ - · X is a divalent group of the general formulas C ^and c wherein R. represents a straight-chain or branched C _{1 -C 7} -alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4 owns; the C ₁ ^ -C. radical is an ethylene group or a trans-vinylen group; 8841/0791 w 1 or 0; and Z is a divalent group of the general formulas ice - (CH ₂ ) -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) - and - (CH ₂ ^ -O-CH ₂ - where ρ is an integer with a value from 5 to 7, q is an integer with a value from 1 to 3 and t represent an integer from 3 to 5; with the proviso that when Z contains a double bond, the C ₁ -C ₁₄ radical represents a trans-vinylene group, characterized in that a cyclopentenone of the general formula wherein R ' _{denotes a C 1} -C 6 alkoxy group or a protecting group such as a tri- (C. -C.) - alkylsilyloxy group, and R' denotes a protecting group such as a tri (C 1 -C 6) alkylsilyloxy group and Z denotes the has the meanings given above; with a connection of the general formulas and H "Rc 80.9841 / 0791 wherein L is a group of the general formulas -Cu-C = CR ₇ , -Cu-S- / \, R ₇ in which R _{7 represents} a C 1 -C 4 alkyl group, and a group of the general formula in which P is a protective group, such as a group of the general formula -Si-R, in which R _{11 is} a tri-lower (C ₁ -C.) -alky! group, and m, n, w and X are as indicated above Have meanings, mean; to a compound of the general formula 0? ^R 2 • H ^X ^ (CH ₂ ) _W -CX Pc / - MCH ₂ ) ^ - ⁷ ₍ in the R '^ / R ¹ «, w, P, n, m, Z and X have the meanings given above, converts, followed by
a) the splitting off of the protective groups and treatment with a carbonyl _{reducing agent such as sodium borohydride /} or a stereoselective reducing agent such as lithium-per- 809841/0791 hydro-9ß-boraphenalyl hydride, to form a compound the general formula (CH ₂ ) _w -yx in which Z, R, w, X, Y, m and η have the meanings given above own; followed by treatment with an oxidizing agent such as Jones reagent to produce a compound of the general type formula YX W j ( ^CH > in the R., w, X, Y, Z, η and m the meanings given above own; or b) splitting off the protective group, reducing the Δ bond and treating with a carbonyl reducing agent such as sodium borohydride, lithium tris (sec-butyl) borohydride or lithium perhydro-9b-boraphenalyl hydride _/ with formation of a compound of the general formula 809841/0791 / Z-C-R HO VCH ₂ -CH ₂ - (CH ₂ J _W -Y 'm in which Z, R ,, w, X, Y, η and m have the meanings given above own, followed by treatment with an oxidizing agent such as Jones reagent to form a compound of the general formula - ^(CH 2> w "* in which Z, R ,, w, Y, n, m and X have the meanings given above own; cJ after which the 11-hydroxyl group of the compounds of Steps a) and b) with formation of the alcohol ester of the general formula C ₁₃ -C ₁₄ (CH ₂ ) _W -Y 809841/0791 can starve, wherein R ₁ . represents a C 1 -C ₁ alkanoyl group. 5. Process for the preparation of optically active prostanoic acid derivatives the general formula insane
X in the W is a group of general formulas R ₅ O ^ HR ₅ O C and c " wherein Rj is a hydrogen atom or a C1 -C4 alkanoyl group represents; 1.0 R _{1 is} a hydroxyl group or a C 1 -C 6 alkoxy group; R_ is a hydrogen atom, a hydroxyl group or a C 1 -C 4 alkanoyloxy group; Y is a trivalent group of the general formulas OH 'CH ₂ - J X is a divalent group of the general formulas 803841/0791 C. and 'η' in which R is a C ₁ -C "alkyl group, a hydrogen atom, a phenoxy group or one having halogen atoms, trifluoromethyl groups and / or methoxy group represents phenoxy group substituted; η 0 or an integer with a value from 1 to 4;
m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; the C ₁ -C 1 radical is an ethylene group or a trans-vinylene group; w 0 or 1; and
Z is a divalent group of the general formulas ice cream - (CH ₀ ) -, -CH ₀ -CH = CH-CH ₀ - (CH ₀ ) -, - (CH ₀ ).-0-CH ₀ - and ~ (CH _O } -S-CH _O -2p λ 2 2 q 2t 2 2 ' where ρ is an integer with a value from 5 to 7,
