DE2355540A1 - NEW DERIVATIVES OF PROSTAGLANDINANALOGA AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

DR. HISS. "Ti / - ^^»; - ^J - ^WÖLFF '2 3 SSS Λ Ω

DR.JUfc.HA.vj ::; ικ. ßuL ^ D0.04U

FRANKFURT AM MAlN-HOCHSl "NOV. 2, 1973

Our No. 18,986

Pfizer Inc.
New York, NY, V.St.A.

New derivatives of prostaglandin analogues and processes for their production

The present invention relates, of course, to novel analogs occurring prostaglandins and various new 'intermediates and reagents for their preparation. In particular the invention relates to neuew-pentanorprostaglandins.

The prostaglandins are C-20 unsaturated fatty acids that show various physiological effects. For example, the prostaglandins of the E and A series are effective vasodilators [cf. Acta Physiol. Scand. _s vol. 64; Pp. 332-333 (1965) and Life Sci., Vol. 6; S. HH9 ^ 55 (1967) 3 and reduce the systemic arterial blood pressure after intravenous administration (vasodepressive effect) [Federation Proc, Vol. 23 i p. 327 (196 Acta Physiol. Scand. Vol. 6k, p. 332 ff. (1965); Acta Med. Scand., Vol. I8.3, pp. 423-430 (1968) and Acta Physiol Scand., Vol. 75, pp. 16I - I69 (1969) 3- A · - other known

409821/1 181

physiological effect of PGE and PGE “is that as a bronchodilator [Brit. Med. J., Vol. 4, pp. 723-726. (1969) 3.

Another important physiological role played by the natural prostaglandins in connection with the port planting cycle. PGEp is known to be able to induce labor = [cf. J. Obstet Gynaec. Brit, Cwrlth. _a Vol. 77, pp. 200-210 (I97O): and Contraception, Vol. 4, p. 293 (1971) 3 and to be useful for fertility control. Contraception, Vol. 3, p. 173 (1971) 3 Various prostaglandins of the E and F series have been used as a means of inducing labor in mammals (BE-PS 754 158 and DT-PS 2 034 641) and for PGF ₁ , PGF ₃ and PGF-, as a means of controlling the reproductive cycle (SA-PS 69 / 6O89). Patents granted.

Other known physiological activities of PGE. are the inhibition of gastric acid secretion (Shaw and Ramwell, in "Worcester Symp. on Prostaglandins", New York, Wiley, 1968, pp. 55-64) and also the inhibition of platelet aggregation [Brit. Med. J., Vol. 2, pp. 468 472, (1967)]. '.

It has recently become known that such physiological effects only last for a short period of time after Administration of a prostaglandin is produced in vivo. The reason for this rapid wear off Effectiveness can be seen in the fact that natural prostaglandins are fast and effective through metabolism, and v / earth deactivated by ß-oxidation of the carboxylic acid side chain and by oxidation of the 15 α-hydroxyl group , ("Cf. Acta Physiol. Scand., Vol. 81, p. 396 (1971) and the

409821/1181

literature cited there-3

Accordingly, it was desirable to create analogs of prostaglandins which exhibited physiological activities, which are equivalent to those of the natural compounds, their selectivity of action and their duration of action however, is increased. It was to be expected that an increased selectivity of action would reduce the serious side effects, especially gastrointestinal side effects that are common after systemic administration of natural Prostaglandins were observed (see Lancet, 536, 1971).

The subject of the invention is a process for the preparation of "compounds of the structure

- N

·· ■■ - '. · R

and their C ^ epimers,

wherein Ar is phenyl, 3 »4-dimethoxyphenyl ~ / 3, lJ-methylenedioxyphenyl-r, 3, {t, 5-trimethoxyphenyl- _/ α- or β-naphthyl-. or monosubstituted phenyl group, where the substituent is a halogen atom, a trifluoromethyl, phenyl, lower-alkyl or lower-alkoxy group, -R is a hydrogen atom or a lower alkyl group; η and m. each whole numbers from 0 to 3, vjobei the sum of η and m does not exceed the number 3; ■

k 0 9 8.2 1/1 1 8 1

W is a double bond or a double cis bond; Z is a single bond or a trans double bond;

tr OH

M is a keto group or one of the groups · £ """or -z £ ~.

N and L together form a single bond, or, if L is a hydrogen atom, N represent an α-hydroxyl group, and in what

X denotes a p-phenylphenoxycarbonyl-tetrazolyl group or a group -CONHR ", in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having H to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms, in which the substituent is a methyl or methoxy group or '■

is a halogen atom; an alkylsulfonyl group with 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group wherein the substituent is a Is methyl, or methoxy group or a halogen atom, represents, and wherein L, M and N are selected to have the structure of a prostaglandin of the. A, E or F series is completed, "■

the .lower alkanoyl, pormyl or benzoyl esters of any free hydroxyl groups in the C, C ₁₁ or n which is characterized in that one

a) when N is an α-hydroxy group and L is a hydrogen atom, and Ar, n, m, M, Vi, X and Z have the aforementioned meanings, these compounds by treating the 11- and 15-tetrahydropyranyl ethers of a compound of the above formula I with a suitable acid produces;

b) when N and L together form a single bond,

M is a keto group, and Ar, n, m, R, W _9, X and Z have the aforementioned meanings, these compounds by reacting a compound of the above formula I in which N is

409821/1181

α-hydroxy group, L is a hydrogen atom and M is a keto group are, and Ar, n, m, R, VJ, X and Z-aforementioned meaning own with. a suitable dehydrating agent manufactures;

c) when N is a cc-hydroxy group, L is a hydrogen atom and

M represent the group ·; """^{> Η} or the group <^ ^0H , '""'" OH. '''"" Yi

and Ar, n, R, W and Z have the aforementioned meaning, these compounds by reaction of a compound: of the formula I, in which N is an α-hydroxy group, L is a hydrogen atom and M is a keto group, and Ar, n, m, R , V /, X and Z have the aforementioned meaning, prepared with a suitable reducing agent and optionally separates the 9 ^a ~ and 9 ~ isomers; '"

d) when N is an α-hydroxy group and L is a hydrogen atom are, Ar, R, h, -m, M and.X have the aforementioned meaning, and W and Z represent single bonds, these compounds by catalytic reduction of a compound of the formula I produces, in which Ar, .R, n, m, M and X the aforementioned meaning own; W, if Z is a trans double bond, a single bond or a cis double bond, and Z, if W is a cis double bond, represent a single bond; ■ - ". · ■ .-"

e) when N is a cc-hydroxy group and L is a hydrogen atom represent, and Ar, R, n, m, X and M the aforementioned meaning have a single bond and Z a trans double bond mean these compounds by selective reduction of a compound of the formula I or the Tri- '.

alkylsilyl esters £ - a compound of the formula I, in which X is a COOH group, Ar, R, n, m, X and M have the aforementioned meanings, and W and Z double bonds represent,

0 9 8 2 1/118

f) those compounds of the formula I,

where X is a COOR? group, where R 'is a hydrogen atom , converted into their above-mentioned esters and substituted amides by reaction with suitable esterification and amidation reagents,

and optionally _> by reacting these compounds with the corresponding acylating agents ^ the 9a, 11a- ¹ and 15a-lower alkanoyl- _J formula and benzoyl esters "" of any free hydroxyl groups - produces.

In particular, the invention relates to a method of joining the structure

CIA)

and their C, epiiners,.

wherein Ar is a phenyl, 3 ₃ 4-dimethoxyphenyl-7 _> "3, ^z i-methylene-dioxyphenyl-r, 3, ^, 5-trimethoxyphenyl, α- or β-naphthyl or monosubstituted phenyl group, the substituent being a halogen atom , represents a trifluoromethyl, phenyl, lower, alkyl or lower alkoxy group, -R denotes a hydrogen atom or a lower alkyl group; η and m are always integers from 0 to 3 »where the sum of η and m the number does not exceed 3; W represents a single bond or a cis double bond ;; and Z represents a single bond or a trans double bond, and in which

409821/1181

- «. 7 '-

X represents a p-phenylphenoxycarbonyl, tetrazoyl group or a group -CONHR ", in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms, wherein the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group having 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl or methoxy group or a halogen atom represents _ .-- · -.
the lower alkanoyl, formyl or benzoyl esters of. any free hydroxyl groups in the CQ, C or C .- 'position, as well as the pharmaceutically acceptable S.alze these compounds, ^r -the is characterized in that., sl), the 11- and 15-Tefcrahydropyranyläther the. Compounds of the formula I are treated with a suitable acid; b) a compound of the formula,

(CH ₂ ) _n -Q- (CH ₂ ) _ffi Ar '' (IB) -

in which Ar, n, m, R, VJ, X and Z have the abovementioned meanings, reduced with a suitable reducing agent and the 9a _r and 9ß-isomers are then separated; c) a compound of the formula IA, v / orin Ar, 'R, n, m and. X have the aforementioned meaning, and ¥, if Z - is a trans double bond, a single bond or a cis double bond, and Z, if V / is a cis double bond, mean a single bond, is catalytically reduced to a compound of the formula IA, wherein Ar ₃ R and N have the aforementioned meaning, and W and Z are single bonds;

'4098 21 / -11 81

d) the Dxmethylxsopropylsilylderivat of a compound of the formula IA, wherein X is the group -COOR ', where R ^{1 is} a hydrogen atom, and where Ar, R, η and m have the aforementioned meaning, W a cis double bond and Z a trans Double bond, is selectively catalytically reduced to a compound of the formula IA, in which Ar, R and η have the abovementioned meaning, W is a single bond and Z is a trans double bond- · 'represent *

that e) those compounds of the formula I in which X is a COOR ¹ group, where R ^{1 is} a hydrogen atom, are converted into their abovementioned esters and substituted amides by reaction with suitable esterification and amidation reagents, and optionally, by reaction of these compounds with the appropriate acylating agent, the 9ot and ISa-lower alkanoyl, formyl and benzoyl esters of any free hydroxyl groups are prepared.

The invention also relates to a method for making compounds of the structure

OH ^{CCH2) n} ~ ° ~ ^v ~ "2'in ·

and their C ^ epimers,

in which Ar is a phenyl, 3, ^ - Dlxnethoxyphenyl-, 3, ^ - Methylenedioxyphenyl-, ^, ^^ - trimethoxyphenyl-, α- or '

represents ß-naphthyl or monosubstituted Pheriylgruppe, in which the substituent is a halogenator, a

409821/1181

Trifluoromethyl ,. Phenyl, iaiedere alkyl or lower .. Is alkoxy group;

R represents a hydrogen atom or a lower alkyl group; η and m are integers from 0 to 3, where the sum. of η and m does not exceed number 3; ' ;; . ·· V / a single bond or a cis double bond; .Z represent a single bond or a trans double bond, . . ■ * "and where X is p-phenylphenoxycarbonyl group, tetrazolyl group or

means a group —CONFIR ", in which R" is an alkanoyl group having from 2 to 10 carbon atoms or a cycloalkanoyl group having from 4 to 8 carbon atoms; represents an aroyl or substituted aroyl group having 7 to 11 carbon atoms, in which the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfanyl group of 1 to 7 carbon atoms; an arylsulphonyl or substituted arylsulphonyl group, the substituents being a methyl, methoxy group, or a halogen atom. is, means ': • the lower alkanoyl, formyl or benzoyl ester be—'. dear free hydroxyl groups! i _n C.- - and C --- Sfellung

.that is characterized by ₃ that. .-.

a) the 11- or 11- and 15-tetrahydropyranyl _{ethers "a" compound of the formula IB 3} v; or in Ar, R, m, n, V /, X and Z have the aforementioned meaning, are treated with a suitable acid;

b) a compound of the formula IB, in which Ar, X, R, m, 'and η have the aforementioned meaning, and W, if Z is a trans double bond, a single bond or cis double bond, and Z, if W is a cis- Is a double bond, represents a single bond, is catalytically reduced to obtain a compound of the formula IB, in which Ar, X, n, m and R are as defined above, and ¥ and Z are single bonds;

409821/1181

- 1 ο -

c) the dimethylisopropylsilyl derivative of a compound of the formula IB, in which Ar, R, m., and η have the aforementioned meaning have, X a COOH group, V / a cis double bond and Z represent a trans double bond, is selectively catalytically reduced to form a compound of Formula IB, in which Ar, X, R, m and η have the aforementioned meaning, W is a. Single bond and Z is a trans double. bond represent, maintain; . ,

that gene compound of the formula IB, in which X is a COOR * - Group in which R 'is a hydrogen atom, by reaction with suitable esterification or ami-. dating agents are converted to their esters or substituted amides,

and that optionally the lower alkanoyl, formyl or benzoyl esters of any free 11- and 15-hydroxyl groups by reaction of these compounds »' be prepared with the appropriate acylating agent.

even
The invention relates to a method for producing

Connections of the structure

(CH ₂ ) _n -0- (CH ₂ ) _m Ar (XC)

and their C ^ epimers,

where Ar, a phenyl, 3, ^ - dimethyloxyphenyl, 3,4-meth.ylenedioxyphenyl, j5, * J, 5-trimethoxyphenyl ~, α- or ß-naphthyl- or monosubstituted phenyl group, in which the substituent is a halogen atom:, a trifluoromethyl-, Is phenyl, lower alkyl or lower alkoxy group; '■ "' - ..

409821/1181

R represents a hydrogen atom or a lower alkyl group; 'η and m are each integers from 0 to 3, the ·· - sum of η and in not exceeding 3 ;. ^: ■ W and L each one. Single bond or a cis double bond; -.

Z is a single bond or a trans double bond represent;

and in which X denotes a p-phenylphenoxycarbonyl or tetrazolyl group or a group -CONHR ", in which · · R" denotes an alkanoyl group having 2 to 10 carbon atoms or a cycloalkanoyl group. H to 8 carbon atoms; an aroyl or substituted aroyl group with 7 to. 11 represents carbon atoms in which the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group of 1 to 7 carbon atoms; represents an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl, methoxy group or a halogen atom; the lower alkanoyl, formyl or benzoyl esters of the C 6 -hydroxyl group, which is characterized in that a compound of the formula IB

wherein Ar, R, m, n, W, X and Z have the aforementioned meaning, reacted with a suitable dehydrating agent will; .

and those compounds of formula I,

A 0 9 8.2 1/1 1 8 1

wherein X is a COOR 'group in which R * is a hydrogen atom ₃ is _Λ by reaction with suitable esterification or. Amidation reagents are converted into their abovementioned esters or substituted amides, and optionally, by reacting these compounds with appropriate acylating agents, the C ^ -lower alkanoyl, formyl or benzoyl esters are prepared '.

The invention also relates to a method of production of connections of the structure

OTHP

and their C ₁ ^ epimers, as well as their Cq and C ^ epimers, wherein Ar is a phenyl, 3, i {-dimethoxyphenyi-7y; 3 ^ - Mefciiylen- dioxyphenyl-r, _{3> ίi>>} 5-trimethoxyphenyl · 7 _/ α- "or .beta.-naphthyl" * .. desolate monastic substituted phenyl group, where "the Substituenfc a .Halogenatoin ₃ a Trif luormet.. hy I-, phenyl-, lower-, alkyl- or lower-alkoxy group, _y is; · .- R. is a hydrogen atom or a lower alkyl group; THP is a 2-tetrahydropyranyl group ₃ η and m jevreils integers from 0 to 3, whereby the sum of ti and m does not exceed the number 3.j

VJ is a single bond or a cis double bond; and Z represent a single bond or a trans double bond, and vrorin

409821/1181

. X is a p-pheny! Phenoxycarbonyl or tetrazoyl group or a group -CONHR ", in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms; an aroyl or substituted aroyl group with 7 to 11 carbon atoms, v / oren _; '■ the substituent' is a methyl or "kethoxy group or *. -A halogen atom; an alkylsulfonyl group with. 1. to. ~".

• 7 carbon atoms; an ary, sulfonyl or substituted ary is sulfonyl group, in which the substituent is a “y

. 'represents, ·' "..- ■ ■" '"' _"

which is characterized, that a connection of the Formula II

(ii)

in which Ar, R> n, m> and Z have the meaning mentioned above, with a ylid of the formula - '

wherein X has the aforementioned meaning, is reacted, where, if X is a p-phenyl-phenoxycarbony! group, the compound of the formula II first with an ylid of the formula - "-

) --P = CH-CH ₀ CH ₀ CH ₀
3 2 2 2

4 0 9 8 21/118 1

is reacted, and the product obtained is esterified with p-phenylphenol in order to obtain a compound of the formula II, wherein Ar, R, 'n, in, X and Z have the aforementioned meaning and Ii is a cis double bond, and daii the the compound formed in this way is subsequently reduced, if necessary, in order to obtain a compound of the formula II in which Ar, R, n, m, X and Z have the aforementioned meanings and VJ is a single bond; that a compound of the formula II in which Ar, R, .m .., X and η have the abovementioned meanings, W represents a cis double bond and Z represents a trans double bond, reduced; is to obtain a compound of the formula II in which Ar, R and η have the aforementioned meanings and W and Z represent single bonds; . or that a compound of formula II in which Ar, .R and. η "have the abovementioned meaning, W represent a cis double bond and Z represent a trans double bond, is selectively reduced in order to produce a compound of the formula" II. -'- hold, in which Ar, R, m, X and η have the aforementioned meaning- ', W is a single bond and Z is a trans double bond.

