CH626338A5 - Process for the preparation of prostaglandin analogues - Google Patents

Description

The present invention relates to methods for the preparation of new analogs of some known prostaglandins which differ from the corresponding known compounds in that they have a modified cyclopentane ring structure which shows an oxo substitution at C-II, in contrast to, for example, those PGFA, PGFi or PGE compounds which are substituted by a hydroxyl group at C-11 and / or are oxygen-free at C-9.

The various prostaglandins, their esters, acylates and pharmacologically acceptable salts are extremely effective in causing various biological reactions. For this reason, these compounds are suitable for pharmacological purposes, see for example Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and literature references there.

With the PGE connections t.B. belong to these biological reactions:

(a) stimulation of the smooth muscles (proven e.g. by tests with guinea pig ileum, rabbit duodenum or colon of voles),

(b) the influencing of the lipolytic activity (demonstrated by the antagonism against the release of glycerol induced by epinephrine from isolated rat fat pads),

(c) inhibition of gastric secretion and reduction of undesirable gastrointestinal effects when systematically administered prostaglandin synthetase inhibitors,

(d) combating cramps and facilitating breathing in asthmatic conditions,

(e) swelling of the nasal passages,

(f) the reduction in platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition of platelet aggregation caused by various physical effects (for example arterial injury) or chemical effects (for example ATP, ADP, serotinin, thrombin and collagen) and thrombus formation,

(g) exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical calibrators, regulators of oestrus and the menstrual cycle, and

(h) accelerating the growth of epidermal cells and keratin in animals.

For PGFa compounds, these biological reactions include:

(a) stimulation of the smooth muscles (demonstrated, for example, by tests with guinea pig ileum, rabbit duodenum or colon from voles),

(b) inhibiting gastric secretion and reducing undesirable gastrointestinal effects when systematically administered prostaglandin synthetase inhibitors,

(c) swelling of the nasal spaces,

(d) the reduction in platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition by various physical influences (for example arterial injury) or chemical influences

(e.g. ADP, ATP, serotinin, thrombin and collagen) caused platelet aggregation and thrombus formation, and

(e) Exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical calibrators, regulators of oestrus and the menstrual cycle.

In the PGFß compounds, these biological reactions include:

(a) stimulation of the smooth muscles (proven on s

io

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Tests with guinea pigs ileum, rabbit duodenum or colon of voles),

(b) the inhibition of gastric secretion and reduction of undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors, s

(c) combating cramps and facilitating breathing in asthmatic conditions,

(d) swelling of the nasal passages,

(e) the reduction in the platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition of the effects of various physical effects (for example arterial injury) or chemical effects (for example ADP, ATP, serotinin, thrombin and collagen) caused platelet aggregation and thrombus formation, and

(f) Exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical calibrators, regulators of oestrus and the menstrual cycle.

ch2-z1-coor1

25th

In the case of the PGA compounds, these biological reactions preferably include:

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

(b) inhibition of gastric secretion and reduction of undesirable gastrointestinal effects when systemically administered prostaglandin synthetase inhibitors,

(c) combating cramps and facilitating breathing in asthmatic conditions,

(d) swelling of the nasal passages and

(e) increasing blood flow in the kidney.

IV

wherein Y is cis-CH = CH-, trans-CH = CH-, or-CH2-CH2 or

1S = CH-CH2-means

Room

(1) cis-CH = CH-CH2- (CH2) p-CF2-,

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

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

(4) - (CH2) 3- (CH2) fr-CF2-,

(5) - (CH2) 3- (CH2) r-CH2-,

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

(7) - (CH2) 2-0- (CH2) g-CH2-,

(8) - (CH2) 3-0- (CH2) g-,

CHs- (CH2) g-.

The PGB connections include e.g. to these biological reactions: 35

(a) stimulation of the smooth muscles (proven by tests with guinea pig ileum, rabbit duodenum or colon of voles) and 40

(b) accelerating the growth of epidermal cells and keratin in animals.

o- (ch2) 9-

where g is the number 1, 2 or 3,

Wed

Rs or

Because of these biological reactions, the known prostaglandins are used to examine, prevent, control or alleviate numerous diseases and undesirable physiological conditions in birds and mammals, including humans, farm animals, pets and zoological species, as well as laboratory animals such as mice, rats, rabbits and monkeys.

Some prostaglandin-like compounds that are structurally close to the compounds that can be produced according to the invention are known. In BE-PS 767 704 (Derwent Farm-doc CPI 76109U-B) 9-deoxy-PGD connections are disclosed. US Pat. No. 3,878,239 describes certain PGD analogs substituted on the C-15 or C-16 methyl. For the disclosure of PGDi and PGD2, see Nugteren, et al., Ree. Trav. Chim. Pays-Bas, 85 104 (1966), Granstrom, et al., J. Biol. Chem. 243, 4104 (1968), C. Sih, et al., Biochem. 11, 227 (1972), J. Org. Chem., 38, 215 (1973), and Nishizawa, et al., PROSTAGLANDINS 9,109 (1975). Finally, the following abstracts treat 9-deoxy-PGF-like compounds: Derwent Farmdoc CPI No. 76438S-B, 21092T-B, 39100U-B, 21092T-B, 16843U-B, 13929U-B and 49992T-B.

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

Rs

OR6

ÒR6,

where Rs and R6 are hydrogen or methyl, provided that one of the radicals Rs and Ró is methyl only when the other denotes hydrogen, Li or a mixture of

Rs and

/ Rs

R4

R4,

wherein R3 and R <t, which can be the same or different,

626338

6

Are hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine,

Rev

(l) - (CH2) nr-CH3,

(2)

(3)

-

JT)

he or

-chz

(4) cis-CH = CH-CH2-CH3,

wherein m is a number from 1 to 5, T chlorine, fluorine, the trifluoromethyl radical, an alkyl radical from 1 to 3 carbon atoms or alkoxy radical from 1 to 3 carbon atoms and s is the number 0.1, 2 or 3, the individual radicals T can be the same or different, provided that no more than 2 radicals T can be different from alkyl, provided that R7 only then

, v (T) s

-

means when R3 and R4, which may be the same or different, are hydrogen or methyl, and Ri is hydrogen, an alkyl radical with 1 to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, the phenyl radical or a 1 , 2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms substituted phenyl radical or a pharmacologically acceptable cation.

The inventive method is characterized in that

(1) in corresponding PGF «or PGFß compounds of the formula ho

^ CHa-Zi-COORi

50

ho y-c-II

M-i

-c-R7 ii l-,

(I)

the 11-OH group to form PGD or 9β-PGD compounds of the formula ho.

selectively oxidized and

(2) the reaction product of step (1) dehydrates to form a 9-deoxy-9,10-dedihydro or 13.14 didehy-dro-12.13 (E) -dihydro-9-deoxy-9.10-didehydro -PGD compound of the formula

10th

25th

x CH2-Zl-COORl y-c-c-R7

ii II k-, l-,

^ cha-zï-coor-,

y-c-c-r7 II II

Mi L,

(IV)

15

wherein the substituents are defined above.