q is an integer with a value from 1 to 3 and
t is an integer with a value of 3 to 5
represent; with the proviso that when Z contains a double bond, the C. - C. .-Radical represents a trans-vinylene group; characterized in that a cyclopentenone of the general formula . 0 i Il! / Z-C-R ' in which R 'is a C ^ -Cg -alkoxy group or a protective group,
such as a tri- (C ₁ -C.) - alkylsilyloxy group, and 809841/0791 J2-22 - R 'represents a hydrogen atom, a C 1 -C 4 alkanoyloxy group or a protecting group such as a tri- (C.-C.) alkylsilyloxy group, and Z has the meanings given above with a compound of the general formulas LH and \ _{= (} / \ ₉ where L is a group of the general formulas -Cu-CSC-E ₇ , -CU-S- / \, B ₇ f <? tß ^w I ₁ * j ' Al Li wherein R _{7 is} a C ₁ -C ₇ alkyl group, and Rg is a group of the general formula P-O in which P is a protective group, a group of the general formula -Si-R-, in which R _{11 is} a tri-lower (C ₁ -C.) alkyl group, and m, n, w and X have the meanings given above; to a compound of the general formula 809841/0791 i! C = C
/ B I4 \ (CH ₂ ),., - from left J -ο ^v - (cH ^) r in the R ', ^R ' o ' ^w ' ^P ' ⁿ ' ^m ' i ^e ° t> en have given meanings, converts, followed by: a) the splitting off of the protective groups, the reduction of the Δ bond and the treatment with a carbonyl reducing agent, such as sodium borohydride, with the formation of compounds of the general formulas HO ^ H ,, ZCR ₁ CH ₂ -CH ₂ - (CH ₂ ) _w -y ■ and CH ₂ -CH ₂ - (CH ₂ ) _w - ^(CH 2> n wherein Rj, R ₂ , w, Y, n, m, Z and X have the meanings given above; or 98A1 / 079T - 224 - b) the splitting off of the protective groups, the reduction of the Δ bond and treatment with a stereoselective reducing agent such as lithium tri- (sec-butyl) borohydride or Lithium perhydro-9b-boraphenalyl hydride, and formation of a compound of the general formula H ₂ -CH ₂ - (CH ₂ 7 _W -Y χ j Mpd \ - SI in which R .., R ₂ / w, Y, πι, η and X have the meanings given above; or c) the cleavage of the protective groups and treatment with a carbonyl reducing agent such as sodium borohydride ^ with formation of compounds of the general formulas and OH 0 Il / ^H -Y 809841/079! - 235 - in which R ₁ , Z, R ", w, Y, m, η and X have the meanings given above; or d) the splitting off of the protective groups and the treatment with a stereoselective reducing agent such as lithium tri- (sec-butyl) borohydride or lithium perhydro-9b-boraphenalyl hydride to form a compound of the general formula OH. H _n / ZCR ₁ C = C in which Z, R, R, w, Y, m, η and X are those given above Have meanings; and e) if appropriate, the product from stages a), b), c) and d) to give the alcohol esters of the general formulas and "ZCR ₁ C ₁₃ -C ₁₄ (CH ₂ ) _W -Y 809841/0791 - 2-26 - esterified, in which R ₁ . a C ₉ -C alkanoyl group and R ₉ a C ₉ -C _n -alkanoyloxy group and Z, RR, the C -C radical, w, Y, m, η and X have the meanings given above. 6. Process for the preparation of prostanoic acid derivatives of the general formula in the R _{1 is} a hydroxyl group or a C.-C _f alkoxy group; Y is a trivalent group of the general formulas \ / a V C and .C, Ho ' ^CH 2 ~ HO X is a divalent group of the general formulas and \ / ^R 4 i in the R. a C.-C "-alkyl group, a hydrogen atom, a phenoxy group or one with halogen atoms, trifluoromethyl groups and / or methoxy groups substituted phen 809841/0791 represents oxy group; η O or an integer with a value from 1 to 4 with the Provided that the sum of η and m has a value of 2 to 4; the 0 ..-- C ₁₄ radical is an ethylene group or a trans-vinylene group; w 0 or 1; and Z is a divalent group of the general formulas cis - (CH ₂ ) -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) -, - (CH ₂ J ₄ -O-CH ₂ - and 10 - (CH ₂ J ₄ -S-CH ₂ -, wherein ρ is an integer of 5 to 7, q is an integer of 1 to 3, and t is an integer of 3 to 5; with the proviso that when Z has a double bond, the C _{-C 14} radical represents a trans-vinylene group, characterized in that a cyclopentenone of the general formula Z-C-Rj j in the
