NO762123L - - Google Patents

Description

This invention relates to the production of new prostane derivatives and in particular new prostane derivatives which inhibit gastric acid production in mammals.

According to the invention, a prostane derivative is produced with the formula?

where R is a carboxy or hydroxymethyl radical, a 2 C0 -3 alkoxycarbonyl radical or a C2_5 alkoxymethyl radical, R and R , which may be the same or different, are each a hydrogen atom or a C1_4 alkyl radical, X is an ethylene or vinylene radical, Y is an ethylene or trans-vinylene radical, n is 1, 2 or 3, and R4 is a C^_^-alkyl radical or a phenyl-, phenoxy-, phenylthio- or phenyl(C^_^-alkyl )-radical where the aromatic ring is unsubstituted or substituted with one or more halogen atoms, nitro or phenyl radicals, C, .-alkyl, alkoxy or haloalkyl radicals

J--« 4 or di(C, A-alkyl) amino radicals, provided that when n is 1 and R

x~ 2 3

is an alkyl or•phenyl radical, at least one of R and R is an alkyl radical, and for those compounds where R 1 is a carboxy radical, the pharmaceutically or veterinary acceptable base addition salts thereof.

A suitable meaning for R^" when it is an alkoxycarbonyl radical is, for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl radical, and a suitable meaning for

R^" when it is an alkoxymethyl radical, is, for example, a methoxymethyl, ethoxymethyl/propoxymethyl or butoxymethyl radical.

2 3

A suitable meaning for R or R when one of them is an alkyl radical is e.g. a methyl, ethyl, propyl or buty1 radical.

A suitable meaning for R<4> when it is an alkyl radical is e.g. a propyl, butyl, pentyl, hexyl or heptyl radical, especially an n-butyl radical.

Suitable halogen substituents in R 4 when it is a substituted phenyl-,; phenoxy-, phenylthio- or phenyl(C 2 -alkyl) radical, is, e.g.

chlorine, bromine or fluorine atoms, in particular a chlorine atom, and suitable alkyl, alkoxy and haloalkyl substituents are e.g. methyl-, ethyl'-, methoxy-, ethoxy-, trifluoromethyl- or. 2,2,2-trichloroethyl radical, especially a trifluoromethyl radical.

A suitable meaning for X when it is a vinylene radical is e.g. a cis-viriylene radical. Examples of suitable base addition salts are ammonium salts, alkylammonium salts containing 1 to 4

C 1 -alkyl radicals, alkanolammonium salts containing 1 to 3 2-hydroxyethyl radicals and alkali metal salts, e.g. the ammonium, triethylammonium, ethanolammonium, diethanolammonium, sodium and potassium salts.

The preferred group of prostane derivatives produced according to the invention are those compounds where R1 is a carboxy, 23 methoxycarbonyl or ethoxycarbonyl radical, R and R are each a hydrogen atom, X is an ethylene or cis-vinylene radical, Y is a

4 trans-vinylene radical, and R is a benzyl, phenethyl or phenoxy radical, optionally substituted with a chlorine atom or a trifluoromethyl radical, in particular a benzyl, 3-chlorobenzyl, phenethyl, 2- or 3 - chlorophenoxy or 3-trifluoromethylphenoxy radical.

A preferred compound is 15-[1-(3-chlorophenoxy)cyclobutyl]-11a,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor=5-cis,13-trans-prostadienic acid .

It will be seen that a prostane derivative produced according to the invention contains at least four asymmetrically substituted

carbon atoms, namely carbon atoms 8, 11, 12 and 15 in the prostane nucleus, and that carbonate pm 2 can also be asymmetrically substituted. Although

, the relative configurations at the carbonate beams 8, 11 and 12 have been determined,

it is therefore clear that a prostane derivative prepared according to the invention,

can exist in a variety of racemic and optically active forms. It is to be understood that this invention encompasses the preparation of any of the racemic or optically active compounds of formula I which have the above-mentioned favorable gastric acid-inhibiting properties,

since it is generally known how the racemates bg the optically active forms can be obtained and their gastric acid-inhibiting properties determined.

The new: prostane derivatives of formula I- are prepared according to 12 3 4 to the invention as follows (where R , R , & , R , n, X and Y have the meanings given above unless otherwise stated):

(a) for the preparation of the compounds where R"*" is a carboxy-

' 3 or alkoxycarbonyl radical and R is a hydrogen atom, hydrolysis under acidic conditions of a compound of the formula:

where R is a carboxy<sy>,C 21 ,j-alkoxycarbonyl" or C 2-5~ alkoxymethyl radical, R^ is a tetrahydropyran-2-yl radical, e.g. with acetic acid, or with toluene-p -sulfonic acid in a C1-4-alkanol or (b) for the preparation of the compounds where R1 is an alkoxy-carbonyl radical, reaction of a carboxylic acid of formula I where R1 is a carboxy radical, with a C1-4-diazoalkane, or of a salt thereof, e.g. a sodium or silver salt, with a C 12 -alkyl halide, e.g. an alkyl bromide or alkyl iodide; or ■ (c) for the preparation of the compounds where R 1 is a hydroxymethyl radical, reacting a compound with the formula: 7 where R is a hydroxy-, C 1-6 -alkyloxy-, ureido- or thio-ureido radical, with a nitrite, e.g. sodium nitrite in acetic acid; or (d) for the preparation of the compounds, where R 3 is an alkyl radical, hydrolysis of a tri(C 3 -alkyl)silyl ether with the formula: 3 8 9 10 where R is a: C^^-alkyl radical, and R , R and R which may be the same or different, are each a C^-^-alkyl radical? or (e) for the preparation of the compounds where R 3 is an alkyl radical, selective oxidation, e.g. with Jones reagent, av a compound with the formula:

