CH633006A5 - Process for preparing novel thromboxane analogues - Google Patents

Description

The present invention relates to processes for the preparation of new thromboxane analogs, which are also referred to as thromboxane B2 (11β-homo-lla-oxa-PGF2a). These Ana-55 yoga are particularly useful as a means of controlling the conception cycle.

The compounds which can be prepared according to the invention have the following formula

60

HO

65

HO

CHa-Ii-COORi

Yi-C - C-R7

IL l

LXVI

633 006

4th

wherein

Rj is alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 10 carbon atoms, aralkyl with 7 to 12 carbon atoms, phenyl with 1 or 2 chlorine or fluorine atoms or alkyl radicals with 1 to 4 carbon atoms substituted phenyl,

Room

(1) cis-CH = CH-CH2- (CH2) g-CH2-,

(2) cis-CH == CH-CH2- (CH2) g-CF2,

(3) cis-CH2-CH = CH- (CH2) "- CH2-,

(4) - (CH2) 3- (CH2) g-CH2-,

(5) - (CH2) 3- (CH2) g-CF2-,

(6) -CH2-0-CH2- (CH2) g-CH2-,

R7

(1) - (CH2) -CH m

(2)

3 3

_n— /

(>) - (CHs ")] '

(T) s

, or

(T).

(7)

0- (CH2) g-, or

(8th) -

15 is

where 10 or the number 1, 2 or 3, m is a number from 1 to 5, T is an alkyl radical with 1 to 3 carbon atoms, alkoxy radical with 1 to 3 carbon atoms, chlorine, fluorine or the trifluoromethyl radical and s is the number 1.2 or 3, where the individual

20th

Radicals T can be the same or different, provided that no more than two radicals T are different from alkyl, and provided that R7 is only in which g is the number 1, 2 or 3,

Yj is trans-CH = CH— or -CH2CH2-,

Mj r5 oh or

Rs OH,

represents

where Rs is hydrogen or methyl,

R3 R-t. »

Rs R-t »

or a mixture of

25th

ff

(t),

30 means when R3 and R4, which may be the same or different, are hydrogen or methyl.

Thromboxan B2 has the formula

35

HO

c = c

CHa ^ v (CH2) 3-C00H

M

HO J ^ O- '40 Hx ^ C ^ (CH2) 4-CH3

H OH

45

and can as a derivative of thromboxanoic acid. lla-homo-1 la-oxa-prostanoic acid can be considered, which has the following structure and figures

C00H

o.

and

Rs R4

R3 ^^ 4

The systematic name of thromboxanoic acid is 55 7- [2ß-octyltetrahydropyran-3a-yl] -heptanoic acid.

For comparison, the formula of prostanoic acid is listed

C00H

is whose systematic name is 7- [2ß-octyl-cyclopentan-la-yl] -

is heptanoic acid.

where R3 and R4, which can be the same or different, Was- 65 Thromboxan B2 is also called analogue of PGF2a means serstoff, methyl or fluorine, with the proviso that and is then called Ila-homo-Ila-Oxa-PGF2a.

one of the radicals R3 and R4 only denotes methyl when the other in the formulas above and in the formulas below is hydrogen or methyl, and denote dashed bond lines to the tetrahydropyran

ring or cyclopentane ring substituents in the a configuration, i.e. below the ring level. Boldly marked bond lines to the tetrahydropyran or cyclopentane ring denote substituents in the β configuration, that is to say above the ring plane. The use of a wavy line (- ^ denotes the binding of the substituents in a or β configuration or binding in the form of a mixture of a and β configurations. In particular, reference is made to the description below regarding anomeric mixtures.

The side chain hydroxyl group at C-15 is in the above TXB2 formula in the S configuration. For a discussion of the stereochemistry of prostaglandins, which is also applicable to TXB2, reference is made to Nature 212.38 (1966). Terms such as C-15 and the like denote the carbon atom in the thromboxane or prostaglandin-like compound in the position which corresponds to the carbon atom with the same number in the thromboxane or prostanoic acid.

The molecules of the known prostaglandins have several centers of asymmetry and can be in racemic (optically inactive) form or in one of two enantiomeric (optically active) forms, that is to say clockwise or counterclockwise. The TXB2, which, as already mentioned, can also be called lla-homo-lla-oxa-PGF2a, has similar centers of asymmetry and can therefore also occur in optically active or racemic form. The formula shown represents the special optically active form of the TXB2, which is obtained biosynthetically, e.g. after Samuelsson, Proc. Nat. Acad. Be. USA 71, 3400-3404 (1974). The mirror image of each of these formulas represents the other enantiomer of TXB2. The racemic form of TXB2 contains the same number of both enantiomeric molecules, and one of the formulas above and its mirror image is required to correctly represent the TXB2. For reasons of expediency, the following description, when using the designation thromboxane, “TX” or “TXB”, means the optically active form of the thromboxane-type compound in question, which has the same absolute configuration as TXB2 in Samuelsson biosynthetic production. If it is the racemic form of the thromboxane-like compound, the word «racemic» or the name «dl» is placed in front of the name, i.e. the overall name is e.g. dl-TXB2.

In the present description, an intermediate product of thromboxane synthesis or an intermediate product of thromboxane means any cyclopentane or tetrahydropyran derivative or acyclic compounds which are suitable for the preparation of the various skeletal or side chain analogues of the TXB2.

If a formula is used to represent a thromboxane intermediate, this formula denotes the stereoisomer of the thromboxane intermediate in question which is suitable for the preparation of the TXB analogue of the same relative stereochemical configuration as the biosynthetically produced TXB2.

In the present description, a thromboxane-like (TX-like) product is understood to mean the various tetrahy dropyran derivatives which can be used for at least one of the pharmacological purposes for which TXB2 is used.

The present formulas, which represent a thromboxane-like product, each represent the stereoisomer of the thromboxane-like product which has the same relative stereochemical configuration as TXB2 produced by biosynthesis.

A thromboxane analog is understood to mean that stereoisomer of a thromboxane-like product which has the same relative stereochemical configuration as biosynthetically produced TXB2, or a mixture of this stereoisomer and its enantiomer. Denotes a formula

633 006

thromboxane-like product, the term thromboxane analogue refers to the compound of this formula or a mixture of this compound and its enantiomer.

Because of the asymmetry at C-II of TXB2 and its various hemiacetal analogues, a hemiacetal structure on this carbon atom leads to the presence of two diastereomeric forms: the a-hydroxy and ß-hydroxy anomers. Due to the mutarotation involved in the conversion of TXB2 or its hemiacetal analogs to hydroxyaldehyde (e.g.

HO

c = c

HO

(CH2) 4-CH

/ \

c = c

CH,

C = C

C (CHs) 4-CH3

/ \

H OH

resulting, for example, in water or other solutions, the 11-hydroxyl group is present as an equilibrium mixture of a- and ß-hydroxyanomers, which is represented here by ~ OH.

In the formulas used here (e.g. Formula IV), which do not have a cyclopentane or tetrahydropyran ring because it has been split or undergoes subsequent reactions, the convention explained above for representing the substituents on asymmetry centers in the a or β position is followed, but in the With regard to the level of the various atoms that were present in the ring before its cleavage or will be present in the ring in subsequent stages after synthesis. For example, in Formula IV, the oxygen atom of the 12-hydroxy substituent that was or will be or will be the IIa oxa atom of the tetrahydropyran ring is considered to be planar with C-8 to C-II and C-12. The C-12 side chain is accordingly ß-permanent to this plane and is therefore indicated with a solid solid line, while the C-12 hydrogen atom is a-constant to this plane and is therefore indicated by a broken line.

Thromboxan B2 is known. This connection was developed by B. Samuelsson, Proc. Nat. Acad. Sci. U.S.A. 71,3400-3404 (1974) biosynthetically made from arachidonic acid. It was named by the author as 8- (l-hydroxy-3-oxopropyl) -9.12L-dihydroxy-5,10-heptadecadienoic acid hemiacetal or PHD.

TXB2 is e.g. Obtained biosynthetically from arachidonic acid using the cyclic oxygenase system that is responsible for the production of prostaglandins from arachidonic acid.

TXB2,15-epi-TXB2, their 1 liter (lower alkyl) acetals and pharmacologically acceptable salts have proven to be extremely effective in the generation of various biological reactions. For this reason, these compounds (hereinafter referred to as TXB2 compounds) have been considered useful for pharmacological purposes.

These biological reactions include:

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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(a) stimulation of the smooth muscles (proven by tests with guinea pig ileum, rabbit duodenum or colon of voles) and more specifically and in particular

(b) the influence on the reproductive organs of mammals in the form of contraceptives, abortions, cervical dilators, oestrus and menstrual cycle regulators.

Because of these reactions, these TXB2 compounds are useful for the study, prevention, control or control of undesirable physiological conditions in birds and mammals including humans, farm animals, domestic animals, zoological species and laboratory animals such as mice, rats, rabbits and monkeys to facilitate.

