NO144830B - SUBSTITUTED CYCLOPENTAND DERIVATIVES FOR USE AS INTERMEDIATE BY PREPARING A PHYSIOLOGY ACTIVE PROSTAGLAND CONNECTION OF THE E OR F SERIES - Google Patents

Description

The present invention relates to new substituted cyclopentane derivatives useful as intermediate products in the production of the new physiologically active prostaglandin compounds described in patent 14 3,741.

The prostaglandins are C-20 unsaturated fatty acids that have different physical effects. Prostaglandins of the E and A series are e.g. powerful vasodilators (Bergstrom et al, Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al,

Life Sei. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration- (Weeks and King, Federation Proe. 23:327, 1964, Bergstrom et al, 1965, op. eit; Carlson et al., Acta Med. Scand. 183:423-430, 1968;

and Carlson et al., Acta Physiol. Scand. 75:161-169, 1969).

Another well-known physiological effect of PGE^ and PGE2 is

as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969) ..

Yet another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE2 is known to induce labor (Karim, et al.,

J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman et al., Contraception, £.29 3

(1971) and be useful for the regulation of fertility (Karim,

Contraception, 3, 173 (1971)). Patents have been obtained for a number of prostaglandins of the E and F series for inducing labor in mammals (Belgian patent 754.158 and West German patent 2.034.6 41) and for PGF^, and F3 for regulating the reproductive cycle (South African patent 69/ 6089). It has been shown that luteolysis can take place as a result of the administration of PGF2ct [Labhsetwar, Nature 230, 528 (1971) ] and prostaglandins can thus be used to regulate fertility by a method where stimulation of the smooth muscles is not necessary .

Further known physiological effects of PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, In:

Worcester Symp. on Prostaglandins, New York, Wiley, 1968,

pp. 55-64) and also of the platelet agglomeration (Emmons et al, Brit. Med. J. 2:468-472, 1967).

It is well known that such physiological effects can be induced in vivo for only a short time after the administration of a prostaglandin. Literature indicates that the reason for this rapid cessation of action is that the natural prostaglandins are quickly and efficiently deactivated metabolically by |3-oxidation of the carboxylic acid side chain and by oxidation of the 15<x-hydroxyl group (Anggard et al., Acta, Physiol. Scand. 81, 396 (1971)

and references listed here). It has been shown that the placement of a 15-alkyl group in the prostaglandins increases the duration effect probably by preventing the oxidation of C15-hydroxyl-

group [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1, 319 (1972).

It has of course been considered desirable to produce analogues of prostaglandins which have physiological effects which are similar to the natural compounds, but where the selectivity of action and the duration of action have been increased. Increased selectivity of action would be expected to reduce the serious side effects, especially stomach and intestinal side effects, which are often observed after systemic administration of natural prostaglandins (Lancet, 536, 1971).

According to the invention, intermediate products for the production of physiologically active prostaglandin compounds of the E or F series are provided with the formula:

where Ar is α- or (3-furyl, α- or 3-thienyl, α- or |3-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl wherein the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;

W is a single bond or a cis-double bond;

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

n is an integer from 0 to 5, with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1,

and Z is a single bond.. Their preparation is described in patent 14 3,741.

The intermediate products according to the invention have the formula:

where Ar, n, M, W and Z are as above, and THP is 2-tetrahydropyranyl. The new intermediates according to the invention can be prepared by reacting a compound of formula IVA

where Ar, n and Z are as indicated above, with a ylide of the formula

(CgH5)3P=CH-CH2-CH2-CH2-COO(<_>)

and achieves a connection with the formula

where Ar, n and Z are as indicated above and W is a cis-double bond, and if necessary then hydrogenates the compound to give a compound of formula V where Ar, n and Z are as indicated above and W is a single bond.

The compound of formula V above, wherein Ar and n are as above, W is a cis double bond and Z is a trans double bond, may be reduced to form a compound of formula V above wherein Ar and n are as above and W and Z are single bonds.

The compound of formula V above, wherein Ar and n are as defined above, W is a cis double bond and Z is a trans double bond, may be selectively hydrogenated to form a compound of formula V wherein Ar and n are as defined above, W is a single bond and Z is a trans double bond. The intermediate product according to the invention with the formula: where Ar, n, W, Z and THP are as indicated above, can then be prepared by reacting a compound of formula V

where Ar, n, W and Z are as above, with chromic acid in aqueous sulfuric acid and acetone.

The above reactions are described with reference to compounds where the 15-tetrahydropyranyl ether group is in α-configuration. The 15fS compounds can be prepared in the same way starting from the appropriate 3-configuration compound.