R ', a C ₁ -C ^ alkoxy group or a protecting group such as a Tri- (C ₁ -C ₄ ) -alkylsxlyloxy group, and R ^{1 is} a protected oxygen group, such as a TrI- (CC ₄ ) - alkylsilyloxy group mean and Z has the meanings given above; 25 with a combination of the general formulas 80 9841/0791 - 3-28 - and C = C where L is a group of the general formulas -Cu-C = CR.,, -Cu-S- / 7 »I L50 Ld © ^N ' R ₇ R ₇ Al ~ Li in which R stands for a C ₁ -C ₇ -AlRyIgruppe, and a group of the general formula P-O (CH ₂ ) _m in which P is a protective group, such as a group of the general formula -Si-R ₁₁ , in which R _{11 is} a tri-lower (C -C.) - alkyl group and m, n, w and X have the meanings given above ; to a compound of the general formula in the / w, P, n, m and X mean the above 809841/0791 own, implement, followed by: a) the splitting off of the protective groups and the dehydration to form a compound of the general formula ! I .-Z-C-R C = C H (CH ₂ ) _W -YX in which Z, R, w, m, η and X have the meanings given above own; or b) the splitting off of the protective groups, the reduction of the Δ bond and the dehydration to form a compound the general formula - (CH ₂ ) _W -YX in which Z, R ₁ , w, Y, m, and and X have the meanings given above. 809841/0791 - 250 - 7. Compounds of the general formula CH ₂ ) _d in which R is a hydroxyl group or a C -C alkoxy group, O J. O ρ is an integer with a value from 5 to 7, d is an integer with a value from 3 to 5. 8. Process for the preparation of optically active compounds of the general formula - "ZCE ₁ C ₁₃ -C ₁₄ (CH ₂ Jw-Y in the
W is a group of general formulas \ J ■ 809841/0791 worm R, a hydroxyl group, a tri- (C ₁ -C.) - alkylsilyloxy group or a C ₁ -C - alkoxy group; ± D R "is a hydrogen atom, a hydroxyl group, a tri- (C, -C.) - alkylsilyloxy group or a C" -C _I - alkanoyloxy group; Y is a trivalent group of the general formulas and R ₃ O? CH -, - wherein R- is a hydrogen atom, a tri- (C. -C.) - alkylsilyloxy group or a C ^ -C ₁ - alkanoyloxy group, with the proviso that when W contains an o- ^ CN group, R ^ is a hydrogen atom ; ·
X is a divalent group of the general formulas and A. in which R. represents a C ₁ -C "alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4 with the Provided that the sum of η and m has a value of 2 to 4; 80984 1/0791 $ 2 the C o-CL. radical is an ethylene group or a trans-vinylene group; w 0 or 1; and Z is a divalent group of the general formulas ice cream
_ (CH ₂ ) -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) -, - (CH ₃ ) _t -O-CH ₂ - and where ρ is an integer with a value from 5 to 7,
q is an integer from 1 to 3 and
t represent an integer from 3 to 5; with the proviso that when Z has a double bond, the C -_- C. radical is a trans-vinylene group,
characterized in that there is a cyclopentenone of the general formula .5 in the R 'is a CL-Cg-alkoxy group or a protecting group such as a tri- (C ₁ -C ₄ ) -alkylsilyloxy group, and R 'is a hydrogen atom, a C "-C, - alkanoyloxy group or
a protecting group such as a tri- (C ₁ -C.) - alkylsilyloxy group, and Z has the meanings given above,
with a connection of the general formulas and C «C '■ / V 809841/0791 where L is a group of the general formulas Al Lx wherein R stands for a C -C alkyl group, and a group of the general formula P-O where P is a (CC ₅ ) alkanoyl group or a protective group, such as a group of the general formula -Si-R ₁₁ , where R is a tri-lower (C ₂ -C ₅ ) alkyl group, and m, n, w and X have the meanings given above,
to a compound of the general formula where R ¹ -. / R ' _? «W, P, n, m and X have the meanings given above, converts,
followed by: 809841/0791 It - 234 - a) splitting off the protective groups to form a compound the general formula wherein R-, R ", w, Y, n, m, X and Z have the meanings given above own; and b) if appropriate, the Δ bond is reduced to form a compound of the general formula CH ₂ -CH ₂ - (CH ₂ ) _W -YX in which R ₁ , R ", w, n, m, Y, X and Z have the meanings given above; or c) if appropriate, the products of stages a) and b), in which R _{1 represents} a hydroxyl group, are dehydrated under