The following formula has further new compounds which can be prepared according to the invention

ch2-z1-coor1

y-c-II

Wed

(IV A)

-c-r7

il

Li where Y = CH —CH2— and Ri, Ri, Li, Mi and Zi are defined above.

According to the invention, these new compounds of the formula IV A are obtained by:

(1) in corresponding PGD «or PGEi compounds of the formula ho ho ch2-zi-c00ri

Y-C — Ç-R7 ii ii mi li

(I A)

where Y is —CH = CH— or trans —CH = CH—, the 11-OH group to form PGD or 9 î-PGD compounds of the formula ch2-zi-coori y-c-c-R7

II Ii

Mi Li

(II A)

selectively oxidized,

65 (2) the reaction product of the formula II A from stage (l) iso-, T »merized to form l3, l4-dihydro-l2, l3 (E) -didehy-iX 'dro-PGD- or l3, l4- Didehydro-l2, l3 (E) -didehydro-9i-PGD compounds of the formula

7

626 338

hc

^ CHa-Zn-COOR,

: h-ch2-c-II

Wed

-c-R7

w left

CH2-, where g has the meaning given above, it is a “cis-4,5-didehydro-PGi” compound. If g is the number 2 or 3, these compounds (III A) are still identified as “2-homo” or “2a, 2b-dihomo” compounds s.

New compounds which can be produced according to the invention, in which Zi represents the rest and

(3) the reaction product of step (2) dehydrates to form 9-deoxy-9,10-didehydro- or 13,14-didehy-dro-12,13 (E) -didehydro-9-deoxy-9,10- didehydro-PGD compound of the formula ch2-z1-coor1

(IV A)

10th

o o- (cha) -

or

15

mn ln

25th

wherein the substituents are defined above.

Compounds of the formula IV obtained in accordance with the invention, in which R 1 is hydrogen, can be converted into the corresponding salts or also esters.

The free acids (Ri = H) can be prepared from compounds of the formula IV obtained in which 30 Ri is different from hydrogen.

Those prostaglandin analogs in which Zi denotes a cis-CH = CH-CH2- (CH2) g-CH2 or cis-CH = CH-CH2- (CH2) S-CF2 residue are called "PG2" compounds Designated 35. The latter compounds are also “2,2-difluoro” -PG-like compounds. If g denotes the number 2 or 3, the prostaglandin analogues in question are referred to as “2a-homo” or “2a, 2b-dihomo” compounds, since in this case the side chain terminated by a carboxyl group instead of the 7 carbon atoms of PGEi has 8 or 9 carbon atoms. These additional carbon atoms are considered to be inserted between the C-2 and C-3 positions. These additional carbon atoms are therefore numbered C-2a and C-2b, 45 counting from the C-2 to the C-3 position.

Zi means e.g. a - (CH2) 3— (CH2) g — CH2— or - (CH2) 3 - (CH2) g - CF2 radical, where g has the meaning given above, these are “PGi” compounds . If g denotes the number 2 or 3, then these are again “2a-homo” and “2a, 2b-dihomo” compounds.

If Zi is a radical CH2-0-CH2- (CH2) g-CH2-, the compounds in question are referred to as “5-oxa-PGi” compounds. If g means the number 2 or 3, it is again «2a-homo» - or «2a, 2b- 55

dihomo »connections.

Zi is a - (CH2) 2-0- (CH2) g-CH2 radical,

where g has the meaning given above, the compounds in question are referred to as “4-oxa-PGi” compounds. If g is the number 2 or 3, 60 the compounds are additionally identified as «2a-homo» or «2a, 2b-dihomo» compounds.

If Zi denotes a radical - (CH2) 3 - O - (CH2) g—, in which g has the meaning given above, there are “3-oxa-PGi” compounds. If g is the number 2 or 3, the compounds are also identified as «2a-homo» or «2a, 2b-dihomo» compounds.

Does Zi mean the rest ice — CH2 —CH = CH - (CH2) g—

^ S> * - ch2- (ch2) g-

means, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor- or 3,7-inter-m-phenylene-4,5,6-trinor-PG-like compounds, if g is 1. If g is 2 or 3, these compounds are additionally described as «2a-homo» or «2a, 2b-dihomo» compounds.

The new prostaglandin analogues mentioned, which have an eis — CH = CH radical in the C-13 to C-14 position, are termed “cis-13” compounds. If there is a - CH2CH2 residue in the C-13 / C-14 position, then these are "13,14-didehydro" compounds.

If the radical Y (C-13 / C-14) is a = CHCH2 radical, the compounds in question are named after the cyclopentane ring structure, as discussed above. These are "13,14-didehydro-13,14-didehydro" compounds. In the given representation, the 12,13-didehydro-13,14-dihydro compounds represent the geometric E isomers, corresponding to the E and Z nomenclature for describing the possible geometric isomers of a ring carbon atom which is formed by double bond with a Carbon atom is linked outside the ring. These compounds are thus additionally identified as “12,13- (E) -didehydro-13,14-dihydro” -PG analogs, see Blackwood, J.E. et al., J. of Chem. Doc. 8, 30 (1968).

If R7 is a - (CH2) m — CH3 radical, in which m has the meaning given above, it is “19.20-dinor”, “20-nor”, “20-methyl” or “ 20-ethyl »compounds, where m is 1, 2, 4 and 5, respectively.

R7 represents a radical of the formula

-cha

<n,

<y where T and s have the meaning given above, if s is 0, the compounds are referred to as “17-phenyl-18,19,20-tinor” compounds. If s is 1, 2 or 3, these are «17- (substituted phenyl) -18,19,20-trinor» compounds.

R7 is a residue of the formula

(t).

wherein T and s have the meaning given above,

626338

where neither R3 nor R4 represent methyl, if s is 0 they are “16-phenoxy-17,18,19,20-tetranor” compounds. If s is 1, 2 or 3, the formula correspondingly represents “16- (substituted phenoxy) -17,18,19,20-tetranor” compounds. One of the radicals R3 and R4 means methyl or both radicals R3 and R4 Methyl, then the compounds with the above radical R7 are “16-phenoxy” or “16- (substituted phenoxy) -18,19,20-trinor” compounds or “16-methyl-16-phenoxy” or ^ - (Substituted phenoxy) -18,19,20-trinor »compounds.

If R7 denotes an eis — CH = CH - CH2 - CH3 residue, then these are “PG3” or “eis-17,18-didehydro” compounds, depending on whether Zi has a cis-CH = CH- (CH2) g — C (R2) 2, where R2 is hydrogen or fluorine, or another radical.

If at least one of the radicals R3 and R4 is not hydrogen, then these are (apart from the 16-phenoxy compounds discussed above) 16-methyl compounds (one of the radicals R3 and R4 means methyl), 16,16-dimethyl compounds (both radicals R3 and R4 means methyl), 16-fluorine compounds (one of the radicals R3 or R4 means fluorine), or 16,16-difluoro compound (both radicals R3 and R4 mean fluorine). 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 relevant epimer mixture «(16RS)» is also possible.

If Rs is the methyl radical, the compounds in question are “15-methyl” compounds. If Re means the methyl radical, it is the “15-methyl ether”.