h<y>or R is a C^_4-alkyl radical and R has the above-mentioned meaning, after which isomers if necessary. 9-oxo and 11-oxo products are separated in the usual way, e.g. by chromatography. A starting material of formula II wherein R 5 is a carboxy-2 3 radical, R and R are each a hydrogen atom, X is a cis-#inylene- radical and Y is a trans-vinylene radical, can be prepared by reacting 43-formyl-2,3,3a3,6a3-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)-cyclopenteno[b]furan (VT) with a phosphonate reagent of the formula (C₁₋-4-Alkoxy)^O.CHjCOR, where R is a group of the formula

in the presence of a strong base, to give an enone VII. Enone VII is reduced, e.g. with aluminum triisopropoxide or diisobornyloxy aluminum isopropoxide to an enol VIII, which is hydrolysed, e.g. with potassium carbonate in methanol, to remove the protective 4-fehyi^ benzoyl radical, to form a diol IX. the biolen is protected as the bis(tetrahydropyranyl ether) X by reaction with dihydropyran, because the lactone ring is reduced to a lactol XI using e.g. diisobutyl aluminum hydride. The lactol XI is then treated with et (4-carboxybutyl)triphenylphosphonium bromide in the presence of a strong base to give a compound XII, which is oxidised, e.g. with Jones reagent, to form a starting material of formula II. The conditions used in the preparation of the compound XIl£ can of course be chosen so that one mainly obtains either the 5-cis or 5-trans compound, in a known manner.

A suitable phosphonate reagent (MeO) ^PO.CHjCOR where R is a 1-butylcyclopentyl radical can be prepared from cyclopentanecarboxylic acid known therein by alkylation with butyl bromide in the presence of a

strong base, to form 1-butylcyclopentane carboxylic acid, and conversion to the methyl ester, which is then treated with dimethyl methyl phosphonate or diisopropyl methyl phosphonate in the presence of a strong base such as butyl-lithium,-- Analogous phosphonate reagents. where R<4> is an alkyl, phenyl or phenylalkyl radical, which is necessary for the preparation of other starting materials II, can be prepared in an exactly similar manner.

A suitable phosphonate reagent where R is a 1-phenoxy or 1-Tphenyl-thio-cycloalkyl radical can be prepared from the known cycloalkane carboxylic acid by bromination with bromine and red phosphorus, working up the reaction mixture in methanol to form the corresponding methyl-1- bromocycloalkane carboxylate, which is reacted with the required phenol or thiophenol to give the desired starting material II.

A corresponding starting material of formula II where X is an ethylene radical can be obtained by selective hydrogenation of a corresponding compound of formula II where X is a cis-vinylene radical.

A corresponding starting material of formula II where Y is an ethylene radical can be prepared by hydrogenation of a corresponding enone intermediate VII to form a saturated ketone, which is then used in the above-described reaction sequence instead of simple VII.

A starting material of formula III can be prepared from a corresponding prostane derivative of formula I where R^ is a carboxy or

7 alkoxycarbonyl radical, by reacting it with a compound R NHj* e.g. hydroxyamine or semicarbazide, in the presence of sodium acetate, to form et-derivative XIII which is reduced, e.g. with lithium aluminum hydride, to form the desired starting material III

A starting material of formula IV can be prepared from a bis-(tetrahydropyranyl ether) XII by hydrolysis of the tetrahydropyranyl groups to form a starting material of formula V (R^==carboxy) and oxidation with dichlorodicyanobenzoquinone to an enone XIV. The enone XIV is silylated to a tris(trimethylsilyl) derivative XV, which is treated with a Grignard reagent 3 ... R Mg.halogen to form an alcohol XVI. The silyl groups are removed, and the acid is esterified to form an ester XVII, which is monosilylated with R8R9R10Si.NEt2 in acetone wet approx. -20°C to form a silyl derivative XVIII; which is oxidized with Collins reagent to a starting material IV (R^* = methoxycarbonyl).

It should of course be understood that an optically active compound

the product according to the invention can be obtained either by cleavage of

a corresponding racemate or by carrying out the reactions described above starting from an optically active intermediate, e.g. an optically active aldehyde VI.

As indicated above, the new prostane derivatives produced according to the invention have the ability to inhibit the production of stomach acid in mammals, and they have the advantage that they are relatively non-toxic, which means that there is a high "therapeutic ratio" between toxic dose and effective dose. E.g. 15-[1-(3-kylbrophenoxy)-cyclobbutyl]-lia,15-dihydroxy-9-oxo-16,17,18,19,20-pentanebr-5-cis,13-trans-prostadienic acid inhibits gastric acid formation to a degree of 89% wet

an experiment on an anesthetized rat, at a subcutaneous dose of 20 ug/kg, and to a degree of 65% in an experiment on a Heidenhain's marsupial, at a dose of 0.5 ug/kg i.v., but does not produce symptoms of acute toxicity 1 the dog at doses up to 500 yg orally.

When a prostan derivative produced according to the invention is to be used for reducing gastric acid production in humans, it is used in essentially the same way as it is known to use prostaglandin E2 or (15S)- or (15R)-15-methyl-prostaglandin E2-methyl ester for similar purpose. Such prostaglaridine analogs have been administered orally, in aqueous solution, in doses of 2.5 to 4.0 mg for prostaglandin E2, and 100 to 200 µg for (15S)- and (15R)-15-methyl prostaglandin E2 methyl ester. The latter compound has been found to promote the laying of gastric ulcers in Chinese subjects by oral administration in an amount of 150 ug in 20 ml of water at 6-hour intervals in

Two weeks.

The new prostane derivatives of formula I can thus be incorporated

in pharmaceutical or veterinary medicinal preparations together with a

pharmaceutical or veterinary acceptable diluent or carrier.

The preparation is preferably in the form of a tablet or capsule or an essentially aqueous solution, and a preferred preparation is an essentially aqueous solution containing 100 to 500 ug/ml, preferably 150 to 300 ug/ml of the prostane derivative.

The preparations can be prepared in the usual way and can contain usual pharmaceutical excipients in addition to the active ingredient and the diluent or carrier. E.g. the preparations can be stabilized in a known manner, e.g. by adding dimethylacetamide,. an alkali metal or alkaline earth metal bisulfite or a C4_1Q

saturated aliphatic tertiary alcohol.