Formation of a compound of the general formula ii> ' _w -y 8098 wherein Z, R, the C. -C, radical, w, Y, n, m and X are those given above Have meanings; or d) the product of step c) optionally further with a Acetone cyanohydrin and a basic catalyst such as sodium carbonate to form a compound of the general formula 13-C ₁₄ - (CH ₂ ) _W -Y treated in which R ₁ , Z, the CL ₃ -C ₄ radical, w, Y, n, m and X have the meanings given above; or e) the products of steps a) and b) with a carbonyl reducing agent, such as sodium borohydride, with the formation of compounds of the general formulas 0 I. Ii! • Z-C-Ri ₁₃ -C ₁₄ - (CH ₂ ) _W -Y and - (CH ₂ ) _W -Y 2'n 809841/0791 reduced, where R, R, the C _-C. radical, w, Y, m, m and X have the meanings given above; or f) the products of stages a) and b) with a stereoselective Reducing agents such as lithium tri- (sec-butyl) borohydride or lithium perhydro-Qb-boraphenalyl hydride ^ with formation a compound of the general formula treated in which R, R, Z, the C ₁₃ -C. radical, w, Y, n, m and X have the meanings given above; or g) the products of stages e) and f) of the IIA-hydroxy type with an oxidizing agent such as Jones reagent to form a compound of the general formula treated in which R., Z, w, Y, m, η and X the above Have meanings; or h) the products of stages a), b), c), d), e), f) and g), in which 809841/0791 _{1 represents} a hydroxyl group to form an arboxylic acid ester represents a group; or Esterified carboxylic acid ester, wherein Rv is a C.-C ^ - i) the hydroxyl groups of the above compounds are esterified to form the alcohol esters of the products of stages a) to g). Compounds of the general formula wherein IO w 0 or 1; m 0 or an integer with a value from 1 to 4; η 0 or an integer with a value from 1 to 4 with which Provided that the sum of η and m has a value of 2 to 4; and P is a protective group, such as a group of the general formula -Si-R .. ^, in which R .... is a C.-C _fi -alkyl group. 10. Compounds of the general formula ) ^ C X; 0-P- ^V (CK ₂ ) ^ . 809841/0791 wherein Q is an iodine atom, a tri-lower (C ₁ -C,) alkyltin radical Lithium atom or a group of the general formulas t and R7 _L £ Z 'UX ^ Al LX R7 R7 wherein R represents a C ₁ -C ₇ alky group; P is a protective group, such as a group of the general formula -Si-R ₁₁ , in which R _{11 represents} a C ₁ -C, -alkyl group; w 0 or 1; m 0 or an integer with a value from 1 to 4; and 10 η 0 or an integer with a value from 1 to 4, with the Provided that the sum of η and m has a value of 2 to 4, mean. 11. Process for the preparation of the compounds of the general formula Li @ C ₃ H ₇ -C = C-Cu H in the
w 0 or 1; P is a protecting group such as trimethylsxlyl group;
η 0 or an integer with a value from 1 to 4;
20 m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and 8098A1 / 0791 X is a divalent group of the general formulas r and where R is a C.-C ₇ alkyl group, a hydrogen atom,
represents a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups, mean, characterized in that one is a connection the general formula Li / H Vc ^ 4CH ₂ ) _V H ^/ (CH ₂ ) -CX P-O S / 10 in which w, P, n, X and m have the meanings given above sit, reacts with copper (I) -1-pentyne. 12. Process for the preparation of the compounds of general my formula L # (CH ₃ ) ₃ Ai ^{e H} (CH ₂ ) ^ JX P-O 809841/0791 - 24t) - wherein W 0 or 1; P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and
X is a divalent group of the general formulas / R4 R ₄ / ^V E in which R. represents a C.-C ^ alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups,
characterized in that a compound of the general formula Li HI / i ■ c = c H ^V (CH ₂ ) ^ in which w, P, n, m and X have the meanings given above, with a tri-lower (C ₁ -C ₅ ) -alkyl-aluminum compound, such as trimethylaluminum. 8098A1 / 0791 13. Process for the preparation of a compound of the general my formula (C ₄ H ₉ ) SN H. H (CH ₂₎ r-CX PO (CH ₂₎ ^ wherein