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

Examples of cycloalkyl radicals with 3 to 10 carbon atoms are the cyclopropyl and 2-methylcyclopropyl radicals.

Examples of aralkyl radicals with 7 to 12 carbon atoms are the benzyl, 2-phenylethyl and 1-phenylethyl radical.

Examples of radicals of the formula in which T is 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 represent 0.1, 2 or 3, with the proviso that no more than 2 Radicals T are different from alkyl, are 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-, (0-, 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-toiyl,

(3-, 4-, 5- or 6-) chloro-o-tolyl-,

4-chloro-2-propylphenyl-,

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-) methyl-2-fluorophenyl,

o-, m- or p-trifluoromethylphenyl,

(o-, m- or p-) methoxyphenyl,

(o-, m- or p-) ethoxyphenyl and

(4- or 5-) chloro-2-methoxyphenyl.

The prostaglandin analogs obtained according to the invention correspond to the prostaglandins described above in that they show a prostaglandin-like effect.

In particular, the new prostaglandin analogs prepared according to the invention correspond to the known prostaglandins, since they can be used for all of the purposes described above and can be used in the same way as the prostaglandin in question.

The prostaglandins described above all cause multiple biological reactions, even at low doses. In numerous applications, the known prostaglandins also show a very short duration of the biological effect. In contrast, the new prostaglandin analogs produced according to the invention are much more specific in their action and they have a much longer duration of action. Each of these new prostaglandin analogs is therefore surprisingly more useful for at least one of the above-mentioned pharmacological purposes than the known prostaglandins mentioned, since it has a different and narrower spectrum of biological action than the known prostaglandin and is therefore more specific in its action and less and less produces undesirable side effects as the prostaglandin used for the same purpose. Furthermore, because of the longer duration of action, fewer and smaller doses of the new prosaglandin analog are used to achieve the desired result.

A further advantage of the new prostaglandin analogs obtained according to the invention, in particular the preferred PG analogs below, compared to the corresponding prostaglandins is that the new analogs can be administered orally, sublingually, intravaginally, buccally or rectally with success in cases in which who only succeed in prostaglandin with intravenous, intramuscular or subcutaneous injection or infusion. The additional possible routes of administration are advantageous because they facilitate the maintenance of uniform levels of this compound in the body by means of fewer or smaller doses and enable self-administration by the patient.

The new prostaglandin analogs mentioned can therefore be administered for different purposes in different ways, for example intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically and in the form of sterile implants for the prolonged action. Sterile aqueous isotonic solutions are preferred for intravenous injection or infusion. In these cases, Ri is preferably hydrogen or a pharmacologically acceptable cation because of the increased water solubility. Sterile solutions or suspensions of the acid, a salt or ester in aqueous or non-aqueous media are used for subcutaneous or intramuscular injection. For oral or sublingual administration, tablets, capsules and liquid preparations such as syrups, elixirs or simple solutions containing the usual pharmaceutical carriers are used. Suppositories are used in a known manner for rectal or vaginal administration. A sterile tablet or silicone rubber8 is used as tissue implant

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chuk capsule or other object that contains or is impregnated with the active ingredient.

The new PG analogs prepared according to the invention can be used for the above purposes in the form of the free acid, as esters or pharmacologically acceptable salts. When using esters, the ester radical is within the definition of Ri. Alkyl esters with 1 to 12 carbon atoms are preferred, and especially 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 prostaglandin analogs obtained according to the invention, which are useful for the above purposes, are salts with pharmacologically acceptable metal cations, ammonium, amine or quaternary ammonium cations.

Particularly preferred metal cations are those of the alkali metals, for example lithium, sodium and potassium, and the alkaline earth metals, for example magnesium and calcium, although the cationic forms of other metals such as aluminum, zinc and iron also 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, dedecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, a-phenylethylamine , Ethylenediamine, diethylenetriamine and the like, aliphatic, cycloaliphatic and araliphatic amines having 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, and water-solubilizing or hydrophilic group-containing amines such as mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino- l-butanol, 2-amino-2-ethyl-l, 3-propanediol, 2-amino-2-methyl-l-propanol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amy l-phenyl) diethanolamine, galactamine, N-methylgycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like.

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

The new PG analogs prepared according to the invention are preferably used for the above purposes in the form of the free hydroxyl compound or as lower alkanoates. Examples of lower alkanoate residues are the acetoxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, hepta-noyloxy and octanoyloxy residues and the branched chain alkanoyloxy isomers of these residues. Acetoxy compounds are particularly preferred among the alkanoates. The free hydroxyl compounds and the alkanoyloxy compounds are usually used as the free acids, esters or salts as described above.

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

The number 1 or 3 and in particular 1 in the carboxyl-terminated side chain g is preferably 1, which means that the chain has the natural length of the prostaglandins. If R7 is - (CH2) m-CH3, m is preferred therein

3. In compounds in which R7

JT) s

-or or / -r \

'

means, s is preferably 0 or 1 and T is chlorine, fluorine or the trifluoromethyl radical.

In compounds in which at least one of R3 and R4 is methyl or fluorine, preferably Rs and Rß are both hydrogen. In compounds in which at least one of the radicals Rs and R6 is methyl, R3 and R4 are preferably both hydrogen. In compounds in which R7 is a residue or (T) S

, preferably R3, R4, Rs and Re are all hydrogen.

Compounds in which a methylene group has been replaced by an oxa group (i.e. -O- instead of -CH2-) prefer this replacement at C-5 (compared to C-4- and C-3)

on.

Furthermore, the 15-hydroxyl or 15-methoxy group is preferably of the a configuration, that is to say the hydroxyl group is present in the new cis-13-PG analogs in the present illustration in the 15-epi configuration and not in the 15-epi configuration -Configuration if they are not eis-13 PG analogues.

The following schemes describe preferred methods by which the new prostaglandin analogs can be made.

Scheme A

chs-zi-coori y-c -c-r

-r y-c mi li

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Scheme B

HO

V -CH2-Zi-C00RI

ÇC.-.- c-

0 i p ü ^ Mi Li

CHa-Zx-COORi

Y-C-C-R

mi li

In schemes A and B above, T and s have the meaning given above.

Ri has the meaning given above, but is usually not a pharmacologically acceptable cation in the various rearrangements, but rather hydrogen or an ester group.

The other residues are defined above.

Shame A shows a preferred embodiment of the process according to the invention for converting the PGF-like product of the formula CI to the new PGD-like compound CV. The compound of the formula CI can be prepared by known methods.

In the process described, the compound of the formula CI at C-II is selectively oxidized according to the invention with respect to the C-9 position, e.g. with Jones reagent. In order to achieve a high selectivity, the reaction is conveniently carried out between -20 and -60 ° C. Particularly preferred reaction temperatures are between -55 and -30 ° C.

When working up the product mixture, the pure PGD-like compound of the formula CV is obtained.

Scheme B shows the second stage of the process according to the invention, namely the conversion of the PGD-like compound CXI into a 9-deoxy-9,10-didehydro-PGD-like compound CXII.