The following examples shall serve to further illustrate the invention.

Example 1

A solution of 15-(1-butylcyclopentyl)-9-oxo-yl-15-bis(tetrahydro-6-pyran'-2-yloxy)-16,17,18,19/20-pentanor-5-cis#13-. trans-prostadienic acid (93 mg) in tetrahydrofuran (2.1 ml) and a 1:1 v/v mixture of acetic acid and water (5.8 ml) were stirred at 45°G for 4 hours. The solvents were evaporated under reduced pressure and the residue was chromatographed on a column of Mallinkrodt CC4 silica gel (4.4 g) using 30% acetone in cyclohexane as eluent. Evaporation of the solvent gave the molar C-15 epimer of 15-(l<-butylcyclopentyl)-11a, 15-dihydrobxy-9-oxo-16,17,18,19,20-pentanbr-5-cis,13-trans- prostadic acid, Ry a 0.3, (3% volume/volume acetic acid in ethyl acetate), The nuclear magnetic resonance spectrum in deuterated acetone showed the following characteristic values (6 values):

3,9, ,5H, multiplet, ^CH-0 and -0-H,

5,4, 2H, multiplet, cis-olefinic protons,

5.75; 2H, multiplet, trans-olefinic protons

The mass spectrum for the 1,11,15-tris(trimethylsilyl)-9-methoxyme derivative showed (M-CH3)+ = 636.3935 (calculated for C34H65N05Si3=636.3913).

The bis(tetrahydropyranyl ether) used as starting material can be prepared as follows: n-butyllithium (71 ml of a 1.37M solution in hexane) was added to a solution of diisopropylamine (14.2 ml) in tetrahydrofuran (150 ml) at 178°C in an atmosphere of argon. After stirring for 10 minutes at -78°C, the solution was warmed to <*>0°C, and cyclopentanecarboxylic acid (5 g) was added. After stirring at 0°C i

25 minutes, butyl bromide (6.1 ml) was added, and the resulting

product was stirred at 0°C for 5 hours, then cooled to room temperature i

-1 hour.: The mixture was neutralized with hydrochloric acid, bg the organic solvents were evaporated under reduced pressure. The resulting solution was acidified to pH 1 with hydrochloric acid and extracted

with ethyl acetate (2 x 75 ml). The combined organic solutions were washed with hydrochloric acid (2 x 50 ml), water (50 ml), saturated sodium bicarbonate solution (2 x 50 ml) and brine (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was distilled (96°C, 6.35 mm Hg) for. to give 1-butylcyclopentanecarboxylic acid as a clear oil. The NMR spectrum in deuteriochloroform had the following characteristic signals (6-values)s 0.9, 3H, triplet, -CH3(J = 6 Hz),

10.5, 1H, multiplet, -COOH 1-butylcyclopentanecarboxylic acid (6.1 g) was dissolved in diethyl ether,

and an ethereal solution of dlazomethane, cooled to 0°C, was slowly added until the solution retained a permanent yellow color. Excess diazomethane was evaporated in a stream of argon, and the organic solvent was evaporated under reduced pressure to give methyl-1-butyl-cyclopentanecarboxylate as a clear oil, whose n.m.r. spectrum in deuteriochloroform had the following characteristic signals $5- values) s 0.9, 3H, triplet, CH^-CH, (J 10 Hz), 3.65, 3H, singlet, -C00CH3Butyl-iitium (37.2 ml of a 1.43 M solution in hex an- ) was added to a solution of dimethyl methylphosphonate (5.75 mL) in dry tetrahydrofuran (100 mL) at -70°C in an atmosphere of argon. After lp minutes

methyl 1-butylcyclopentanecarboxylate (4.89 g) was added dropwise,

and the mixture was stirred for 2 hours at -70°C. * The cold reaction mixture was poured into rapidly stirred 1N hydrochloric acid (56.6 ral), and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The mixture was extracted with diethyl ether (3 x 100 mL), the combined extracts were washed with brine (2 x 100 mL) and dried, and the solvents were evaporated under reduced pressure to give dimethyl-2-(l-butylcyclopentyl) -2-oxoethyl-phosphidnate. The nuclear magnetic resonance spectrum (N.M.R.) in deuteriochloroform showed the following -..v characteristic bands (6-values): 0

3.15, 2H, doublet, -C-CH2-, (JC.H 2_p" = 22 Hz),

3.85, 6H, doublet, (CH3O)2<P=->, (<J>CH_p =<1>1 Hz).

Dimethyl r2-(1-butylcyclopentyl)-2-oxoethylphosphonate (2.48 g) was suspended in toluene (40 ml) in an atmosphere of argon, and 43-formyl-2,3,3α£,6α3-tetrahydro-α-oxo -5α-(4-phenylbenzoyloxy)-cyclopenteno[b]furan (2.10 g) was added to the ice, followed by aqueous sodium hydroxide (7.5 mL of a 1 IM solution). The two-phase mixture was stirred vigorously for 3 hours, the layers were allowed to settle, and the toluene was separated. The aqueous layer was extracted with ethyl acetate (4 x 10 mL), the combined organic extracts were washed with brine and dried, and the solvent was evaporated to dryness. Trituration of the residue with ether gave the enone, 40-[3-(1-Butylcyclopentyl)-3-bxo-1-trans-propenyl]-2,3,3aØ,6a3^tetrahydro-5a-(4-phenylbenzoyloxy)-2 -oxocyclopenteno[b]furan, Rp =0.8 (50% vol/vol ethyl acetate in toluene). The N.M.R. spectrum in deuteriochloroform showed the following characteristic bands (6 values):