These TXB2 compounds, which are extremely effective smooth muscle stimulators, are also highly active in enhancing other known smooth muscle stimulators, such as oxytocin agents such as oxytocin and the various ergot alkaloids including their derivatives and analogs. These compounds are therefore useful, for example, instead of or together with less than the usual amounts of known stimulators, e.g. to relieve the symptoms of paralytic ileus or to fight or prevent atonic uterine bleeding after miscarriage or delivery, to reject the placenta as well as during the puerperium. For the latter purposes, the TXB2 compound is administered by intravenous infusion immediately after the miscarriage or childbirth at a dose of about 0.01 to about 50 (ig / kg body weight per minute until the desired effect is achieved. Subsequent doses are given during the Puerperium in an amount of 0.01 to 2 mg / kg body weight per day injected or infused intravenously, subcutaneously or intramuscularly, the exact dose depending on the age, weight and condition of the patient or animal.

The TXB2 compounds that can be used instead of oxytocin to induce labor are used in pregnant females such as cows, sheep and pigs, and in humans at or near the time of birth, or in the case of intrauterine death of the fetus from about 20 weeks before the time of birth. For this purpose, the compound is infused intravenously in a dose of 0.01 to 50 (ig / kg body weight per minute, until or almost until the end of the second stage of labor, ie the expulsion of the fetus. The compounds are particularly useful if have not started natural contractions one or more weeks after the birth, or 12 to 60 hours after the membrane has ruptured without the natural contractions having started, or oral administration is also possible.

The compounds are also useful for controlling the conception cycle in menstruating female mammals and humans. Menstruating female mammals are understood to mean those that are already mature enough to menstruate, but are not yet so old that regular menstruation has ceased. For the above purpose, the TXB2 compound is administered systemically in a dose of 0.01 to about 20 mg / kg of body weight, expediently during the period that begins approximately at the time of ovulation and ends approximately at the time of the menses or shortly before. Intravaginal and intrauterine administration are also possible. Furthermore, embryo or fetus ejection is caused by similar administration of the compound during the first or second third of normal gestation or pregnancy.

These compounds are also useful for producing cervical dilatation in pregnant and non-pregnant female mammals for gynecological and obstetric purposes. When caused by these connections

Cervical enlargement is also observed during labor and clinical abortion. In cases of infertility, the cervical enlargement caused by these connections serves to facilitate sperm movement to the 5 uterus. The cervical enlargement caused by the thromboxanes is also useful in surgical gynecology such as D and C (cervical dilation and uterine curettage), where mechanical dilatation can cause uterine perforation, cervical strain, or infection. It is also advantageous for diagnostic procedures that require an extension for tissue examination. For these purposes, the thromboxanes are administered locally or systemically.

TXB2 e.g. is administered orally or vaginally in doses of about 5 to 15 200 mg / treatment to an adult woman, with 1 to 5 treatments per 24 hours. The TXB2 can also be administered intramuscularly or subcutaneously in doses of approximately 1 to 25 mg / treatment. The exact amounts depend on the age, weight and condition of the patient or animal. 20 These compounds are also useful in farm animals as an abortion agent (especially in heifers intended for slaughter), as an aid for determining the heat and for regulating or synchronizing the heat. Farm animals include horses, cattle, sheep and pigs. The regulation or synchronization of the oestrus enables more effective control of conception and contractions and enables the herd owner to give birth to all female animals in short, predetermined periods. This leads to a higher percentage of live births than with a natural process. The TXB2 compound is injected or administered in feed in doses of 0.1 to 100 mg / animal / day and can be combined with other agents such as steroids. The dosage regimes depend on the animal species treated. For example, mares receive the TXB2 connections 5 to 8 35 days after ovulation and return to oestrus. Cattle are treated at regular intervals within a 3-week period, so that all animals become hot at the same time.

Some of the 11-oxaprostaglandin-40-like compounds described above are known, see BE-PS 830 423 (Derwent Farmdoc CPI No. 0197IX) and Tetrahedron Letters 43: 3715-3718 (1975).

The first process according to the invention for the preparation of the new compounds of the formula

45

50

55

CH2-Ii-COORi

Yi-C-R7

U

LXVI

in which the substituents are defined above is characterized in that

(1) a thromboxane intermediate of the formula

60

65 (R33CO2M

CHa-Zi-COORi

Yi-C-C-R7

• Ii I!

Mi Li

LXIV

633 006

wherein Rb Zb Yj, Lj and R7 have the meaning given above, R33 is an alkyl radical having 1-4 carbon atoms, hydrolyzes and

(2) from the reaction product of step (1) of the formula

CHa-Zi-COOR-j ^

or a mixture of this compound and its enantiomer, wherein R31, Z1; Rj, Yt, M3, L, and R7 have the meaning given above, oxidized with lead tetraacetate.

The reaction product of this step is then converted into the dialkylacetal to form a compound of the formula

R31 0

LXV

Yi-C-R7

IH

(R330) 2.HC

CH3COO

the rest R33 converted into hydrogen by dealkylation.

According to a further method according to the invention, new compounds of the formula

CHz-Z.i-CH20H

CH2-I'COORi

Ya-C-C-R7

II II

M3 Li

HO- ^ 0

wherein R31J R33, Z1; Rj, Y1; M3, Lx and R7 have the meaning given above.

The compounds obtained are then converted into the desired compounds of the following formula

HO

LXVII

Yi-C-C-Rv

II H

Mi Li

25 (R330) 2HC

CH2-Z1-COOR1

. HO-

(LXIV)

prepared in which the substituents have the meaning given above. These compounds are obtained according to the invention by first preparing compounds of the formula LXVI, as described above, and then reducing them to the primary alcohol.

The starting compounds of the formula LXIV used in the first process can be prepared as follows:

First, compounds of the formula R31 become 0

* Yi -C-C-R7

II II

Mi Li

30 transferred.

Another preferred variant for the preparation of the starting compounds of the formula LXTV used in the process according to the invention is based on a compound of the formula

35

OHC CH3COO

CMz ~ Zi-C00Ri

I.

: oo '^ vy1- (

40

• C-R,

Ma prepared in which R31 represents a hydroxyl-replacing group, Yx, Lb Rj, R7 and Zi are defined above and

M,

or

R <

OR

3 1

Yl-c c-r7 M3 Li or a mixture of this compound and its enantiomer-50 ren, wherein Zh Y1; M3, Lj and R7 have the meaning given above to oxidize with lead tetraacetate, a compound of the formula

55

0R3 1

means, where R5 is hydrogen or methyl and R31 is a hydroxyl-hydrogen-replacing group by using a compound of the formula

CH2-Z1-COOR1

v, Tr ^

M3 LI

0H CH3COO '

65 arises, where Zu Y1; M3, Lj and R7 have the meaning given above. This compound is then converted to the dialkyl acetal to form a thromboxane intermediate of the formula

633 006

8th

M3 Li where ZI; R33, Y1? M3, Lx and R7 have the meaning given above.

This compound is then converted into the desired starting compound of the formula

HO

CH2-Z.1-COOH

HO

Yi-C-C-R

Mi Li wherein Zj, Yb Ml5 Lls R7 and R33 have the meaning given above.

The novel thromboxane analogs which can be prepared according to the invention and in which Yj denotes -CH2CH2- are referred to as 13,14-dihydro compounds.

If R7 denotes the radical - (CH2) m-CH3, then it is «19.20-dinor», «20-nor», or «20-methyl». “20-ethyl” compounds if m is the number 1,2,4 or 5 is.

If R7 means the remainder, there are «16-phenyl-17,18,19,20-tetranor» compounds if s means 0. If s is the number 1, 2 or 3, the compounds are referred to as “16- (substituted phenyl) -17,18,19,20-tetranor” compounds.

R7 means a remainder

(T) s are «17-phenyl-18,19,20-trinor» compounds if s is 0. If s is the number 1, 2 or 3, there are again «17- (substitutedphenyl) -18,19,20-trinor» compounds.

If R7 means the rest, the compounds are «18-phenyl-19,20-dinor» when s is 0. If s is the number 1, 2 or 3, then there are “18- (substituted phenyl) -19,20-dinor” compounds. If R7 means a radical, there are “19-phenyl-20-nor” compounds if s is the number 0. If s is the number 1, 2 or 3, these are "19- (substitutedphenyl) -20-nor" compounds.

R7 means a remainder

- 0

where neither R3 nor R4 are methyl, these are "16-phenoxy-17,18,19,20-tetranor" compounds if s is 0. If s denotes the number 1, 2 or 3, the compounds are referred to as “16- (substituted phenoxy) -17,18,19,20-tetranor” compounds. If one of the radicals R3 or R4 is methyl or both radicals R3 and R4 are methyl groups, the compounds having the above radical R7 are “16-phenoxy- or 16- (substituted-phenoxy) -18,19,20-trinor” compounds or "16-methyl-16-phenoxy or -16- (substituted phenoxy) -18, 19,20-trinor" compounds.