w 0 or 1; P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m O or an integer with a value from 1 to 4, with the Provided that the sum of η and m has a value from 2 to 4 be-10 sits; and X is a divalent group of the general formulas C. and _c ' ^R 4 wherein R _{4 is} a C ₁ -C ^ alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted with halogen atoms, trifluoro-15 methyl groups and / or methoxy groups,
mean; characterized in that one a) an aldehyde of the general formula o = c χ ι (CH ₂ ) _m 809841/0791 in which X, η, and m have the meanings given above, with a Grignard reagent of the general formula HC ^ C-MgJ, in which J stands for a chlorine atom or a bromine atom and w denotes 0 or 1,
5 to a compound of the general formula HC = C- (CH ₂₎ -C HC ν - ₂ 'm in which w, n, m and X have the meanings given above, reacts; b) introduces a protective group, so that a compound of the general formula -O wherein w, P, n, m and X have the meanings given above own, receive, followed by: c) treatment with tri-n-butyltin hydride in the presence of bisazobutyronitrile. 809841/0791 3ö 14. Process for the preparation of the compounds of the general formula I H ^N C = C ACH. ^H ' ^(CH 2 ^} w7 ^C _v J worxn
5 w O or 1; P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and X is a divalent group of the general formulas r ' and ^R 4 / H. where R. is a C ^ -C ^ alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted by halogen atoms, trifluoromethyl groups and / or methoxy groups,
mean, characterized in that one a) an aldehyde of the general formula O = C j 809841/0791 1 * 0 with a Grignard reagent of the general formula HC = C- (CEL) - MgJ, in which J stands for a chlorine atom or a bromine atom and w denotes 0 or 1, is reacted so that a compound of the general formula HC = C- (CH ₂₎ -CX hc / ^ (CH -γζ receives, in the w, n, m and X the meanings given above own; b) introduces a protective group, so that a compound of the general formula / - (CH ₂ HC = C - (CH ₂ ) _W -CX receives, in the w, P, n, m and X the meanings given above own, and c) the protected compound in solution with diisoamylborane and anhydrous Trimethylaminoxxd reacts; and 15 d) the protected compound in the diisoamylborane and trimethylamine oxide solution with iodine to form a compound of the general formula H' " P-O 809841/0791 2 * 5 - treated, in which w, P, n, m and X have the meanings given above own. 15. The method according to claims 13 and 14, characterized in that the products of claims 13 and 14
with an alkyllithium compound such as n-butyllithium
a compound of the general formula Li H H | Γ * Ϊ7 \ _f "* V PO (CH ₂ ; converts, in which w, n, X, m, P and w have the meanings given above own. 16. Process for the preparation of compounds of the general formula in the
w 0 or 1;
m 0 or an integer with a value from 1 to 4; η 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and
P is a protective group, such as a group of the general formula 809841/0791 - 2 / f6 - -Si-R ₁ -, in which R represents a C ₁ -C -alkyl group, are characterized in that a compound of the general formula ir - «2 ' w P ^X where P, w, n, m and X have the meanings given above, with a copper (I) iodide tributylphosphine complex implements. 17. Process for the preparation of compounds of the general formula cc worxn w 0 or 1; P is a protecting group such as trimethylsilyl group; η 0 or an integer with a value from 1 to 4; m 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; and