6.55, 1H, doublet, -CH=CH-C0-, (J-•» 18 Hz),

6.85, 1H, double doublet, -CH=CH-C0- (J^» 18.0Hz), (J1_4= 7.0 Hz),

7,5, 7H, multiplet, aromatic protons,

8,1, 2H, doublet,

The enone (0.75 g) was stirred under an atmosphere of argon at 70°C with a 0.36 M solution of diisobornyloxy aluminum isopropoxide in toluene (104 mL, 25 equivalents) for 48 h. After cooling the reaction mixture to room temperature, it was saturated with water

sodium hydrogen tartrate (40 mL) was added and the solution was stirred rapidly at room temperature for 30 minutes. The aqueous layer was separated and extracted with ethyl acetate (3 x 25 mL), the combined organic extracts were dried, and the solvent was evaporated to give a

mixture of isoborneol and the mixed epimers of the unsaturated alcohol, .43-[3-(1-butylcyclopentyl)-3-hydroxyl-trans-propenyl]-2,3,3αØ,6α|3-tetrahydro-5α-( 4-phenylbenzoyloxy)-2-oxocyclopenteno[b]-furan, Rp = 0.4 (50% v/v ethyl acetate in toluene), which was used without purification in the next reaction.

The mixture of isoborneol and epimers: unsaturated alcohols prepared above was stirred vigorously for 2 hours with finely powdered anhydrous potassium carbonate (208 mg) in a mixture of dry methanol (7.5 ml) and dry methylene chloride (0.25 ml). 1N hydrochloric acid (3.0 mL) was added, followed by ethyl acetate (100 mL). The organic layer became

separated,: washed successively with saturated sodium bicarbonate and saturated saline; dried and evaporated to dryness, and the residue chromatographed on "Florisil" magnesium silicate (180 g). Elution with ether removed the by-products, isoborneol and methyl-4-phenylbenzoate, and

subsequent elution with ethyl acetate gave a mixture of the epimeric dioies, -oxocyclopenteho[b]furan,

Rp = 0.3 (ethyl acetate).

To a solution of the epimeric diols (443 mg) in methyl ene dichloride (10 ml) under an atmosphere of argon was added successively. redistilled 2,3-dihydropyran (1.16 mL) and a solution of anhydrous . toluene-p-sulfonic acid in tetrahydrofuran (28 µl of a 0.1 M solution).

After 15 minutes, pyridine (7 drops) was added, followed by ethyl acetate (40 mL). The solution was washed successively with sat. sodium bicarbonate solution and saturated saline and was dried.

Evaporation of the solvents gave a mixture of epimeric bis-tetrahydropyraryl ethers as a clear oil, Rp 0.8 (50% v/v ethyl acetate in toluene). To a solution of the epimeric bis-tetrahydropyranyl ethers (1.38 mmol) in dry toluene (10 mL) under an atmosphere of argon wet

-78°C was added to a solution of diisobutylaluminum hydride in toluene (1.06 ml of a 1.95 M solution). After 20 minutes the reaction was . quenched by dropwise addition of methanol (5 ml), and after after an additional 15 minutes at room temperature, a mixture of 1:1 v/v saturated saline/water (25 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The extract was washed with saturated saline and dried, and the solvents were removed steamed too. to give a mixture of epimers and bis-(tetrahydropyrahyl ether) lactolene, 43-[3-(l-butylcyclopehtyl)-3-(tetrahydropyran-2-yloxy)- 1-trans-propenyl]-2,3,3aØ,6aØ-tetrahydro-2-hydroxy-5a-(tetrahydro-.pyran-2-yloxy)cyclopenteno[b]furan, Rp = 0.3 (50% v/v ethyl acetate in chloroform). .(4-carboxybutyl)triphenylphosphonium bromide (9.05 g) and potassium t-Butoxide (4.4 g) was suspended in dry toluene (130 mL) under an atmosphere of argon and stirred at 90°C for 30 min to give a deep red 0.151 M toluene solution of the ylide which was allowed to cool to room temperature. The lactol (585 mg) was dissolved in dry toluene (15 mL)

under an atmosphere of argon, and the ylide solution was added (21 mL of the 0.151 M toluene pp solution). After 10 minutes at room temperature

became. water (1 ral) added and toluene evaporated. The remaining aqueous solution was extracted with ether (3 x 2 mL), adjusted to pH 4 with oxalic acid and extracted with ether (2 x 20 ml) to give an acid extract. The combined sour extracts were dried, and evaporation of the solvents gave the mixed C-15 epimers of 15-(1-but<y>lc<y>chloro<p>ent<y>l)-9<x-hydroxy -lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadic acid, Rp = 0.4 (10% v/v methanol in methylene dichloride ), which was purified by dry column chromatography on Merck "Kieselgel 60", particle size 0.063-0.2 mm,

developed in ethyl acetate.

Eri solution of 15-(1-butylcyclopentyl)-9α-hydroxy-11a,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadioic acid ( 100 mg, 0.178 mmol) in acetone, (2 mL) at 0°C was treated with 8N chromic acid (58 µl, 0.46 mmol) for 45 min. Isopropanol was added and the solution was diluted with ethyl acetate (15.ml), washed with brine (10ml) and dried. Evaporation of the solvent gave the mixed C-15 epimers of 15-(1-butyl-cyclopentyl)-9-oxo-lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19-20-pentanor -5-cis,13-trans-prostadienic acid, Rp 0.7 (3% vol/vol acetic acid in ethyl acetate).