The invention also relates to a method of making compounds of the structure

R OTHP ■. · .-

409821/1181

and their C- _t - epimers ₃

where Ar · a phenyl-, 3;> ¹ f ~ Dlraefchoxyph.enyl- / Ss ^ dioxyphenyl-, 3, ^, 5-trimethoxyphenyl'7 _/ α- or · β-cupfciiyl- "-". or an inonosubstituted phenyl group, where the substituent represents a halogen atom, a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group: R is a hydrogen atom or a lower alley group "THP a 2-tetrahydropyrany! group ₃ η and m each 'gaiize numbers from 0 to 3, the sum of n and m not exceeding the number';"'= · .-' ■ ·

W is a single bond or a cis double bond ^ Z. a single bond or a trans double bond .'.--. ' represent, and .V7orin

X is a p-phenylphenoxycarbonyl or tetrazoly group or a group -CONHR " ₃ in which R" is an alkanoyl radical with 2 to 10 carbon atoms or a cycloalkanoyl group with H to 8 carbon atoms; an aroyl or substituted aroyl group with 7 to 11 carbon atoms, where the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group with 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent represents a methyl or methoxy group or a halogen atom,

which is characterized in that a compound of the formula HA

4 0 9 8 21/118 1

- J6 -

in the aforementioned meaning Ar, R, η, m, X, w and Z possess, .with chromic acid in aqueous sulfuric acid: and Acetone. Is 'converted:'. "" "" "'..

The invention also relates to a method for producing compounds of the structure

CH ₂ ) _n -0- (CH ₂ ) _B1 Ar-

CHI)

in the ar. a phenyl, 3,4-dimethoxyphenyr, 3, ⁱ -methylenedioxyphenyl, 3, ⁱ L, 5-trimethoxyphenyl, ex- or ß-naphthylbder monosubstituted pheny! group, in which the substituent is a halogen atom, a trifluoromethyl · Is phenyl, lower alkyl or lower alkoxy group;

η and m are whole numbers from 0 to 3a where the Sum of ri "and m does not exceed the number - and Q '^ represent a p-Biphenylcarbonylrest that thereby is characterized in that a compound of the formula

QO ^

CHO

wherein Q has the aforementioned meaning, with a compound of the formula ■ · '

409821/1181

lower-alkyl-O · lower-alkyl-O "^

_r C- (OH ₂ ) _n -O- (CH ₂ ) _m Ar

in which m, η and Ar have the aforementioned meaning, implemented will.

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

Q ¹ O *

. Cxv)

in which Ar is a phenyl, 3,4-dimethoxyphenyl, 3 ** 1-methylenedioxyphenyl, 3 .%> 5-Tfimethoxyphenyi- ₃ α- or β-naphthyl or monosubstituted phenyl group, in which the substituent is a halogen atom , is a trifluoromethyl, phenyl, lower alkyl, or lower alkoxy group; . -

R represents a hydrogen atom or a lower alkyl group; h and m jev / eils whole numbers from Ö to 3, the sum of η and m not exceeding the number 3; and Q. ¹ : represent a hydrogen atom or a p-biphenylcarbonyl radical, cdaa. is characterized in that a, compound ^ of the formula III "

4 0 9 8 21/1181

> P

in which Ar, η, m and Q have the aforementioned meaning ,, reduced; is in order to obtain a compound of the formula IV, in which Ar, η and Q have the aforementioned meanings and R represents a hydrogen atom, and that the 8ot and 8ß isomers are optionally separated; -; ^: 'that a compound of the formula III is reacted with a suitable alkylating agent to give a compound of the * formula IV, in which Ar, n, m and Q have the aforementioned meaning and R is a lower alkyl radical, to'':' - .:

obtain; *. . .

and that optionally a compound of the formula IV, in which Ar, η and R have the aforementioned meaning and Q represents a biphenylcarbonyl radical, treated with EpCO to obtain a compound of formula IV wherein Q is a hydrogen atom; where the 8α- and 8β-isomers are optionally separated ^

and a process for the preparation of compounds of structure

THBO

I) THP

40 9821/1181

in which Ar is a phenyl, 3> ⁱ f-dimethoxyphenyl ->. ^ 3 _;> 4-methylenedioxyphenyl, 3, ^, 5-trimethoxyphenyl, α- or β-naphthyl or monosubstituted phenyl group, in which the Substituent is a halogen atom, a trifluoromethyl, phenyl lower alkyl or lower alkoxy group; .. Pure. Hydrogen atom or a lower alkyl group; THP is a 2-tetrahydropyranyl group; · ... . ". ';' ■ η and m are integers from 0 to 3, where the Λ ■ ·" _ sum of η and m does not exceed the number 3; · Z is a single bond or a trans double bond; and Y represents an oxygen atom or the group cT ^ "

represent, -thas is characterized _s that a compound, of the formula -.

• '■ · ■ ~ .Y · "

0 '

in which Ar ₃ R, m ₃ η and Z have the aforementioned meaning and Y = O, in the presence of an acidic catalyst. 2,3-Dihydropyran is reacted in order to obtain a compound of the formula V, in which Ar, R, m, η and Z have the aforementioned meanings and Y = O; that a compound of the formula V, in which Ar, R, m, η and Z have the aforementioned meaning and Y = 0, is reacted with Oi isobutylaluminum hydride to obtain a compound of the formula V in which Ar , R, m, η and Z have the aforementioned meaning, and Y is the group: ^ ~ "~, to obtain; or

that a compound of the formula IV in which Ar, R, m and ri have the aforementioned meaning, Z is a trans double bond

40 9 821/1181

In general, the invention relates to compounds of the structure

and their C c epimers \,.

where Ar is phenyl, 3> ^ ~ dißiethoxyphenyl3 ₇ . 3i ^ -Methylene - dioxyphenyl, 3, ⁱ l ₃ 5-triinethoxyphenyl ^ cc, or β-naphthnyl: or monosubstituted pienyl group, where the substituent is a halogen atom, a trifluoromethyl, phenyl, lower-alkyl or represents lower alkoxy group means -. · "R a water s first off atom or a lower alkyl group; η and ra each .integer numbers from 0 to 3> where the sum of η and rfl does not exceed the number 3; W a single bond or a cis double bond; Z a Single bond or a trans double bond; M a keto group or one of the groups ■ ζ "" **. Or ■ ςΓ ""... "

N and L together form a single bond, or, if L is a hydrogen atom, N represent an α-hydroxyl group, and xiTorin. ·

X denotes a p-phenylphenoxycarbonyl, tetrazolyl group or a group -CONHR ", in which R" is an alkanoyl radical with 2 to 10 carbon atoms or a cycloalksnoyl group with h to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms, in which the substituent is a methyl or methoxy group or

409821/1 181

-. 2ο -

and Y = O, j is catalytically reduced by one compound of the formula V, in which Ar, R, m and η have the aforementioned meaning, and Y = O and Z are one Are single bind.

409821/1181

a halogen atom. Is; an alkylsulfonyl group having J to 7 carbon atoms; , represents an arylsulfonyl or substituted arylsulfonyl group, wherein the substituent is a methyl or methoxy group or a halogen atom, "and wherein L, M and M are selected so that _a structure of a prostaglandin of the. A, E or F Row completes v / ird ^. ". ■

The invention particularly includes compounds of the general formulas:
OH

(IA)

and their C ^ epimers,
0

OH

and their C ^ epimers, as well as

-O-CCH ₂ ) _m Ar

(IB)

(IC)

^v 0H

and their C epimers,

wherein Ar, m, n, R, X, Y and Z have the aforementioned meanings.

40982 1/1181

The invention also includes compounds of the structure

OTHP.

and their C _g and C ^ epimers, wherein Ar

a phenyl, 3, ^ - dimethoxyphenyl, 3,4-methylene

dioxypnenyl-, 5, ^, - 5-trimethoxyphenyl-j, α- or .ß ~ I

or "monosubstituted phenyl group, where" the · "substituent represents a .halogen atom, a trifluoromet hy 1-, 'phenyl- ^' lower-alkyl or lower-alkoxy group _> means-." .- / -

R. A water atom or a lower alkyl group - _y - ''. "THP a 2-tetrahydropyrany! Group, η and m each whole
Numbers. From 0 to "3, where the sum of n / tünd ία the number 3
does not exceed; . -. "

VJ is a single bond or a cis double bond; and
Z is a single bond or a trans double bond
represent, and where - ... · "·., .-

: 'X is a p-phenylphenoxycarbonyl or tetrazoyl group
or a group -CONHR ", in which R" is an alkanoyl radical
2 to 10 carbon atoms or a cycloalkanoyl group
with * i is up to 8 carbon atoms; an aroyl or substituted aroyl group with 7 to 11 carbon atoms / in which the substituent * is a methyl or kethoxy group or -.- ~
a Halogenatotu is an alkyl sulfonyl group with. i.bis. ^: . 7 carbon atoms; an arylsulfonyl or substitution ^"r 7
ated arylsulfonyl group ^ where the substitute is a "-_."
Is methyl or Hethoxygrupp'e or a halogen atom, .represents ^ '. . ·. - .. - '■ "■■■■; - · -. ^ - ■

4098 21/1181

as well as connections of the structure

THPO ^N

(CH ₂ ) _n -O- (CH ₂ ) Ar

(HB)

ÖTHP

and their C ₁ , epimers, "'

tiorin Ai * a Phenyl- _y 3 _> ⁱ -DlirrethQ>; ypiaenyl- / 3 !, ¹ J-Ketiiyler dloxyphenyl-, 3 _y * i, 5-Trlmethoxyphenyl-7 ,. α- or β-napiatliyl- or monasubstituted. Piienylgruppej where the · 'substituent is a Haiogenatοία, a Trlfluorraethyl- ;, Piienyl · -;,. "!!!«; ^! V / as.ss only off atom or a lower alkyl group ^;. '. THP is a Z-tetrahydropyranyl group, η and m each are integers from 0 to 3j where the sum of n and m does not exceed the number 3; . - ";'■.

VJ a single junction or a cls double junction ^ Z is a single bond or a trans double bond. · "-" represent, and, in which

X is a p-phenylphenoxycarbonyl or tetrazolyl group or a group -CONHR " _s in which R" is an alkanoyl radical with 2 to 10 carbon atoms or a cycloalkanoy group with k to 8 carbon atoms; an aroyl or substituted aroyl group having J to 11 carbon atoms, wherein the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group having 1 to 7 carbon atoms; an arysulfonyl or substituted arylsulfonyl group, v / or in which the substituent is a methyl or methoxy group or a halogen atom, represents 0

409821/1181

The invention also relates to compounds of the structure

(III)

in the Ar a phenyl ,. . 3y ^ -Dimethoxyphenyl-, 3,4-methylenedioxyphenyl, 3 "**, 5-trimethoxyphenyl, _a - or ß-naphthyl or nionosübstituierte Phenyl is group wherein the substituent is a halogen atom, a Trifluorraethyl-, phenyl , represents lower alkyl or lower alkoxy group; η and m are each integers from 0 to 3, the sum of η and m not exceeding the number 3, and Q is a para-biphenylcarbonyl radical ^

Connections of the structure

(IV)

in which Ar is a phenyl, 3,4-dimethoxyphenyl,. '3, ^ - methylenedioxyphenyl -, - 3,4,5-trimethoxyphenyl, a ~ or ß- naphthyl or monosubstituted phenyl group, where the Substituents a halogen atom, a trifluoromethyl, Represents phenyl, lower alkyl or lower alkoxy group;

409821 / 1181-

R is a hydrogen atom or a lower alkyl group; η and m are each integers from ο to J ₃ where the sum of η and m does not exceed the number 3, and Q ^{1 is} a hydrogen atom or a p-bipheny! carbonyl-. rest mean
as well as connections of the structure

(V)

\ / 7
THPO ^ N ^ X / ^ CCHpJ ^ -O-iCH,) Ar

QTHP

. Ar is an Pherlyl-, 3,4-dimethoxyphenyl, 3, * t-methylenedioxyphenyl, 3> 4.5 ~ trimethoxyphenyl, _a - or ß-naphthyl, or monostubstituierter phenyl, the substituent is a halogen atom vrobei , represents a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group; THP is a 2-tetrahydropyrany group; η and m are each integers from 0 to 3, the sum of η and m not exceeding the number 3; Z is a single bond or a trans double bond; and

TT

Υ an oxygen atom or the group "

mean.
Preferred compounds are those of the formula I,

. QTT - "

wherein M is a group T; > ^{L a} single bond and

'""H
N represents an α-hydroxyl group and its C 1-4 epinteres, and in which η and m are each 0, and Ar is a phenyl group, the prostaglandin being PGE ₂ ; wherein η and m are each 0, and Ar is a phenyl group, the presotaglandin being PGF _2a ; where η = 0 _s m = 0- and Ar is a

409821/1181

Are phenyl, where the prostaglandin is PGF _β ; where η = O, m = O and Ar are a phenyl group, the prostaglandin being PGA „; where η = O, m = 1 and Ar is a phenyl group, where the prostaglandin is PGE ₂ , as well as the compounds where η = O, m ^ 1

and Ar are phenyl, the prostaglandin being PGP _2α .

Further preferred compounds are those of formula IA, in which η and m are each 0, in which η and m are each 1, in which X is a tetrazolyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom _f

η and m are each 0, Ar is a phenyl group, vrorin X. a group -CO-NHR " , where R" is a methylsulfonyl group, and W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0 and Ar is a phenyl group, as well as those compounds of Formula IA, in which X is a group -CO-NHR ", where R" is a methylsulfonyl group, and W is a cis double bond, Z is a trans double bond, »R is a hydrogen atom, η and m are each 0 and Ar is an m- Represent methoxyphenyl group.

Further preferred compounds are those of the formula IB where η and m are each 0, where η and m are each 1, where X is a -CONHR "group in which R" is an acetyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0 and Ar is a phenyl group; in which -CONHR ", where R" is an acetyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m, respectively 0 and R are m-methoxyphenyl group; wherein X is a tetrazolyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0 and Ar is a phenyl group; and where X

409821/1181

a -CONHR "group in which R" is a methylsulfonyl group W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0 and Ar is Are phenyl group.

Particularly preferred compounds are the 16-phenoxy-PGEp-p-biphenyl esters, 16-phenoxy-PGF ^ -p-biphenyl esters and the 16-phenoxy-PGF 2ß-p-biphenyl _esters .

The C ^ epimers of the compounds are also preferred of formula II. '

Other preferred prostaglandins are as follows: A compound of the formula I in which η and m are each O ₃ Ar a phenyl group and the prostaglandin is PGEp. A compound of the formula I in which η and m are each 0, Ar is a phenyl group and the prostaglandin is PGP. A compound of formula I in which n = 0, m = 0 _s R is a phenyl group, and · the prostaglandin PGF are _OSS. A compound of the formula I ₃ in which n = 0, m = 1, Ar is a phenyl group and the prostaglandin is PGEp. A compound of the formula I in which n = 0, m = 1, Ar is a phenyl group and the prostaglandin is PGF-. A compound of Formula II wherein η and m are each O.

to

A compound of the formula II in which η and m are each 1

A compound of the formula III, in which η and m are each 0

A compound of the formula III in which η and m are each 1

Particularly preferred prostaglandins are the following: A compound of the formula II in which X is the fourth subgroup, R "is an acetyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0, and Ar is a phenyl group.

A compound according to formula II in which X is the third subgroup represents, W is a cis double bond, Z is a trans "

4Ö9821 / 1181

Double bond, R a "hydrogen atom, η and m each O, and 'Ar are phenyl.

A compound according to formula II in which X is the fourth subgroup and R "denotes a methylsulfonyl group, W a cis double bond, Z a trans double bond, and R a Hydrogen atom, η and m each Ό ,, and Ar a phenyl group are.

A compound according to formula II in which X is the fourth sub-group and R "denotes a methylsulfonyl group, W a cis double bond, Z a trans double bond, R a Hydrogen atom, η and m each 0, and R an m-methoxypheny group are, '

A compound according to formula III, in which X is the fourth subgroup represents, R "an acetyl group, W an ice-. Double bond, Z is a trans double bond, R is hydrogen atom, η and m are each 0, and Ar is a phenyl group.

A compound of formula III, in which X is represented according to the fourth sub-group, R "is an acetyl group, W is a cis double bond, Z is a trans double bond, R atom is _hydrogen,: η and m are each 0, and Ar represents a m-methoxyphenyl group.

A compound according to formula III, in which X is the third subgroup, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0, and Ar is a phenyl group.

A compound according to formula III, in which X represents the fourth subgroup, and R "is a methylsulfonyl group, W a cis double bond, Z a trans double bond, R a hydrogen atom, η and m each 0, and Ar a Eheny! Group.