Conversion of the new intermediate products according to the invention to the physiologically active prostaglandin compounds of formula I is described in patent 143,741.

The following examples are given to illustrate the production of the new intermediates. In these examples, all temperatures are given in °C, all melting and boiling points are uncorrected and all biological test data are expressed in

% effect of PGE2 or administered at the same level

(ie PGE2 = 100) if nothing else is stated.

Example 1

a) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2ft-(3a-(tetrahydropyran-2-yloxy)-4-phenylbut-T-y1)cyclopentyl-la-yl]acetaldehyde, y - hemiacetal

A solution of 1457 mg (3.2 mmol) of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)cyclopentane -la-yl]acetic acid, γ-lactone in 15 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere.

5.0 ml was added dropwise to this cooled solution

20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics)

at such a rate that the internal temperature did not exceed " about -65° (3 minutes). After further stirring for 30 minutes at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to The reaction mixture was - added 150 ml of ether, washed with 50% sodium potassium tartrate solution (1 x 50 ml), dried (Na2SO4), concentrated and chromatographed, gave 1200 mg (81.5%) of 2-[5α-hydroxy- 3α-(tetrahydropyran-2-yloxy)-20-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)-cyclopent-1-yl]acetaldehyde, γ-hemiacetal.

b) 9a- hydroxy- lla, 15a- bis-(tetrahydropyran-2- yloxy)- 16-phenyl- cis- 5- ai- tetranor- prostenic acid

10.8 ml (21.1 mmol) of a 1 .96M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1200 mg (2.6 mmol) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2(3-(3α-(tetrahydropyran-2-yloxy)- 4-phenyl-but-l-yl)cyclopent-la-yl]-acetaldehyde, γ-hemiacetal prepared above in 7.0 mL of dry dimethyl sulfoxide over 20 min. After stirring for an additional 2 h at room temperature,

the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate

(3 x 100 mL) and the combined organic extracts were washed once with water (50 mL), dried (MgSO 4 ) and evaporated to a dry residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of high Rf impurities, 880 mg of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl 1-cis-5-ui-tetranor-prostenic acid was obtained.

Infrared spectrum (CHC1.,) showed a carbonyl adsorption

at -1

at 1715 cm

The product obtained can be converted to 16-phenyl-w-tetranor-13,14-dihydro-PGF2a by hydrolysis with a 65:35 mixture of acetic acid and water and purification by column chromatography on Mallinckrodt CC-4 silica gel using ethyl acetate

as eluent.

Example 2

9- oxol- la, 15a- bis-(tetrahydropyran-2- yloxy)- 16- phenyl- cis- 5-a)- tetranor- prostenic acid

To a solution, cooled to -10° under nitrogen, of 880 mg

(1.68 mmol) 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-w-tetranorprostenic acid in 15 ml of analytical grade acetone was added dropwise to 0.75 ml (2 mmol) of Jones reagent. After 20 minutes at -10°, 0.75 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and was then mixed with 100 ml of ethyl acetate, washed with water (3 x 25 ml), dried (MgSO 4 ) and concentrated , and gives 775 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-co-tetranorprostenic acid. Infrared spectrum (CHC1-.) showed

-1

carbonyl adsorptions at 1710 and 1735 cm

Example 3

9a- hydroxy- lla, 15a- bis( tetrahydropyran-2- yloxy)- 16-( 2- thienyl)-cls- 5- trans- 13- a)- tetranor- prostadic acid

5.7 ml (11.4 mmol) of a 2 .2M solution of sodium methylsulfinyl methide in dimethylsulfoxide. A solution was added dropwise to this red ylide solution

of 1.03 g (2.2 mmol) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-20-(3α-(tetrahydropyran-2-yloxy)-4-(2-thienyl)-trans -1-buten-1-yl)cyclopent-la-yl]-acetaldehyde, Y-hemiacetal in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3

with 10% aqueous hydrochloric acid. The acidic solution was extracted

with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed 1 time with water (10 mL), dried (MgSO 4 )

and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and the filtrate concentrated to give 1.02 g of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13- u)-tetranor-prostadic acid. Infrared spectrum shows a strong band at 1700 cm^ along with absorptions between 2800 to 2600 cm* for the carboxyl group.