Example 2 The procedure described in Example 1 was repeated, using 43-[3-(1-butylcyclohexyl)-3-hydroxy-1-trans-propenyl7-2,3,3a3,6a3-tetrahydrp-5a-(4-phenylbenzoyloxy )-2-oxo-cyclopenteno-[b]furan instead of 43-[3-(1-butylcyclopent)-3-hydroxy-1-trans-propenyl]-2,3,3a3,6a3-tetrahydro-5a-(4 -phenylbenzoyloxy)-2-oxo= cyclopenteno[b]furan, to form 15-(1-butylcyclohexyl)-lia,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis ,i3-trans-prostadienic acid, Rp ^ 0.3 (3% v/v acetic acid in ethyl acetate). The N.M.R. spectrum in defatted acetone showed the following characteristic values (6 values) s

4.0, 2H, multiplet, ^CH-0-, 5.4, 2H, multiplet, cis-olefinic protons,

5.5, 3H, multiplet, -0H

5,7, 2H, multiplet, trans-olefinic protons The above product was prepared via the following intermediates (N.M.R. spectra are for deuteriochloroform solutions (6 values)\s

40r[3-(1-butylcyclohexyl)-3-hydroxy-1-trans-prbpenyl]-2,3,3aØ-r6aØ-tetrahydro-5a-hydroxy-2-oxocyclopentenotb]furan, =0.3 (ethyl acetate) 40- [3-(1-Butylcyclohexyl)-3-(tetrahydropyran-2-yloxy)-1-trans-propenyl]-2,3,3aØ,6aØ-tetrahydro-2-oxo-5a-(tetrahydropyran-2-yloxy)cyclopenteno [b]furan, Rp - 0.8 (50% vol/vol ethyl acetate in toluene)»

, 40-[3-(1-butylcyclohexyl)-3-(tetrahydropyran-2-yloxy)-1-trans-propenyl]-2,3,3aØ,6aØ-tetrahydro-2-hydroxy-5a-(tetrahydropyran-2- yloxy)cyclopenteno[b]furan, Rp = 0.3 (50% vol/vol ethyl acetate in chloroform)„ ! . 15-(1-Butylcyclohexyl)-9α-hydroxy-11a,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadieric acid, Rp =0 ,4 (10% vol/vol methanol in methylene dichloride)0 15-(1-butylcyclohexyl)-9-bxo-lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-peritanor- 5-cis,13-trans-prostadioic acid, R , = 0.7

(3% vol/vol acetic acid in ethyl acetate).

The allyl alcohol used as starting material in this part was prepared by repeating the second part of Example 1 using cyclohexane carboxylic acid instead of cyclopentane carboxylic acid to form the following intermediates

1-butylcyclohexane carboxylic acid,

0.9, 3H, triplet, -CH3(J = 10 Hz)

10.8, 1H, multiplet, -C00H,

methyl-1-butylcyclohexane-carboxylic acid

0.85, 3H, triplet, -CH2CH3 (J = 10 Hz),

3.65, 3H, singlet, -CO0CH3Butyl lithium (25.8 mL of a 1.37 M solution in hexane) was added to a solution of diisopropyl methylphosphonate (6.38 g) in dry tetrahydrofuran (60 mL ) at -70°C in an atmosphere of argon. After 10 minutes, a solution of methyl 1-butyl cyclohexane carboxylate was obtained

(3.5 g) in dry tetrahydrofuran (5 ml) added dropwise, and the mixt

was stirred at -70°C for 2 hours and then at room temperature for 1.6 hours, The reaction mixture was poured into rapidly stirred 1N hydrochloric acid

(35.4 mL), and the mixture was extracted with diethyl ether (2 x 100 mL). The pooled extracts were washed with saturated saline (2 x 100 ml)

and dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure to give diisopropyl 2-(1-butylcyclohexyl)-2-oxoethylphosphonate.

The N.M.Ro.spectrum in deuteriochloroform showed the following characteristic bands (5-values)s

1.35, 12H, doublet, -OCH(CH3)2, (JCH_CH3<=><6.>5 Hz)

3,1, 2H/ doublet, -CI-CH2-, fJCH2-P a 21 Hz)

4,8, 2H, multiplet, -OCH(CH3)2(JCH_C<H>3<=>S' 5 Hz)•

Butyl lithium (7.7 mL of a 1.43 M solution in hexane) was added slowly to a stirred solution of diisopropyl-2-(1-butylcyclohexyl)-2-oxoethylphosphonate (4.52 g) in dry 1.2 -dimethoxyethane (50 ml) at -70°C in an atmosphere of argon. After 20 minutes, 40-formyl-2,3,3afJ,6a3-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)cyclopenteno[b]-furan was solid. (3.5 g) was added, the suspension was allowed to warm to room temperature and was stirred for 3 hours. The solution was neutralized by the addition of acetic acid, and the solvents were evaporated under reduced pressure. The residue was partitioned between brine and ethyl acetate, and the aqueous layer was re-extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were dried, the organic solvents were evaporated under reduced pressure, and the residue was triturated with

ether to give the enone 40-[3-(1-butylcyclohexyl)-3-oxo-1-trans-propenyl]-2,3,3aB,6ap-tetrahydro-5a-(4-phenylbenzoyloxy)-2-oxo-cyclopenteno [b]furan, R^, = 0.8 (50% v/v ethyl acetate in toluene).

The N.M.R. spectrum in deuterated acetone showed the following characteristic bands (<Sr values) s

7.85, 2H, singlet, -CH=CH-C0-,

7,6, 7H, multiplet, aromatic protons,

8,15, 2H, doublet,

The enohete (2.3 g) was stirred under an atmosphere of argon at -70°C with a 0.36 M solution of diisobornyloxy-aluminium isppropoxide in toluene (64 ml) for 24 hours, and at room temperature for a further 72 hours.

Saturated aqueous sodium hydrogen tartrate (60 mL) was added to the reaction mixture and the solution was stirred rapidly at room temperature for 30 minutes. The aqueous layer was separated and extracted with ethyl acetate (3 x 50 mL), the combined organic extracts were dried, and the solvent was evaporated to give a mixture of isoborneol and the mixed epimers of the desired 40-[3-(1-butylcyclohexyl )-3-hydroxyT-1-trans-prdpenyl]-2,3,3a0,6afJ-tetrahydro-5a-(4-phenylbenzoyloxy)-2-oxocyclopenteno[b]furan, Rj, = 0.5 (50% vol/ volume of ethyl acetate in toluene), together with an amount of 40-[3-(1-butylcyclohexyl)-3-hydroxy-1-trans-propenyl]-2,3,3a3,6a3-tetrahydrb-5a-hydroxy-^ 2-oxocyclopenteno[b]furan and probably isopropyl-4-phenylbenzoate formed as by-products, which were used without purification in the next step.