If at least one of the radicals R3 and R4 is not hydrogen, it is (apart from the 16-phenoxy compounds above) 16-methyl- (a radical R3 or R4 means methyl), 16,16-dimethyl- (both radicals R3 and R4 are methyl), 16-fluorine (one of R3 or R4 is fluorine) and 16,16-difluoro (both R3 and R4 are fluorine) compounds. Those compounds in which R3 and R4 are different from one another contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible, namely «(16S)» and «(16R)». The invention also relates to the C-16 epimeric mixtures “(16RS)”.

If R5 is methyl, the compounds are referred to as 15-methyl compounds. If R33 is an alkyl radical, then it is a matter of TXB-like IIa or IIß-alkyl acetals or, preferably, in the form already used, "11-deoxy-11a or IIß-alkoxy-TXB" compounds.

According to the invention, compounds with both epimeric configurations of the hydroxyl group at C-15 can be obtained. As previously mentioned, the biosynthetically produced TXB2 am has the C-15 S configuration. According to the present presentation, the 15-hydroxyl group in the biosynthetically obtained TXB2 is in the a configuration. According to the present agreement on the presentation of the thromboxane analogs, the 15-epi-TXB2 has the 15-hydroxyl group in the β configuration. Those new thromboxane analogs in which the 15-hydroxyl group has the same absolute configuration as 15-epi-TXB2 at C-15 are thus referred to as 15-epi compounds. If the term "15-epi" is missing, the compounds in question have the same configuration of the 15-hydroxyl group as TXB2, that is to say 15a configuration.

The novel thromboxane analogs which can be prepared according to the invention are thus named after the system of Nelson, N.A., J. Med. Chem. 17,911 (1974).

Examples of alkyl radicals with 1 to 12 carbon atoms are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl radical and their isomeric forms .

Examples of cycloalkyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl radicals, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclo-butyl, 2-methylcyclobutyl -, 3-Propylcyclobutyl-, 2,3,4-tri-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

ethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cyclohept -, Cyclooctyl-, Cyclononyl- and Cyclo-decylrest.

Examples of aralkyl radicals having 7 to 12 carbon atoms are benzyl, 2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (l-naphthylethyl) - and 1 - (2-Naphthylethyl) rest.

Examples of phenyl radicals substituted by 1 to 3 chlorine atoms or alkyl radicals having 1 to 4 carbon atoms are the p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyi, m -Tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl.

Examples of residues of the formula

JT) S

wherein T represents an alkyl radical with 1 to 3 carbon atoms, fluorine, chlorine, the trifluoromethyl radical or an alkoxy radical with 1 to 3 carbon atoms and s represents the number 0, 1, 2 or 3, with the proviso that no more than two radicals T of alkyl are different, the phenyl, (o-, m- or p-) tolyl-, (o-, m- or p-) - ethylphenyl-, 2-ethyl-p-tolyl-, 4-ethyl-o- tolyl-, 5-ethyl-m-tolyl-, (o-, m- or p-) propylphenyl-, 2-propyl- (o-, m- or p-) tolyl-, 4-isopropyl-2,6- xylyl-, 3-propyl-4-ethylphenyl-, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5) -trimethylphenyl-, (o-, m- or p-) fluorophenyl-, 2-fluoro- (o-, m- or p-) tolyl-, 4-fluoro-2,5-xylyl-, (2,4-, 2,5-, 2, 6-, 3,4- or 3,5-) difluorophenyl, (o-, m- or p-) - chlorophenyl-, 2-chloro-p-tolyl-, (3-, 4-, 5-or 6-) Chloro-o-tolyl-, 4-chloro-2-propyl-phenyl-, 2-isopropyl-4-chlorophenyl-, 4-chloro-3,5-xylyl-, (2,3-, 2,4 -, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyl-, 4-chloro-3-fluorophenyl-, (3- or 4-) chloro-2-fluorophenyl-, o- , m- or p-trifluoromethylphenyl, (o-, m- or p-) methoxyphenyl-, (o-, m- or p-) ethoxyphenyl-, (4- or 5-) chloro-2-methoxyphenyl- and 2,4-dichloro (5- or 6-) methylphenyl residue.

The new thromboxane analogs obtained according to the invention correspond to the TXB compounds described above in that they have a TXB2-like effect.

In particular, the TXB analogs disclosed herein correspond to the TXB2 described above in that these analogs are useful for the same purposes as TXB2 and can be used in the same manner as this.

TXB2 causes biological reactions, even in low doses. In the above applications, however, TXB2 has an uncomfortably short duration of biological activity. In contrast, the new thromboxane analogs according to the invention are much more selective in causing TXB2-like biological reactions, and they also have a considerably longer duration of action. Each of these new thromboxane analogs is therefore surprisingly more useful than the latter for at least one of the pharmacological purposes specified for TXB2, since it has a different and narrower spectrum of bilogical action and is therefore more specific in its action and has fewer and less undesirable side effects than TXB2 generated when used for the same purpose. Because of the longer duration of action, fewer and smaller doses of the new thromboxane analogs are often used to achieve the desired result.

Another advantage of the new thromboxane analogs mentioned and in particular the below named vor633 006

Preferred TXB analogs are that these analogs can be successfully administered orally, sublingually, intravaginally, buccally or rectally. These routes of administration are advantageous because they allow the levels of the compounds in the body to be maintained at lower, shorter or smaller doses and allow self-administration by the patient.

The new thromboxane analogs produced according to the invention can thus be administered for different purposes in different ways, e.g. intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically and in the form of sterile implants for longer lasting effects. Sterile aqueous isotonic solutions are preferred for intravenous injection or infusion. For subcutaneous or intramuscular injection, e.g. sterile solutions or suspensions of acid, a salt or ester used in aqueous or non-aqueous media. Tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions with common pharmaceutical carriers can be used for oral and sublingual administration. Suppositories can be prepared in a known manner for rectal or vaginal administration. For tissue implants, e.g. a sterile tablet or silicone rubber capsule or other form that contains or is impregnated with the active substance.

The new TXB analogs obtained according to the invention can be used for the above purposes as primary alcohols or in the form of the free acid, in the form of esters or as pharmacologically acceptable salts. When using esters, the ester residue is preferably within the definition of Rj. However, preference is given to alkyl esters having 1 to 12 carbon atoms, and in particular the methyl and ethyl esters because of the optimal absorption of the corresponding compounds by the body or the animal system. Straight chain octyl, nonyl, decyl, undecyl and dodecyl esters are preferred because of their prolonged action in the body.

Pharmacologically acceptable salts of the thromboxane analogs obtained according to the invention, which are useful for the above purposes, are especially salts with pharmacologically acceptable metal cations, ammonium, amine or quaternary ammonium cations.

Particularly preferred metal cations are those of the alkali metals, e.g. Lithium, sodium and potassium, and the alkaline earth metals, e.g. Magnesium and calcium, although the cationic forms of other metals such as aluminum, zinc and iron fall within the scope of the invention.

Pharmacologically acceptable amine cations are derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine , Ethylenediamine, di-ethylenetriamine and similar aliphatic, cycloaliphatic and araliphatic amines with up to about 18 carbon atoms, furthermore heterocyclic amines, for example Piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl-substituted derivatives such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, as well as water-solubilizing or hydrophilic Group-containing amines such as mono-, di- and tri-ethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1, 3-propanediol, 2-amino-2- methyl-l-propanol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amylphenyl) -diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like. Wei9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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10th

Other useful amine salts are the basic amino acid salts, e.g. with lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium ion and the like.

In view of an optimal combination of biological specificity, potency and duration of action, certain new compounds are preferred.

G is preferably the number 1 or 3 and in particular the number 1, that is to say corresponding to the natural chain length of TXB2. If the other side chain consists of a residue - (CH2) m-CH3, m is preferably the number 3.

In the compounds in which R7

(T).

or

(T) <

- (CH2)

//

(T)

//

or

(CHa) -

(T),

the corresponding subgroups of TXB analogs with a different tetrahydropyran ring structure also apply as equally preferred embodiments of the invention.

The following scheme describes procedures by which the new thromboxane analogs are made; This scheme also includes the preparation of starting compounds of the formula LXIV.

10th

Scheme I

means, s and 1 are preferably 0 or 1, while T represents chlorine, fluorine or the trifluoromethyl radical.

In the compounds in which at least one of the radicals R3 or R4 consists of methyl or fluorine, Rs is preferably hydrogen. In the compounds in which R5 is the methyl group, R3 and R4 are preferably both hydrogen atoms. In the compounds in which R7

35

40

^ 3 1 0,

HO

CH2-Z1-COOR1

Y1-C-C-R7

H H

M3 Li

LXI

R31 0

CHa-Zi-C00Ri

CHsCOOr ^ yj-c-C-Rt II H

M3 Li

LXII

R3, R4, Rs and R6 are preferably all hydrogen atoms.