The compound of the formula CXII is preferably obtained from the compound CXI by mildly acid-catalyzed dehydration. Organic acids such as acetic acid, trifluoroacetic acid, citric acid, oxalic acid or p-toluenesulfonic acid are suitable for this purpose. Diluents such as tetrahydrofuran, methanol, ethanol or water are used. A diluent is preferably chosen which leads to a homogeneous reaction mixture. Dehydration is usually rapid at temperatures between room temperature and 40 ° C. Furthermore, the compound of the formula CXI can also be left to stand in a column with acid-washed silica gel, the product CXII generally being formed within 1 to 5 days by dehydration.

In all of the reactions described above, the products can be freed of starting material and contaminants in a conventional manner, e.g. by using silica gel chromatography followed by thin layer chromatography.

As already mentioned, the processes according to the invention lead, depending on the situation, to acids (Ri = hydrogen) or esters.

If an alkyl ester has been obtained and an acid is desired, known methods of saponification can be used.

If a saponification process would cause undesired dehydration of the prostaglandin analog, enzymatic processes are preferably used to convert esters into their acid, see e.g. U.S. Patent 3,761,356.

If an acid has been obtained and an alkyl, cycloalkyl or aralkyl ester is desired, the esterification can advantageously be carried out by reacting the acid with the relevant diazo hydrocarbon. In this way e.g. get the methyl esters with diazomethane. In an analogous manner, e.g. with diazoethane, diazobutane, l-diazo-2-ethylhexane or diazodecane the ethyl, butyl and 2-ethyl-hexyl or decyl ester. The cyclohexyl and benzyl esters are also formed with diazocyclohexane and phenyldiazomethane.

The esterification with diazo hydrocarbons is preferably carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably in diethylate, with the acid, which is expediently present in the same or a further inert diluent. After the esterification has ended, the solvent can be evaporated off and the ester obtained is usually purified in a conventional manner, preferably by chromatography. The contact between acid and diazohydrocarbon should preferably not be longer than is necessary for the desired esterification, in particular about 1 to about 10 minutes, so that undesired molecular changes are prevented. Diazo hydrocarbons are known or can be prepared by known methods, see e.g. Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

Another preferred method for esterifying the carboxyl group of acidic compounds with alkyl, cycloalkyl or aralkyl radicals consists in converting the free acid into the silver salt, which is then reacted with an alkyl group. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phen-ethyl iodide and the like. The silver salts can be prepared by conventional methods, for example by dissolving the acid in cold dilute aqueous ammonia, evaporating excess ammonia under reduced pressure and then adding the stoichiometric amount of silver nitrate.

Various methods are available for producing the new phenyl or substituted phenyl esters from aromatic alcohols and the PG-like acids, which differ in terms of yield and product purity.

According to a preferred method, the PG-like compound is converted into a tertiary amine salt, which is then reacted with pivaloyl halide to give the mixed anhydride, which is then reacted with the aromatic alcohol. Instead of pivaloyl halide, an alkyl or phenylsulfonyl halide such as e.g. Use p-toluenesulfonyl chloride, see e.g. BE-PSS 775 106 and 776 294, Derwent Farmdoc Nos. 33705T and 3901 IT.

Another preferred method is to use the coupling agent dicyclohexylcarbodiimide, see Fieser et al., "Reagents for Organic Synthesis", pp. 231-236, John Wiley and Sons, Inc., New York, (1967). The PG-like compound is usually contacted with 1 to 10 molar equivalents of the aromatic alcohol in the presence of 2 to 10 molar equivalents of dicyclohexylcarbodiimide in pyridine as a solvent.

However, a preferred new process for the preparation of the esters consists of the following stages:

(a) Formation of a mixed anhydride from the PG-like compound and isobutyl chloroformate in the presence of a tertiary amine and

(b) reaction of the anhydride with the aromatic alcohol in question.

The mixed anhydride usually forms easily at temperatures in the range of -40 to + 60 ° C and preferably10

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wise from -10 to + 10 ° C, where the reaction rate is sufficiently fast and side reactions are kept to a minimum. The chloroformate is preferably used in an excess of 1.2 to 4.0 molar equivalents per mole of PG-like compound. The reaction is preferably carried out in a solvent, especially acetone, although other relatively non-polar solvents such as acetonitrile, methylene chloride and chloroform can also be used. The reaction can be carried out in the presence of a tertiary amine, e.g. Triethylamine, and the co-formed amine hydrochloride usually crystallizes out, but does not have to be removed before carrying out the next process step.

The aromatic alcohol is preferably used in equivalent amounts or in a substantial stoichiometric excess to ensure that all of the mixed anhydride is converted to the ester. Excess alcohol can be separated according to known methods or given in the present description. e.g. by crystallizing. The tertiary amine not only serves as a basic esterification catalyst, but is also a convenient solvent. Further examples of suitable tertiary amines are N-methylmorpholine, triethylamine, diisopropylethylamine and dimethylaniline. 2-Methylpyridine and quinoline can also be used, but lead to a slow reaction. A strongly hindered amine, e.g. 2,6-dimethyllutidine, but is not useful because of the slow reaction rate.

The anhydride is generally reacted smoothly at room temperature (about 20 to 30 ° C.) and can be monitored in a conventional manner by thin-layer chromatography.

The reaction mixture can be worked up on the ester in a known manner and the product can be purified, e.g. by silica gel chromatography.

A solid, free-flowing crystalline form can be obtained from solid esters by recrystallization from various solvents such as ethyl acetate, tetrahydrofuran, methanol or acetone, by cooling or concentrating a saturated solution of the ester in the solvent or by adding a miscible non-solvent such as diethyl ether, hexane or water . The crystals are usually collected in a conventional manner, e.g. by filtration or centrifugation, washed with a little solvent and dried under reduced pressure. They can also be dried in a stream of warm nitrogen or argon or by heating to about 75 "C. For many applications, these crystals are usually pure enough, but they can be recrystallized in the same way to increase purity after each recrystallization achieve.

The new compounds obtained in free acid form by the processes according to the invention can be converted into pharmacologically acceptable salts by neutralizing them with suitable amounts of the relevant inorganic or organic bases, examples of the corresponding cations and amines having been listed above. The conversion can be carried out according to various known processes for the production of inorganic, that is to say metal or ammonium salts. The choice of process depends in part on the solubility properties of the salt to be produced. In the case of inorganic salts, it is usually advisable to dissolve the acid obtained according to the invention in the stoichiometric amount of a hydroxide, carbonate or bicarbonate corresponding to the desired salt.

Such use of sodium hydroxide, sodium carbonate or sodium bicarbonate results, for example, in a solution of the sodium salt. When the water evaporates or when a water-miscible solvent of moderate polarity is added, e.g. a lower alkanol or a lower alkanone, the solid inorganic salt is usually obtained.

To produce an amine salt, the acid obtained according to the invention can be dissolved in a solvent of moderate or low polarity. Examples of the former are ethanol, acetone and ethyl acetate, for the latter diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is preferably added to this solution. If the resulting salt does not precipitate, it is usually obtained by adding a miscible, low polarity diluent or by concentrating in solid form. If the amine is relatively volatile, an excess can easily be evaporated off. For less volatile amines, the use of stoichiometric amounts is preferred.