The novel intermediates of the following formulas are also a feature of the present invention

40 9 821/118

- 3ο -

235554Q

(CH ₂ ) _n -0- (CH ₂ ) _m Ar OTHP

(IV)

(V)

(CH ₂ ) _n -0- (CH ₂ ) _m Ar OTHP

and their C _g and C epimers,

wherein Ar is a phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl ,, 3,4,5-trimethoxyphenyl-, cc- or ß-naphthyl- or monosubstituted phenyl group, the substituent being a halogen atom, a trifluoromethyl, phenyl, is lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group;

THP is a 2-tetrahydropyranyl group;

η and m are each integers from 0 to 3 ₉ where the sum of η and m does not exceed the number 3; W. a single bond or a cis double bond; Z is a single bond or trans double bond; and X is a first subgroup comprising the group -COOR ', where RT is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 9 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a

1/118

α- or ß-naphthyl group, a phenyl or monosubstituted one Phenyl group in which the substituent is a halogen atom, a lower alkyl or lower alkoxy group, represents j

a second subgroup is selected from a p-phenylphenoxycarbonyl group consists;

is a third subgroup consisting of a tetrazolyl group, or finally: t

is a fourth subgroup, which consists of the group -CONHR ", in which R" is an alkanoyl radical with 2 to 10 Carbon atoms, a cycloalkanoyl radical with 4 to 8. Carbon atoms, an aroyl or substituted aroyl radical having 7 to 11 carbon atoms, in which the substituent a methyl or methoxy group or a halogen atom is; an alkylsulfonyl group having 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group, ″ wherein the substituent is a methyl or methoxy group or a halogen atom.

The starting materials for the various new compounds are commercially available or can be prepared by well known methods. For example, to produce dimethyl 2-oxo ~ 3-phenoxypropylphosphonate, the starting material for the synthesis of 16-phenoxy-prostaglandins, a solution of dimethylmethylphosphonate in tetrahydrofuran is cooled to -78 C under a nitrogen atmosphere, and then n-butyllithium is slowly added dropwise in hexane too. After stirring, methyl 2-phenoxyacetate is added dropwise. After 3 to H hours at -78 ⁰ C, the reaction mixture warmed up to ambient temperatures, -neutralisiert with acetic acid and in a rotary evaporator to a white gel

AO9821 / 1 1 81

constricted. The gelatinous material is taken up in water, the aqueous phase is extracted with chloroform, and the. combined organic extracts are washed again, dried and concentrated, the desired Product is obtained. .

To produce substituted 16-phenoxyprostaglandins, you need substituted phenoxyacetic acid ^ which are prepared by condensation of the corresponding phenol with a haloacetic acid or a haloacetic acid ester in the presence of a base [cf. Acta Chem. Scandinavica, Vol. 5 »p. 519 (1951.) or Agri. Food Chem., Vol. * ", P. ! \ 9 (1956) 3. The condensation of bromomethyl acetate with sesmol in the presence of sodium methylate leads to the methyl 3,4-methylenedioxyphenoxy-acetic acid ester. Similarly, p-chlorophenoxyacetic acid, 3j ^ j5 ~ trimethoxyphenoxyacetic acid and p-phenylphenoxyacetic acid can be prepared.

These acids can be converted into the Esters and converted therefrom into the phosphonates, as before for the unsubstituted 16-phenoxy starting compounds has been described.

Phenylpropoxyacetic acid is required to produce the starting materials for the 16-phenylpropoxy-prostaglandins. This is after the in Bull. Soc. Chim., Vol. 51 _a p. 691 (1932), converted into the ester and from it into the phosphonate, as described above for the 16-phenoxy compound.

Required for the production of the 16-benzyloxyprostaglandins one benzylglycolic acid, which according to the in HeIv. Chim. Acta,.

409821/1181

Bd.! Β, S. II30 (1933) described processes, represents and according to standard methods in the ester and therefrom according to the method described for the 16-phenoxy compound. drive into the phosphonate is transferred.

If 16 ~ phenethoxyprostaglandins are desired, the phenethoxyacetic acid is prepared, for example, according to the method of. Rothstein, Bull. Soc. Ch ^ im., Vol. 51, p. 69I (1932) heri and converts this into the ester and therefrom into the phosphonate according to that described for the 16-phenoxy compound Procedure. · '.

To produce the 17-phenoxyprostaglandins, 3 ~ phen-

■ - ■

oxypropionic acid (product from Aldrieh Chem. Co. No. PI6OO-I) was converted into the ester and from it into the phosphonate, as described above for the 16-phenoxy compound ₉ .

4-Phenoxybutyronitrile is used to produce the 18-phenoxyprostaglandins (Kodak product, No. 1414) with a 10 $ aqueous-methanolic hydrogen chloride- Solution heated under reflux in order to convert this compound into 4-phenoxybutyric acid, which is necessary for conversion into the phosphonate, as before for the 16-phenoxy compound described, is suitable.

5 ~ phenoxyvaleric acid is used to produce the 19-phenoxyprostaglandins required, which according to the in J. Am. Chem. Soc, Vol. 50, p. 1967 (1928) " prepared and, as before for the 16-phenoxy compound " described, can be converted into the phosphonate.

The following scheme A gives an overview of the Synthesis route:

409821/1181

Scheme A

Ar- (CHg) _n -O- (CHg J _n

Ii

-OCK

■ 3

. (CHg) _n -O- (CHg) ₁₁ Ar ₀

CH ₂ ) _n -0- R

409821/1181.

As can be seen from scheme A, there is the 1st stage in the complete synthesis (1> 2) in the condensation of the corresponding ester with a dialkyl methylphosphonate, the ketophosphonate 2 being obtained. These esters are obtained as previously described.

in .the stage 2 } 3 the ketophosphonate 2 .with the,

known; [J. At the. Chem. SoC ₉ -Bd. 93, p. 1 * 191 (197D3 aldehyde H converted, whereby the enone 3 is obtained after chromatography or crystallization.

The enone 3, in a mixture of tertiary alcohols 13 and are converted by reaction with the corresponding Metällalkyl l4, and the isomers 13 and I ¹ I can be separated by Sulenchromatographie. The enone 3 can be reduced with zinc borohydride or trialkylborohydrides, such as lithium triethylborohydride, to a mixture of alcohols U and 5, which can be separated as described above. Ethers such as tetrahydrofuran or 1,2-dimethoxyethane are generally used in this reaction , although methanol is sometimes preferred to ensure specificity of the reduction. Broad transformations of compound 4 are shown in Scheme B:

The reaction stage 4 ^ 6 is a base-catalyzed one

Transesterification, with the p-biphenyl-carbonyl protecting group Will get removed. This is most conveniently done with potassium carbonate in methanol or methanol-tetrahydrofuran as'

Solvent carried out. Stage 6 > 7 brings

the protection of the two free hydroxyl groups with an acid-labile protecting group. Any sufficient acid-labile group is satisfactory; however, the most common protective group is a tetrahydropyranyl

409821/1181

group made into the molecule by treating it with dihydropyran and an acidic catalyst in an anhydrous Medium can be introduced. The catalyst is common p-toluenesulfonic acid.

40982 1/1 181

• - 37 "-

Scheme B

• HO

(CH ₂ ) _n -0- (CH ₂ ) _m Ar

tHFÖ

ί CH ₂ J _n -O - (- CH ₂ ) _m Ar ΌΤΗΡ:

1 ■ '·

THPO

THPO "

. (CH ₂ ) _n ~ O- (CK ₂ ) _m Ar "OTHP

10

■ ir

(CH ₂ ) _n -0- (CH ₂ ) _m Ar

H '0Ή

11

nO- (CH ₂ ) _m Ar

4 09821/1181

- 38 -

The level 7 $ ■ 8 is a reduction of the lactone 7 to

Hemiacetal 8 using diisobutylaluminum. hydride in an inert solvent. The reaction temperatures are lower, generally one temperature from -60 ° to -70 ° Cj preferred. However, it can also higher temperatures are applied when persuasive ^ kion does not run. Connection 8 is used if desired purified by column chromatography. "

The reaction stage 8 ^ 9 is a Wittxg condensation,

wherein the hemiacetal 8 is ^{reacted with (i} } -carbohydroxy-n-butyl) -trI-phenylphosphonium bromide in dimethyl sulfoxide in the presence of sodium methyl sulfinyl methide. The connection 9 is cleaned as described above,

The transformation 9 ^ 12 is acidic. Hydrolysis of the

Tetrahydropyranyl groups. Any acid can be used which in the course of the deprotection process does not cause degradation of the molecule; however, a 65% aqueous acetic acid is mostly used. The product is cleaned as described above.

The stage 9> 10 is an oxidation of the secondary

Alcohol 9 to ketone 10. This can be effected by any oxidizing agent that does not attack the double bonds is used; however, in the Usually Jones reagent preferred. The product is cleaned as outlined above.

The level 10 ^ 11 is in the same way as the

Stage 9 l · 12 -done. The product will show how

shown above, cleaned.

4 0 9 8 2 1/118 1

Stage 11 > 15 is an acid-catalyzed dehydration. Any acid that does not cause extensive decomposition of the product can be used in the process; however, the most common method consists in dissolving the compound 11 in an excess of a 97% formic acid, subsequent dilution with ice water and extraction of the product after consumption of the starting materials. The product is cleaned as described above. To prepare prostaglandin derivatives 12'-18 ', compound 4 in scheme B can be replaced by compounds 5, 13, and 14 of scheme C.

Scheme C

OH

H ₂ ) _n -0 ~ (CH ₂ ) _m Ar

Ί1 ¹

(CH ₂ ) -0- (CH ₂ ) _m Ar

4 09821/1181

Scheme C (cont.)

Oh

(CH ₂ ) _n ~ 0- (CH ₂ ) _m Ar 16

(CH ₂ J _n -O- (CH ₂ ) _ra 18 «

409821/1 181

Scheme D.

ο ii CO *

19th

(CH ₂ ) _n -0- (CH ₂ ) _m Ar X) H

20th

C = O

409821/1

20 ^s

Scheme D shows the synthesis of precursors of 13,14-dihydro-15-substit .- (D-pentanorprostaglandins. In the

Level 3 > 19 + 19 ^f becomes the enone 3 by using a

the complex metal hydride reducing agents LiAlHu, NaBH ₁ J, KBHu, LiBH ₁ J or Zn (BH ^) ₂ are reduced to the tetrahydro compound. NaBHu is particularly preferred. The products and 19 ¹ are separated by column chromatography. Furthermore, compounds H and 5 of scheme A can be catalytically reduced with hydrogen to give compounds 19 and 19 ', respectively. The stage at which the double bond is reduced is "not critical, and the hydrogenation of compounds 6 or 7 of Scheme B also results in useful intermediates for the 13,1 ^ -dihydroprostaglandin analogs of the invention. This reduction can be performed either with a homogeneous catalyst, such as Tris-Ctriphenylphosphinhchlorrhodium, or with a heterogeneous catalyst such as platinum, palladium or rhodium is in the just-described synthesis of the compounds in place of ² J and 5, the substituted compounds 13 and Ik used. the conversion of the compounds 19, 19 ', 20' and 20 in the corresponding prostaglandins follows the path shown in scheme B, wherein compound 4 by 19, 19 ¹ , 20 and 20 is replaced, and the 13.1 ² J-dihydro - PGEp, PGA - and PGP series of prostaglandin derivatives are obtained, which are attached to carbon offatom 15 have hydrogen or a lower alkyl group. Scheme E explains the preparation of the various reduced 15-substits. - co-pentanorprostaglandin-Vo. runners.

409821/1181

19th

OH
ι

Scheme E

THPO

(CH ₂ ) _n -0- (CH ₂ ) _m Ar /

OTHE

THPO

OTHP

22nd

• OH -

TKPO '

H * OTHP

23

409821/1181

Stage 19> 22 is performed as in Scheme B for

H ^ - 9 was explained. The connection 22 can both

as a precursor for a 13,14-dihydro-15-substit -) .- Ui-pentanorprostaglandin the "2-series" as well as an intermediate for the compound 23> a precursor of 13,14-dihydro-15 ~ substit .- (ü-pentanorprostaglandins the "1-

Series ", can be used. The level 22> 23 is through

catalytic hydrogenation using the catalyst,

which described for the reduction of H > 19 in Scheme D.

ben was executed. Intermediate products of type 21 are produced by selective reduction of the 5jö-cis double bond low temperatures using catalysts,

like them for 4 - ^ 19 and 17> 23 were described,

manufactured. For this reduction, the use of a palladium-on-carbon catalyst and a reaction temperature., from -20 ° C particularly preferred. The intermediate products of type 21 are not only precursors of the 15-substit.-u> -pentanorprostaglandins of the "1 series"

according to path 9 ^ 15 of scheme B, but also

Runner of compounds of type 23 according to the path already for the 'Stage 22> 23 was described.

The 15-substit.-α ^ -pentanorprostaglandins of the E. and F _{la series} can also be obtained directly from the corresponding prostaglandin analogs of the "2 series" by first protecting the hydroxyl group, the cis double bond, by introducing dimethylisopropylsilyl groups selectively reduced and the protecting group removed.

The introduction of the protecting group is usually carried out by Treating the prostaglandin analog with dimethyl iso-

409821/1181

Propylchlorosilane and triethylamine cause the reduction

is carried out as explained above for 9 ^ 21,

and the removal of the protecting group is brought about by the reduced protected compound with a Mixture of acetic acid and water in the ratio 3 ^ 1 Contacted for 10 minutes or until the reaction is substantially complete.

The C r epimers of 21, 22 and 23 can be used as precursors of the 15-epi series of the prostaglandin derivatives described above, and the 15-lower-alkyl-'15-substit.-üi-pentanorprostaglandins, which are used in the 5 * 6- and / or the 13,14-position are reduced, and their C ₁ c ~ epimers can be prepared from the correspondingly substituted analogs of 9 and 19, the synthesis of which can be carried out according to schemes A and B.

The 13, l ^ -dihydro-15-lower-alkyl-15-substit. - cw-pent anorprostaglandins are accessible from the appropriately substituted precursors according to scheme E.

In the methods described above, when purification by chromatography is desired, appropriate ones become appropriate chromatographic supports including neutral alumina and silica gel are used, xrobei silica gel

WUT with a clear mesh size of 0.248 to 0.074 / is generally preferred. Ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane or η-hexane carried out as explained below in the examples

4 0 9 8 21/1181

The above formulas describe optically active compounds. It is obvious, however, that the Speaking racemates are valuable thanks to their content of the aforementioned biologically active optical isomers Have biological effectiveness, and it should be noted that such racemates also by includes the preceding formulas and also claims them

will «The racemic mixtures will be according to the same Methods such as those used for the synthesis of the optically active species, easily prepared by instead of optically active starting materials corresponding racemic precursors can be used.

Numerous "tests in vivo and in vitro have shown that that the new prostaglandin analogues physiologically

■ Ν.

have logical efficacies similar to those of are comparable to natural prostaglandins. These tests included, among other things, a test for the effect on an isolated smooth muscle of a guinea pig uterus, Guinea pig ileum and rat uterus, a test for inhibition of a histamine-induced Brochospasm in guinea pigs, as well as test reference. the Effect on canine blood pressure, inhibiting one Stress-induced ulceration in the rat; inhibition of gastric acid and pepsin secretion in the In rats and dogs, the inhibition of collagen- or ADP-induced platelet aggregation and the one Abortionic efficacy in rats and guinea pig marriages after luteolytic and non-luteolytic Mechanisms.

The physiological effects observed in these tests were valuable in determining the usefulness

4 0 9 8 21/1181

the test substance for the treatment of various natural and pathological conditions. Such particular usages include: An antihypertensive one Effectiveness ^ an effectiveness as a bronchodilator, one antitrombogenic activity, antiulcerogenic activity, smooth muscle activity [useful as Anti-fertility drugs, for inducing labor and as an abortion agent} as well as a Anti-fertility effect by a mechanism that does not affect the smooth muscles, e.g. after a luteolytic mechanism, and also the temporal one Coordination of the oestrus cycle in breeding animals.

The new compounds have more selective activity profiles than the corresponding naturally occurring prostaglandins. And in many cases they show a longer duration of activity. For example, l6-phenoxy ~ u> -tötranorprosfcaglandin E "which zeigt- a stimulating effect on the smooth muscle to that of comparable PGEP is _a in the inhibition of histamine-induced bronchospasm in guinea pigs inactive. Furthermore, although the threshold dose of hypotensive effects of lö-phenyoxy-tn-tetranor-PGE ,, in dogs is higher than that of PGE ₂ , the duration of action of this compound is considerably longer than that of PGEp · Die 15-substit. -u> -Pentanorprostaglandxne of PGE _n , F, F. _ß , F _2ß and 13, l ⁱ i-Dihydro-PGF _{2ß have a} similar stimulation effect on the smooth muscles, while the corresponding derivatives of Aq-, A.-, A "- and 13,14-dihydro-PGAp series have gastric antisecretory / antiulcerogenic activity.