Example 4

9-oxol-lla, 15g-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-. cis- 5- trans- l 3- cii- tetetphanor- prostadic acid

To a solution cooled to -10° under nitrogen of 1.02 g (1.86 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5 -trans-13-w-tetranor-prostadic acid in 18 ml of analytical grade acetone was added dropwise to 0.82 ml (2.04 mmol) of Jones reagent. After 20 minutes by

-10° was added 0.260 mL of 2-propanol and the reaction mixture was stirred for a further 5 minutes and was then combined with 75 mL of ethyl acetate, washed with water (3 x 10 mL), dried (MgSO 4 )

and concentrated, giving 952 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-w-tetranor-prostadioic acid which was chromatographed on silica gel by applying

ethyl acetate as eluent and gives 760 mg of pure compound. In the same way, the corresponding 3-thienyl compounds which are epimeric at C₁ can be prepared.

Example 5

9a-hydroxy-llg, 15a-bis-.(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-o)-tetranorprostenic acid

To a solution of 5150 mg (11.6 mmol) of (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 10.1 ml of dry dimethyl sulfoxide is added 10.8 ml (21.1 mmol) of a 1.96 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution is added dropwise a solution of 1300 mg (2.6 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-20-(3a-(tetrahydropyran-2-yloxy)-4-( 2-thienyl)but-1-yl)cyclo-pent-la-yl]-acetaldehyde, ■f-hemiacetal in 7.0 ml of dry dimethyl sulfoxide during 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture is poured onto ice water. The basic, aqueous solution is acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution is extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts are washed once with water (50 ml), dried (MgSO 4 ) and evaporated to a solid residue in The solid residue is triturated with ethyl acetate and filtered. The filtrate is purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of high R₂ impurities, 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-io-tetranor-prostenic acid is obtained.

Example 6

9-oxol-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-a)-tetranorprosthenic acid

To a solution cooled to -10° under nitrogen of 950 mg (1.68 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ur -tetranorprostenic acid in 15 ml acetone of analytical quality is added dropwise to 0.75 ml (2 mmol) of Jones reagent. After 20 minutes at -10°, 0.75 ml of 2-propanol is added and the reaction mixture is stirred for a further 5 minutes. and then combined with 100 ml of ethyl acetate, washed with water

(3 x 25 ml), dried (MgSO 4 ) and concentrated, -and gives 9-oxo-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-a> -tetranorprostenic acid.

Example 7

a) Methyl- 9g- acetoxy- llg-( tetrahydropyran-2- yloxy)- 15- oxo- trans- 13- 16- ( 3- thienyl)- ix)- tetranorprostenoate

To a suspension of 110 mg (2.61 mmol) of a 57.0% dispersion of sodium hydride in mineral oil in 20 ml of dimethoxyethane was added 646 mg (2.61 mmol) of dimethyl-2-oxo-3-(3-thienyl) propyl phosphonate. The mixture is stirred at room temperature for 1 hour under nitrogen. To this suspension is added a solution of 0.947 g (2.37 mmol) of impure aldehyde prepared in example 6 in 4 ml of dimethoxyethane. The resulting somewhat cloudy brown solution is stirred at room temperature for 2 hours under nitrogen. The reaction is then stopped by addition of glacial acetic acid to pH 7 and concentrated by rotary evaporation. The crude product is purified by column chromatography on silica gel and

gives the desired methyl 9α-acetoxy-11a-(tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-(3-thienyl)-co-tetranorprostenoate.

b) Methyl- 9a- acetoxy- ria-( tetrahydropyrah- 2- yloxy)- 15- hydroxy- trans- 13- 16-( 3- thienyl) - co- tetranorprostenoate

To a solution of 1.60 g (2.17 mmol) of the enone prepared in ia) in 6.5 ml of dimethoxyethane was added dropwise 2.17 ml (1.08 mmol) of a 0.5 M Zn(BH4)2)- solution in dimethoxyethane. After stirring at room temperature under nitrogen i

3 hours the reaction was stopped by the dropwise addition of a

saturated aqueous solution of sodium bitartrate until gas evolution ceased. The heterogeneous solution is stirred at room temperature for 5 minutes, diluted with methylene chloride, dried (anhydrous magnesium sulfate) and concentrated to give methyl-9α-acet6xyl-lla-(tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16- (3-thienyl)-w-tetranorprostenoate.

c) Methyl- 9a- acetoxy-lla, 15g- dihydroxy- trans- 13- 16-( 3- thienyl)- αV- tetranorprostenoate and methyl- 9a- acetoxy- 11a, 15a- dihydroxy- trans- 13- 16-( 3 - thienyl) - co-tetranor-prostenoate

A solution of 1.60 g (2.16 mmol) of impure THP ether prepared in b) in 10.7 ml of a 65:35 mixture of acetic acid:water re-

stirred at 40 1 2° under nitrogen for 2.5 hours. The reaction mixture is then concentrated to give impure epimeric diol mixture.

