NO751974L - - Google Patents

Description

(lj5S)-Substituted Sul f inyl Prostaglandin Compounds.

Summary.

The present invention relates to new (1^S)-substituted sulfinyl-prostaglandins {2o<-substituted-3P - [(1S)-substituted sulfinyl-trans-2-octenyl]-1-oxygenated cyclopentane and 2oc-substituted-3p- [ (IS)-substituted sulfinyl-trans-2-octenyl]-4«,-hydroxy-1-oxygenated cyclopentanj' compounds of the formulas:

wherein R"*" is hydrogen or alkyl containing from one to three carbon atoms;

R 2 is hydrogen or hydroxyl;

~ R 3 is alkyl containing from one to six carbon atoms, cycloalkyl containing from five^ to seven carbon atoms, chloromethyl, trichloromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, p-chloroethyl, ^-chloroethyl, c\-chloro-p-trichloroethyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, 2,4-dichlorophenyl or 2,5-dichlorophenyl;

W is a saturated bond or a cis double bond;

the wavy line (•§) represents the ^ or fl configuration and non-toxic, pharmaceutically acceptable salts of these compounds.

The present invention also relates to new methods for producing compounds with formulas (A) and (B) from known (15S)-hydroxyprostaglandins.

Background.

1. The invention.

The present invention relates to (1^S)-substituted sulfinyl-prostaglandins {2<x-substituted-3p- C(1S)-substituted sulfinyl-trans-2-octenyl)-1-oxygensf cyclopentane and -2o^-substituted-3P - £(1S)-substituted-sulfinyl-trans-2-octenyl]-4ok-hydroxy-1-oxygenated cyclopentane^ compounds and new methods for their preparation.

More specifically, the invention relates to new prostaglandin-like compounds with formulas (A) and (B) above (whose nomenclature is discussed in more detail below) and new methods for producing these compounds from known (15S)-hydroxyprostaglandins.

2. Previous work.

Prostaglandins have classically been described as chemically related 20-carbon chain hydroxy fatty acids that have a basic skeleton of prostanic acids:

Prostanic acid.

The prostaglandins that have a hydroxyl group at the C-ll position and a keto group at the C-9 position are known as the PGE series, and those that have a hydroxyl group instead of the keto group are known as the PGF series and are further described with the designation or p to indicate the configuration of the hydroxyl group in the said position. The natural compounds are (X-hydroxy substituted compounds. They can contain different degrees of unsaturation in the molecule, particularly at C-5, C-lj5 and C-17 and the unsaturation is also indicated by a designation. Thus, for example, PGE -^ to a prostanic acid which has a trans olefin bond at the l^ position. For an overview of prostaglandins and definition of primary prostaglandins, one can see, for example, S. Bergstrøm, Recent Progress in Hormone Research 22, pp. 153-175 (1966) and Science 157, page J>82 (1967) by the same author.

Prostaglandins are widely distributed in mammalian tissues and they have been isolated from natural sources in very small amounts. In addition, a number of naturally occurring prostaglandins have been prepared by chemical synthesis, see, for example, J.Am.Chem.Soc. 91, 5675 (1969), J. Am. Chem. Soc. 92, 2586 (1970) and J. Am. Chem. Soc. 93, 1489-14-93 (1971) and references cited herein, W.P. Schneider et al., J. Am. Chem. Soc. 90, 5895'

(1968). U. Axen et al., Chem. Commun., 303 (1969), and W.P. Schneider, Chem. Commun., 304 (1969).,

Because of the remarkable breadth of biological and pharmaceutical properties possessed by this family of compounds, a high degree of interest has been attached to such compounds and accordingly we have discovered new (13S)-sulfinyl-prostaglandin j2<*-substitu .ert-3fb- [ (IS)-substituted sulfinyl- trans-2-octenyl lj -1-oxygenated cyclopentane and ^-substituted ^ - [(IS)-substituted sulfinyl- trans-2-octenyl] -4 <*-hydroxy-l-oxygenated cyclopentane compounds.

Further description of the invention and pre-

t drawn designs.

As discussed above, prostaglandins have, in the main, classically been named using the nomenclature for the 20-carbon chain hydroxy fatty acids which are the basic skeleton of the prostanic acid. For naturally occurring prostaglandins, this nomenclature has proven to be sufficient.

But the increasing complexity of the new compounds according to the invention makes it obvious that a more systematic nomenclature must be used.