Furthermore, the 15-hydroxyl group is preferably not in the epi configuration, i.e. it is in the configuration if you draw the formulas as shown.

Compounds which correspond to two or more of the above preferences are particularly preferred. These preferences describe preferred compounds within each general formula of new thromboxane analogs.

With regard to the preferences, it should also be mentioned that the various thromboxane-tetrahy-dropyran ring structures used here (for example hemiacetals and IIa or IIβ-alkyl acetals) each represent a special “parent structure” which is helpful in the naming and classification of the thromboxane analogs . If a formula reproduces a genus of TXB analogs according to the invention with a certain tetrahydropyran ring structure, then the other genera of TXB analogs with one of the remaining tetrahydropyran ring structures described here are likewise preferred classes of compounds. For example, for each genus of TXB-like products according to a formula, the corresponding ll-deoxy-llla-methoxy-TXB2-like products are preferred to the same extent as the TXB-like products.

If a subset of TXB analogs with any tetrahydropyran ring structure is described as preferred, then

50

55

60

(R330) aH

CH3COO

65

(R

CHa-Zi-COORi

• C— C-R?

II H

M3 LI

LXIII

V

33

H0- \.

• COORj

Y1.-C-C-RT

I! II

Mi Li

LXIV

11

633 006

Scheme I (continued)

HO

R33 o 0

HO

\ y

CH2-Z1-C00R1

Yl "fi ^

Mi Li

LXV

CH2-ZI-CH20H

Y 1 "C C ~ Ry

I! H

Mi Li

LXVI

CH2-Zi-C00H

Yi ~ C-C-Ry

II II

Mi Li

LXVII

The reaction scheme shows a process for the preparation of various TXB2 analogs from the compound LXI. The scheme provides a preferred method of making compounds in which Yx is trans-CH = CH-.

Preferred embodiments are described below:

According to the scheme, the compound of the formula LXI is converted into the aldehyde LXII by reaction with lead tetraacetate in benzene. The reaction is rapid at temperatures of about 40 to 60 ° C and is usually complete in about 45 minutes to 2 hours. The resulting product of the formula LXII has a limited shelf life and is therefore converted into the acetal LXIII without further purification.

The dialkylacetal LXIII is prepared by known methods for the preparation of acetals from aldehydes, e.g. by reaction with an alkanol in the presence of an orthoalkane carboxylic acid trialkyl ester and catalytic amounts of acid, compare the appendix. If R33 is the methyl group, this reaction is carried out by treating the compound LXII with methanol, methyl orthoformate and pyridine hydrochloride. The pure product of formula LXIII is isolated in a conventional manner, e.g. by chromatography.

5 The compound of formula LXIV is prepared from compound LXIII by removing the diacyl or bis ether groups using the methods described above. Means e.g. R31 is an acyl radical, so sodium methylate in methanol is used in a stoichiometric amount, where the trihydroxyacetal LXIV is obtained. When using aqueous methanolic sodium hydroxide solution, both acyl protecting groups and the Rx ester group are removed.

The compound of formula LXV is then prepared according to the invention from compound LXIV by hydrolysis of the acetal-15 group, using known methods for the hydrolysis of tetrahydropyranyl ethers (i.e. acetic acid, water and tetrahydrofuran) and the product LXV is obtained. Stricter hydrolysis conditions lead directly to the product of the formula LXVI, in which R6 is hydrogen.

In the reactions of the reaction scheme, the use of C1-esters, in particular the lower alkyl esters, is preferred.

In the reactions of the above scheme, diastereomeric mixtures other than anomeric mixtures can be isolated immediately and separated in a conventional manner, e.g. by chromatography.

Optically active TXB analogs and related products can be obtained from optically active intermediates according to the process steps of the above schemes. Racemic 30 TXB2 analogs are e.g. obtained from the corresponding racemic TXB2 intermediates, that is, from racemic intermediates, racemic products are obtained in the above reactions.

In all of the reactions 35 described above, the products can be freed of starting material and contaminants in a conventional manner. For example, the products of the various process stages are freed from the corresponding starting materials and 40 impurities by means of silica gel chromatography, which is monitored by thin-layer chromatography.

As already mentioned, the above processes lead differently to primary alcohols, acids (R! = Hydrogen) or esters.

Was e.g. If an alkyl ester is obtained while an acid is being sought, known saponification processes can be used for PGF-like compounds. If appropriate, free acids are also produced by enzymatic processes for converting PGE esters or their acids. Here, e.g. the TXB-like methyl ester combined with enzyme powder and hydrolyzed, see US Pat. No. 3,761,356.

If an acid has been obtained while aiming for an alkyl, cycloalkyl or aralkyl ester, e.g. the esterification expediently by reacting the acid with the corresponding diazo hydrocarbon. For the production of the methyl 55 esters e.g. Diazomethane used. With diazoethane, di-azobutane, l-diazo-2-ethylhexane or diazodecane, the ethyl, butyl, 2-ethylhexyl and decyl esters are obtained. The cyclohexyl and benzyl esters can be obtained analogously with diazocyclohexane and phenyldiazomethane.

The esterification with diazo hydrocarbons is preferably carried out by reacting a solution of the diazo hydrocarbon in a suitable inert solvent, preferably in diethyl ether, with the acid, which is expediently present in the same or a different inert diluent. After the esterification has ended, the solvent is usually evaporated off and the ester is optionally purified in a conventional manner, preferably by chromatography. The contact between acid and diacoal

45

50

60

65

633 006 12

Hydrogen should no longer be used as the ester analyzer, but also as a convenient solvent. Further tion required, preferably about 1 to about 10 mi. Examples of suitable tertiary amines are N-methylmorphonutes in order to avoid undesired molecular changes. lin, triethylamine, diisopropylethylamine and dimethylaniline. Diazo hydrocarbons are known or can also be used after known 2-methylpyridine and quinoline, and known methods can be prepared, see e.g. Organic Reac- 5, however, leads to a slow reaction. For example, a heavily hindered ion, John Wiley and Sons, Inc., New York, N.Y. Vol. 8, S. Amin, such as 2,6-dimethyllutidine, is not useful 389-394 (1954). because of the slow reaction rate.

Another preferred process for the preparation of Al- The reaction with the anhydride usually takes place kyl, cycloalkyl or aralkyl esters consists in the conversion smooth at room temperature (about 20 to 30 ° C) and can in the conation of the free acid into the corresponding silver salt, which is then conventionally followed by thin-layer chromatography with an alkyl iodide. Examples will be suitable.

Iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide. The reaction mixture can be worked up by using tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide methods, then the ester is usually used, phenethyl iodide and the like. The silver salts are cleaned, e.g. by silica gel chromatography.

made by conventional methods, e.g. by dissolving the solid esters by crystallization from numerous acids in cold, dilute aqueous ammonia, excess solvents such as ethyl acetate, tetrahydrofuran, methanol, excess ammonia are removed under reduced pressure and and acetone or by cooling or concentrating a saturated - then the stoichiometric amount of silver nitrate adds. th solution of the ester in the solvent or by adding a

For the production of phenyl- or substituted phenyl-miscible non-solvents such as diethyl ether, hexane or esters from corresponding aromatic alcohols and the 2 <> water are converted into free-flowing crystalline form. The free TXB acids are available in various methods.Crystals are generally used in a conventional manner, which collects in terms of yield and product purity, e.g. by filtering or centrifuging, distinguish little from each other. Washed solvent and dried under reduced pressure

According to one method, the TXB connection can be in a net. One can also be placed in a warm nitrogen or argon tertiary amine salt which flows with pivaloyl halide 25 or dry by heating to about 75 ° C. This is converted to the mixed anhydride, which in turn is usually reacted with crystals for numerous applications with sufficient aromatic alcohol. Instead of pure, but they can be recrystallized in the same way from pivaloyl halide, one can also become an alkyl or aryl, the purity increasing with each recrystallization, use suifonyl halide, e.g. p-Toluenesulfonylchloride (see- According to the present methods in the form of the free acid, BE-PSS 775 106 and 776 294, Derwent Farmdoc No. 30, new compounds can be obtained by neutralizing with 33705T and 39011T). suitable amounts of the corresponding inorganic or organic

A further preferred method consists in converting the bases into pharmacologically acceptable salts of the coupling agent dicyclohexylcarbodiimide, compare. The conversions take place e.g. according to various Fieser et al., "Reagents for Organic Synthesis", pp. 231-236, known processes for the preparation of inorganic, the John Wiley and Sons, Inc., New York, (1967). The TXB-like 35 is called metal or ammonium salts. The choice of the process compound with 1 to 10 molar equivalents of the aro- depends in part on the solubility properties of the alcohol to be prepared in the presence of 2 to 10 molar equivalents of the salt. In the case of inorganic salts, it is usually advisable to use dicyclohexylcarbodiimide in pyridine as solvent, to add the acid obtained according to the invention to water. which is the stoichiometric amount of a hydroxide,

A preferred new process for the production of these 40 carbonates or bicarbonates according to the desired ester, however, consists of the following stages: Salt contains. With sodium hydroxide, sodium carbonate or sodium

(a) Formation of a mixed anhydride from the TXB verium bicarbonate gives a solution of the bond and isobutyl chloroformate in the presence of an sodium salt. On evaporation of the water or addition of a tertiary amine and water-miscible solvent of moderate polarity, such as

(b) reacting the anhydride with the corresponding aro- 45 e.g. a lower alkanol or a lower alkanone, matical alcohol. the solid inorganic salt can be obtained.