In the following examples, the infrared absorption spectra were recorded with a Perkin-Elmer Model 421 infrared spectrophotometer. Unless otherwise specified, undiluted samples were used. The ultraviolet spectra were recorded on a Cary Model 15 spectrophotometer. The nuclear magnetic resonance spectra were recorded with a Varian A-60, Ä-60D or T-60 spectrophotometer in deuterochloroform solutions with tetra-methylsilane as the internal standard (downfield). The mass spectra were recorded with a double-focusing high-resolution mass spectrometer CEG model 11 OB or a gas chromograph / mass spectrometer LKB model 9000. Unless otherwise stated, trimethylsilyl derivatives were used.

The solvent system A-IX used in thin layer chromatography consists of ethyl acetate / acetic acid / 2,2,4-trimethylpentane / water in a ratio of 90: 20: 50: 100 (compare M. Hamberg and B. Samuelsson, J. Biol. Chem 241, 257 [1966]).

Skellysolve B is a mixture of isomeric hexanes.

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

The melting points were recorded with a Fisher-Jones or Thomas Hoover melting point apparatus.

The specific rotations [a] were recorded on solutions in the designated solvent at room temperature with an automatic polarimeter Perkin Elmer model 141.

Example 1 PGD2 or PGD2 Methyl Ester Compare Scheme 1

A. 2.0 g PGFza and 50 ml methylene chloride are treated with 688 mg n-butylboronic acid. The reaction mixture is then stirred vigorously and heated to reflux, with evaporated methylene chloride being replaced by the addition of 5 ml portions. This is carried out for about 25 minutes and about 20 to 25 ml of methylene chloride are added. The resulting distillate becomes clear. Then 10 ml of dihydropyran and then 150 mg of pyridine hydrochloride are added. After 20 hours the reaction is complete and the methylene chloride is removed under reduced pressure, the residue is combined with 30 ml of methanol and 13 ml of 3N aqueous potassium hydroxide solution. The resulting solution is left to stand for 2 hours and then treated with 5 ml of 30% hydrogen peroxide and 30 ml of water. The methanol is removed under reduced pressure and the aqueous residue is diluted with 100 ml of water and extracted twice with diethyl ether. The aqueous phase is washed with 25 ml of 2 N aqueous

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GER acidified potassium bisulfate solution and extracted with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, 3.3 g of an oil are obtained, which is chromatographed on 100 g of acid-washed silica gel. The column is packed with 75% ethyl acetate in hexane and eluted. The corresponding PFG2 ..- 15 -T etrahydropyranyl ether is obtained.

B. 2 g PGF2 «-15-tetrahydropyranyl ether in 75 ml acetone io are cooled to - 45 ° C and then mixed with 1.2 ml Jones reagent. The mixture is at -35 to 30 minutes

-45 ° C, then 0.5 ml of isopropanol are added, followed by stirring for 15 minutes. Then the reaction mixture is poured into a mixture of ice, water and diethyl ether. The mixture is extracted with diethyl ether and the combined ether extracts are washed with saturated sodium chloride solution and dried over sodium sulfate.

After filtering, the solvent is removed by rotary evaporation. The 1.8 g of crude product 20 obtained in this process are chromatographed on 360 g of silica gel washed with acid, eluting with 45% ethyl acetate in hexane. 800 mg of PGD2-15 tetrahydropyranyl ether are obtained.

C. 800 mg of PGD2-15 tetrahydropyranyl ether in 20 ml of acetic acid and 10 ml of water are heated to 40 ° C. for 2 hours and then diluted with 100 ml of water and freeze-dried. The residue is chromatographed on 50 g of acid-washed silica gel, which is packed with 20% ethyl acetate in hexane. When eluting with 35 to 65% ethyl acetate in hexane, 500 mg of a colorless oil are obtained, which crystallizes 3 »on standing, melting point 62.8 to 63.3 ° C .; IR absorptions at 3380,3000,2720,2680,1745,1725,1710, 1435,1405,1325,1315,1270,1240,1200,1155,1080,1040,1025, 1015,990,980,965,935,735 and 705 cm-1; NMR absorption at 0.89.4.14.4.5.5.53 and 5.73 ô. The mass spectrum 35 shows peaks at 334,316,245 and 190.

D. Esterification with excess diazomethane in ether gives the methyl ester.

If the procedure of Example 1 is repeated, but with the various PGF-like compounds described in the present description, the relevant PGD compounds are obtained.

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Example 2

15-methyl-PGD2 methyl ester

A solution of 200 mg 15-methyl-PGF2 «methyl ester in

10 ml acetone is cooled to -40 ° C. and then 0.15 ml Jones reagent is added. The solution is then stirred for 50 minutes at -35 ° C., then 0.1 ml isopropanol is added and the solution becomes 15 The mixture is poured into a mixture of ice and saturated sodium chloride solution and extracted with diethyl ether

Ether extracts are made with saturated sodium bicarbonate solution

solution and saturated sodium chloride solution, washed over

Dried sodium sulfate and concentrated to give 0.20 g of an oil. The crude product thus obtained is 15 g

Chromatographed silica gel, which with 30% ethyl acetate in

Hexane is packed, with 30 to 60% ethyl acetate in hexane 60

is eluted. 0.12 g of pure product are obtained.

IR absorption at 3440, 2940, 2860, 1735, 1440, 1375,

1315, 1240, 1220, 1200, 1170, 1075, 1055, 1035, 975 cm-1;

NMR absorptions at 0.89, 1.25.3.65, 4.50 and 5.506.

The procedure of Example 2 is repeated, but with 65

the various 15-methyl-PGF compounds described in the present description, the 15-methyl-PGD compounds in question are obtained.

Example 3

16,16-Dimethyl-PGD2 (formula CV: Ri = hydrogen, Zi = eis - CH = CH - (CH2) 3—, Y = trans-CH = CH-R3 and R4 of Li = methyl, Rs and R6 of Mi. = Hydrogen, R7 = n-butyl) or its methyl ester. Compare Scheme A.

A. 1.62 g of 16,16-dimethyl-PGF2a are converted into 1.03 g of 16,16-dimethyl-PGF2u-15-tetrahydropyranyl ether according to the procedure of Example 1, Part A; NMR absorption at 0.87, 0.67-2.83, 3.25-4.38, 4.73, 5.12 and 5.2-5.80; IR absorptions at 3400, 2940, 2870, 1710, 1200, 1135, 1115, 1075, 1050, 1020, 1005 and 975 cm-1.