In the description that follows, the compounds will therefore be named as substituted cyclopentanes where the cyclopene tank iron will be numbered as follows:

Thus (dl)-PGE^ which has the structure will

systematically be named as (dl)-2^-(6-carboxyhexyl)-^fb-1^^-hydroxy- trans-l-octenyl )-4c*.-hydroxy-l-oxocyclopentane. According to the conventions that have already been established in this field, the chain linked to the C-j5 carbon atom in the pyclopentane ring of naturally occurring prostaglandins which has a trans-doublet close to the aforementioned C-3 carbon atom will figuratively be produced by a structural con -figuration formula in the following way

The use of the symbol "(S)" in front of a substituent describes the absolute stereochemistry of that substituent according to the Cahn-Ingold-Prelog rules [see Cahn et al., Angew. Chem. Inter. Edit., Vol. 5, P-385 (1966), errata p. 511, Cahn et al. Angew. Chem., Vol. 78, p. 413 (1966), Cahn and Ingold, J. Chem. Soc., (London), 1951, P-612, Cahn et al., Experientia, Vol.

12, p. 81 (1956), Cahn., J. Chem. Educ, Vol. 41, p. 116 (1964)]. Due to the interdependence of the named substituent with the other substituents in the compound having the designation or p , when describing the absolute configuration of a substituent determine the absolute configuration of all substituents in the compound and thus the absolute configuration of the compound itself.

Thus, GPE^ the naturally occurring anti-mero structure shown in formula (1) has the systematic designation 2*X-(6-carboxyhexyl)-3&- f(3S)-hydroxy-trans-1-octenyl-4^ -hydroxy-l-oxocyclopentane if one uses the nomenclature used in the subsequent description, that is to say that the compounds will be named as substituted cyclopentanes. The designation (3S) for the configuration of the hydroxy substituent on the chain attached to the C-3 carbon in the cyclopentane ring determines the interdependence of that substituent with regard to the other substituents that have or p designations and thus this gives the absolute configuration of the compound itself .

The new method for the production of new compounds with the formulas (A) and (B) is reproduced in the following reaction kernel:

Preparation of compounds of formula (A).

Preparation of compounds of formula (B).

2 "5

where R , R and W are defined as above; and

R 4 is alkyl containing from one to three carbon atoms.

It can be seen that formula (A) is composed of formulas (Illa) and (iVa) and formula (B) is composed of formulas (Illb) and (iVb).

The terms "alkyl containing from one to six carbon atoms" and "alkyl containing from one to three carbon atoms" include both straight and branched alkyl groups and the broken line ( | ) represents the 'V configuration.

The known compounds with the formula (la) are: 2<x-(6-carboxyhexyl)-3P-[(3S)-hydroxy-trans-1-oethene-nylJ-1-oxocyclopentane (11-deoxy-PGE-^),

2%-(6-carboxy-cjLs-2-hexenyl)-3p-[_(3S)-hydroxy-trans-1-octenylj-1-oxocyclopentane (11-deoxy-PGE2),

2ck-(6-carboxyhexyl)-3|>- L(3S )-hydroxy- trans-1-octenylj-4<x-hydroxy-1-oxocyclopentane (PGE^) and

2<\-(6-carboxy-c_ls-2-hexenyl)-3β-[(3S ^hydroxy-trans-1-octenyl-4*-hydroxy-1-oxocyclopentane (PGEg).

The known compounds with the formula (1b) are: 2o(-(6-carboxyhexyl)-3p-L(3S)-hydroxy-trans-1-octenyl]-10L-hydroxycyclopentane (11-deoxy-PGF1a),

2β-(6-carboxyhexyl)-3β-β(3S)-hydroxy-trans-1-octenyl]-β-hydroxycyclopentane (11-deoxy-PGFβ),

2N (6-carboxy-_cJLs-2-hexenyl)-3β-C^S^hydroxy-trans-1-octenyl]-1<\-hydroxycyclopentane (11-deoxy-PGF^),

2<K-(6-carboxy-cis-2-hexeny1)-3|i-C(3S)-hydroxy-trans-1-octenyl]-1(b-hydroxycyclopentane (11-deoxy-PGFg^ ),

2<x-(6-carboxyhexyl.)-3p- C(3S)-hydroxy- trans-1-octenylj -4oL-hydroxy-lc<-hydroxycyclopentane (PGFlt<),