X is a divalent group of the general formulas 809841/0791 \ / \ / ^R 4 C and c ' wherein R. is a C ^ -C ^ -alkyl group, a hydrogen atom, a Phenoxy group or one with halogen atoms, trifluoromethyl groups and / or methoxy groups is substituted phenoxy group, mean characterized in that a compound of the general formula C = C po, - ₂ , _m with a solution of phenylthio copper ximsetzt. 18. Compounds according to claim 1, characterized in that that w is a group of the general formula . represents. 19. Compounds according to claim 18, characterized in that the group R- is a hydroxyl group or a C.-C ₆ alkoxy group, the group R _{5 is} a hydrogen atom and the group R _{3 is} a hydrogen atom. 809841/0791 20. Compounds according to claim 19, characterized in that the group R. is a phenoxy group or one with halogen atoms, Trifluoromethyl groups and / or methoxy groups substituted Represents phenoxy group. 21 compounds according to claim 19, characterized in that the group R. represents a hydrogen atom or a C. -C ₇ -alkyl group. 22. Compounds according to claim 21, characterized in that the radical Z is a divalent group of the general formula ice 10 -CH ₂ -CH = CH- (CH ₂ ) - represents, in which q is an integer with a value of 1 to 3. 23. Compounds according to claim 20, characterized in that the group W is a group of the general formula "2 represents, in which R ^ and R ^ those in claims 1 to 22 have given meanings. 24. Compounds according to claim 23, characterized in that the radical Z is a group of the general formula 20 -CH ₂ -CH = CH- (CH ₂ ) - represents, in which q is an integer with a value of 1 to 3. 809841/0791 25. Compounds according to claim 24, characterized in that that the group R "represents a hydroxyl group. 26. Compounds according to claim 23, characterized in that the group R ^ represents a hydrogen atom. 27. Compounds according to claim 22, characterized in that the group W is a divalent radical of the general formula represents. 28. Compounds according to claim 1, characterized in that that the group W is a group of the formula Ii represents. 29. Compounds according to claim 28, characterized in that the group R _{1 is} a hydroxyl group or a C ₁ -C ^ alkoxy group shown. 30. Compounds according to claim 29, characterized in that the group R. is a hydrogen atom or a C ^ -C ^ -alkyl group represents. 31. Compounds according to claim 28, characterized in that the group R. is a phenoxy group or one with halogen atoms, Trifluoromethyl groups and / or methoxy groups denotes phenoxy group substituted. 809841/0791 - 2SfÖ - 32. Compounds according to claim 30, characterized in that Z is a divalent radical of the general formula -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) - represents, in which q is an integer with a value of 1 to 3. 33. Compounds according to claim 31, characterized in that Z is a divalent radical of the general formulas - (CH ₂ ) -, - (CH ₂ ) _t -O ~ CH ₂ - and - (C ₂ ^ ₂ represents in which ρ is an integer with a value of 5 to 7 and t is an integer with a value of 3 to 5. 34. Compounds according to claim 1, characterized in that that W is the group of the formula 15 represents. 35. Compounds according to claim 34, characterized in that the group R. represents a hydrogen atom or a C ₁ -C ₇ -alkyl group. 36. Connections according to claim 34, characterized net that the group R. is a phenoxy group or one with halogen atoms, Trxfluormethylgruppen and / or methoxy groups is substituted phenoxy group. OPJG λ; AL '^ oPicu \ 809841/0791 37. Compounds according to claim 35, characterized in that the group Z is a divalent group of the general formula -CH ₂ -CH = CH- (CH ₂ ) - represents, in which q is an integer with a value of 1 to 3. 38. Compounds according to claim 36, characterized in that the group Z is a divalent group of the general Formulas - (CH ₂ ) -, - (CH ₂ ) _t -S-CH ₂ - represents where ρ is an integer with a value of 5 to 7 and t is an integer with a value of 3 to 5. 39. Compounds according to claim 1, characterized in that that W is a group of the general formula 15 represents. 40. Compounds according to claim 39, characterized in that the group R- is a hydroxyl group or a C ^ -C ₆ -alkoxy group, R ₁ - is a hydrogen atom, the group R ~ is a hydrogen atom and Y is in claims 1 to 39 20 has given meanings. 41. Compounds according to claim 40, characterized in that the group R is a phenoxy group or one with halogen atoms, Trifluoromethyl groups and / or methoxy groups 8098 A1 / 0791 - 26 * 2 - represents substituted phenoxy group. 42. Compounds according to claim 40, characterized in that the group R.