The above-mentioned mixed anhydride is easy to produce an amine salt, the inventive

at temperatures in the range from - 40 to + 60 ° C and pre-made acid in a suitable solvent, preferably from - 10 to +10 ° C, at which the reaction mixture or low polarity are dissolved. Examples of first-speed is sufficiently high, side reactions still 50 re are ethanol, acetone and ethyl acetate, for which the latter are kept diethyl-minimal. The chloroformic acid isoether and benzene. Then at least one sto-butyl ester is preferably added to the solution, preferably in excess, for example of a chiometric amount of the amine which corresponds to the desired cation, corresponding to 1.2-4.0 molar equivalents per mol of the TXB compound. Falls the resulting sets. The reaction preferably does not take place in a solution salt, so it usually becomes with the addition of a mixing agent, in particular in acetone, although other relatively 55 bar diluents of low polarity or in the case of a non-polar solvent such as acetonitrile, methylene chloride or steamed in solid Get shape. If the amine is relatively volatile, chloroform can be used. The reaction in excess can be easily removed by evaporation. Presence of a tertiary amine, e.g. Triethylamine, executed In the case of less volatile amines, use is preferred, and the amine hydrochloride formed at the same time is in critical-stoichiometric amounts.

usually removes, but must not be removed before the next process. 60 salts with quaternary ammonium cations cannot be removed. be made by the acid obtained according to the invention

The aromatic alcohol is preferably mixed in an equivalent solution to the stoichiometric amount of the quaternary amount in question or in a substantial stoichiometric excess of ammonium hydroxide in aqueous solution and used to ensure that the entire mixture subsequently evaporates off the water.

hydride is converted into the ester. Excess aromatic 65 In the following examples, the infrared absorber alcohol is e.g. according to the present description or ion spectra with an infrared spectrophotometer Perkin-known methods, e.g. by crystallizing. Elmer model 421 or 137 added. Unless otherwise stated The tertiary amine is not only used as a basic esterification catalyst, undiluted samples were used. The ultra

13

633 006

violet spectra were recorded on a Cary Model 15 spectrophotometer. The nuclear magnetic resonance spectra were recorded with a Varian A-60, A-60D or T-60 spectrophotometer in Deutorochloroform solution with tetramethylsilane as the internal standard (downfield). The mass spectra were recorded with a double-focusing high-resolution mass spectrometer CEC Model 21-110B or a gas chromatograph / mass spectrometer LKB Model 9000; unless otherwise stated, the trimethylsilyl derivatives were used.

The solvent system A-IX used in thin layer chromatography consisted of ethyl acetate / acetic acid / cyclohexane / water 90: 20: 50: 100, see M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966). Skellysolve B is a mixture of isomeric hexanes.

A silica gel chromatography is understood to mean elution, collecting the fractions and combining those fractions which, according to thin-layer chromatography, contain the pure product free of starting material and impurities.

The melting points were carried out with a Fisher-Johns or Thomas Hoover melting point apparatus.

Preparation 1

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19, 20-heptanor-PGFla (Rj, R3, and R4 from Lx and R5 from Mj = hydrogen , Z3 = oxa, Yx = trans-CH = CH-, g = 1, R7 = phenoxy).

A. 1 g of 3,7-inter-m-phenylene-4,5,6-trinor-PGF10-methyl ester in 200 ml of methanol is cooled to 0 ° C. in an ice bath. An ozone stream produced in a conventional ozone generator is passed through the mixture until the starting material is completely consumed. The resulting ozonide is treated with dimethyl sulfide with stirring, after which the mixture is allowed to warm to room temperature. Then the mixture is washed and concentrated, the residue is chromatographed to give the corresponding aldehyde. 4 g of benzoyl chloride are added dropwise to about 4.5 g of the aldehyde and 20 ml of pyridine, and the resulting mixture is stirred at 25 ° C. for about 24 hours. The reaction mixture is then cooled to 0 ° C. and 5 ml of water are added with stirring over the course of 10 minutes. The resulting mixture is extracted with diethyl ether, the ether phase is washed with sodium bisulfate solution, sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the corresponding dibenzoate.

B. When using 2-oxo-3-phenoxypropylphosphonic acid dimethyl ester instead of the 2-oxo-heptylphosphonic acid di-methyl ester, the corresponding product.

C. The reaction product is then reduced accordingly.

D. The reaction product according to Part C is in a solution of 2% potassium bicarbonate in methanol for 24 hours

- Stirred at 25 ° C. The resulting mixture is acidified to pH 4 or 5 with sodium bisulfate and concentrated to dryness, the residue is extracted with ethyl acetate and the ethyl acetate extracts are washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture is concentrated in vacuo, the residue is subjected to silica gel thin layer chromatography to give the title compound as a free acid.

Preparation 2

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18, 19,20-heptanor-PGFla-9,15-diacetate (Rj and R3 and R4 of

Lj = hydrogen, Zj =

"0" *

CH;

R31 = benzoyl, Yx = trans-CH = CH-, Rs of M3 = methyl, R7 = phenoxy, R31 of M3 = benzoyl).

A. A solution of 800 mg of the reaction product according to preparation 1 and 250 mg of 1-butane boronic acid in 25 ml of methylene chloride is heated under reflux. After 15 minutes, the methylene chloride is slowly distilled off. Fresh methylene chloride is added each time the volume has decreased to about half of the initial volume.

15 After 90 minutes, all methylene chloride is removed under reduced pressure to give the cyclic boronate.

B. 2 ml of acetic anhydride are added to a solution of 0.8 g of the reaction product according to Part A in 5 ml of pyridine. The mixture is stirred for about 4 hours in a nitrogen atmosphere.

20 stirred and then mixed with 50 ml of water, whereupon the mixture was stirred for a further hour. The resulting mixture is then extracted with ethyl acetate, the combined organic extracts are washed, dried and concentrated to give the corresponding 15-acetate.

25 C. The reaction product according to Part B is dissolved in methanol and water (2: 1) and mixed with a 30% methanolic hydrogen peroxide solution (about 4 equivalents per equivalent of cyclic boronate). The reaction mixture is kept under stirring at room temperature until the silica gel thin layer chromatography shows the complete hydrolysis of the boronate ester.

D. A solution of 0.60 g of the reaction product according to Part C in 70 ml of dry acetone is cooled to −20 ° C., then 2.8 ml of trimethylsilyldiethylamine are added. After 35 30 minutes, a further 2.8 ml of trimethylsilyldiethylamine are added. After 1 hour the reaction mixture is cooled to -70 ° C. and 150 ml of cooled (-70 ° C.) diethyl ether are added. This mixture is then poured into 100 ml of ice-cold saturated sodium bicarbonate solution and extracted three times with diethyl ether. The combined ether extracts are washed with ice-cold saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give the 11-silylated compound.

45 E. According to Part B, the reaction product according to Part E is acylated at C-9, giving the corresponding compound.

F. This compound is then dissolved in 25 ml of tetrahydrofuran and a solution of tetra-n-butylammoniumfluoro-50 rid in tetrahydrofuran is added. This reaction mixture is stirred at 65 ° C. for 2 hours and then cooled to room temperature. The resulting mixture is concentrated under reduced pressure, the residue is diluted with saturated sodium chloride solution and extracted with ethyl acetate. 55 The organic extract is washed with 2 M aqueous potassium bisulfate solution and saturated sodium chloride solution and dried over magnesium sulfate. Concentration under reduced pressure gives the title compound.

60

65

Preparation 3

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18, 19,20-heptanor-15-acetate-l, 9-lactone

(Zi =

633 006

14

Yj = trans-CH = CH-, M3 =

h oc-

CH- ^

R3 and R4 from L! = Hydrogen, R7 = phenoxy).

A. 35 mg 3,7-inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGFla-15-acetate (see preparation 2, part C), 39 mg triphenylphosphine and 33 mg of 2,2'-dipyridyl disulfide in 0.5 ml of dry oxygen-free benzene are stirred at room temperature for 18 hours, then the mixture is diluted with 25 ml of benzene and refluxed for 24 hours. The pure product is isolated from the reaction mixture by silica gel chromatography.