B. 4.35 g of the reaction product according to Part A and 150 ml of acetone are purged with nitrogen for several minutes. This mixture is then cooled to -40 ° C, whereupon a solution of 2.67 M Jones reagent (2.83 ml) is added dropwise with stirring over the course of 10 minutes, the reaction temperature being at -35 to -45 ° C is held. After 60 minutes, 2 ml of isopropanol are added, then the reaction mixture is diluted with saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give 4.8 g of crude product. 2.40 g of crude product are diluted with 90 ml of a mixture of acetic acid and water (2: 1), the resulting solution is heated to 35 ° C. with stirring for 3 hours, then cooled to room temperature, diluted with 200 ml of water and freeze-dried. This process is repeated for the remaining 2.4 g of crude product. The freeze-drying residues are combined to give 3.52 g of crude product, which is purified on 500 g of silica gel packed in Skellysolve B with 25% ethyl acetate. Elution with 25 to 75% ethyl acetate in Skellysolve B gives 1.57 g of pure 16,16-dimethyl-PGD2. Further chromatographic purification gives 1.34 g of pure product, NMR absorptions at 0.83, 0.87, 0.68-3.23, 3.86.4, 50.4.88 and 5.2-6, 0 ò; IR absorptions at 3430, 2950, 2920, 2860, 2660, 1735, 1715, 1385, 1235, 1165, 1110, 1065, 1025, 995 and 975 cm'1. The mass spectrum of the tris-trimethylsilyl derivative shows peaks at 596, 497, 506, 416, 353 and 201. The high-resolution mass spectrum shows a demethylated peak at 581.3502.

C. The reaction product according to Part B is treated with a slight stoichiometric excess of diazomethane in ether, giving the 16,16-dimethyl-PGD2 methyl ester; NMR absorptions at 0.7-3.1, 3.67, 3.7-3.9, 4.3-4.6 and 5.3-5.7 Ò.

Example 4

2,2-difluoro-13,14-dihydro-PGD2 methyl ester (formula CV: Ri = methyl, Zi = cis-CH = CH- (CH2) 2-CF2-, Y = —CH2CH2—, R3 and R4 of Li and Rs and Ré of M = hydrogen, R7 = n-butyl).

Compare Scheme A.

A. The 13,14-dihydro-2,2-difluoro-PGF2a methyl ester: Ri = methyl, Zi = cis-CH = CH- (CH2) 2-CF2-, Y = -CH2CH2-, R3 and R4 of Li and R3 and Ré of Mi = hydrogen, R7 = n-butyl is prepared as follows:

3 a, 5 a-Dihydro-2 ß-carboxaldehyde-1 a-cyclopentane-acetic acid-7-lactone is aeylated with benzoyl chloride, the 3 a-benzoyl-oxy-5 a-hydroxy-2ß-carboxaldehyde-1 a- cyclo-pentanoacetic acid-y-lactone obtained. This 3a-benzoyloxy compound is then reacted with the corresponding Wittig reagent to give the 3a-benzoyloxy-5a-hydroxy-2ß- (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid-Y-lactone. According to a known regulation, this compound is then converted into the 3a-benzoyloxy-5a-hydroxy-2ß- (3-oxo-

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octyl) -la-cyclopentanacetic acid-7-lactone transferred. The above unsaturated lactone is used to produce the 3a-benzoyloxy-5a-hydroxy-2ß - [(3S) -3-hydroxy-octyl] -la-cyclopentanacetic acid-7-lactone. This compound is then deacylated and etherified, the corresponding compound, namely a 3 a, 5 a-dihydro-2β - [(3S) -3-hydroxyoctyl] -l a-cyclopen-tanoacetic acid-Y-lactone-bis- ( tetrahydropyranyl ether). This compound is alkylated with the Wittig reagent 3,3-difluoro-4-carboxybutyltriphenylphosphonium bromide, whereby the 2,2-difluoro-13,14-dihydro-PGF2a-11,15-bis- (tetra-hydropyranyl ether) is obtained. This compound is then esterified with a slight stoichiometric excess of diazomethane in ether, giving the 2,2-difluoro-13,14-dihydro-methyl ester II, 15-bis (tetrahydropyranyl ether). The title compound is obtained from this by mildly acidic hydrolysis of the 11,15-bis-tetrahydropyranyl ether groups.

B. 1.50 g of the reaction product according to Part A are converted into the 2,2-difluoro-13,14-dihydro-PGF2a-methyl ester-15-tetrahydropyra-nyl ether by the method of Example 1, Part A.

C. The product according to Part B is then converted into the 2,2-difluoro-13,14-dihydro-PGD2-15-tetrahydropyranyl ether according to the procedure of Example 1, Part B.

D. The product of Part C is then hydrolyzed to form the title compound using the procedure of Example 1, Part C. The mass spectrum of the title compound shows a basic peak at 485.3196 and further peaks at 533, 477, 458, 443, 387, 371, 368, 281 and 173; IR absorptions at 3420, 3000, 2970, 2860, 1765, 1735, 1445, 1350, 1320, 1270, 1215, 1200, 1150 and 1090 cm-1.

Example 5

2a, 2b-Dihomo-PGD2-15-methyl ether (formula CV: Ri = hydrogen, Zi = cis-CH = CH- (CH2) s-, Y = trans —CH = CH -, R3 and R4 of Li = hydrogen, Rs and Rö of Mi = hydrogen or methyl, R7 = n-butyl). Compare Scheme A. 1.0 g of 2a, 2b-dihomo-PGF2a-15-methyl ether and 25 ml of acetone are cooled in an ice / methanol bath. Then Jones reagent (1 ml, 2.67 millimoles chromium trioxide) is added over 1 minute. The mixture is stirred at -20 ° C for 20 minutes, then 1 ml of isopropanol is added. The mixture is stirred for a further 10 minutes at -20 ° C and then diluted with 100 ml of water and extracted with diethyl ether. The ether extracts are washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The resulting mixture is concentrated under reduced pressure and 40 ° C, whereby a water-containing oil is obtained. For this purpose, 75 ml of benzene are added, and 0.87 g of an orange oil is obtained on evaporation. The aqueous phases are extracted with methylene chloride and the methylene chloride extracts are dried over magnesium sulfate after washing with water. Concentration under reduced pressure and 40 ° C gives 1.0 g of an orange oil. The oils are combined and chromatographed on 100 g of silica gel washed with acid while eluting with 25 to 75% ethyl acetate in Skelly-solve B to give 197 mg of the title compound as a pale yellow oil. The mass spectrum shows peaks at 394, 392, 376, 362, 344, 321, 289 and 273; IR absorptions at 3400, 3000, 2930, 2860, 2670, 1735, 1710, 1460, 1410, 1380, 1275, 1200, 1095, 1080 and 975 cnT1; NMR absorptions 0.7-1.1.1.1-2.6, 2.6-3.2, 3.3, 3.4-3.72, 4.4-4.64, 5.38 -5.62 and 6.25-6.85 Ô.

Example 6

PGDi (formula CV: Ri = hydrogen, Zi = - (CH2) 5-, Y = trans-CH = CH—, R3 and R4 of Li =

Hydrogen, Rs and Re of Mi = hydrogen, R7 = n-butyl). Compare Scheme A.

A. Following the procedure of Example 1, Part A, 2.0 g of PGFia are transferred to 2.0 g of PGFiu-15 tetrahydropyranyl ether.

B. According to the procedure of Example 1, Part B, the product according to Part A is converted to 0.90 g PGDi-15-tetrahydropyranyl ether.