Represented alkyl group net that the group R. is a hydrogen atom or a 5 43. Compounds according to claim 41, characterized in that that the group Z is a divalent group of the general formula ice cream -CH ₀ -CH = CH-CH ₀ - (CH ₀ ) 2 2nd Z q represents, in which q is an integer with a value of 1 to 3. 44. Compounds according to claim 42, characterized in that that the group Z is a divalent group of the general formulas - (CH ₂ ) -, - (CH ₂ ) _t -0-CH ₂ - and - (CH ₃ ^ -S-CH ₃ - 15 represents where ρ is an integer with a value from 5 to 7 and t represent an integer with a value from 3 to 5. 45. Compounds according to claim 27, characterized in that the group R "represents a hydroxyl group. 46. nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene-20 17,18,19,20-tetranor-13-trans-prostenoic acid. 47. nat- (and ent) -15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-5-cis, 10-prostatrienoic acid. 48. Nat- (and ent) -lloC, 15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadic acid. 809841/0791 49. nat-15 (S), 16 (R) - (and ent-15 (R), 16 (S)) -HeC, 15-dihydroxy-9-oxo-15, le-trimethylene-1B-trans-S -cis-prostadic acid. 50. nat-15 (R), 16 (S) - (and ent ~ 16 (S), 16 (R)) -llo (, 15-dihydroxy-9-oxo-15, lo-trimethylene-lB-trans- S-cis-prostadia- acid. 51. Nat- (and ent) -llc (, 15-dihydroxy-9 ~ oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenoic acid. 52. nat- (and ent) -9-OXO-15,16-tetramethylene-17,18,19,20-tetranor-15,13-trans-prostadic acid. 53. nat-15 (S), 16 (R) - (and ent-15 (R), 16S)) - 15-hydroxy-9-OXO-15, lo-trimethylene-IS-trans-prostenic acid ethyl ester. 54. Nat-15 (R), 16 (S) - (and ent-15 (S), 16 (R)) - 15-hydroxy-9-OXO-15, lo-trimethylene-IS-trans-prostenic acid ethyl ester. 55. nat-15 (R), 16 (R) - (and ent ~ 15 (S), 16 (S)) - 15-hydroxy-9-OXO-15, lo-trixethylene-lS-trans-prostenic acid ethyl ester. 56. Nat-15 (S), 16 (S) - (and ent-15 (R), 16 (R)) - 15-hydroxy-9-OXO-15,16-trimethylene-13-trans-prostenic acid ethyl ester. 57. Nat- (and ent) -llo (, 15-dihydroxy-9-oxo. 58. nat-15 (R), 16 (R) - (and ent-15 (S), 16 (S)) - 15-hydroxy-9-OXO-15, lo-trimethylene-IS-trans-prostenoic acid. 59. nat- (and ent) -9t *, HoC, 15-trihydroxy-15,16-tetramethylene-17,18,19, 20 <-tetranor-13-trans-5-cis-prostadienoic acid. 60. nat-15 (S), 16 (R) - (and ent-15 (R), 16 (S)) - 9 «, hat, 15- Trihydroxy-15, lo-trimethylene-IS-trans-S-cis-prostadienoic acid. 809841/0791 Se 2 ^ 4 - 61. nat-15 (R), 16 (S) - (and ent-15 (S), 16 (R)) -9tf, lle (, 15-trihydroxy-15, lo-trimethylene-lS-trans-S- cis-prostadic acid. 62. nat- (and ent) -9t <, 15-dihydroxy-11-oxo-IS, 16-tetramethylene-17,18,19, 20-tetranor-13-trans-5'-cis-prostadienoic acid. 63. nat- (and ent) -9ϋ (, lltf, 15-trihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-5-cis-prostadienoic acid. 64. Nat- (and ent) -IS-hydroxy-Q-oxo-IS, 16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-5-cis, 10-prostatrienoic acid. 65. Nat- (and ent) -9iC / ß-cyano-15-hydroxy-9-oxo-15, 16-tetramethylene-17,18,19, 20-tetranor-5 - cis-13-trans-prostadic acid. 66. Process for the preparation of the compounds of the general formulas 'Z-C-R. and Il (CH,)