According to the methods of preparations 2 and 3, the various PGFa-like compounds of the formula XL are converted into PGFa-9,15-diacylate L or PGFa-15-acylate-1,9-lactone LXIX according to scheme B.

example 1

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18, 19,20-heptanor-TXB methyl ester (formula LXVI: Rt = methyl, Zj =

-0-0-CH,

R6 = hydrogen, Y1 = trans-CH = CH-, R3 and R4 of Li and R5 of Mj = hydrogen, R7 = phenoxy).

(Compare scheme).

A. A solution of 800 mg of 3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-tetranor-PGFla-methyl ester-9,15-diacetate in 32 ml of dry benzene, 1.21 g of lead tetraacetate (recrystallized from acetic acid and dried under reduced pressure over potassium hydroxide) are added at 50 ° C. in a nitrogen atmosphere. The reaction conditions are maintained for about 70 minutes, then the reaction mixture is filtered through Celite and the filtrate is washed with saturated sodium chloride solution. The filtration is repeated and the second filtrate is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure and room temperature, the {m-2 - [(1 'S) -3' -oxo-1 '-hydroxypropyl] - (2S, 3R, 6R) -3,6-dihydroxy-

7-phenoxy-trans-4-heptenphenoxy} acetic acid methyl ester-3,6, l'-triacetate of the formula LXII.

B. The crude reaction product according to Part A is dissolved in 16 ml of dry methanol, 2.5 ml of trimethyl orthoformate and 175 mg of pyridine hydrochloride and the mixture is stirred for about 60 hours at room temperature in a nitrogen atmosphere. Then about 30 ml of dry benzene are added and the methanol is expelled by concentration under reduced pressure. The benzene-containing solution is washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated to a residue. This is chromatographed on silica gel while eluting with 50 to 75% ethyl acetate in hexane. The fractions containing the pure dimethyl acetal of the reaction product from Part A are combined to give the thromboxane intermediate of formula LXIII.

C. A solution of 110 mg sodium and 10 ml dry methanol is prepared in a nitrogen atmosphere, then a solution of 420 mg of the reaction product according to Part B in 5 ml dry methanol is added. The resulting mixture is stirred for 1/2 hour at room temperature, then mixed with 0.5 ml of acetic acid and then with benzene. The methanol is virtually completely removed by concentration under reduced pressure and the resulting benzene-containing solution is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to a crude product which is chromatographed on silica gel while eluting with 2% methanol in ethyl acetate. Fractions are obtained from pure (m-5 2 - [(l'S) -3'-oxo-l'-hydroxypropyl] - (2S, 3R, 6R) -3,6-dihydr-oxy-7-phenoxy-trans-4 -heptenphenoxy} -acetic acid-methyl-ester-dimethylacetal.

D. A mixture of 187 mg of the reaction product according to Part C is treated in a nitrogen atmosphere with a mixture of 4 ml of acetic acid, 2 ml of water and 1 ml of tetrahydrofuran for about 4 hours. The resulting mixture is then stirred in vacuo at room temperature for about 1 hour and then freeze-dried. The residue is chromatographed on silica gel while eluting with 1% methanol in ethyl 15-acetate, giving the 3,7-inter-m-phenylene-3-oxy-16-phenoxy-4,5,6,17,18, 19,20-heptanor-ll-deoxy-lla- and 1 lß-methoxy-TXB-methyl ester and 3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20- heptanor TXB1 methyl ester.

E. A solution of 300 mg of the reaction product according to 20 part B in 5 ml of dry methanol is in a nitrogen atmosphere.

re treated at room temperature with 10 ml sodium methylate solution (120 mg sodium dissolved in 10 ml methanol) for 45 minutes. Then 6 ml of water are added and the mixture is stirred for a further 135 minutes in order to hydrolyze the methyl ester. So-25 then added 2.5 ml of 85% phosphoric acid in water, whereupon a part of the methanol is removed under reduced pressure. The aqueous residue is extracted with ethyl acetate, the extracts are dried over sodium sulfate and concentrated, giving a residue from the free acid 30 of the formula LXV.

F. The residue according to Part E is dissolved in 12 ml of tetrahydrofuran and treated at room temperature for 4 to about 35 hours with 9 ml of water and 1 ml of 85% phosphoric acid. Then the mixture is saturated with sodium chloride and with

35 ethyl acetate extracted. The ethyl acetate extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated, the residue is chromatographed on silica gel, the compounds 11-deoxy-llla-and-llß-methoxy-3,7-inter-m-phenylene-3-oxa -16-phenoxy-40 4,5,6,17,18,19,20-tetranor-TXBi and 3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17, 18,19,20-tetranor-TXB1 receives.

Example 2

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19, 45 20-heptanor-TXBj methyl ester.

(Compare scheme, part I and II).

A. The reaction product according to preparation 3 is converted into the reaction product of example 1, part C in solution according to the instructions of example 1, parts A, B and C.

50 B. The title compound is formed according to the procedure of Example 1, Part D, E and F.

55

Example 3

2-decarboxy-2-hydroxymethyI-TXB2 (formula LXVII: Zj = cis-CH = CH- (CH2) 3-, Yt = trans-CH = CH-, R5 from M1; R3 and R5 from Lx and R6 = hydrogen, R7 = n-butyl).

750 mg ll-deoxy-lla-methoxy-TXB2 methyl ester, dissolved in 50 ml diethyl ether, are reacted with 500 mg lithium aluminum hydride at room temperature with stirring. As soon as the starting material has been completely used up (determined by thin layer chromatography), 1 ml of water is carefully added. Then 0.8 ml of 10% aqueous sodium hydroxide solution is added and the resulting mixture is stirred for 12 hours. Then magnesium sulfate is added with stirring, the mixture is filtered through magnesium sulfate and concentrated to a residue which contains pure 2-decarboxy-2-hydroxymethyl-11-deoxy-l la-methoxy-TXB2.

65

15

633 006

According to a known method, the above reaction product is converted into the title compound.

If the procedure of Example 3 is repeated, but with the various 11-deoxy-11a or -1β-methoxy-TXB or TXB-like compounds described above, the corresponding 2-decarboxy-2-hydroxymethyl is obtained -11-deoxy-l la- or -1 lß-methoxy-TXB or TXB-like products.

If the processes of Examples 1 or 2 are repeated, but using the corresponding PGF2a-like compounds instead of the starting material used there, the compounds 11-deoxy-l la-methoxy- or -1 lß-methoxy-TXB!

TXBb 13,14-dihydro-l 1-deoxy-l la-methoxy- or-1 lß-methoxy-TXB j,

13,14-dihydro-TXBj,

11-deoxy-l la-methoxy or -1 lß-methoxy-TXB2, 13,14-dihydro-TXB2

or their 15-epimers and the methyl esters thereof.

If the procedure of Example 1 is repeated, but with one of the PGFa starting materials described above, the 11-deoxy-l la-methoxy-TXB2-, 11-deoxy-l lß-methoxy-TXB2-, 11- Deoxy-l la-methoxy-TXBr, 11-deoxy-l 1 ß-methoxy-TXBr, TXB2- or TXBr-like compounds in the form of the free acid, the methyl ester or 15-epimers, which have the following structural characteristics:

16-methyl,

16,16-dimethyl,

16-fluorine,

16,16-difluoro,

17-phenyl-18,19,20-trinor-,

17- (m-trifluoromethylphenyl) -18,19,20-trinor-, 17- (m-chlorophenyl) -18,19,20-trinor-, 17- (p-fluorophenyl) -18,19,20-trinor- , 16-methyl-17-phenyl-18,19,20-trinor-, 16,16-dimethyl-17-phenyl-18,19,20-trinor-, 16-fluoro-17-phenyl-18,19,20 -trinor-, 16,16-difluoro-17-phenyl-18,19,20-trinor-, 16-phenoxy-17,18,19,20-tetranor-, 16- (m-trifluoromethylphenoxy) -17.18, 19,20-tetranor-, 16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 16- (p-fluorophenoxy) -17,18,19,20-tetranor-,

16-phenoxy-l 8,19,20-trinor-, 16-methyl-16-phenoxy-18,19,20-trinor-,

15,16-dimethyl,

15,16,16-trimethyl-,

16-fluoro-15-methyl,

16,16-difluoro-15-methyl-,

17-phenyl-18,19,20-trinor-15-methyl-, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-15-methyl-, 17- (m-chlorophenyl) -18.19, 20-trinor-15-methyl-, 17- (p-fluorophenyl) -18,19,20-trinor-15-methyl-, 16-methyl-17-phenyl-18,19,20-trinor-15-methyl- ,

15,16,16-trimethyl-17-phenyl-18,19,20-trinor-, 16-fluoro-17-phenyl-18,19,20-trinor-15-methyl-, 16,16-difluoro-17- phenyl-18,19,20-trinor-15-methyl-,

15-phenoxy-17,18,19,20-tetranor-15-methyl-,

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-15-methyl-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-15-methyl-,