Example 3

The procedure described in Example 1 was repeated using the appropriate 15-substituted bis-(tetrahydropyranyl ether) as starting material, and reduction of enonene with 5 equivalents of diisobornyloxy aluminum isopropoxide for 6 hours, to form the following products: (a) 15- [1-(3-Chlorobenzyl)cyclobutyl]-110,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadioic acid, R^= 0.14 ( glacial acetic acid: ethyl acetate: toluene = 3:50:50 by volume), N.M.R. in

deuterated acetone (6 values):

3.9-4.4, 2H, multiplet, CH-OH

7,1-7,4, 4H, multiplet, aromatic protons The mass spectrum of the 1,11,15-tris(trimethylsilyl)-9-methoxyme derivative showed M<+>m 705.3467 (calculated for C36HgoClN05Si3 705.3464.

15-[1-(3-chlorobenzyl)cyclobutyl]-bis(tetrahydropyranyl-etherene) used as starting material was prepared by a series of reactions as described in the second part of Example 1, using 3-chlorobenzyl bromide instead of butyl bromide, to form methyl 1-(3-chlorobenzyl)cyclobutanecarboxylate, m.p. 147-156°C/10 mm Hg, N.M.R. in deuteriochloroform (6 values):

1.7-2.6, 6H, multiplet, -CH2-CH2-

3,1, 2H, singlet, -CH«Ar

3,7, 3H, singlet, -C00CH3

6.9-7.4, 4H, multiplet, aromatic protons,

which was used instead of methyl-1-butylcyclopentanecarboxylate in the last part of the reaction run.

(b) 15-(1-phenethylcyclobutyl)-lia,15-dihydroxy-9-oxo-16;17,18,-19,;20-pentanor-5-cis,13-trans-prostadioic acid, Rp = 0.6 (3% vol/vol glacial acetic acid in ethyl acetate), N.M.R. in deuterated acetone (6 values): 4.0-4.3, 2H, multiplet, -CH(OH)-

7.25, 5H, singlet, aromatic protons.

The mass spectrum for the 1,yl,15-tris(trimethylsilyl)-9-methoxyme derivative showed (M-Me)+= 670.3788 (calculated for C3gH60NO5Si3670.3775).

The 15-(1-phenethylcyclobutyl)-bis(tetrahydropyranyl ether) used as starting material was prepared by the reaction process described in the second part of example 1 using phenethyl bromide instead of butyl bromide, to form methyl 1-phenethylcyclobutane carboxylate, Rj, = 0, 9 (ethyl acetate), N.M.R. in deuteriochloroform (6-values)p

3,7, 3H, singlet, -C00CH3

7,25, 5H, singlet, aromatic protons,

which was used instead of methyl-1-butylcyclopentanecarboxylate in the last part of the reaction. (c) 15-(1-benzylcyclobutyl)-11a,15-dihydroxy-9-oxo-16,17,18,-19,20-pentanor-5-cis,13-trans-prostadioic acid, R , =0, 4 (2% volume/volume glacial acetic acid in ethyl acetate), N.M.R. in deuterated acetone (6 values):

3.9-4.3, 2H, multiplet, ^TCH-OH

7,3, 5H, singlet, aromatic protons.

The mass spectrum for 1,11,15-tris(trimethylsilyl)-9-methoxy de±lvated viste (MHÆe)<+>= 656.3590 (calculated for C35H5gN05Si3 = 656.3619).

The 15-(1-benzylcyclobutyl)-bis(tetrahydropyranyl ether) used as starting material was prepared by the reaction process described in the second part of example 1, using benzyl bromide. instead of butyl bromide, to form methyl 1-benzylcyclobutanecarboxylate, R^, = 0.8 (ethyl acetate), N.M.R. in deuteriochloroform (6 values): 1.7-2.6, 6H, multiplet, -CH2C<H>2<->3.2, 2H, singlet, -CH2Ar 3.7, 3H, singlet, -C00CH37.3, 5H, singlet, aromatic protons, which were used instead of methyl-1-butylcyclopentanecarboxylate in the remainder of the reaction.

Example 4

The procedure described in Example 1 was repeated, using 15-[1-(3-chlorophenoxy)cyclobutyl]-9-bxo-lla,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19, 20-pentanor-5-cis,13-trans-prostadioic acid in place of the 15-(1-butylcyclopentyl) starting material, to form 15-[1-(3-chlorophenoxy)cyclobutyl]-lia,15-dihydroxy-9-oxo- 16,17,18,19,20-pentanor-5-cis,13-trans-prostadic acid,

Rp 0.3 (3% vol/vol acetic acid in ethyl acetate). The N.M.R. spectrum

in deuterated acetone they showed the following characteristic values (6-values)p

6>8-7.4, 4H, multiplet, aromatic protons.

The mass spectrum for the 1,11,15-tris(trimethylsilyl)-9-methoxyme derivative showed M<+>■ 707.3220 (calculated for C35H58ClN06Si3 = 707.3257).