C. According to the procedure of Example 1, Part C, 210 mg of the title compound are obtained from the reaction product according to Part B.

Example 7

cis-4,5-didehydro-PGDi or 15-epi-cis-4,5-didehydro-PGDi (formula CV: Ri = hydrogen, Zi = cis-CH2-CH = CH- (CH2) 2-, Y = trans -CH = CH -,

R3 and R4 of Li = hydrogen, Rs and R6 of Mi = hydrogen, R7 = n-butyl).

A. 0.97 g of 15-epi-cis-4,5-didehydro-PGFi "are prepared according to the procedure of Example 1, Part A in 1.2 g of 15-epi-cis-4,5-didehydro-PGF" -15 - tetrahy dropyranyl ether transferred.

B. 0.65 g of the reaction product according to Part A are reacted according to the procedure of Example 1, Part B to 0.98 g of 15-epi-cis-4,5-didehydro-PGD 1-15-tetrahydropyranyl ether.

C. 980 mg of the reaction product according to Part B are converted into the 15-epi title compound by hydrolysis according to the procedure of Example 1, Part C, whereby 150 mg of this product are obtained. The mass spectrum of a silylated derivative shows a basic peak at 640.3813.

If the procedure of Example 7, parts A to C, is repeated using the (15S) -epimeric starting material, the title compound cis-4,5-didehydro-PGD 1 is obtained; IR absorptions at 3420, 3000, 2920, 2860, 2660, 1735, 1715, 1450, 1390, 1165, 1135, 1075 and 970 cm-1. The mass spectrum of a silylated derivative shows a basic peak at 568.3431 and further absorptions at 553, 550.497, 478, 463, 407, 388, 356 and 299. NMR absorptions at 0.6-1.8, 2.3-2, 5, 4.4-4.7, 5.2-5.7 Ô.

Example 8 cis-4,5-didehydro-PGD i-methyl ester The title compound is obtained by esterifying the product according to Example 7 with excess diazomethane in ether; IR absorptions at 3440,3010,2930,2860,1740, 1440,1360,1255,1235, 1200, 1165,1135,1030, 985 970 cm-1. The mass spectrum of a silylated derivative shows a basic peak at 410.3204 and further absorptions at 595, 579, 593, 420, 405, 340, 199 and 173; NMR abroptions at 0.6-2.5, 2.5-3.7, 3.68, 3.8-4.2, 4.3-4.6 and 5.1-5.6 Ô .

Example 9

cis-4,5-didehydro-PGD 1 -methyl ester-15-methyl ether According to the procedure of Example 1, part B, the cis-4,5-didehydro-PGFi «methyl ester-1 5-methyl ether is converted into the title compound. The mass spectrum shows peaks at 380, 365, 349, 348, 309, 291, 259, 227, 141 and 105; IR absorptions at 3440, 2930, 2860, 1730, 1440, 1250, 1190, 1170, 1085, 1035, 980 cm-1; NMR absorptions at 0.7-1.1-1.1-3.1, 3.29, 3.35-3.65, 3.68, 4.45-4.68 and 5.3-5, 6 Ó.

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Example 10

cis-4,5-didehydro-15-methyl-PGD i-methyl ester According to the procedure of Example 1, part B, 200 mg of cis-4,5-didehydro-15-methyl-PGFi «methyl ester in 0.02 g the title compound transferred, base peak in the mass spectrum at 524.3465 and further peaks at 509, 506, 453, 434 and 363; NMR absorption at 0.90, 1.27, 3.66, 4.56 and 5.3-5.92 ò, characteristic infrared absorption at 3440.1750 and 980 cm-1.

Example 11

5-oxa-PGDi methyl ester (formula CV: Ri =

Methyl, Zi = -CH2-0- (CH2) 3-, Y = trans-CH = CH-, R3 and R4 from Li = hydrogen, Rs and Rö from Mi = hydrogen, R7 = n-butyl).

A. According to the procedure of Example 1, Part A, 0.85 g of 5-oxa-PGFi methyl ester is converted into 0.58 g of 5-oxa-PGFi methyl ester 15-tetrahydropyranyl ether; NMR absorptions at 0.88.0.8-2.6.2.88, 3.48.3.67, 3.2-4.4-4.7 and 5.28-5.65 ô; IR absorptions at 3430.1740, 1440.1365, 1320, 1260, 1200, 1170, 1115, 1075, 1020 and 985 cm "1.

The mass spectrum of the bis-trimethylsilyl derivative shows a basic absorption at 600.3847.

B. According to the procedure of Example 1, Part B, 1.00 g of the reaction product according to Part A is converted to 0.45 g of 5-oxa-PGDi-methyl ester-15-tetrahydropyranyl ether; NMR absorptions at 0.87, 0.7-3.05, 3.05-4.28, 3.64, 4.47, 4.72 and 5.17-5.78 Ô.

C. The title compound is obtained by hydrolysis following the procedure of Example 1, Part C. This gives 0.45 g of the product according to Part B 0.20 g of the title compound; NMR absorptions at 0.87.3.50.3.63.4.05.4.46 and

5.47 Ò; IR absorptions at 3440.2930, 2860.1740.1440, 1370.1255.1225, 1195.1175, 1115.1010, 970 cm-1. The mass spectrum of the bis-trimethylsilyl derivative shows a basic absorption at 514.3112 and further peaks at 499, 496, 443, 425, 424, 353, 334, 199 and 173.

Example 12

9-Deoxy-9,10-didehydro-PGD2 (formula CXII: Ri = hydrogen, Zi = cis-CH = CH- (CH2) 3-, Y = trans-CH = CH -, R3 and R4 of Li and Rs and R6 from Mi = hydrogen, R7 = n-butyl). Compare Scheme B.

Amounts of PGD2 are subjected to silica gel chromatography until about 3.9 g of less polar (than PGD2) impurities are obtained from eluate fractions.

The 3.9 g of less polar impurities are then chromatographed on 1.2 kg silica gel packed with 5% acetone in methylene chloride, eluting with 10 to 15% acetone in methylene chloride. This gives the partially purified title compound (1.2 g), which is chromatographed on 200 g of neutral silica gel, which is packed with acetic acid, methanol and chloroform (1: 1:18). The column is washed with 800 ml of acetic acid, methanol and chloroform (1: 1: 48) and then the above partially purified product is applied to the column. Elution with acetic acid, methanol and chloroform (1: 1: 48) gives 0.56 g of the title compound as a yellow oil; IR absorptions at 3450, 15 2980, 2900, 2700, 1740, 1720, 1600, 1460, 1440, 1410, 1350, 1240, 1170, 1025 and 970 cm-1; NMR absorptions at 0.90.4.15, 5.60, 6.60 and 7.65 ô. The mass spectrum shows a basic peak at 478.2912.

Using the procedure of Example 12, all 20 PGD-like compounds described herein are converted into the corresponding 9-deoxy-9,10-didehydro-PGD-like compounds.

Example 13

25 9-Deoxy-9,10-didehydro-13,14-dihydro-PGD2

(Formula CXII: Ri = hydrogen, Zi = ice—

CH = CH - (CH2) 3 -, Y = - CH2CH2 -, Rs and R4 of Li = hydrogen, Rs and Re of Mi = hydrogen, R7 = n-butyl).