2^-(6-carboxyhexyl )-3£>- f (3S)-hydroxy-trans-1-octenyl J-4w-hydroxy-1|b-hydroxycyclopentane (PGF^ ),

2<>r (6-carboxy- c 1 s-2-hexeny 1)-30- C(3s)-hydroxy-trans-1-octenyl]-4<A-hydroxy-1<x-hydroxycyclopentane (PGF^) , and

2<x-(6-carboxy-cls-2-hexenyl)-J>p-L(3S)-hydroxy-trans-1-octenyl-4o<-hydroxy-lfo-hydroxycyclopentane (PGF^).

The compounds with the formulas (la) [and (lb)] are converted into their corresponding alkyl esters, the compounds with the formulas (Ila) [and (llb)] we treat with an excess of diazo-alkane, for example diazomethane, diazoethane, diazopropane in ether or ethyl acetate or mixtures thereof in the usual way.

The ester compounds of the formulas (IIa) and (IIb)] are reacted with a substituted sulfenyl chloride of the formula C1SR where R"5 is defined as above in the presence of an amine base for example triethylamine, N-methylpyrrolidine, pyridine, preferably triethylamine in an organic solvent for example diethyl ether, tetrahydrofuran, dimethoxyethylene glycol preferably diethyl ether, at temperatures from 0°C to 35°C preferably at room temperature (about 20°C) to provide the ester compounds of the formulas (iii) and [and (lIIb)J .

Appropriately substituted sulfenyl chlorides of the formula ClSR^er:

methyl sulfenyl chloride,

ethyl sulfenyl chloride, propyl sulfenyl chloride,

isopropyl sulfenyl chloride,

n-butylsulfenyl chloride,

isobutylsulfenyl chloride,

n-pentylsulfenyl chloride,

isopentylsulfenyl chloride,

n-hexylsulfenyl chloride and

cyclopentylsulfenyl chloride,

cyclohexylsulfenyl chloride,

cyclobeptylsulfenyl chloride,

chloromethylsulfenyl chloride,

trichloromethylsulfenyl chloride,

trifluoromethylsulfenyl chloride,

chlorodifluoromethylsulfenyl chloride,

dichlorofluoromethylsulfenyl chloride,

ib-chloro ty Isulfenyl chloride,

<*-chlorine sulfenyl chloride,

W,-chloro-(i- trichlorothy lsulfenyl chloride, benzenesulfenyl chloride,

p-toluenesulfenyl chloride,

p-chlorobenzenesulfenyl chloride,

2.4- dichlorobenzenesulfenyl chloride and 2.5- dichlorobenzenesulfenyl chloride.

The ester compounds of the formulas (ila) [and (illb)] are hydrolyzed to provide the corresponding free acids of the formulas (iVa) [<p>g (iVb)J. The hydrolysis of the esters is carried out biologically, preferably enzymatically, using a pancreat lipase preparation to cleave the ester groups and thus give them free acids.

The free acid compounds with the formulas (IVa) and (ivb) can also be supplied in the form of their pharmaceutically acceptable salts, i.e. salts which do not have a significant negative effect on the pharmaceutical properties of the parent compounds. Suitable pharmaceutically acceptable salts include, for example, the salts of sodium, potassium, aluminium, calcium, iron, magnesium, ammonia and the like. The salts may be prepared in a conventional manner and, for example, are readily prepared by treating the corresponding free acids with about one mole equivalent of a pharmaceutically acceptable base per mole equivalent of free acid. Suitable pharmaceutically acceptable bases include, for example, sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, trimethylamine, triethylamine, tripropylamine, p-(dimethylamine)ethanol, p-(diethylamine)ethanol, arginine, lysine, caffeine, procaine and the like. The reaction is usually carried out in aqueous solution, alone or together with an inert, water-miscible organic solvent, at temperatures between 0°C and 30°C and preferably at room temperature. Suitable inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, dioxane, tetrahydrofuran and the like. The salts can be prepared by conventional methods for ion exchange.