The starting material that was used in the above method was obtained by the course of the reaction described in the second part

of Example 1, using methyl 1-1-(3-chlorophenoxy)-cyclobutanecarboxylate instead of methyl-1-butylcyclopentanecarboxylate, and reduction of the enone, with 5 equivalents of diisobornyloxyammonium isopropoxide for 6 hours. Methyl 1-1-(3-chlorophenoxy)cyclobutanecarboxylate was prepared as follows:

Bromine (75 g) was added dropwise over a period of

2 hours to one mixture of cyclobutanecarboxylic acid (25 g) and red

phosphorus (1.5 g). After carefully heating the mixture on a steam bath for 3 hours, excess bromine was removed under a rapid stream of argon. After cooling, the product was poured into methanol

(100 ml) which had been cooled in an ice bath, and bee stirred for 1 hour. The methanol-opium extract was then poured into brine (250 mL) and extracted with diethyl ether (4 x 150 mL). The combined organic extracts were evaporated to dryness, the residue was dissolved in diethyl ether (100 ml), washed with aqueous sodium thiosulphate solution (2 x 25 ml), aqueous sodium bicarbonate solution (2 x 25 ml) and brine (25 ml). and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oil which was distilled under vacuum to give methyl 1-bromocyclobutanecarboxylate

(b.p. 110°C/100 mm Hg), = 0.6 (ethyl acetate). The N.M.R. spectrum i

Deuteriochloroform had the following characteristic values (6-values):

1.8-3.2, 6H, multiplet, -CH2~

3,9, 3H, singlet, -COOCHg.

Methyl 1-bromocyclobutanecarboxylate (10 g), 3-chlorophenol (6.7 g) and finely ground variegated potassium carbonate (3.58 g) were heated at 100°C in dry dimethylformamide (50 ml) under an atmosphere of argon for 56 h . The reaction mixture was then cooled to room temperature, poured

in water (50 ml) and extracted with diethyl ether (3 x 100 ml). The combined organic solutions were washed with dilute aqueous sodium hydroxide (2 x 25 mL) and water (2 x 25 mL), dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil which was distilled under vacuum. The main faction,

a pale yellow oil (b.p. 105°C/0.1 mm Hg) was finally purified by dry column chromatography on Merck "Kieselgel 60" (particle size 0.063-0.2 mm), eluting with toluene, to give methyl 1-1 -(3-chlorophenoxy)cyclobutanecarboxylate as a clear oil, Rp = 0.6 (toluene). The N.M.R. spectrum in deuteriochloroform showed the following characteristic absorptions (6 values):

1.8-2.9, 6H, multiplet, -CH^-

3,7, 3H, singlet, -C00CH3

6.4-7.4, 4H, multiplet, aromatic protons.

Example 5

The procedure described in Example 4 was repeated using the appropriate 15-(1-substituted-phenoxy)cyclobutyl-bis(tetrahydropyranyl ether) as starting material, to give the following products:

(a) 15-[1-(2-chlorophenoxy)cyclobutyl]-llo,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadioic acid, Rp = 0.5 (2% v/v glacial acetic acid in ethyl acetate), N.M.R. in deuterioacetone (6 values):

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

The mass spectrum for the 1,11,15-tris(trimethylsilyl)-9-methoxyme derivative showed (M-Me)<+>■ 692.3023 (calculated for C 34 H 55 ClNOgSi 3 - 692.3026).

(b) 11a, 15-dihydroxy-9-oxo-15-<[1-(3-trifluoromethylphenoxy)-cyclobutyl]-16,17,18,19,20-pentanor-5-cis,13-trans-prostadioic acid , Rp = 6.5 (3% v/v glacial acetic acid in ethyl acetate), N.M.R. in deuterio-acetone (6-values)p

7.05-^7.45, 4H, multiplet, aromatic protons.

The mass spectrum for the .1,11,15-tris(trimethylsilyl)^9-methoxyme derivative showed (M-Me)+ = 726.3268 (calculated for C35H55F3NOgSi3 = 726.3285). The starting material was prepared by the procedure described in the second part of Example 4, using the appropriate phenol in place of 3-chlorophenol, to give:

(a). methyl 1-(2-chlorophenoxy)cyclobutanecarboxylate, Ry ■= 0.6 (toluene), N.M.R. in deuteriochloroform (6-valent)s 1.8-3.0, 6H, multiplet, -CH23.7, 3H, singlet, -CO0CH3 (b) methyl 1-1-(3-trifluoromethylphenoxy)cyclobutanecarboxylate, Rp = 0.6 (toluene), N.M.R. in deuteriochloroform (6 values):

1.8-3.0, 6H, multiplet, -CH2~.

3,7, 3H, singlet, -C00CH3

6,7-7,5, 4H, multiplet, aromatic protons, which were used instead of methyl 1-1-(3-chlorophenoxy)-cyclobutane carboxylate in the rest of the reaction described.

Example 6 15-[1-(3-chlorophenoxy)cyclobutyl]-11a,15-dihydroxy-9-oxo-16,17,18,1?,20-pentanor-5-cis,13-trans-prostadioic acid (12, 5 mg) was dissolved in dry methanol (250 µl), and an ether solution of diazpmethane. was added dropwise until the solution remained yellow. Profit

of diazomethane was removed under a stream of argon, and the product was isolated by evaporating the organic solution to dryness under reduced pressure. The product was purified by thin layer chromatography on

"Kieselgel 60" F-254 plates, developed 1 ethyl acetate, to give methyl-15-[1-(3-chlorophenoxy)cyclobutyl]-lia,15-dihydrobxy-9-oxo-16,17,18,-

19,20-pentanor-5-cis,13-trans-prostadienoate, Rp = 0.5 (3% v/v glacial acetic acid in ethyl acetate). The N.M.R. spectrum in deuterated acetone showed the following characteristic features (6 values)s

3.65, 3H, singlet, -COOCH-

6.8-7.4, 4H, multiplet, aromatic protons. The mass spectrum of 11,15-bis(trimethylsilyl)-9-methoxyme<1>

the derivative showed M + = 649.2996 (calculated for C 33 H 52 ClN 06 Si 2 = 649.3018).

Example 7

The procedure described in Example 1 was repeated using 15-[1-(3-trifluoromethylphenoxy)cyclobutyl]-9-oxo-lla,15-bis(tetrahydropyran-2-yloxy)-16, 17, 18, 19, 20- pentanor-13-trans-prostenic acid instead of 15-(1-butylcyclopentyl-9-oxo-lla,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13 -trans-prostadienic acid to give 15-[1-(3-trifluoromethylphenoxy)cyclobutyl]-11a,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-13-trans-prostenic acid, Rp = 0.5 (3% vol/vol glacial acetic acid in ethyl acetate). The N.M.R. spectrum in deuterated acetone shows the following characteristic signals (6 values):

5.2-5.9, 3H, very broad singlet, OH . 5,8, 2H, multiplet, trans-olefinic protons

7.05-7.5, 4H, multiplet, aromatic protons. The mass spectrum for the 1,11,15-tris(trimethylsilyl)-9-methoxyme derivative showed (M-Me)"*V= 728.3407 (calculated for C 35 H 57 F 3 NO 6 Si 3 = 728.3398).