30 A. Following the procedure of Example 1, 13,14-dihydro-PGF2 is converted to 13,14-dihydro-PGD2.

B. According to the procedure of Example 12, the product is converted according to Part A to the title compound.

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Example 14

9-deoxy-9,10-didehydro-2,2-difluoro-13,14-di-hydro-PGD2-methyl ester (formula CXII: Ri = methyl, Zi = cis-CH = CH- (CH2) 2-CF2- , Y = -CH2CH2-, R3 and 40 R4 of Li = hydrogen, Rs and R6 of Mi =

Hydrogen, R7 = n-butyl). Compare Scheme B.

The title compound is prepared from the product of Example 4 using the procedure of Example 12. The mass spectrum of a silylated derivative shows a basic peak at 45 458.2664 and further peaks at 443, 387, 368, 358, 330 and 173; IR absorptions at 3440, 3020, 2920, 2860, 1770, 1705, 1590, 1545, 1350, 1315, 1270, 1215, 1195, 1090, 1050 and 975 cm-1.

B

Claims (2)

626338 2 PATENT CLAIMS 1. Process for the preparation of a new prostaglandin analogue of the formula ch2-z1-coor1 yc — c-r7 Ii II mj li wherein Y cis-CH = CH—, trans-CH = CH— or —CH2-CH2- or = CH-CH2- means Zi (1) cis-CH = CH-CH2- (CH2) g-CF2-, (2) cis-CH = CH-CH2- (CH2) g-CH2-, (3) cis-CH2-CH = CH- (CH2) g-CH2-, (4) - (CH2) 3- (CH2) g-CF2-, (5) - (CH2) 3- (CH2) g-CH2-, (6) -CH2-0-CH2- (CH2) g-CH2-, (7) - (CH2) 2-0- (CH2) g-CH2-, (8) - (CH2) 3-0- (CH2) g-, ch2- (ch2) g-, O- (CHa) - R3 R4, R4, or a mixture of Rs and R3 R4 R4, in which R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that 35 one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, Rt (l) - (CH2) m-CH3, (2) (3) _. JT) s - ° {2f - 50 55 -CHz <2T (T), or (4) cis-CH = CH-CH2-CH3, wherein m is a number from 1 to 5, T is chlorine, fluorine, the trifluoromethyl radical, an alkyl radical of 1 to 3 carbon atoms or alkoxy radical of 1 to 3 carbon atoms and s is 0.1, 2 or 3, the individual radicals T may be the same or different 60, provided that no more than 2 radicals T can be different from alkyl, provided that R7 only then 65 where g is the number 1, 2 or 3, JT) S -er ■ 626 338 4th means when R3 and R4, which may be the same or different, are hydrogen or methyl, and Ri is hydrogen, an alkyl radical with 1 to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, the phenyl radical or a through 1, 2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms substituted phenyl radical or a pharmacologically acceptable cation, characterized in that (1) the corresponding PGE «or PGE i compounds of the formula in which Y" cis-CH = CH - or trans-CH = CH- means the 11-OH group is selectively oxidized to form PGD or 9p-PGD compounds of the formula ho yc — cr, (1) cis-CH = CH-CH2- (CH2) r-CF2-, (2) cis-CH = CH-CH2- (CH2) g-CH2-, (3) cis-CH2-CH = CH- (CH2) g-CH2-, (4) - (CH2) 3- (CH2) g-CF2-, (5) - (CH2) 3— (CH2) g-CH2—, (6) -CH2-0-CH2- (CH2) g-CH2-, (7) - (CH2) 2-0- (CH2) r-CH2-, (8) - (CH2) 3-0- (CH2) g-, (9) or (10) -) g "' 0 ° "(CH2) n" where g is the number 1, 2 or 3, Mi Are hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, R? (l) - (CH2) m-CH3, (iv) 10th 15 (2) (3) -K3T or (4) cis-CH = CH-CH2-CH3, 25 in which m is a number from 1 to 5, T is chlorine, fluorine, the trifluoromethyl radical, an alkyl radical of 1 to 3 carbon atoms or alkoxy radical of 1 to 3 carbon atoms and s is 0, 1, 2 or 3, the individual radicals T can be the same or different, provided that no more than 2 radicals 30 T can be different from alkyl, provided that R7 only then 35 <T) S ■ Rs ORö or Rs ORô, in which Rs and Ró are hydrogen or methyl, provided that one of the radicals Rs and R6 is methyl only if the other denotes hydrogen, Li rT ^ R4, R3 ^ "^ R4, or a mixture of RT ^ R4 and R3 '' ~ ^ R4, wherein R3 and R4, which can be the same or different, means when R3 and R4, which may be the same or different 40, are hydrogen or methyl, and Ri is hydrogen, an alkyl radical with 1 to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, the phenyl radical or represent a phenyl radical substituted by 1, 2 or 3 chlorine atoms or alkyl radicals having 1 to 3 carbon atoms 45 or a pharmacologically acceptable cation, characterized in that (1) in corresponding PGFA or PGFβ compounds of the formula 50 ho ho ch2-z1-coor1 y-c-c-r-7 ii ii (I) the 11-OH group to form PGD or 9β-PGD-60 compounds of the formula 65 , ch2-z1-coor1 (II) II II Mi Li 3rd 626 338 selectively oxidized and (2) the reaction product of step (1) dehydrates to form 9-deoxy-9,10-didehydro- or 13,14-didehy-dro-12,13 (E) -didehydro-9-dioxy-9,10- didehydro-PGD compound of the formula ch2-z1-coor1 y-c-c-r7 II II Mi Li (IV) ORÓ, 10 in which Rs and R6 are hydrogen or methyl, provided that one of the radicals Rs and R6 is methyl only if the other denotes hydrogen, Li 15 wherein the substituents are defined above. 2. The method according to claim 1, characterized in that that compounds obtained in which Ri is hydrogen are converted into the corresponding salts. 3. The method according to claim 1, characterized in that compounds obtained in which Ri is hydrogen are converted into the corresponding esters. 4. The method according to claim 1, characterized in that saponified compounds in which Ri is different from hydrogen are saponified to free acid. 5. The method according to claim 1, characterized in that hydroxy groups present in the 15-position are etherified as intermediates while the first stage is being carried out. 6. Process for the preparation of a new prostaglandin analogue of the formula Rs 20th 25th CH2-Z1-COOR1 (IV A) Y-C-C-R7 H i y Mi Li where Y '= CH-CH2-, Room (2) the reaction product of formula II A from stage (1) isomerized to give 13,14-dihydro-12,13 (E) -didehy-dro-PGD- or 13,14-dihydro-12,13 ( E) -didehydro-9i-PGD compounds of the formula and (3) the reaction product of step (2) dehydrates to form a 9-deoxy-9,10-didehydro- or 13,14-didehydro-12,13 (E) -didehydro-9-deoxy-9,10-didehydro-PGD compound of the formula ^ ch2-z1-coor1 y-c-c-r wherein the substituents are defined above.