16-phenoxy-18,19,20-trinor-15-methyl-,

15,16-dimethyl-16-phenoxy-18,19,20-trinor-,

13,14-dihydro,

16-methyl-13,14-dihydro-,

16,16-dimethyl-13,14-dihydro-,

16-fluoro-13,14-dihydro-,

16,16-difluoro-l 3,14-dihydro-, 17-phenyl-18,19,20-trinor-13,14-dihydro-, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-l 3,14-dihydro-, 17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-, s 17- (p-fluorophenyl) -18,19,20-trinor-13,14 -dihydro-, 16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro -, 16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, io 16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-, 16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro-, 15 16-phenoxy-18,19,20-trinor-13,14-dihydro-,

16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-, 2,2-difluoro-,

2,2-difluoro-16-methyl-,

2,2-difluoro-16,16-dimethyl-,

20 2,2-difluoro-16-fluorine,

2,2-difluoro-16,16-difluoro-, 2,2-difluoro-17-phenyl-18,19,20-trinor-,. 2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-, 2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-, 25 2.2 -Difluoro-17- (p-fluorophenyl) -18,19,20-trinor-, 2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16 , 16-dimethyl-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16-fluoro-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16,16 -difluoro-17-phenyl-18,19,20-trinor-, 30 2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-nor-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-, 35 2,2-difluoro-16-phenoxy-18,19,20-trinor-,

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-, 13,14-dihydro-l 5 -methyl-,

15,16-dimethyl-13,14-dihydro-, 15,16,16-trimethyl-13,14-dihydro-, 40 16-Fluror-13,14-dihydro-15-methyl-, 16,16-difluoro- 13,14-dihydro-15-methyl-,

17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-

15-methyl,

45 17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-15-methyl-,

17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-15-methyl-,

15,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, so 15,16,16-trimethyl-17-phenyl-18,19,20-trinor-13,14- dihydro,

16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-,

16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-55 methyl-,

16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-15-methyl-, 16- (m-trifluoromethyIphenoxy) -17,18,19,20-tetranor-13,14-di-hydro -15-methyl-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-6015-methyl-,

16- (m-Huorphenoxy) -17,18,19,20-tetranor-13,14-dihydro-15-methyl-,

16-phenoxy-l 8,19,20-trinor-13,14-dihydro-15-methyl-, 15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-, 65 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-, 2,2-difluoro-15-methyl-15,16-dimethyl-, 2,2-difluoro-15-methyl- ,

2,2-difluoro-16,16-difluoro-15 -methyl-,

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Os

17th

633 006

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-dimethyl-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-fluoro-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-hexa-nor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-17- (m-trifluoromethyl-phenyl) -

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa- 17- (m-chlorophenyl) -

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-17- (p-fluorophenyl) -

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3.7 -inter-m-phenylene-3-oxa-16-methyl-17-phenyl-

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16,16-dimethyl-17-phenyl-

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa- 16-fluoro-17-phenyl-

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16,16-difluoro-17-phenyl-

4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-

heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16- (m-trifluoromethyl-phenoxy) -

4,5,6,17,18,19,20-heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16- (m-chlorophenoxy) -

4,5,6,17,18,19,20-heptanor-l 3,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-16- (p- £ luorphenoxy) -

4,5,6,17,18,19,20-heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-15-

methyl-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16-dimethyl-13,14-dihydro-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16,16-trimethyl-13,14-dihydro-,

3,7-inter-m-pheny len-3-oxa-4,5,6-trinor-16-f luor-13,14-dihy-dro-15-methyl-,

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-3-oxa-l 7-phenyl-4,5,6,18,19,20-hexa-nor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-3-oxa-17- (m-trifluoromethyl-phenyl) -4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3rd , 7-Inter-m-phenylene-3-oxa-17- (m-chlorophenyl) -4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3,7- Inter-m-phenylene-3-oxa-17- (p-fluorophenyl) -4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3,7-inter-m -phenylene-3-oxa-15,16-dimethyl-17-pheny 1-4,5,6,18,19,20-hexanor-13,14-dihydro-, 3,7-inter-m-phenylene-3 -oxa-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-, 3,7-inter-m-phenylene-3-oxa- 16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3,7-inter-m-phenylene-3-oxa-16,16 -difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3,7-inter-m-phenylene-3-oxa-16-phenoxy- 4,5,6,17,18,19,20-heptanor-13,14-dihy dro-15-methyl-, 3,7-inter-m-phenylene-3-oxa-16- (m-trifluoromethyl-phenoxy ) -4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-, 3,7-inter-m-phenylene-3-oxa-16- (m-chlorophenoxy) -4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-, 3,7-inter-m-pheny len-3-oxa-16- (pf luorphenoxy) -4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-, 3,7-inter-m-phenylene -4,5,6-trinor-, 3,7-inter-m-phenylene-4,5,6-trinor-16-methyl-, 3,7-inter-m-phenylene-4,5,6-trinor -16,16-dimethyl-, 3,7 -inter-m-phenylene-4,5,6 -trinor- 16-fluoro-,

3,7-inter-m-phenylene-4,5,6-trinor-16,16-difluoro-, 3,7 -inter-m-phenylene-17-phenyl-4,5,6,18,19,20 -hexanor-, 3,7-inter-m-phenylene-17- (m-trif luormethylphenyl) -4,5,6,18,19,20-hexanor-, s 3,7-inter-m-phenylene-17 - (m-chlorophenyl) -4,5,6,18,19,20-he-xanor-,

3,7 -inter-m-phenylene-17- (p-fluorophenyl) -4,5,6,18,19,20-hexanor-,

3,7-inter-m-phenylene-16-methyl-17-phenyl-4,5,6,18,19,20-io hexanor-,

3,7-inter-m-phenylene-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-,

3,7-inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-he-xanor-,

15 3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-,

3,7-inter-m-phenylene-16- (m-trifluoromethylphenoxy) -4,5,6,17,18,19,20-heptanor-, 3,7-inter-m-phenylene-16- (m- chlorophenoxy) -20 4,5,6,17,18,19,20-heptanor-, 3,7-inter-m-phenylene-16- (p-fluorophenoxy) -4,5,6,17,18,19 , 20-heptanor,

3,7-inter-m-phenylene-4,5,6-trinor-15-methyl-, 3,7-inter-m-phenylene-4,5,6-trinor-15,16-dimethyl-, 25 3 , 7-inter-m-phenylene-4,5,6-trinor-15,16,16-trimethyl-, 3,7-inter-m-phenylene-4,5,6-trinor-16-fluoro-15- methyl-, 3,7-inter-m-phenylene-4,5,6-trinor-16,16-difluoro-15-methyl-, 3,7-inter-m-phenylene-17-phenyl-4,5, 6,18,19,20-hexanor-15-methyl-,

30 3,7-inter-m-phenylene-17- (m-trifluoromethylphenyl) -4,5,6,18,19,20-hexanor-15-methyl-, 3,7-inter-m-phenylene-17- (m-chlorophenyl) -4,5,6,18,19,20-hexanor-15-methyl-,

3,7-inter-m-phenylene-17- (p-fluorophenyl) -4,5,6,18,19,20-he-35 xanor-15-methyl-,

3,7-inter-m-phenylene-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-,

3,7-inter-m-phenylene-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-, 40 3,7-inter-m-phenylene-16- fluoro-17-phenyl-4,5,6,18,19,20 -he-xanor-15-methyl-,

3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-,

3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-hepta-45 nor-15-methyl-,

3,7-inter-m-phenylene-16- (m-trifluoromethylphenoxy) -4,5,6,17,18,19,20-heptanor-15-methyl-, 3,7-inter-m-phenylene-16 - (m-chlorophenoxy) -4,5,6,17,18,19,20-heptanor-15-methyl-, 50 3,7-inter-m-phenylene-4,5,6-trinor-13,14 -dihydro-,

3,7-inter-m-phenylene-4,5,6-trinor-16-methyl-13,14-dihydro-, 3,7-inter-m-phenylene-4,5,6-trinor-16,16 -dimethyl-13,14-dihydro-,

3,7-inter-m-phenylene-4,5,6-trinor-16-fluoro-13,14-dihydro-, 55 3,7-inter-m-phenylene-4,5,6-trinor-16, 16-difluoro-13,14-dihy-dro-,

3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-17- (m-trifluoromethylphenyl) -60 4,5,6,18,19,20-hexanor-13,14-dihydro-, 3,7-inter-m-phenylene- 17- (m-ch! Orphenyl) -4,5,6,18,19,20-hexanor- 13,14-dihydro-,

3,7-inter-m-phenylene-17- (p-fluorophenyl) -4,5,6,18,19,20-he-xanor-13,14-dihydro-, 65 3,7-inter-m- phenylene-16-methyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-,

633 006

18th

3,7-inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-,

3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-hepta-nor-13,14-dihydro-,

3,7-inter-m-phenylene-16- (m-trifluoromethylphenoxy) -

4,5,6,17,18,10,20-heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-16- (m-chlorophenoxy) -