409821/1 181

Particularly useful for fertility control, abortion and labor for die.Einleitung of the L6-Phenoxycu-tetranorprost ^ Landine are ^{Ε ρ} ~ * ~ ^F 2a ^and F ₂ ~ ß ^ ^{Ser en} due particularly excellent. Stimulation effectiveness on the smooth muscles and at the same time reduced effects on blood pressure. Similarly, the substituted Uh-pentanorprostaglandins of the PGE ^ -, ^PGP Ocf ^{s PGF} la ~ ^and 13, l ⁱ i-Dihydro-PGF _2a series are useful for "fertility control, including abortion and induction of labor" because of The new 15-substit-tt'-pentanorprostaglandin -13,14-dihydro-Ep analogs can be used to treat peptic ulcers. The new prostaglandins with a ß-OH group in 15- Position are generally less effective, although they are often more selective than the corresponding cc-hydroxyl epimers. Furthermore, the prostaglandins _3, which have a ß-hydroxyl group in the C. [- position, are valuable intermediates for prostaglandins with an α- Hydroxyl group in the C _1- position by subjecting it to a cyclic process comprising an oxidation and a reduction on the carbon atom in the 15-position.

The new 15-lower alkyl compounds of the invention have the same efficacy profile as the prostaglandin analogs of the invention in which R is hydrogen from which they are derived. Their special usefulness is based on the fact that their duration of action is much larger than that of the aforementioned compounds in which R is a hydrogen atom; and in in such cases, where this is essential, the 15-lower-alky compounds are generally preferred. The prostaglandin analogues, which have a β-hydroxy group

409821/1181

am "Cj-, and which have an O _ -ledrIg-alkyl group, have an effect similar to that of their epimers. In some cases, however, the selectivity exhibited by these compounds is greater than that of the epimers. compounds. the new compounds can be used in the formulations and verschiedensten.pharmazeutischen they can comparable ^u schiedenartigsten paths in the same catfish like natural prostaglandins, "for example, be administered by intravenous, oral, intravaginal, intra- and extra-amniotic way.

To initiate an abortion, tablets or an aqueous suspension or alcoholic solution of 16-phenoxy-O ^ tetranorprostaglandin, expediently at oral doses of 0.1 to 20 mg, can be administered, 1 to 7 doses being used per day . A suitable form of use for intravaginal administration are lactose tablets or a. Tampon, which is impregnated with this agent. Suitable doses for these treatments are 0.1 to 20 mg / dose, with 1 to 7 doses being used. A suitable formulation for intra-amniotic administration is an aqueous solution containing 0.05 to 10 mg / dose, using 1 to 7 doses. A suitable formulation for extra-amniotic administration is an aqueous solution containing 0.005 to 1 mg / dose, with 1 to 5 doses being used Doses from 0.05 to 50 pg / min, administered as an intravenous infusion over a period of approximately 1 to 2k hours. For the timing of the oestrus cycle of pigs, sheep, cows or horses

4 0 9 8 21/1 18

- 5ο -

a solution or suspension containing 0.03 to 30 mg / day, 16-phenoxy-u> -tetranarprostaglandin, administered subcutaneously for 1 to H days.

Like the 15-substit.-ω-pentanorprostaglandins of the E series, are the 15-substit. ~ o> -pentanorprostaglandins of the A-series valuable gastric antisecretory and antiulcerogenic agents. These are used to treat peptic ulcers Compounds preferably administered orally in the form of capsules or tablets at doses of 0.001 to 0.1 mg / kg / day.

For the production of the aforementioned dosage forms or the numerous other possible forms, various inert diluents, excipients or carriers can be used. Such substances are for example: water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohol, Gum, polyalkylene glycols, petrolatum, cholesterol and other known carriers for drugs. These pharmaceutical compositions can optionally contain auxiliary substances such as preservatives, humectants, Contain stabilizers or other therapeutic agents such as antibiotics.

Numerous modifications are possible to the upper side chain of the new prostaglandins; Modifications of this type generally do not change the basic biological activity of the prostaglandin, although they can further increase the selectivity and duration of action and reduce the toxicity. For example, a tetrazoyl radical, as shown in US Pat. No. 177,102, can be introduced. For example, has l6-phenoxy-PGE ₂ ~ tetrazolyl the same

409821/1181

Usability as 16-phenpxy-PGEp-ester: i.e. it is for Induction of labor or abortion and inhibition gastric acid secretion and for the treatment of peptic ulcers useful.

Another modification of the upper side chain that can be made in the new prostaglandins is the substitution of the carboxylate residue in the C ^ position by a carboxyamide residue. The processes for preparing these compounds are described in US Pat. No. 260,518. The novel compounds of structures II and III (where X is a CONHR "group, where R" has the aforementioned meaning) can be prepared from compounds 9 and 10 of Scheme B (or the corresponding 15-epimers or 15- 'lower alkyl derivatives of 9 and 10) by reaction with appropriate isocyanates and subsequent. Hydrolysis can be produced with dilute acid. The utility of N-methylsulfonyl-lo-phenoxy-PGEp-carboxamide, for example, is the same as that of 16-phenoxy-PGE ₂ -esters.

A particularly advantageous ester is the p-biphenyl ester. Such esters are, as shown in the following examples, by simply adding p-Phenylphenol to the prostaglandin in methylene chloride 'in the presence of a dehydrating agent, e.g. Dicyclohexylcarbodiimide and stir overnight. Although subsequent p-biphenyl esters are not more effective in in vitro smooth muscle tests, The Lö-Phenoxy-w-tetranor-PGEp- and -PG turned out to be p-biphenyl ester in the test for an abortion leading effect considerably more physiologically effective than the free acids.

4 0 9 8 2 1/118 1

The following examples serve to further illustrate the invention. In these examples, all temperatures are given in ⁰ C, all melting and boiling points uncorrected.

example 1

Dimethyl 2-oxo-3-phenoxypropyl phosphonate

A solution of 33.2 g (268 mltol) Dimethylmethylpheisphonat in 360 ml of dry tetrahydrofuran was cooled under Äxty Λ ^ v ^ jS, atmosphere! -Trockenen nitrogen to -78 ⁰ C the stirred phosphonate solution was mixed with 118 / ral a 2.3 * * Molar solution of n-butyllithium ir / hexane (Alfa Inorganics, Inc.) added dropwise for 18 minutes at such a rate that the reaction temperature never rose above -65 A. After further stirring for 5 minutes at -78 ⁰ C was added dropwise 22.2 g (131 mmol) of methyl 2-phenoxyac ^ Bat wmraen added at a rate that the Reaiitionstemperatur less than -7O ° C was (20 minutes ^). After 3.5 hours at -78 ⁰ C the reaction was allowed to warm to ambient temperature. It w "Irde with 14 ml of acetic acid, and neutralized to a rotationsverdampft► / white gel The gelatinous material was taken up in 175 ml of water, the aqueous ₃ i * was hase 3 NiAl with 100 ml of chloroform / aie combined organic extracts were washed again ( 50 cm H ₂ O) _y -over magnesium sulfate, to give a crude residue concentrated (Wasserstr ^ filpumpe) and distilled: bp I72 - 175 ⁰ C /

mm, with 24.6 g of dimethyl-2-oxo ~ 3-phenoxypropyl- ■ phnsphnnat were obtained. -

A09821 / 1 181

--53.-

π η hoi

■ 5 * §

3 '

6η) centered doublet for (CH ^ O) -PO-; a

• 3 -

4.7 ^δ (2 H) for C ₆ H ₅ O-CH 2H) zentrie

.-CO;

, 24

ex δ (J = 23 cps,

let

for -CO-CH ₂ -P- and a multi-

ee

example A.

2-na-p-PhenylbenzoyToxy-Se-hydroxy ^ ß- (3-oxo-4-phenoxytrans-l-butene- l-yl) -cyclopent-l <x-yl ^ acetic acid-γ-lactone:

5, ^ g of ^{dimethy l-2 i} -oxo-3-phenoxypropylphosphonate (21 mmol) in 200 ml of anhydrous ether were mixed with 7 »9 ml (19 mmol) of a 2.5 molar solution of n-butyllithium in n-hexane ( Alfa Inorganics, Inc.) under a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, a further 400 ml of anhydrous ether and then 6.0 g (17 mmol) of 2-f3a-p-phenylbenzoyloxy-5ahydroxy-2ß-formylcyclopentan-lcx.-yl5] -acetic acid-γ-lactone were added all at once and 50% ml of anhydrous ether was added. After 35 minutes, the reaction mixture was treated with 5 ml of glacial acetic acid and washed 4 times with 100 ml of saturated sodium carbonate solution each time, 2 times with 100 ml of water, once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated, with 5.2 g of 2- [3α-ρ-phenylbenzoyloxy-5a-hydroxy-2ß- (3-oxo-4-phenoxy ~ transl-buten-l-yl) -cyclopent-lOL-yl j-acetic acid-Y-lactone as a solid after column chromatography (Baker- Silica gel with a mesh size of 0.248 to 0.074 mm), which after crystallization from a mixture of methylene chloride and hexane had a melting point of 112-114 ° C.

0 9 8 21/118

- 5'ί -

The IR spectrum (KBr) of the product showed absorption bands at 1775 cm " ¹ (strong), 1715 cm" ¹ (strong), 1675

-1

(medium) and I63O. cm (medium), polygamy to carbonyl groups were attributable, and a band at 970 era for the trans double bond.

Example J.

2- [3a-p-phenylbenzoyloxy-5ci-hydroxy-2ß- (3a-hydroxy-4-phenoxy-trans-l-buten-l-yl) -cyclopent-ia-yl ' ^ -acetic acid-'v-lactone:

A solution of 5.1 g (10.5 mmol) of 2- [3ot-p-phenylbenzoyloxy-5oc.-hydroxy-2 [beta ]- (3-oxo-4-phenoxy-trans-1-buten-1-yl) -cyclopent -la-yjtj-acetic acid-'placton in 30 ml of dry 1,2-dimethoxyethane was added dropwise under a dry nitrogen atmosphere 'at ambient temperature with 11 ml (5 * 5 mmol) of a 0.5 molar tin borohydride solution. After stirring at room temperature for 2 hours, a saturated sodium bitartrate solution was added dropwise until the evolution of hydrogen ceased. The reaction mixture was stirred for an additional 5 minutes, after which 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the semisolid material obtained was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248 to 0.07 mm) using ether as the eluent. After elution of less polar impurities, a fraction containing 896 mg of 2-r3a-p-phenylbenzoyloxy-50-hydroxy-2ß- (3a-hydroxy-4-phenoxy-trans-1-buten-1-yl) -cyclopent-ia -yXj-vinegar-

acid-γ-lactone, a fraction of 600 mg of the 6

409821/1181

mixed compounds 4 and 5 and finally one Fraction of 1.5 g of 2-f3a-p-phenylbenzoyloxy-5ahydroxy-2ß- (3ß- * hydroxy-4-phenoxy-trans-l-buten-yl ) -cyclopent-la-yli 3-acetic acid-γ-lactone obtained.

The IR spectrum (CHCl _x ) of compound 4 showed strong

-1 carbonyl absorption bands at 1770 and 1715.cm and one Absorption band at 970 cm for the trans double »·" binding.

example %

2- [3a _J 5a-dihydroxy-2ß- (3a-hydroxy-4-phenoxy-trans-ibuten-1-yl) -cyclppent-IG.-yl 3-acetic acid-y-lactone:

A heterogeneous mixture of 846 mg (1.7 mmol) of 2- [3 <xp-Phenylbenzoylox-y-hydroxy-5 ^a 2ß- ^(3a-1} hydrbxy- -phenoxytrans-l-buten-l-yl) -cyclopent -lcc-yl 3 ~ e ^s agic acid-'v-lactony 10 ml of absolute methanol and 120 mg of finely powdered, anhydrous potassium carbonate were stirred at room temperature for 20 hours and then cooled to 0.degree. The cooled solution was added to 1.75 ml of a 1, On. aqueous hydrochloric acid added. After stirring at 0 ° C. for a further 10 minutes, 10 ml of water were added, during which: methyl p-phenylbenzoate was formed at the same time, which was filtered off. The piltrate was saturated with solid sodium chloride, extracted 4 times with 10 ml of ethyl acetate each time, and the combined organic extracts were washed with 10 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated, with 445 mg of the viscous, oily 2- [3 ^a _s 5 ^a -dihydroxy-2ß- (3ahydroxy-4-phenoxy-trans-1-buten-1-yl) -cyclopent-la-yU "} - acetic acid-y-lacto.n were obtained."

409821/1181

The IR spectrum (CHCl ') showed a strong absorption

-1
band at 1772 cm for the lactone carbonyl group and a mean absorption band at 965 ^{cm for} the "trans double bond.

example

2- [5o-Hydroxy-3a- (tetrahydropyran-2-yloxy-2β- (3a-tetrahydropyran-2-yloxy- ¹ i-phenoxy-trans-1-buten-1-ylj-cyclo ~ ^l pent-ICL-yl 3-acetic acid-y-lactone:

A solution of 445 mg (1.46 mmol) _2-f3a> 5a-Dihydroxy-2ß- (3a-hydroxy-4-phenoxy-trans-l-buten-yl) ~ 3 ~ loyl ^{cyclopent-ES5} is äure ^s-y lactone in 5 ml of anhydrous methylene chloride and 0.4 ml of 2,3-dihydropyran was added at 0 ⁰ C under an atmosphere of dry nitrogen with 5 mg of p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ethereal solution was washed once with 15 ml of saturated sodium bicarbonate solution and then once with 15 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, whereby 752 mg (over 100 %) crude 2- [5 ^a -Tetrahyd.ropyran-2-yloxy-4-phenoxytrans-1-buten-1-yl) -cyclopent-ia-y3i J-acetic acid-γ-lactone were obtained.

The IR spectrum (CHCl,) showed a mean absorption band at 970 mm "for ^ trtns double bond and at 1770 cm for the lactone carbonyl group.

Example ST

2- [5a-Hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3a-tetra hydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl) -cyclopenfc-la-yl 3-aeetaldehyde-v-hemiacetal:

409821/1181

Butene 4-phenoxy-trans-l-tetrahydropyran-2-yloxy-A solution of 690 mg (l, ² f6 mmol) of 2-hydroxy-r5 ^a 3ct- (tetrahydropyran-2-yloxy) -2ß- (3 ^a -l-yl) -cyc'lopent-ia-yl-acetic acid 3 ^': y-lactone in 8 ml of dry toluene was cooled under a dry nitrogen atmosphere to -78 ⁰ C. This cooled solution was treated with 2.0 ml of a 20% solution of -lgen Diisobutylaluminiumhydrdd in η-hexane (Alfa Inorganics, Inc.) was added dropwise at such a rate · added such that the internal temperature never exceeded -65 ⁰ C increased (15 minutes) . After further stirring for 45 minutes at -78 ⁰ C, anhydrous methanol was added until gas evolution ceased ^ ,. and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then treated with 100 ml of ether, washed H times with 20 ml of a 50 # sodium-potassium tartrate solution, dried over NapSOjj, and concentrated, whereby 613 mg of 2 - '[ 5 < ¹ -hydroxy-3 ^a ~ (tetrahydropyran-2-yloxy) -2ß '- (3 ^a -tetrahydropyran-2-yloxy-4-phenoxy-trans-1-butenl-yl) -cyclopent-1-yl> / acetaldehyde-γ-hemiacetal were obtained.

example

9a-Hydroxy-lla _J i5ot-bis- (tetrahydropyran-2-yloxy) -10-phenoxy-cis ~ 5-trans-l3- "ü> -tetranor-prostadienoic acid:

A solution of 1.6 g (3 _S 6 mmol) (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in S ₃ O ml dry dimethyl sulfoxide was mixed under a dry nitrogen atmosphere with 3.24 ml (6.5 mmol) of a 2 .0 molar solution of sodium methylsulfinyl methide in dimethyl sulfoxide. A solution of 613 mg (1.29 mmol) of 2-r5 ^a -hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3 ^a -) was added dropwise to this red ylide solution. -tetrahydropyran-2-yloxy-4-phenoxy-trans- 'l-buten-l-yl) -cyclopent-ia-yl3-acetaldehyde-v-hemiacetal

409821/1181

in 5jO ml of dry dimethyl sulfoxide was added over the course of 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution is washed twice with 20 ml of ethyl acetate each time and acidified to a pH of 3 with 10 # aqueous hydrochloric acid. The acidic solution was extracted 3 times with 20 ml of ethyl acetate each time, and the combined organic extracts were washed once with 10 ml of water, dried over magnesium sulfate and evaporated to a solid residue. This solid residue was triturated with ethyl acetate, and the filtrate was evaporated, whereby 75 ² ^ ^m g of 9 ^a ~ hydroxy-11a, 15 ci-bis (tetrahydropyran-2-yloxy) -16-phenoxycis ~ 5-trans -13-ü> - 'tetranorprostadiensäure were obtained.

The IR spectrum (CHCl3) showed a strong band at

-1
1720 cm for the carboxyl group.

example

9-Oxo-llG., 15 ^CL -bis- (tetrahydropyran-2-yloxy) -l6-phenoxycis-5-trans-13-ü> -tetranor-prost adienoic acid:

A solution, cooled to -10 ° C, of 754 mg (1.3 mmol) 9a-hydroxy-llcx, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-u> - tetranor-prostadieric acid in 13 ml of reagent grade acetone was added dropwise with 0.56 ml (1.41 mmol) of Jones reagent. After 20 minutes at -10 ⁰ C 0.260 ml of 2-propanol was added, and. the reaction mixture was stirred for a further 5 minutes, after which it was combined with 75 ml of ethyl acetate, washed 3 times with 10 ml of water, dried over magnesium sulfate and concentrated, giving 752 mg of 9-oxo-IIQ., 150-fais- (tetrahydropyran -2-yloxy) -l6-phenoxy-cis-5-trans-13-tü-tetranor-

409821/1181

prostadic acid obtained on silica gel under "Chromatographed using ethyl acetate as the eluent was iay being 505 mg of the pure compound 10 were obtained.