The bis-tetrahydropyran-2-yloxy starting material was prepared as follows: 15-[1-(3-trifluoromethylphenoxy)cyclobutyl]-9a-hydroxyllla,15-bis(tetrahydropyran-2-yloxy)-16,17,18, 19 i20-pentanor-5-cis,13rtrans-prostadic acid (400 mg) was dissolved in a mixture of dry ethanol and benzene (3:2 v/v, 25 mL), and tris(triphenylphosphine)rhodium chloride (150 mg) were added. The solution was stirred for 2 1/2 hours at room temperature under an atmosphere of hydrogen, then filtered through a pad of "Celite" diatomaceous earth. The organic solvents were evaporated under reduced pressure. The product was purified by dry column chromatography on "Kieselgel 60" (particle size 0.063-0.2 mm) eluting with 20% v/v acetone in cyclohexane, to give bis(tetrahydropyranyl terfcn), 15-[1-(3-trifluoromethylphenoxy) cyclobutyl]-9α-hydroxy-llo,15-bis(tetrahydro-pyran-2-yloxy)-16,17,18,19,20-pentanor-13-trans-prostenic acid, Rp = 0.8 (3% vol/ volume of glacial acetic acid in ethyl acetate on "Kieselgel 60" F-254 thin layer chromatography plate, impregnated with silver nitrate.

A solution of the bis(tetrahydropyranyl ether) (450 mg) i

acetone (5 ml) at 0°C was stirred with 8N chromic acid (170 µl) for 45 min. Isopropanol (0.2 mL) was added and the solution was diluted with ethyl acetate (25 mL), washed with brine (2 x 10 mL) and dried. Evaporation of the solvent gave the mixed C-15 epimers of 15-[1-(3-trifluoromethylphenoxy)cyclobutyl]-9-oxo-11a,15-bis(tetrahydropyran-2-yloxy)-13-trans-prosthenic acid, Rp = 0.68 (3% volume/volume glacial acetic acid in ethyl acetate).

Claims (3)

1.. Analytical method for the preparation of therapeutically active prostane derivatives with the formula: where R is a carboxy- or hydroxymethyl radical, e2 t C, 3,--alkoxycarbonyl radical or a 5-alkoxymethyl radical, R pg R , which can be the same or different, h<y>er is a hydrogen atom or a C^^-alkyl radical , X is an ethylene or vinylene radical, Y is an ethylene or trans-vinylene radical, n is 1, 2 or 3, and R<*>is a C^-alkyl radical or a phenyl-, phenoxy-, phenylthio- or phenyl-(Cj^^-alkyl) radical where the aromatic ring is unsubstituted or is substituted with one or more halogen atoms, nitro or phenyl radicals, C^-alkyl -, alkoxy or haloalkyl radicals or di-(C, , -alkyl) amino radicals, provided that when n is 1 and R is a .. -L-t■23 alkyl or phenyl radical, at least one of R and R is a alkyl radical? and for the compounds where R 1 is a carboxy radical, the pharmaceutically or veterinary acceptable base addition salts thereof, characterized in that a) for the preparation of the compounds where R 1 is a carboxy or alkoxycarbonyl radical, and R 3 is a hydrogen atom, are hydrolysed under acidic conditions a compound with the formula? 5 • • where R is a carboxy-, C2-5-alkoxycarbonyl- or C2-5-alkoxymethyl radical, and R6 is a tetrahydropyran-2-yl^radicalj or b) for the preparation of the compounds where R1 is an alkoxycarbonyl radical, a carboxylic acid is reacted with formula I where R1 is a carboxy radical, with a C^^-diaCoalkane, or a salt thereof with a C^^-alkyl halidej or c) for the preparation of the compounds where R1 is a hydroxy- methyl radical, is a compound with the formula reacted? ;where..'R is a hydroxy, C 1_4 alkoxy, ureido or thioureido radical, with a nitrite, in acetic acid? or d) for the preparation of the compounds where R 3 is an alkyl radical, a tri (C 3 -alkyl) silyl ether with the formula is hydrolysed: 3 8 9' IO 1 where R is a C₁-alkyl radical, and R , R and R , which may be the same or different, are each a C₁-alkyl radicalj or e) for the preparation of the compounds where R is an alkyl- radical; a compound with the formula 3 5 is selectively oxidized where R is a C 2 -alkyl radical, and R has the above stated be interpretation, where possibly isomeric 9-oxo and 11-oxo products are separated in the usual way, and optionally the compounds where R1 is a carboxy radical are converted into acceptable salts thereof.;2. Method as stated in claim 1 a) and b), characterized in that the starting material is used where R<*> is a carboxy-, methoxycarbonyl- or ethoxycarbonyl-2 3 radical, R and R are each a hydrogen atom, X is an ethylene or cis-vinylene radical, Y is a trans-vinylene radical, R is a benzyl, 3-chlorobenzyl^, phenethyl-, 2- or 3-chlorophenoxy^ or 3-trifluoro-methylph enoxy radical, and n is 1, 2 or 3. : 3. Process as stated in claim la) for the production of 15-[1-(3-chlorophenoxy)cyclobutyl]-11a,15-dihydroxy-9-oxo-16,17,18,- 19;20-pentanor-5-cis,13-trans-prostadienic acid, characterized in that a starting material is used 2 3 4 of formula II where R and R are each hydrogen, R is 3-chlorophenoxy, n is 1 and R is carboxy or converted thereto.