The crude product is purified by column chromatography on silica gel, and gives the desired methyl-9α-acetoxy-lla,15B-dihydroxy-trans-13-16-(3-thienyl)-w-tetranorprostenoate and the epimeric methyl-9a-.acetoxy-lla,15a -dihydroxy-trans-13-16-(3-thienyl)-w-tetranor-prostenoate.

d) Methyl-9a-acetoxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)- ai-tetranorprostenoate

A mixture of 0.223 g (0.510 mmol) of the chromatographed diol in c), 0.14 ml (1.53 mmol) of dihydropyran, 4.2 ml of methylene chloride and 1 crystal of p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, washed with saturated aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate) and concentrated to give the desired methyl-9α-acetoxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3 -thienyl) -co-tetranor-prostenoate.

e) 9a-hydroxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-to-tetranorprostenic acid (according to the invention)

A homogeneous solution of 0.26 3 g (0.4 36 mmol) of the crude bis-THP ester prepared in d), 1.3 ml (1.30 mmol) of 1.0 N aqueous sodium hydroxide solution, 1.3 ml of methanol and 1 .3 ml of tetrahydrofuran is stirred under nitrogen overnight. The reaction is then stopped by the addition of 1.30 ml (1.30 mmol) of a 1.0 N aqueous hydrochloric acid solution. The solution is diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concentrated, giving the crude product. The crude product is purified by column chromatography on Baker "Analyzed" silica gel (60-200 mesh), and gives 9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-w -tetranor-"prostenic acid.

f) 9-oxo-lla, 15a-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(3-thienyl)-a-tetranorprostenic acid (according to the invention)

To a solution, cooled under nitrogen to -15 to

-20° of 0.201. g (0.371 mmol) of chromatographed acid prepared 1 e) in 4.0 ml of acetone is added dropwise 0.163 ml (0.408 mmol)

of Jones reagent. The reaction is stirred cold for 15 minutes and is then stopped by the addition of 0.194 ml of isopropanol. The reaction is stirred cold for 5 minutes and then diluted with ethyl acetate. The organic solution is washed with water (2 x)

and saturated salt solution (1 x), dried (anhydrous magnesium sulfate)

and is concentrated and gives the desired 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(3-thieny])-w-tetranorprostenic acid.

Example 8

9g- hydroxyl- lla, 15a- bis- (tetrahydropyran- 2- yloxy) - 17- ( 2- fuiryl) - cis- 5- trans - 13— 03— tris norpros t adiene sy re

To a solution of 3.36 g (7.6 mmol) of (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide in a dry nitrogen atmosphere in 15.0 ml of dry dimethyl sulfoxide was added 7.0 ml (14.0 mmol)

of a 2.0M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.3 g (2.81 mmol) of 2-[5g<->hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-(tetrahydropyran-2-yloxy) )-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-la-yl]-acetaldehyde, Y-hemiacetal in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After further

After stirring for 2 hours at room temperature, the reaction mixture was poured onto ice water. The slightly basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acidified solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh)

by using ethyl acetate as eluent. After removal of high R^ impurities, 1.53 g of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-w-

trisnor-prostadic acid•

Example 9

9- ox- lla, 15a- bis-(tetrahydropyran-2- yloxy)- 17-( 2- furyl)- cis- 5- tr ans- 13- ai- trisnor- prostadic acid

To a solution cooled to -10° under nitrogen of 1.1 g (2.01 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5 -trans-13-w-trisnor-prostadic acid in 20 ml of analytical grade acetone was added dropwise to 0.88 ml (2.2 mmol) of Jones reagent. After 20 minutes at -10°, 0.260 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and 75 ml of ethyl acetate was added, washed with. water (3 x 10 mL), dried (MgSO 4 ) and concentrated to give 425 mg of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5- trans-13-a)-trisnor-prostadic acid.

Claims (1)

Substituted cyclopentane derivative for use as an intermediate in the preparation of a physiologically active prostaglandin compound of the E or F series with the formula: where Ar is α- or 3-furyl, α- or 3-thienyl, α- or 3-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; W is a single bond or a cis-double bond; Z is a single bond or a trans double bond; n is an integer from 0 to 5, with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1, and Z is a single bond, characterized in that it has the formula: where Ar, n, M, W and Z are as above, and THP is 2-tetrahydropyranyl.