Example f?

9-Oxq-lia, 15a-dihydroxy-16-phenoxy-cis-5-trans-a3-tt> tetranor-prostadienoic acid:

A solution of 505 mg (0.9 mmol) of 9-oxo-IIIa, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-tiH · tetranor-prostadienoic acid in 6.3 ml of a mixture of glacial acetic acid and water in a ratio of 65-35 .wurde was stirred under nitrogen at 25 ° C. for 18 hours and concentrated by rotary evaporation. The crude oil obtained was chromatographed by column chromatography on silica gel (Mallinckrodt CC-4 ν with a mesh size of 0.1 * f7 to 0.07 * 1 mm) using ethyl acetate as the eluent. After elution of the less polar impurities, the oily 9 ~ Οχο-1ΐα, 15α-dihydroxy-Lö-phenoxy-cis-S-trans - ^ - «> -tetranor-prostadic acid was obtained in an amount of 210 mg.

The IR spectrum (CHCl _7. ) Showed a broad band at

-1 " "

1725 cm for the carbonyl absorptions and a band at 970 cm " ¹ for the 13.1 * i-trans double bond.

example

9a, lia, 15a-trihydroxy-16-phenoxy-cis-5-trans-13-iotetranor-prostadienoic acid:

A mixture of 375 mg (0.65 mmol) 9 ^a ~ hydroxy- "lia _> l5ä-

409821/1181

- 6ο -

bis- (tetrahydropyran-2-yloxy) ~ 16-phenoxy-cis-5-trans-13- <y-tetranor-prostadienoic acid, 6.5 ml of acetic acid and 3.5 ml of water were stirred under nitrogen at room temperature for 20 hours. The resulting clear solution was concentrated under reduced pressure and the residue (380 mg) was dissolved in ethyl acetate. The ethyl acetate solution was washed with 20 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to a "clear oil. Chromatography on silica gel (Mallinckrodt CC-7) using chloroform and then ethyl acetate as eluent led to the desired 9 ^a jll ^a > 15 ^a -Trihydroxy-16-phenoxy-cis-5-trans-13-ty-tetranor-prostadienoic acid as a colorless oil weighing 98 mg.

example

9a-Hydroxy-lia, 15a-bis- (tetrahydropyran-2-yloxy) -l6-phenoxya. ^ - tetranor-prostanoic acid:

A mixture of 190 mg (0.33 mmol) 9a-r-hydroxy-lla, 15abis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-ti) -tetranor-prostadienoic acid, and 150 mg of 5 -% palladium on carbon in 10 ml of methanol was stirred under a hydrogen atmosphere for 60 hours at room temperature. The mixture was filtered and concentrated to give the 9 £ x-hydroxy-11a, 15a-bis (tetrahydropyran-2-yloxy} -16-phenoxy-u> -tetranor-prostanoic acid.

example 1%

9 a, lia, 15 a-Trihydroxy-16-phenoxy-üh-tetranor-prostanoic acid:

The hydrolysis of 20 mg of 9a-hydroxy-lla, l5a-bis- (tetra-

409821/1181

- 6l -

hydropyran-2-yloxy) -16-phenoxy-u> -tetranor-prostanaic acid was carried out with 0.5 ml of acetic acid and 0.3 ml of water under nitrogen at room temperature for 20 hours. Purification, as described in Example 10, gave pure 9 ^a / 11 ^a al5 ^a -trihydroxy-16-phenoxy-tu-tetranorprostanoic acid.

example

9-Oxo-ila, 15a-dihydroxy-16-phenoxy-U} -tetranor-prostanoic acid: .

A solution of 186 mg (0.3 mmol) of the product of Example 11 in 3 ml of acetone was, as described in Example 8, oxidized with 0.14 ml (0.35 mmol) of Jones reagent. Isolation of the product and hydrolysis with acetic acid and water at room temperature, as described in Example 9, led to pure 9 ~ 0χο-1ΐα, 15α-dihydroxy-16-phenoxy- (γ-tetranorprostanoic acid.

example

9-0x0-15 a-hydroxy'-Lö-phenoxy-cis-SiO-trans - ^ - cr-tetranar prostatric acid:.

A mixture of 52 mg (0.1 mmol) 9-oxo-lla, i5a-dihydroxy l6-phenoxy-cis-5rtrans-13 ~ ü> -tetranor-prostadienoic acid with 0.2 ml of 97% formic acid was stirred at 25 ° C. for 2.5 hours. After adding 5 ml of ice water to the reaction mixture, which is then extracted with ethyl acetate, dried over sodium sulfate and concentrated a crude oil was obtained. The chromatography

4 0 9 8 21/1181

the crude product on Sillkagel (Mallinckrodt CC-J) using a mixture of methylene chloride and ethyl acetate as the eluent led to the desired 9-oxo-15tt-hydroxy-16-phenoxy-cis-5, 10-trans-13-u> tetranor-prostatrienoic acid.

example

9-oxo-15o-hydroxy-16-phenoxy-io-tetranor-prost-10-enoic acid:

9-oxo-lla, 15a-dihydroxy-l6-phenoxy-U! -Tetranor-prost ansäure was prepared as described in Example 'lh, treated with 97% formic acid and -igev in the colorless oily 9-0xo-15 ° - Hydroxy-16-phenoxy-tt ⁱ -tetrahor-prost-10-enoic acid transferred. .

example

2- [3a-p-phenylbenzoyloxy-5o-hydroxy-2 [beta ]- (3-hydroxy-3-methyl- ^ - phenoxy-trans-1-buten-1-yl) -cyclopent-ia ~ yi J-acetic acid - ^ - lactone:

A cooled to -78 ⁰ C solution of 2- [3-p-Phen5r? .Benzoyloxy 5a-hydroxy-2ß- (3-oxo-4-phenoxy-trans-l-buten-l-yl) -cyclopent-LCC yi! -acetic acid-v-lactone in a mixture of ether and tetrahydrofuran was added dropwise with one equivalent of a 2N solution of methyllithium in ether. After stirring at -78 ⁰ C for 15 Hinuten the reaction mixture was treated with sufficient glacial acetic acid such that the pH value was brought to. 7 The mixture was diluted with methylene chloride, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated, the oily epimeric alcohols being obtained.

409821/1181

th were. The crude product was purified by column chromatography on Sllikagel, wherein 'the desired 2- [3-p-Phenylben'zyloxy-5 ^{a-hydroxy-2ß-} (3-hydroxy-3-methyl-4-phenoxy-trans-l-butene l-yl) -cyclopent-ia-y; ii J- acetic acid-y-lactone was obtained, the llct 9-oxo-according to the previously for the 'production of 15 <x-dihydroxy-l6-phenoxy-cis-5 -trans-13-u> -tetranor-prostadienoic acid can be converted ^{into the compounds 17 and * \ 17 f.}

example Ιμ,

9β, I5 ^CL -trihydroxy-16-phenoxy-5-cis-13-trans-o> tetranor-prostadienoic acid:

A solution of 50 mg of 9-Oxo-lia. _J 15a.-dihydroxy-16-phenoxycis-5-trans-13- "cu-tetranor-prostadiens ^ ure in 2.5 ml of absolute methanol, which had cooled to 0 ° C, was added dropwise with a solution of 25 mg of sodium borohydride in 1 ml of absolute methanol were added. The reaction mixture was ^{stirred under nitrogen at 0} ° C. for 2 hours and then concentrated. The residue was taken up in methylene chloride, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to 16-phenoxy-PGP _{? a} and to the desired 9β, 11ct, 15 ^a -trihydroxy-16-phenoxy-5-cis-13-trans-i uf-tetranor-prostadienoic acid.

example

2-r3cc-p-phenylbenzy3, oxy-5a-hydroxy-2ß- (3a-hydroxy-ilphenoxy-but-1-yl) -cyclopent-ia-y] i ] -acetic acid-y-lactone

40S821 / 1181

A heterogeneous solution of 2.5 g of 2-f3 ^a ~ ^{p-phenyl-benzoyloxy-5-hydroxy-a} 2ß- (3 ^a --hydroxy- ⁱ i-phenoxy-trans-l-buten-yl) -cyclopent-ia -yl] acetic acid-y-lactone and 0.25 g of 5% palladium-on-charcoal in 30 ml of absolute methanol was stirred under an atmosphere Wasserstoffdr-piece ¹ I hours. The mixture was then filtered and concentrated to give 2- / 3a-p-phenylbenzoyloxy-5oHhydroxy-2ß-

oxy
(3-oxo-4-phen / -but-1-yl) -cyclopent-ici-y2 ^ "" acetic acid- ^u • Λ-lactone was obtained.

A solution of 1.9 g of the crude hydrogenation product in 20 ml of absolute methanol was admixed with excess sodium borohydride, and the solution was stirred at room temperature under nitrogen for 2 hours and then concentrated. The residue was diluted with 0.1 m hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Purification of the crude residue by silica gel chromatography led to 2- [3 ^a -p-phenylbenzyloxy-5tt-hydroxy-2ß- (3 ^a -hydroxy-4-phenoxy-but-1-yl) -cyclopent-la-yl ^ -acetic acid-y-lactone and the 3ß-hydroxy epimer.

This was dissolved in the 13, l ^l-dihydro-1 E ₂ - and ~ F compounds, using the methods used in Example 5 to 9 transferred.

Example iff

9a-Hydroxy-lla, 15a-bis (tetrahydropyran-2-yloxy) -l6-phenoxy-13-transti> -tetranor-prostenic acid:

A heterogeneous mixture of 800 mg of 9 ^a -hydroxy-lla, l5a-bis- 409821/1181

(tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5-trans-13-ci? - tetranor-prostadienoic acid and 8O mg of 5 -% palladium on carbon in 10 ml of absolute methanol was under one atmosphere of hydrogen pressure at - Stirred at 22 ° C for 5 hours. The mixture was then filtered and the piltrate was concentrated to give 9a-hydroxy-lla, l5o.r-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-13-trans-u> -tetranorprostitute acid.

The usual hydrolysis with acetic acid and water led to the 16-phenoxy-PGP _la «.

Example ^ 2Q Λ 2 - · - - · .-

ν '

9-0χο-1ΐα _? ± 5 α-dihydroxy-16-phenoxy-13-trans- ω-tetranorprostenic acid:

A solution of 72 mg of g-Oxo-lia _J l5a-dihydroxy-l6-phenoxycis-5-trans-13- ^t ^ "tetranor-prostadienoic acid in 5 ml of anhydrous ether was mixed with 450 mg of dimethylisopropylchlorosilane and 36 mg of triethylamine at room temperature The reaction mixture was ^{cooled to 0 °} C., methanol was added, and the resulting solution was washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in 6 ml of methanol and there were 30% mg of 5 % palladium-on-charcoal were added The resulting mixture was stirred under one atmosphere of hydrogen pressure for K hours at -22 ° C. After filtration and concentration of the filtrate, the residue was washed with a mixture of acetic acid and water in the ratio of 65:35 during 10 minutes for room

409821/1181

-.66 -

temperature stirred. The mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated, which, after purification by Silkagel chromatography, gave 9-oxo-IIK, ISa-dihydroxy-Lö-phenoxy- ^ - transui-tetranor-prostenic acid.

Example 2 (p

4- (tetrazol-5-yl) butyl triphenylphosphonium bromide

A mixture of 16.2 g (0.10 mol) of 5-bromovaleronitrile, 26.2 g (0.10 mol) of tripheny! Phosphine and 100 ml of toluene was heated to reflux temperature for 16 hours with stirring under a nitrogen atmosphere. The thick white suspension obtained was cooled to room temperature and filtered. The residue was washed with benzene and ari. dried in the air, whereby 33.0 g of an xireißen, crystalline Pest substance with a melting point of 230 to 232 ^O C was obtained, which was found to be 4-cyanobutyl-triphenylphosphoniurfibromide.

Analysis calculated for C ", H BrNP:

C 65.10; H 5.47; K 3.30-; Found: C, 65.01; H 5, ^ 0; N 3.19-

A mixture of 10 _s 0 g (23.5 mmol) of the aforementioned phosphonium salt, l> 60 g (30.0 mmol) ammonium chloride, 0.032 g (0.76 mmol) lithium chloride, 1.91 g (29.3 mmol) Sodium azide and 50 ml of dimethylformamide were heated to 127 ° C. (oil bath) for 18 hours under a nitrogen atmosphere and with stirring. The resulting suspension was cooled and filtered. The residue was washed with dimethylformamide, and the combined filtrates and wash water were concentrated (water pump pressure, approx.

409821/1181

^ 5 ° Ο). The oily residue was ^{crystallized from water at 0} ° C. and air-dried. to give a white crystalline solid (8.11 g) to yield 100-.102 ⁰ C of melting point. The product was urakistallized from a mixture of methanol and ether, 7.18 g of white prisms with a melting point of 197 - ""206'C - were obtained. An analytical sample was prepared by crystallization from 2-propanol, whereby a white crystalline powder with a melting point of _{212-213 ° C. was obtained 3} which was ^ - (tetrazol-S-ylI-butyltriphenylphosphonium bromide.

Analysis calculated for p ^^^

· - c 59.10; H 5.17; N ii.99; _; p 6.63; Br 17.09

found: C. 59.35; H-5.28; N 12.31; P 6.78.5 Br. 17.2 (

Example *

1- (Tetrazol-5-yl) -9a-hydroxy-lia, i5a-bis (tetrahydropyran 2-yloxy) -l6-phenoxy-cis-5-trans-13-u> -tetranor-prostadiene:

A solution of 1.49 g of 4- (tetrazol-5-yl.) - butyltriphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 ml of dry dimethyl sulfoxide was added to 3.24 ml a 2.0 molar solution of sodium methylsulfinyl methide mixed in dimethyl sulfoxide This solution was added dropwise with 615 mg of 2- [5tt-hydroxy-3 ° - (tetrahydropyran-2-yloxy) -2β- (30L-tetrahydropyran-2-yloxy-4-phenoxy-transl-buten-1-yl) - cyclopent-ia-y3s 3-acetaldehyde-y-hemiacetal added in 5.0 ml of dry dimethyl sulfoxide for 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured into ice water.

409821/1 181

The basic aqueous solution was acidified with O, In HCl and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was chromatographed, whereby the! - (tetrazol-5-yl) -9tt-hydroxy-lia, l ^ a-bis (tetrahydropyran-2-yloxy ) -16 ~ phenoxy-cis-5-trans-13- ^ tetranor prostadiene was obtained.

example 2 $, '

: [4- (Methanesulfonylaminocarbonyl) -butyl3 ~ triphenylphosphonium bromide: :

A mixture of 0.950 g (O ₃ mol) of methanesulfonamide and 180 g (0.01 mol) of 5-bromovaleric acid chloride was added. ·. heated in a steam bath until dip gas evolution ceased (approx. 5 minutes). The brown reaction mixture was allowed to cool and taken up in methylene chloride. The methylene chloride solution was treated with Darco, filtered and diluted with hexane with cooling to give the white, crystalline N-methanesulfonyl-5-bromovaleramide weighing 2.22 g (86.0 % yield) and melting point 88-89 ° C was obtained.

The NMR spectrum (CDCI,) showed a broad singlet at 4.26 to 3.95 ^δ for NH, a multiplet at 3.66 to 3.23 for -CH ₂ Br, and a singlet at 3.31 δ for SO ₂ -CH, a multiplet at 2.63 to 2.20 δ for -CH ₂ CO and a "multiplet at 2.12-1.52 δ for CH ₀ -CH _0. The IR spectrum (CHCl-.) Showed a strong absorption band at 1720 cm, which can be assigned to the carbonyl group.

A 0 9 8 2 1/1 1 8 1

■ - 69 -

A solution of 2.20 g (8.57 mmol) of the previously prepared N-methanesulfony 1- 5-brOmvalerainid, 2.2 ^l \ . g (8.57 mmol) of triphenylphosphine and 20 ml of acetonitrile were heated to reflux temperature overnight under nitrogen. The solution was then concentrated by circulation evaporation and the solid obtained was triturated 4 times with hot benzene. The triturated solid was recrystallized from a mixture of absolute ethanol and ether, the white crystalline [4- (methanesulfony1-aminocarbonyl) butyl] - triphenylphosphonium bromide weighing 2.80 g (63.7 g) % Yield) and a melting point of ISO to 191 ⁰ C was obtained.