/ 2 m + n worm Z is a divalent group of the general formulas - (CH ₂ ) _p -, -CH ₂ -CH = CH-CH ₂ - (CH ₂ ) -, - (CH ₃ ) ^ O-CH ₃ - and 809841/0791 _t -S-CH ₂ - wherein ρ is an integer of 5 to 7, q is an integer of 1 to 3, and t is an integer of 3 to 5; R _{1 is} a hydroxyl group or a C 1 -C 4 alkoxy group; R- is a C.-C 1-4 alkyl group, a hydrogen atom, a phenoxy group or a phenoxy group substituted with halogen atoms, trifluoromethyl groups and / or methoxy groups; η ^0: or an integer having a value of 1 to 4; and m is 0 or an integer with a value from 1 to 4, with the proviso that the sum of η and m has a value from 2 to 4; mean, man
characterized in that / a connection of the general formula in which Y is a trivalent group of the general formulas V _β ^ ^and ^ CH ₂ - R ₃ o ' wherein R _{3 represents} a hydrogen atom, a tri- (C ₁ -C.) - alkylsilyloxy group and a C -C alkanoyl group and Z, R-, n, m. Y and X have the meanings given in claims 1 to 45, dehydrated by heating. 809841/0791 67. The method according to claim 2, characterized in that the product of the method according to claim 2, wherein R_ represents a hydroxyl group, is esterified to form the alcohol ester, wherein R- represents a C ₂ -C ₅ alkanoyloxy group. 68. Process according to claim 2, characterized in that the product of the process according to claim 2, in which R _{1 represents} a hydroxyl group, is esterified to form the acid ester in which R, represents a C -C alkoxy group. 69. The method according to claim 2, characterized in that the product of the method according to claim 2, wherein R "represents a hydroxyl group, is esterified to form the alcohol _{ester, wherein R 3 represents} a C 1-6 alkanoyl group. 70. The method according to claim 3, characterized in that the product of the method according to claim 3, wherein R "! Represents a hydroxyl group to form the acid ester esterified, wherein R is a C - C alkoxy group. 71. The method according to claim 4, characterized in that that one obtains the product of the process according to claim 4, wherein R. is a hydroxyl group esterified to form the Säureesters, wherein R ₁ represents a C ₁ -C _fi alkoxy group. 72. Process according to claim 5, characterized in that the product of the process according to claim 5, in which R _{1 represents} a hydroxyl group, is esterified to form the acid ester in which R _{1 represents} a C ₁ -C 1 -alkoxy group. 1 Xo 73. The method according to claim 5, characterized in that the product of the method according to claim 5, wherein Rp represents a hydroxyl group, with the formation of the alcohol 8098A1 / 0791 esters esterified, in which R "is a C" -C alkanoyloxy group represents. 74. The method according to claim 2, characterized in that the Y-hydroxyl group is formed with the formation of the alcohol ester 5 esterified. 75. The method according to claim 3, characterized in that that the Y-hydroxyl group is esterified to form the alcohol ester. 76. The method according to claim 4, characterized in that the Y-hydroxy group is formed with the formation of the alcohol ester esterified. 77. The method according to claim 5, characterized in that that the Y-hydroxyl group is esterified to form the alcohol ester. 78. The method according to claim 6, characterized in that that the product of the process of claim 6, wherein R- is a hydroxyl group, is formed with the formation of the acid ester esterified, wherein R represents a C.sub.1 -C.sub.1 alkoxy group. 79. The method according to claim 6, characterized in that that the Y-hydroxyl group is esterified to form the alcohol ester. 80. The method according to claim 4, characterized in that that the Λ. -Binding of the product of stage a) reduced. 80984 1/0791