4,5,6,17,18,19,20-heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-16- (p-fluorophenoxy) -4,5,6,17,18,19,20-

heptanor-13,14-dihydro-,

3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-15-methyl-, 3,7-inter-m-phenylene-4,5,6-trinor-15,16 -dimethyl-13,14-dihydro-,

3,7-inter-m-phenylene-4,5,6-trinor-15-, 16,16-trimethyl-l 3,14-dihydro-,

3,7-inter-m-phenylene-4,5,6-trinor-16-fluoro-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-4,5,6-trinor-16,16-difluoro-13,14-dihy-dro-15-methyl-,

3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-17- (m-trif luormethylphenyl) -4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-, 3,7-inter- m-phenylene-17- (m-chlorophenyl) -4,5,6,18,19,20-he-xanor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-17- (p-fluorophenyl) -4,5,6,18,19,20-hexanor- 13,14-dihydro-l 5 -methyl-, 3,7-inter- m-phenylene-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-, 3,7-inter-m-phenylene-15,16,16 trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-, 3,7-inter-m-phenylene-16-fluoro-17-phenyl-4,5, 6,18,19,20-he-xanor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-hepta-

nor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-16- (m-chlorophenoxy) -

4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-,

3,7-inter-m-phenylene-16- (p-fluorophenoxy) -4,5,6,17,18,19,20-

heptanor-13,14-dihydro-15-methyl-,

5-oxa-,

5-oxa-16-methyl,

5-oxa-16,16-dimethyl-,

5-oxa-16-fluorine,

5-oxa-16,16-difluoro-,

5-oxa-17-phenyl-18,19,20-trinor-,

5-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-,

5-oxa-17- (m-chlorophenyl) -18,19,20-trinor-,

5-oxa-17- (p-fluorophenyl) -18,19,20-trinor-,

5-oxa-16-methyl-17-phenyl-18,19,20-trinor-,

5-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-,

5-oxa-16-fluoro-17-phenyl-18,19,20-trinor-,

5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-,

5-oxa-16-phenoxy-17,18,19,20-tetranor-,

5-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-,

5-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-,

5-oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-,

5-oxa-16-phenoxy-18,19,20-trinor-,

5-oxa-15,16-dimethyl-,

5-oxa-15,16,16-trimethyl-,

5-oxa-16-fluoro-15-methyl-,

5-oxa-16,16-difluoro-15-methyl-,

5-oxa-17-phenyl-18,19,20-trinor-15-methyl-,

5-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-15-me-

thyl

5-oxa-17- (m-chlorophenyl) -18,19,20-trinor-15-methyl-, 5-oxa-17- (p-fluorophenyl) -18,19,20-trinor-15-methyl- , 5-oxa-15,16-dimethyl-17-phenyl-18,19,20-trinor-, 5-oxa-15,16,16-trimethyi-17-phenyl-18,19,20-trinor-, 5th -Oxa-16-fluoro-17-phenyl-18,19,20-trinor-15-methyl-, 5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-15-methyl- , 5-Oxa-16-phenoxy-17,18,19,20-tetranor-15-methyl-, 5-Oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-15-methyl -,

5-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-15-methyl-, 5-oxa-13,14-dihydro-,

15 5-oxa-16-methyl-13,14-dihydro-, 5-oxa-16,16-dimethyl-13,14-dihydro-, 5-oxa-16-fluoro-13,14-dihydro-, 5- Oxa-16,16-difluoro-13,14-dihydro-, 5-oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-, 20 5-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-,

5-oxa-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-, 5-oxa-17- (p-fluorophenyl) -18,19,20-trinor-13,14 -dihydro-, 5-oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, 25 5-oxa-16,16-dimethyl-17-phenyl-18,19, 20-trinor-13,14-dihy-dro-,

5-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-,

5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihy-

dro-,

30 5-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-, 5-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13, 14-dihydro,

5-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

35 5-oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

5-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-15-methyl-, 5-oxa-13,14-dihydro-15-methyl-, 5-oxa-15,16- dimethyl-13,14-dihydro-, 40 5-oxa-15,16,16-trimethyl-13,14-dihydro-, 5-oxa-16-fluoro-13,14-dihydro-15-methyl-, 5- Oxa-16,16-difluoro-13,14-dihydro-15-methyl-, 5-oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-, 5-oxa- 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-di-45 hydro-15-methyl-,

5-oxa-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-15-methyl-,

5-oxa-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-15-methyl-,

so 5-oxa-15,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

5-oxa-15,16,16-trimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

5-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-55 methyl-,

5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihy-dro-15-methyl-,

5-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-15-methyl-,

60 5-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-15-methyl-,

5-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihy-dro-15-methyl-,

5-oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihy-65 dro-15-methyl-,

C.

Claims (4)

633 006 2nd PATENT CLAIMS 1. Process for the preparation of new compounds of formula CH2-Zi-C 00Ri and / Rs Yi-C-R7 l! J, LXVI bliss Rj is alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 10 carbon atoms, aralkyl with 7 to 12 carbon atoms, phenyl, phenyl substituted with 1 or 2 chlorine or fluorine atoms or alkyl radicals with 1 to 4 carbon atoms, Z, (1) cis-CH = CH-CH2- (CH2) g-CH2-, (2) cis-CH = CH-CH2- (CH2) g-CF2, (3) cis-CH2-CH = CH- (CH2) "- CH2-, (4) - (CH2) 3- (CH2) g-CH2—, (5) - (CH2) 3- (CH2) g-CF2-, (6) -CH2-0-CH2- (CH2) g-CH2-, 0- (CH2) g-, or (8) -r ^> r - CH2- (CH2) g-, where g is the number 1, 2 or 3, Yj is trans-CH = CH-or-CH2CH2-, M, or Rs ^ OH Rs OH, represents where R5 is hydrogen or methyl, R3 R-3: # Rs R4 .., or a mixture of R3 R4 is wherein R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 and R4 only means methyl when the other is hydrogen or methyl, and R7 (1) - (CH2) m-CH3, 15. (T) s i - \ X (2) ~ 0 ~ v>, or CO. 20th J (3) ~ (CH2) r is 25 where 10 or the number 1, 2 or 3, m is a number from 1 to 5, T is an alkyl radical with 1 to 3 carbon atoms, alkoxy radical with 1 to 3 carbon atoms, chlorine, fluorine or the trifluoromethyl radical and s is the number 1, 2 or 3 mean, where the individual radicals T may be the same or different, under the measure 30-be that no more than two radicals T are different from alkyl, and with the further proviso that R7 only then 35 (t). // if R3 and R4, which may be the same or different, are hydrogen or methyl, characterized in that 40 (1) a thromboxane intermediate of the formula HO 45 (Rs30) 2H ( HO 50 CHs-Zi-COORi Yi ~ C II Ii Mi Li LXIV wherein Rj, Z1; Yb Lj and R7 have the meaning given above and R33 is an alkyl radical having 1-4 carbon atoms, hydrolyzed and 55 (2) from the reaction product of step (1) of the formula 60 R £ T CHz-Z.i-C00ft, LXV Yi-C-C-RT ÌU 65 the rest R33 converted into hydrogen by dealkylation. 2. Process for the preparation of new compounds of the formula 3rd 633 006 HO HO- ^ D wherein , CH2-l! -CH2OH Yi-C-C-R, IU (1) cis-CH = CH-CH2- (CH2) g-CH2-, (2) cis-CH = CH-CH2- (CH2) g-CF2, (3) cis-CH2-CH = CH- (CH2) g-CH2-, (4) - (CH2) 3- (CH2) g-CH2-, (5) - (CH2) 3- (CH2) g-CF2-, (6) -CH2-0-CH2- (CH2) g-CH2-, (7) 0- (CH2) g-, or (8) || - CH2- (CH2) g- means where g is the number 1, 2 or 3, Y! means trans-CH = CH- or -CH2CH2-, M, Rs ^ OH or r5 oh, is where R5 is hydrogen or methyl, P \ 3 R Az 9 Rs or a mixture of rs r <. and y R3 A is wherein R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 and R4 only means methyl when the LXVII 5 is other hydrogen or methyl, and R7 (1) -CH2) m-CH3, 10th (2) -O- Û CO. 15 (3) - (CH2), , or (T). // means 10th where 10 or the number 1, 2 or 3, m is a number from 1 to 5, T is an alkyl radical with 1 to 3 carbon atoms, alkoxy radical with 1 to 3 carbon atoms, chlorine, fluorine or the trifluoromethyl radical and s is the number 1.2 or 3 means, where the individual radicals T can be the same or different, provided that no more than two radicals T are different from alkyl, and with the further requirement that R7 only then 30th -0- / (T), means when R3 and R4, which may be the same or different, are hydrogen or methyl, characterized in that 35 according to the process of claim 1, a compound of formula HO Ii CH2-Z.1 -COORi HO 0 Yi-C-C-R7 IL !!. LXVI wherein the substituents are defined above, and then reduced to the primary alcohol. 50