The IR spectrum - (KBr) of the product showed a strong absorption at 5.85 p which is attributable to the carbonyl group. The NMR spectrum (CDCI,) - showed a complex multiplet at 8.14 to 7.27 δ for the aromatic protons, a "· multiplet at 4, OQ to 3.30 δ for -CH ₂ P, a singlet at 3 , 12 ^δ for-SO ₃ CH ₃ : -, a multiplet at 3.00 to 2.38 δ for -CH ₂ CO and a multiplet at 2.23 to 1.38 ^δ for "CH ₂ CH ₂ -. A titration of the solid gave a value pKa 1/2 of 5.25.

Example 2% .

p-Bipheny 1-9-oxo-ll ei, IScC-dihydroxy-Lö-phenoxy-cis-.5-trans-13-üi-'tetranor-prostadienoate:

A solution of 50 mg (0.13 mmol) 9-oxo-lla, i5a-dihydroxyl6-phenoxy-cis-5-trans-13- (i> -tetranor-prostadienoic acid, and 63 mg (0.4 mmol) of p-pheny! phenol in 10 ml of dry Methylene chloride was mixed with 825 mg (0.4 mmol) of dicyclohexylcarbodiimide added, and the solution was stirred at room temperature overnight. After narrowing it became

'409 821/1 181

- 7ο -

Crude product was purified by silica gel chromatography to give the desired p-biphenyl ester having a melting point of 100 - 102 ⁰ C was incurred.

Analysis: calculated for ^ -zf ^ -zfpf. ^:

C 75.53; H 6.71; Found: C, 75.65; H. 6.83.

example

p-Biphenyl ~ 9tt _J lia-, 15 ^CL -trihydroxy-16-phenoxy-cis-5 ~ trans-13- (y-tetranor-prostadienoate:

A solution of 106 mg of 9 ^a , ll ^α , 15 ^α "" ■■ trihydroxy · ■ -16-phenoxy ~ cis-5-trans-13 - «> ■ -tetranor ~ prostadienoic acid and 189 mg of p-phenylphenol in 30 ml 600 mg of dicyclohexylcarbodiimide were added to dry methylene chloride, and the solution was stirred at room temperature overnight. After concentration, the crude product was purified by silica gel chromatography, 80 mg of pure p-biphenyl ester having a melting point of 101-103 ° C. being obtained

Analysis calculated for CUjiH nOg:

C 75.25; H 7.06;
Found: C, 75.38; H 7.30.

409821/1181

example

Phenethyl-9-oxo-llfx,
trans-13 - &; - tetranor prostadienoate

A mixture of O-phenethyl-NjN'-dicyclohexyl-isourea, prepared by reacting phenethyl alcohol and dicyclohexylcarbodiimide, and 9-oxo-il, 15-dihydroxyl6-phenoxy-cis-4; rans-13-a> -tetranor- prostadiensäüre stirred in methylene chloride and I Dimethylformamid.wurde at room temperature overnight. After filtration, concentration and chromatography on silica gel, the pure phenethyl ester was obtained.

In a similar way, the benzyl, cyclopropyl and CycloQctylester using benzyl alcohol, Cyclopropanol or Obtain cyclooctanol.

example

J15α-trihydroxy-16-phenoxy-cis-5-trans-13- -tetranor-prostadienoate

An ethereal solution von.loomg Sa l6-phenoxy-cis-5-trans-13 <u-tetranorprostadiensäure was treated with an excess of ethereal diazomethane until a yellow color remained. After concentration, pure methyl 9aslla ₅ 15a-trihydroxy-16-phenoxy-cis-5-trans-13- oi- tetranorprostadienoate was obtained.

Similarly, using Diazodecari (produced by oxidation of dodecylhydrazone) dodecyl-9ot, .lla> 15a-trihydroxy-16-phenoxy-cis-5-trans-13-w-tetra- ■ nor-prostadienoat produced.

409 821/1181

example 2%

9β, 11rx, 15a-trihydroxy-16-phenoxy-cis-5-trans-13 - ^ - tetranor prostadienoic acid; Tris-hydroxymethylamino methane salt

A solution of 0.70 mmol, 9β, 11cc, 15a- ^T ^ ihydroxy-16-phen-. oxy-cis-5-trans-13-to-tetranor-prostadienoic acid in 35 ml of dry acetonitrile, which was heated to 80 ° C., was mixed with a solution of 86 mg (0.68 mmol) of tris-hydroxymethylamine © - methane in O ₃ 15 ml of water are added while stirring vigorously. The mixture was allowed to cool to room temperature, and the tris-hydroxymethylamino-methane salt of 9ßiHoc, 15 _a -trihydroxy-l6-phenoxy-cis-5-trans-13- prostadienoic · ^UJ -tetranor- was collected.

example

9-oxo-lla _} 15a ~ bi-sformyloxy-16-phenoxy-cis-5-trans-13- ^iy tetranor-prostadic acid - \

A solution of 0.1 mmol of 9-Oxo-llrt,
phenoxy-cis-5-trans-13- ^{<: ü} -tetranor-prostadienoic acid in 0.5 ml of dry tetrahydrofuran was treated with 29 mg (0.33 mmol) of formic acid-acetic anhydride and 35 mg (0.33 mmol) of 2.6 lutidine offset. The solution was stirred for 1 hour under nitrogen at room temperature and then 36 mg of water was added. The mixture was stirred for an additional hour at room temperature and then diluted with ethyl acetate. The diluted solution was _{washed with 0.1N HCl 9} water and brine and then dried over sodium sulfate. Chromatography of the crude product on silica gel resulted in the desired bisformyloxy compound.

409821/1181

example

tetranor-prαs tadiens acid

A solution of 0.2 mmole 9β, llo, _a 15a "dihydroxy-16-phenoxycis-S-tparis-l ^ - ^^ tetrarior-prostadienoic acid in 3," ml pyridine was mixed with 12q mg C1 »Q mmol) pivaloyle chloride. The solution was stirred at H5 ° C under nitrogen for 4 hours and then cooled to room temperature. 40 mg of water was added and the mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate. The diluted solution was diluted with dilute HCl, Washed water and saline solution. Concentration and purification by chromatography on silica gel gave the desired trispivaloyloxy acid. " .. -

Example 3®

1- (TetrazQl-5-yl) -9fj; -hydroxy-11 ^, 15ης-bis- (tetrahydropyran-2-yloxy) -16-p, henoxy-cis-5-trans-13- ^ te tr anor prostadiene ; ' ' - "

3.24 ml of a 2.0 molar solution of sodium methylsulfinyl methide in dimethyl sulfoxide were added to a solution of I ₃₁ ^ S g of 4- (tetrazol-5-yl) butyltriphenylphosphomium bromide under a dry nitrogen atmosphere in βyO ml of dry dimethyl sulfoxide. This solution was mixed dropwise with a solution of 615 mg of 2-C 5ix-hydroxy-3a '- (tetrahydropyran-2-yloxy) -2ß- (3a- (tetrahydropyrah-2-yloxy) - ⁱ l-phenoxy-trans-l- buten-lyl) -cyclopent-lcE ~ yl3-acetaldehyde-y-hemiacetal in 50 ml of dry dimethyl sulfoxide was added for 20 minutes. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was acidified with ο., Ϊ́η HCl and then

A 0 9 8 2 1/1 1 8 1

extracted with ethyl acetate. The residue obtained after evaporation of the solvent was chromatographed and gave 680 mg of pure, colorless, oily

pyran-2-yloxy) -l6-phenoxy-cis-5-trans-13 ~ w-tetranorprostadien,

Example 32Ϊ

• *

l- (Tetrazol-5-yl) -9 _a> llft, 15a-trihydroxy-l6-phenoxy-cis- 5-trans-15- ^ ^J -teti ^> anor-prostadien __

A solution of 3,000 mg of 1- (tetrazol-5-yl) -9a-hydroxylIaal5a ~ bis (tet "rahyäropyran-2-yloxy) -l6-phenoxy-cis-5-trans-13 - ^ - tetranor-prostadiene in 6 ml of a mixture of glacial acetic acid and water in a ratio of 65-35 was stirred under nitrogen at 25 ° C. for 18 hours and then concentrated by rotary evaporation : 0.1 * 17 to ο J074 mm) using mixtures of chloroform and ethyl acetate as eluent after elution of x <reniger polar impurities that was colorless oily l- (tetrazol-5-yl) -9 _rx> lla, 15Ti-t: rihyäroxy-lö-phenoxy-cis ^ -trans-l ^ - ^ - tetranor-prostadiene with a weight of 22o mg (8o # yield) obtained.

example

1- (tetrazol-5-yl) -9-oxo-llod, 15 '-bis- (tetrahydropyran-2-yloxy) · l6-phenoxy-cis-5-trans-13 ~ ^ ^{7 -tetranor-pr>} ostadien

A solution, cooled to -15 ° C, of βοο mg l-tetrazol-5-yl) -9a-hydroxy-ll _a , 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13 - ^{<; c} '-tetranor-prostadiene in 12 ml of reagent-grade acetone was added dropwise under nitrogen with 0.6 ml of Jones' reagent. After 30 minutes at -Io C 0.6 ml of "2-propanol were added, the Re-

4 0 08 21/118 1

Action mixture was stirred for a further 5 minutes, after which it was combined with 75 ml / ithylacetat, washed three times with 10 ml of water each time, dried over sodium sulfate and then concentrated, whereupon 50 mg of the colorless oily 1- (tetrazol-5-yl) -9- oxo-llas15a ~ bis- (tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5-trans-13- ^ii? tetranor prostadiens were obtained.

example

1- (Tetrazol-5-yl) -9-oxo-lltx, 15a ~ dihydroxy-16-phenoxy-cis- 5-trans-13- ^ - tetranor-prostadiene

A solution of 508 mg of 1- (tetrazol-5-yl) -9-OXO-II ₁ *, bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13- ⁱ <^; - Tetranor prostadiene in 10 ml of a mixture of glacial acetic acid and water in a ratio of 65:35 was stirred at 25 ° C. for 20 hours under nitrogen and then concentrated by rotary evaporation. The crude oil obtained was purified by column chromatography on silica gel (MaI-linckrodt CC-7 'clear mesh size: 0.147-0.07 ¹ lm) using mixtures of chloroform and ethyl acetate as the eluent. After elution of more polar impurities, the colorless, oily l- (Te'trazol-5-yl) -9-oxo-llo!, 15ct-dihydroxy-l6-phenoxy-cis-5-trans-13 - ^ - tetranor- prostaiia weighing 240 mg were obtained.

example

N-methanesulfonyl-9nt-hydroxy-llrx, 15rt-t> is- (tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5 ~ trans-13- ^ü3 -tetränor-

prostadienamide. - -

A solution of 1.7 g of C ^ - (methanesulfonylaminocarbonyl) butyl triphenylphosphonium bromide in 6, ο ml 'dry Dimethyl sulfoxide under a dry nitrogen atmosphere

409821/1 181

phere was 3j2 ml (6> 5 mmol) of a 2 molar solution of ο sodium methylsulfinylmethide in dimethyl sulfoxide versetzt.- To this red ^Y lid solution was added dropwise a solution of 6lo mg (1.29 mmol) of 2- [5RT-hydroxy -3tr (te trahydropyran-2-yloxy) -2β- (3a ~ (tetrahydropyran-2-yloxy) - ⁱ l-phenoxy-trans-l-buten-l-yl) cyclopent-lr _I -yl3-acetaldehyde-y hemiacetal in 5 ml of dry dimethyl sulfoxide for 20 minutes. After further. / Stirring for 2 hours at room temperature. The reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (3 × 20 ml), and the combined organic extracts were washed once with 10 ml of water, dried over sodium sulfate and evaporated to an oil. Chromatography on silica gel gave 6SH mg of pure, oily N-methanesulfonyl -9a-hydroxy-ΙΙ ^ χ, 15a-bis- (tetrahydropyran-2-yloxy) -l6-phenoxy-cis-S-trans-lS - ^ - tetranor-prostadienamide.

Example 3g "

N-methanesulfonyl-9a "l ¹ Ä> - ^l -5 ££ ~ ^tr ihydroxy-l6-phenoxy-cis-5-trans-13 ~ ^{t |!} '-tetranor-prostadienamide

A solution of 250 mg in 5 ml of a mixture of glacial acetic acid and water in a ratio of 65 ^ 35 was stirred at 25 ° C. for 18 hours under nitrogen and then concentrated to a crude oil which was cleared by column chromatography on silica gel (Mallinckrodt CC-7; Mesh size: ο, Ι ¹ }? - ο, ο7 * ί mm) using mixtures of chloroform and ethyl acetate as eluent. After elimination of less polar impurities, the colorless, oily N-methanesulfonyl-9a: jlla, 15tf -trihydroxy-16-phenoxy-cis-5-trans-13- ⁱⁱ - ^i; -tetranor-prostadienamide weighing 180 mg. Liquid-liquid chromatography showed the product to be homogeneous.

+) became 409821/1181

■ - - 77 -

example 3lC

N-Methanesulfony 1-9-OXO-II (^, 15ci-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13 - # '~ tetranor - pröstadiene amide - · ■. ^

A solution, cooled to -Io C, of * 100 mg in 8 ml of reagent-grade acetone was added dropwise under nitrogen with 0.4 ml of Jones reagent. After Jo .Minuten "in -lo ° C o _s, 4 ml of 2-propanol was added and the reaction mixture was stirred for an additional 5 minutes after which it combines with 6o ml of ethyl acetate, washed three times with Io ml of water, dried over sodium sulfate and then was concentrated, whereby 380 mg of the colorless oily N-methanesulfonyl-9-oxo-lJk _s 15a ~ to "" (tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5 "trans-13-ö-tetranorprostadienamid were obtained«

example

N-Methanesulfonyl-9-oxo-l 1-XjISi ^- ^ i s-dihydroxy-16-phenoxy-cis- 5-trans-13 ~ ^a7 ~ tetranor-prostadienemid ___ ^

A solution of 260 mg in 6 ml of a mixture of glacial acetic acid and water in the ratio of 65:35 was at 25 ° C. for 20 hours stirred under nitrogen for a long time and then concentrated to a crude oil, which by column chromatography on silica gel (Mallinckrodt CC-7, clear mesh size: o, l47 ~ o, o74. Mrn) Purified using mixtures of chloroform and ethyl acetate as eluants / T after elution of less polar impurities was the colorless N-methanesulfonyl-9-oxo-lla , ii

tetranor-prostadienamide weighing 130 mg. The product crystallized from ether as colorless crystals with a melting point of 76 ° C.

+) was

4 0 9 8 2 1/118 1

example

9β, 11a ₅ 15cc-trihydroxy ~ 16-phenoxy-cis-5-trans-13 - ») - tetra nor-prostadienoic acid ;

A solution of 0.18 g (0.47 mmol) of 9-oxo-11nr, 15a "dihydroxyl6-phenoxy-cis-5-trans-13 ~" ^ tetranor-prostedic acid in 20 ml of methanol was mixed with to a cold solution of 0.06 "g of sodium borohydride '\ o ml of methanol. After 1 hour at 0 ° C., 4 ml of water are added to the reaction mixture and the mixture is concentrated under reduced pressure. The residue was acidified to pH 3 with 10% hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Chromatography on 20 g of silica gel (Mallinckrodt CC-7) and elution with a mixture of methanol and benzene led to the pure 9β, 11a _J 15a ~ Ti ^> ihydroxy-16-phenoxy-cis-5-trans-13-ta-tetranor Prostadienic acid, which was obtained as a colorless oil and was found to be homogeneous on the basis of a thin-layer chromatogram (C, -H \ - dioxane-HCO H ₅ 15: 5 * 2) and had an R _f value of 0.25.

Example Jk? V ^

N-Benzoyl-9-oxo-II (x, 15α: ~ ^< 3ihydroxy-5-cis-13-trans-16-phenoxy-a ^ -tetranor-prostad3 ^ naI ^

l, o mmol g-

16-phenoxy-cis-5-trans-13-t «-tetranor-prostadienoic acid (Example 8) in 40 ml of tetrahydrofuran was mixed with 2 ml of triethylamine. After stirring for 15 minutes at room temperature, lo.0 ml of a ₃ l molar solution of benzoyl isocyanate in tetrahydrofuran were added. After stirring for a further 4 hours, the reaction mixture is neutralized with acetic acid and the solvent is evaporated off in vacuo. The residue obtained vmrde in

4 0 9 8 21/1181

MethylenchloTid added and washed successively with water and sodium bicarbonate, where _3, after drying and evaporation of the solvent, N-Benzoy 1-9-OXo-IIr _x , 15t bis (tetrahydropyran-2-yl-oxy) -16-phenoxy-cis -5-trans-13-tM-tetranor-prostadienamide was obtained. This intermediate was then hydrolyzed overnight with acetic acid / water (as in Example 9) and purified by column chromatography to give the desired N-Benzoy J. 9-0x0-3. let, 15pt-dihydroxy-5 "cis-l ¹ 3-'trans-l6-phenoxy-a) -tetra nor-prostadienamide was obtained.

example

N-methanesulfonyl-9-oxo-II (jf, 15af-dihydroxy-5-cis-13-trans- 16-phenoxy-w-tetranor-prostadienamide.

l, o mmol 9-oxQ-llaal5a ~ bis- (tetrahydropyran-2-yl-oxy) -16-phenoxy-cis-5-trans-13-u) -tetranor-prostadienoic acid (See. Example 8) in ^ o ml of tetrahydrofuran was with 2 ml of triethylamine are added. After stirring for 15 minutes at room temperature, lo, o ml of an o, l molar Methanesulfonyl isocyanate solution in tetrahydrofuran added. After stirring for a further 4 hours, the reaction mixture was neutralized with acetic acid, and the solvent was evaporated off in vacuo. The residue obtained was taken up in methylene chloride and washed successively with water and sodium bicarbonate, wherein, after drying and evaporation of the solvent, N-Methanesulfony 1-9-OXO-IlOt, 15oi-bis (tetrahydropyran-2-ylroxy) -16-phenoxy-cis-5-trans-13 - (M-tetranor-prostadienamide was obtained. This intermediate product was then treated with acetic acid / Water hydrolyzed (as in Example 9) and purified by column chromatography, the desired M-Methanesulfony1-9-0x0-1%, 15a-dihydroxy-5-cis-13-trans-l5-phenoxy - (»- tetranor-prostadienamide. Obtained became.

409821 / 1T81.

- 8ο -

Example 44

N-acetyl-9a-hydroxy-llCL, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13- u> -tetranor-prostadienamide:

A solution of 5.32 g of 4- (acetamido-carbonyl) -butyl 3-triphenylphosphonium bromide in 10 ml of dry dimethyl sulfoxide was treated with 17.7 ml of a 2.0 molar solution of sodium methyl sulfynyl methide in dimethyl sulfoxide under a dry nitrogen atmosphere. A solution of 0.524 g (1.1 mmol) 2 - * (3a-Hydroxy-3a- (tetrahydrppyran-2-yl ^ oxy) -2ß- (3CE .- (tetrahydropy.ran-2- yloxy) -4-phenoxy-trans-1buten-1-yl) -cyclopent-la-yl J-acetaldehyde-v-hemiacetal in 10 ml of dry dimethyl sulfoxide was added over the course of 20 minutes The basic aqueous solution was washed twice with ethyl acetate (3 × 25 ml), and the combined organic extracts were washed once with 10 ml of water, dried over sodium sulfate and evaporated to an oil. Chromatography on silica gel led to 0.66 g of pure oily N-acetyl ~ 9a-hydroxy-lla _> l5abis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13-0? -1 etr anor-prost adienamide.

Example 43.

N-Acetyl-9 ^a jlli ⁱ 5l5 ^cf 7-trihydroxy-16-phenoxy-cis-.5 ~ trans-13-Oi-tetranor-prostadienamide:

A solution of 0.39 g of N-acetyl-9a-hydroxy-lla, l5a-bis (tetrahydropyEan-2-yloxy) -16-phenoxy-cis-5-trans-13-u> tetranor-prostadienamide in 5 ml of one. Mixture of glacial acetic acid and water in the ratio of 65:35 was at 25 ° C

409821/1181

Stirred for 18 hours under nitrogen and then concentrated to a crude oil which was determined by column chromatography on silica gel (Mallinckrodt CC-7) using mixtures of chloroform and ethyl acetate as Eluent has been purified. After elution of less polar impurities, 95 mg became colorless, oily N-acetyl-9 (x, iia, iSa-trihydroxy-lo-phenoxy-cis-S-trans-13-ü> -tetranor-prostadienamide obtain.

Example 4 & . '

N-Acety l-9-οχο-ΙΙίί ;, IS ^ -bis-C tetrahydropyran-2-yloxy) -

-l ^ - Ui-tetranor-prostadienamxd:

A cooled to -10 ⁰ C solution of 39 mg ** N-acetyl-9 tt ~ hydroxy-LLCI, L 5a-bis- (tetrahydropyran-2-yloxy) -L6-phenoxycis-S-trans-l ^ ^ -tt tetranor Prostadienamide in 10 ml reagent grade acetone was added dropwise with 0.27 ml Jones reagent under nitrogen. After 30 minutes at -10 ⁰ C, ¹ J ml 0 2-propanol ₃ and the reaction mixture was stirred for a further 5 minutes "which it combines with 60 ml of ethyl acetate, washed 3 times with 10 ml water, dried over sodium sulfate and was concentrated , 390 mg of the colorless, oily N-acetyl-9-oxo-lia, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13 - «^ - tetranor-prostadienamide were obtained . '.

example

trans-13-o) -tetranor-prostadienamide:

A solution of 390 mg of N-acetyl-9-oxo-lia _? i5Q.-bis- (tetra-

409821/1181

hydropyran-2-yloxy) -16-phenoxy-cis-5-trans-13 - «> - tet ranor prostadienamide in 8 ml of a mixture of glacial acetic acid and water in the ratio of 65:35 was at 25 ° C for 20 minutes under nitrogen stirred and then concentrated to a crude oil ₃ which was purified by column chromatography on silica gel using mixtures of chloroform and ethyl acetate as the eluent. After elution of less polar impurities, the colorless, oily N-acetyl-SJ-oxo-llcXj ^ a-bis-dihydroxy-16-phenoxy-cis-5-trans-13-tu-tetranor-prostadienamide with a weight of T6 mg was obtained .

409821/1181

Claims (4)

Claims: χ 1. Process for making compounds of the structure H \ h (CH ₂ ) _n -0- (CH ₂ ) _m Ar ■ '■ (D' and their C ^ epimers,. where Ar is a phenyl, 3, U-dimethoxyphenyl7 ^ 3, * i ~ methylenedioxyphenyl, 3,4,5-trimethoxyphenyl · ··, α- or ß-naphthyl-. or monosubstituted phenyl group, where the substituent a halogen atom, a trifluoromethyl-, phenyl-, lower-alkyl * - or lower-alkoxy group means -R a hydrogen atom or a lower alkyl group; η and m are each integers from 0 to 3, the sum of η and m not exceeding the number 3; W is a single bond or a cis double bond; Z is a single bond or a trans double bond; H OH M is a keto group or one of the groups < or - ^ r. . "" ".OH" '"-Η' N and L together form a single bond, or, if L is a water atom, N represent an α-hydroxyl group, and Viorin X is a p-phenylphenoxycarbonyl-tetrazolyl group or denotes a group -CONHR ", in which R" is an alkanoyl radical with 2 to 10 carbon atoms or a cycloalkanoyl group is of 4 to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms in which the substituent is a methyl or methoxy group or 409821/1181 is a halogen atom; an alkylsulfonyl group with 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group wherein the substituent is a Methyl or methoxy group or a halogen atom represents, and wherein L, M and N are selected to have the structure of an A, E or F series prostaglandin is completed, ■ the lower alkanoyl, pormyl or benzoyl esters of any free hydroxyl groups in the C _g , C ₁₁ or C ^ position, characterized in that one a) when N is an α-hydroxy group and L is a hydrogen atom are, and Ar, n, -m, M, V /, X and Z the aforementioned meaning possess these compounds by treating the 11- and 15-tetrahydropyranyl ethers of a compound of the above Formula I with a suitable acid produces; b) when N and L together form a single bond, M is a keto group, and Ar, n, m, R, W, X and Z are mentioned above Have meaning, these compounds by reacting a compound of the above formula I ,. in the N one a-hydroxy group, L is a hydrogen atom and M is a keto group are, and Ar, n, m, R, W, X and Z have the aforementioned meaning, with a suitable dehydrating agent manufactures; c) if N is a ct-hydroxy group, L is a hydrogen atom and M represent the group ·; "'""or the group £""","''""0H''" »Η and Ar, n, R, W and Z have the meaning given above, these compounds by reacting a compound of the formula I in which N is an α-hydroxy group, L is a hydrogen atom and M are a keto group, and Ar, n, m, R, W, X and Z have the aforementioned meanings, with one prepares suitable reducing agent and optionally separates the 9CX and 9β isomers; 409821/1181 d) if N is an α-hydroxy group and L is a hydrogen atom, Ar, R, h, m, M and X have the aforementioned meanings, and W and Z represent single bonds, these compounds are produced by catalytic reduction of a compound of the formula I, in which Ar, R, n, m, M and X have the aforementioned meaning, W, if Z is a trans double bond, a single bond or a cis double bond, and Z, if W is a cis double bond, represent a single bond ; e) if N represents an α-hydroxy group and L represents a hydrogen atom j and Ar, R, n, m, X and M have the aforementioned meanings, ¥ mean a single bond and Z means a trans double bond, ₃ these compounds by selective reduction of a compound of the formula I or the trialkylsilyl ester S. of a compound of the formula I in which X is a COOH group, Ar, R, n, m ₃ X and M have the aforementioned meanings, and W and Z represent double bonds, f) those compounds of the formula I, wherein X is a COOR ¹ group, where R ^{f is} a mass. material atom is converted into their above-mentioned esters and substituted amides by reaction with suitable esterification and amidation reagents, and optionally ^ by reacting these compounds with the corresponding acylating agents, the 9a-, lla- and ISa-lower alkanoyl, formula and benzoyl ester " any free hydroxyl groups. 409821/1181 2. A method of making compounds according to claim 1 of the structure (CH ₂ ) -0- (CH ₂ ) _m Ar R ^ ^{ν /} ΌΗ ^{2 n} (IA) and their C ^ epiners, - wherein Ar is a phenyl, 3, ⁱ {-Dlmethoxyphenyl-7_ _r '3, ⁱ i-Mefcttylenedioxyphenyl-r, 3,4,5-trimethoxyphenyl · ^ α- or ß-naphthyl or monosubstituted phenyl group, where the substituent is Halogen atom, one. Trifluoromethyl, phenyl, lower-alkyl or lower-alkoxy group, R is a hydrogen atom or a lower alkyl group and in integers from 0 to 3, the sum of η and m does not include the number 3 exceeds; W is a single bond or a cis double bond; and Z represent a single bond or a trans double bond and in which X is a p.-pheny! Phenoxycarbonyl, tetrazoy! Group or denotes a group -CONHR ", in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms is; an aroyl or substituted aroyl group with 7 to 11 carbon atoms, wherein the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group having 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent represents a methyl or methoxy group or a halogen atom, 409821/1181 -Bi - the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups in the C _q , C ₁₁ or C ₁ position, and the pharmaceutically acceptable salts of these compounds, characterized in that a) the 11- and 15-tetrahydropyranyl ethers of the * compounds of the formula I are treated with a suitable acid; b) a compound of the formula ₂ -Q- (CH ₂ O _1n Ar - (IB) wherein Ar, n, m, R, W, X and Z are as defined above possess reduc- ed _v with a suitable reducing _agent; and the 9 <Xt and 9β ~ isomers are then separated; c) a compound of the formula IA, wherein Ar, R, n, m and X have the aforementioned meaning, and V /, if Z is a trans double bond, a single bond or a cis double bond, and Z _9, if W is a cis double bond, mean a single bond, is catalytically reduced to a compound of the formula IA, wherein Ar, R and N have the aforementioned meaning, and W and Z are single bonds; d) the dimethylisopropylsilyl derivative of a compound of the formula IA, in which X is the group -COOR ¹ , where R ^{1 is} a hydrogen atom, and in which Ar, R, η and in have the aforementioned meaning, W is a cis double bond and Z is a trans Double bond, is selectively catalytically reduced to a compound of the formula IA in which Ar, R and η have the meanings given above, W is a single bond and Z is a trans double bond; 409821/1181 that those compounds of formula I in which X is a COOR 'group, where R' is a hydrogen atom, by Reaction with suitable esterification and amidation reagents into their above-mentioned esters and substituted ones Amides are converted, and optionally, by reacting these compounds with the corresponding acylating agents, the 9 <j6-, and 15 ^ -lower-alkanoyl-, -Pormyl- and -Benzoyle.ster any free hydroxyl groups produced. 3. A method of making compounds according to claim 1 of the structure. (CH ₂ ) -0- (CH-) _m Ar ^{2 m} and their C ^ epimers, in which Ar is a phenyl- ₃ 3,4-dimethoxyphenyl-., ^, k ~ methylenedioxyphenyl-, ^, ^^ - trimethoxyphenyl- ^ a- or 'ß-naphthyl- or monosubstituted Pheriylgruppe, in which the substituent is a halogen atom, is trifluoromethyl, phenyl, lower alkyl, or lower alkoxy; R is a hydrogen atom or a lower alkyl group; η and m are integers from 0 to 3, the sum of η and m not exceeding 3 j ■. - W is a single bond or a cis double bond; Z represent a single bond or a trans double bond, 409821/1181 and wherein X is p-phenoxycarbonyl group, tetrazolyl group or . means a group —CONHR ", in which R" is an alkanoyl group having from 2 to 10 carbon atoms or a cycloalkanoyl group having from h to 8 carbon atoms; represents an aroyl or substituted aroyl group having 7 to 11 carbon atoms, wherein the substituent is methyl or meth. ■ is Qxy group or a halogen atom; an alkylsulfanyl 'group of 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group . _y wherein the substituent is a methyl, methoxy group or a halogen atom. is, means; the niederenAlkanoyl-, formyl or benzoyl loading "liebiger free hydroxyl groups i _n C - and C r-Stel Luna ■ ^ characterized in that a) the Ii- or 11- and 15-tetrahydropyranyl ethers one A compound of the formula IB wherein Ar, R, m, n, W, X and Z have the aforementioned meaning, are treated with a suitable acid; b) a compound of the formula IB, in which Ar, X, R, m. and η have the abovementioned meanings, and M, if Z is a trans double bond, a single bond or cis double bond. and Z _3, if W is a cis double bond, represents a single bond, is catalytically reduced in order to obtain a compound of the formula IB in which Ar, X, n, m and R have the aforementioned meanings and W and Z are single bonds ; c) the dimethylisopropylsilyl derivative of a compound of the formula IB, in which Ar, R, m, and η have the aforementioned meaning have, X is a COOH group, W is a cis double bond and Z is a trans double bond, selectively is catalytically reduced to a compound of the formula IB, in which Ar, X, R, m and η have the aforementioned meaning own one. Single bond and Z represent a trans double bond to obtain; 40982171181 that that compound of the formula IB in which X is a COOR 'group, in which R ^{1 is} a V / water atom, is converted to its esters or substituted amides by reaction with suitable esterifying or amidating agents, and that optionally the lower alkanoyl, pormyl or benzoyl esters of any free 11- and 15-hydroxyl groups by reacting these compounds' be prepared with the appropriate acylating agent. 4. A method of making compounds according to Claim 1 of the structure IT. ^{// ä} 0H (CH ₂ ) _n -o- (CH ₂ ) _m Ai · -; (ic) and their CL ^ epimers, in which Ar, a phenyl, 3j * ί "dimethyIoxyphenyl, 3, ^ - methylenedioxyphenyl, 3> ^ ₃ 5-triinethoxyphenyl, cc- or β-naphthyl or monosubstituted phenyl group, in which the substituent is a halogen atom, a trifluoromethyl -, phenyl, lower alkyl or lower alkoxy group; R is a hydrogen atom or a lower alkyl group j η. And m are each integers from 0 to 3 * where the -.-. The sum of η and m does not exceed the number 3 ^. Vf and L each have a single bond or a cis double bond; Z is a single bond or a trans double bond represent; 4 0 9 8 21/1181 and wherein X represents a p-phenylphenoxycarbonyl or tetrazolyl group or a group -CONHR ", wherein R" represents an alkanoyl group of 2 to 10 carbon atoms or a cycloalkanoyl group of 4 to 8 carbon atoms; represents an aroyl or substituted aroyl group of 7 to 11 carbon atoms - wherein the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group of 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl, methoxy group or a halogen atom; the lower alkanoyl, pormyl or benzoyl esters of the C _1t _ -hydroxyl group, characterized in that a compound of the formula IB 'OH CCH ₂ ) _n -0-CCH ₂ ) _m Ar wherein Ar, R, m _s n, W, X and Z have the above meanings, is reacted with a suitable Dehydratisierungsmxttel; and those compounds of formula I, wherein X is a COOR ¹ group in which R ^{1 is} a hydrogen atom; means being converted into their abovementioned esters or substituted amides by reaction with suitable esterifying or amidating reagents, and optionally, by reacting these compounds with appropriate acylating agents, the C, -lower-alkanoyl-, -formyl- or - Benzoyl esterJ are produced. 409821/1181 5 · Process for the preparation of compounds of the. structure . OTHP · .'- '■ ·. and their C ₁ ^ epimers., and their Cq and C., _- epimers, in which Ar is a phenyl ;, 3 _a ¹ l-diirtethoxyphenyl7 _J - 3a ^ "methylene - dioxyphenyl, ^, ^ y ^ - ... trimethoxyphenyl ;, · α-'or ß-Napbthyl- mona or substituted phenyl wherein the substituent is a Halogenafcora, a Trdfluormethyl-, phenyl, low 'low alkyl or alkoxy group _represents> means; ·-R. a Hydrogen atom or a lower alkyl group; THP a 2-tetrahydropyranyl group, η and m jexieils integers from 0 to 3> where the sum of ti'und m does not exceed the number 3; W a single bond or · a cis double bond; and Z represents a single bond or a trans double bond, and wherein .X a p-phenylphenoxycarbonyl or tetrazotyl group or a group -CONHR ", in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms; atoms, a substituted aroyl or aroyl group having 7 to 11 JKohlenstof £, wherein - 'the Substituent'eine methyl or Kethoxygruppe or-a. is Öalogenatom; an alkylsulfonyl group with. 1 to: 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl or methoxy group or a halogen atom ₃ "represents, • 409821/1181 characterized in that a compound of the formula II THPO I) THP (ii) in which Ar, R, n, m; and Z have the aforementioned meaning, with an ylid of the formula ) ^ P = CH-CH ₂ - wherein X has the aforementioned meaning, is reacted, where, if X is a p-phenyl-phenoxycarbonyl group, the compound of formula II first with a ylid of formula ■ (CgH) -P = CH- is reacted, and the product obtained is esterified with p-phenylphenol to obtain a compound of the formula II, wherein Ar, R, n, m, X and Z have the aforementioned meanings and W represents a cis double bond, and that -the The compound thus formed is subsequently reduced if necessary to obtain a compound of the formula II in which Ar, R, n, m, X and Z are mentioned above. Have meaning and W is a single compound; that a compound of formula II in which ^: Ar, R, m , X and 409 8 2171181 - 9k - η have the above meaning, W represent a cis double bond and Z represent a trans double bond, is reduced to obtain a compound of the formula II, in which Ar, R and η have the above meaning and W and Z represent single bonds ; . . ' ader that a compound of formula II in which Ar, R and η have the aforementioned meaning, W is a cis double bond and Z represent a trans double bond, is selectively reduced to obtain * a compound of the formula -II, in the. Ar, R, m, X and η have the aforementioned meaning, W a single bond and Z a trans double bond represent. -6. · Process for the preparation of compounds of the structure THPO ^{% V} '\ ^ ^ y ^ . ^ (CH ₂ ) _n -O- (CH ₂ ) _m Ar (IIB) OTHP and their C - ^ - epimers, wherein Ar is a phenyl- ₃ ^, ^ -dimefchoxyphenyl-j- 3 \, h -methylenedioxyphenyl-r ^ 3 _? * l 5-Triraethoxyphenyl · ^ cc- or β-Haphtixyl- • or monosubstituted phenyl groups "xio with 3-substituent. represents a Halogenatoin, trifluoromethyl, phenyl niedräg _y-alkyl or alkoxy niedrlg means .a-R ¥ a5.sserstoffatom or a lower alkyl group THP ^ a 2-tetrahydropyranyl, and η m Jevzeils integers from 0 to 3 > where the sum of n and m is the number 3 not overlooked; ■ · 409821/1181 W is a single bond or a cis double bond; Z represent a single bond or a trans double bond, and in which, X is a p-pheny! Phenoxycarbonyl or tetrazolyl group or a group -CONHR ", in which R" is an alkanoyl radical with 2 to 10 carbon atoms or a cycloalkanoyl group with h to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms, wherein _{t of} the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group having 1 to 7 carbon atoms; represents an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl or methoxy group or a halogen atom,
characterized in that a compound of the formula HA -0- (CH ₂ ) _m Ar. in which Ar, R ₃ n, m, X, V / and 2 have the aforementioned meaning "with chromic acid in aqueous sulfuric acid ^: and acetone is reacted." 7. Process for the preparation of compounds of the structure ".." 409821/1181 CH ₂ ) _n -0- (CH ₂ ) _m Ar in the ar. a phenyl, 3a ^ -dimethoxyphenyl, 3 _a 4-methylenedioxyphenyl, 3 * 4,5-trimethoxyphenyl, α- or ß-naphthyl or monosubstituted phenyl group, wherein the substituent is a halogen atom, a trifluorine thyl · phenyl -, lower alkyl or lower alkoxy group; η and m are integers from 0 to 3 _S where the sum of η and m does not exceed the number; and Q represent my p-biphenylcarbonyl radical, characterized in that a compound of the formula , 0 CHO wherein Q has the abovementioned meaning with a compound of the formula lower-alkyl-O, lower-alkyl-O- , -C - (CH ₂ ) _n -0- (CH ₂ ) _m Ar 0 409821/1181 Iri the m> η and Ar have the above meaning, vice versa8. Process for the preparation of 'compounds of the structure' ^: CCH ₂ ) _n -0- (CH ₂ ) _m Ar in which Ar is a phenyl, 3 ₅ ² l-Diniethoxyphen-yl-, 3,4-Methylendioxyphenyl-, 3 ^^.,. 5 ~ Trimethoxyp'henyl- ₃ o- or ß-Naphthyl- or monosubstituted phenyl wherein the substituent is a halogen atom, a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group; " h and m jex ^ ells integers from 0 to 3> v / obei the sum of η and m does not exceed the number 3; and Q. '. a hydrogen atom or a p-biphenylcarbonyl radical represent, characterized in that a compound of the formula HI -. 0 9 8 21/1181 in which Ar, η, m and Q have the abovementioned meanings, _{y is} reduced to obtain a compound of the formula IV in which Ar, η and Q have the abovementioned meanings and R is a hydrogen atom, and that the 8a and 8ß-isomers be separated if necessary; that a compound of the formula III is reacted with a suitable alkylating agent in order to obtain a compound of the formula IV, in which Ar, n, m and Q are as defined above and R is a lower alkyl radical; and that optionally a compound of the formula IV in which Ar, η and R have the aforementioned meanings and Q is a biphenylcarbonyl radical, with K _? CO is treated to obtain a compound of Formula IV wherein Q is a hydrogen atom; where the and 8 [beta] isomers are optionally separated. 9 · Process for the preparation of compounds of the structure THBO, R ' "ÖTHP in which Ar is a phenyl, 3, ² l-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3, ¹ }, 5-trimethoxyphenyl, α- or ß-naptithyl or monosubstituted phenyl group, in which the substituent is a halogen atom, is trifluoromethyl, phenyl lower alkyl or lower alkoxy group; 409821/1181 R represents a hydrogen atom or a lower alkyl group; THP is a 2-tetrahydropyranyl group; η and m are each integers from O to 3 _S , the sum of η and m not exceeding the number 3; Z is a single bond or a trans double bond; and Ϊ represents an oxygen atom or the group c ^ "" ^ put, characterized in that daia a connection of the Formula IV - - - ' P " , 'fxvl ^; in which Ar, R, m, η and Z have the aforementioned meaning and Y = O, is reacted in the presence of an acidic catalyst with 2j3-dihydropyran to obtain a compound of the formula V in which Ar, R, m, η and Z have the aforementioned meaning and Y = O; '' that a compound of the formula V, in which Ar, R, m, η and Z have the aforementioned meaning and Y = O, is reacted with diisobutylaluminum hydride to obtain a compound of the formula V in which Ar, R ₉ m, η and Z have the aforementioned meaning, and Y the group: is to get; or that a compound of the formula IV, in which Ar, R, m and η ' have the aforementioned meaning, Z is a trans double bond -H OH. 409821/1 181 - loo - and Y = O are _{3 is} catalytically reduced in order to obtain a compound of the formula V, in which Ar, R, m and η have the aforementioned meanings, and Y = O and Z are a single bond. 409821/1181 - löi - '■ "." ·: ■ 23B5S40 : - * Connections of the structure Μ ' ^ -ö-CCKg) ^ - . -H "ÖH ■. · And dereil C ^ -Epinere ·,. ' - ¹ _v · .-; Where Ar is a phenyl-, ^ j ^ -dimethoxyphenyl · ^ 3> * t-methylenedioxyphenyl-r ^ 3,4,5-trimethoxyphenyl- _v α- or β-naphthyl-. · Or monosubstituted phenyl group, where the substituent is a halogen atom, a trifluoromethyl, phenyl, lower-alkyl or lower-alkoxy group, «R is a hydrogen atom or a lower alkyl group; η and m each »whole numbers from 0 to 3j where the sum of η and m does not exceed the number 3; W is a single bond or a cis double bond; Z is a single bond or a trans double bondi M is a keto group or one of the groups - ^ " or % N and L together one. Single tie, or ifL a Hydrogen atom. Is * N represent an α-hydroxyl group, and where ■ X is a p-Piienylphenoxycarbonyl-j-tetrazalyl group or denotes a group -CONHR ", in which R" is an alcohol radical having 2 to 10 carbon atoms or a cycloalkanoyl group is of 4 to 8 carbon atoms; an aroyl or substituted aroyl group with 7 to 11 carbon atoms, wherein the substituent is a methyl or methoxy group or. . is a halogen atom; an alkylsulfohyl group with 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group, in which the substituent is a · Methyl or methoxy group or a halogen atom represents, and wherein L, M and N are selected to have the structure of a prostaglandin of the. A, E or F series is completed. 4098 2'1 / 1 18T Compounds according to claim 11 of the structure OH and their Cj epimers. 1%. Compounds according to claim 11, wherein M is the group * ^ L is a single bond, and N is an α-hydroxyl group, and their C - ^ - epimers. . Compounds according to claim 11 of the structure -0- (OH ₂ ) _m Ar (IB) and their C. "- epimers. A compound according to claim 11 of the structure OH. (CH ₂ J _n -O- (CH ₂ ) _m Ar (IC) and their C, epimers. 409821/1181 . Connections of the structure
OH THPO (CH ₂ ) _n -0- (CH ₂ ) _ra Ar OTHP and. their C 1-4 and C 1-4 epimers, in which Ar is phenyl, 3> 4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3, ^ y5-trimethoxyphenyl-7 _/ α.- 'or .β-Hapiifctiyl- ^ ?.,;:.. jnonosubstitulerte group or- phenyl, where the * · "Substituents a .Halogenatoia, a Trif luarmethyl-, phenyl, low ·; 'represents alkyl or ;; nied'rig alkoxy group" means - .- 'R. A hydrogen atom or a lower alkyl group ^ THP a 2-tetrahydropyranyl group, η and m each; all _{integers. From 0 to 3 3} above. The sum of r ^ and m does not exceed the number 3; ■. VJ is a single bond or a cis double bond; and Z is a single bond or a trans double bond represent, and trorin - ·. . " "X is a p-phenylphenoxycarbonyl or tetrazoiyl group or a group -CONHR"", where R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms; an aroyl or substituted aroy group with 7 to 11 carbon atoms _? "τ ^ οχΊη - '· the substitute must have a methyl or kethoxy group or .- ■ a halogen atom is an alkylsulfmyl group with. 1. to." ...- 7 carbon atoms; an arylsulfonyl or; ^{substitution:} ierte arylsulfonyl, v / orin the substituent is a ", ■: ■ -. '' - methyl · 'or methoxy group or a ₃ Halogenated ^.da3r-': · - · 'represents ^''*.. . · ■ '- - 0 9 8 2 1/118 Connections of the structure , ^ (ΙΙΒ) , ο ^ν \ ^ \ ^. \ CCHo) "- 0- (CH ₀ ) _Ar ΤΗΡΟ ^Χ OTHP. ! and their C. ^ epimers, '' vior-In Ar a Phenyl- _y 3 _J ¹ i-Dlmethaxyph.enyl-7_ _r - 3 _y U -KethyΙεπ-dloxyphenyl-, 3,4 _> 5-Trlmethoxyphenyl-7, _r et- or- ß-Haphfchyl- '· '. or monosubstituted phenyl group, where the "substituent" is a halogen atom, "a fluoromethyl", "phenyl", "" lower— ^{: represents} alkyl or lower-alkoxy group, means: ^ -. ·; · 'R. A Viaass erstoff atom or a lower Alley! Group ^'. ". THP is a 2-tetrahydropyranyl group, η and in whole numbers from 0 to · 3 ₃ where the sum of n and m does not exceed the number 3; - '■ ·". "'."' VJ a single connection or a cis double connection; ' Z. represent a single bond or a trans double bond- ', and in what X is a p-phenylphenoxycarbonyl or tetrazolyl group or a group -CONHR " ₃ in which R" is an alkanoyl radical having 2 to 10 carbon atoms or a cycloalkanoyl group having 4 to 8 carbon atoms; an aroyl or substituted aroyl group having 7 to 11 carbon atoms, wherein the substituent is a methyl or methoxy group or a halogen atom; an alkylsulfonyl group having 1 to 7 carbon atoms; an arylsulfonyl or substituted arylsulfonyl group in which the substituent is a methyl or methoxy group or a halogen atom, e 0 9 8 2 1/118 . A compound according to claim 11, where η and m ", respectively 0, Ar is phenyl, and the prostaglandin is PGE; Ig. A compound according to claim 11, wherein η and m are each 0, ^u Ar is a phenyl group, and the prostaglandin is PGF _? are . A compound according to claim 11, wherein η = .0, m = 0, Ar is phenyl, and the prostaglandin is PGF _no . 2 (p. The compound of claim 11, wherein n = 0, m = 0, Ar is a phenyl group, and the prostaglandin is PGA _p . Compound according to claim 11, wherein η = 0, m = 1, Ar is a phenyl group and the prostaglandin is PGE ₂ 2% ,. A compound according to claim 11, wherein η = 0, m = 1, Ar is a phenyl group, and the prostaglandin is PGP ₀ . d & 2%. The compound of claim 12, wherein η and m are each 0. The compound of claim 12, wherein η and m are respectively 1 are. 2 (J ". Compound according to claim Ik ₃ where η and m jexveils are 0. . A compound according to claim 1h, wherein η and m are each 1. 29. A compound according to claim 12, characterized in that X is a -CO-NHR "group, where R" is an acetyl group represents w a cis double bond, Z a trans double bond, R a hydrogen atom, η and m, respectively 0, and Ar are phenyl. 409821/1181 "Compound according to claim 12, characterized in that X is a tetrazolyl group, W is a cis double bond,
Z trans double bond, R a hydrogen atom, η and in
each is 0, and Ar is a phenyl group. .3er. Compound according to claim 12, characterized in that X is a -CO-NHR "group, in which R" represents a methylsulfonyl group, W a cis double bond, Z a «trans double bond, R a hydrogen atom, η and m
0, and Ar are phenyl. $ 3. Compound according to claim 12, characterized in that X is a group-CO-NHR ", where R" represents a methylsulfonyl group, -W a cis double bond, Z. a trans double bond, R a hydrogen atom, η and m 0, and Ar
are an m-methoxyphenyl group. 3 ^. Compound according to claim 14, characterized in that X is a group-CO-NHR ", where R" represents an acetyl group, W a cis double bond, Z a trans double bond, R a hydrogen atom, η and m each 0, and Ar
are a phenyl group. 32. · Compound according to claim Ik _3, characterized in that X is a group-CO-NHR ", where R" is an acetyl group, W is a cis double bond, Z is a trans double bond, R is a hydrogen atom, η and m are each 0, and Ar
are an m-methoxyphenyl group. Compound according to claim 14, characterized in that X is a tetrazolyl group, W is a cis double bond,
Z is a trans double bond, R is a hydrogen atom, η and m are each 0, and Ar is a phenyl group. 409821/1181 f. Compound according to claim 14, characterized in that X represents a group-CO-NHR "/ R" a methylsulfonyl group, W a cis double bond, Z a trans double bond, R a hydrogen atom, η and m each 0, and Ar are phenyl. 3ΙΓ. Connections of the structure (CH ₂ ) _n -Ö- (CH ₂ ) _m AP in which Ar is a phenyl, 3,4-dimethoxyphenyl, 3, ¹ * -Methylendioxyphenyl-, 3 »^, 5-trimethoxyphenyl, a ~ R- or naphthyl or monosübstituierte biphenyl is group wherein the substituent is a halogen atom , represents a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; η and m are each integers from 0 to _35, where the sum of η and m does not exceed the number 3, and Q is a para-biphenylcarbonyl radical. 3 / £. Connections of the structure Q ^r 0 ^x (CHp) _n -O- (CH ₂ ) _m Ar (IV) in which Ar is phenyl, 3,4-dimethoxyphenyl, 3, ^ - methylenedioxyphenyl, 3, ¹ 1,5-trimethoxyphenyl, <χ- or ß- naphthyl- 4 0 9 8 2 1/118 1 or -monosubstituted phenyl group, where the Substituent represents a halogen atom, a tri fluorine thy 1, phenyl, lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group; η and m are whole numbers from ο to 3 * where the The sum of η and m does not exceed the number 3, and Q 'is a hydrogen atom or a p-biphenylcarbonyl radical mean. . Connections of the structure THPO (CH ₂ ) _n -0- (CH ₂ ) _m Ar OTHP (V) in which Ar is a phenyl, 3,4-dimethoxyphenyl, 3 _J ⁱ * -methylenedioxyphenyl, 3, ¹ 1,5-trimethoxyphenyl, ct ~ or ß-naphthyl, or mono-substituted phenyl radical, the substituent being a halogen atom represents a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group; THP is a 2-tetrahydropyranyl group; η and m are each integers from 0 to 3 _S, where the sum of η and m does not exceed the number 3; Z is a single bond or a trans double bond; and TI Y is an oxygen atom or the group - ' mean. 409821/1181 16-phenoxy-PGE " ₂ -p-biphenyl ester. 16-phenoxy-PGFp-p-biphenyl ester “16-phenoxy-PGF _2ß -p-biphenyl ester. For Pfizer Inc. ίΐ • ο H.i /. (Dr. H.i /. Wolff) Lawyer 0 9 8 21/1181