The compounds of the formulas (A) and (B) exhibit prostaglandin-like biological activities and are therefore useful in the treatment of mammals where the use of prostaglandins is indicated. The compounds (and pharmaceutically acceptable salts) are bronchodilators and therefore useful in treating mammals for bronchial spasms and otherwise when strong bronchodilators are indicated. The compounds are also useful for controlling or alleviating hypertension in mammals and also exhibit depressant activity on the central nervous system in mammals and are useful as sedatives. In addition, the compounds are useful for inducing labor during pregnancy and for inducing menstruation to correct or reduce menstrual irregularities. The compounds also have anti-fertility properties. In addition, they exhibit anti-inflammatory activities and are therefore useful as anti-inflammatory agents.

The compounds of the formulas (A) and (B) can be administered in a wide variety of dosage forms, either alone or together with other pharmaceutically adaptable drugs in the form of pharmaceutical preparations suitable for oral or parenteral administration or inhalation in the case of bronchodilators. Usually, the compounds are supplied as pharmaceutical preparations which mainly consist of the compound and/or salts according to the invention and a pharmaceutical carrier. The pharmaceutical carrier can either be a solid, liquid or an aerosol in which the compound and/or salt is dissolved, dispersed or suspended and the preparation can possibly contain small amounts of preservatives and/or pH buffers. Suitable preservatives that can be used include, for example, benzyl alcohol and the like. Suitable buffers include, for example, sodium acetate and pharmaceutical phosphate salts and the like.

The liquid preparations can be present, for example

in the form of solutions, emulsions, suspensions, syrups or elixirs. The solid preparations can be in the form of tablets, powders, capsules, pills and the like, preferably in unit doses for easy administration and accurate dosages. Suitable solid carriers include, for example, pharmaceutical grades of starch, lactose, sodium saccharin, talc, sodium bisulphite and the like.

Por inhalation, for example, the compounds can be supplied as an aerosol comprising the compounds or salts in an inert propellant together with a further solvent (for example ethanol) together with any preservatives and buffers. Additional general information regarding inhalation of aerosols can be found in US Patent No. 2,969,691

and 3,095,355-

The compounds with the formulas (A) and (B) are usually supplied in dosages of from 0.01 to 10 mg per kg body weight. The exact effective dosage will of course depend on the route of administration, the disorder being treated and the host animal.

It is understood that any of the compounds provided may be separated and/or purified by any suitable separation and/or purification technique,

such as extraction, filtration, distillation, evaporation, crystallization, column chromatography, thin layer chromatography and the like.

Specific illustrations of typical separation and/or purification techniques can be found in the representations and examples described below. But other separation and/or cleaning

techniques can also of course be used.

Further understanding of the invention can be obtained through the following non-limiting representations and examples.

Production 1.

This preparation illustrates methods for the preparation of a pancreatic lipase preparation which can be used to cleave ester groups from carbo-alkoxycyclopentanes. In this preparation, 10 g of impure pancreatic lipase are suspended [see: Biochem. Biophysics Acta. , v. 23, P- 264 (1957) in 65 ml of water at 0°C. The suspension is stirred for one hour at 0°C and centrifuged for 20 minutes at 10,000 x g. The supernatant is separated and kept at 0°C for later use. The precipitate is suspended again in 65 ml of water at 0°C and centrifuged as before. The supernatant liquid is separated and combined with the previously provided supernatant liquid and then added to 130 ml of saturated aqueous ammonium sulphate solution at 0°C with stirring and then allowed to stand for five minutes. The resulting mixture is centrifuged at 10,000 x g for 20 minutes. The supernatant liquid is decanted and the precipitate collected, after which it is dissolved in sufficient water to give 125 ml of solution. 15 ml of saturated aqueous ammonium sulfate solution is then added to the aqueous solution to give a suspension which is then centrifuged at 10,000 x g for 20 minutes. The supernatant liquid is collected and treated with 100 ml of saturated ammonium sulphate to give a new suspension which is then divided into two equal parts. Each part is centrifuged again for 20 minutes at 10,000 x g and in each case the supernatant is discarded (decant ring) and the precipitate is collected. Each precipitate is stored at 4°C before use.

The pancreatic lipase preparation for the ester cleavage is prepared immediately before use by dissolving one of the above-mentioned precipitates in 25 ml of aqueous 0.1 M sodium chloride solution and 0.05 M calcium chloride solution, after which the pH is adjusted to 7.0 by careful addition (i.e. filtration) of a 0.1 M aqueous na -trium hydroxide solution.

Example 1.

Reaction (l).

To a solution of 100 mg of 2<k-(6-carboxyhexyl)-3p-

[(]5S)-hydroxy-trans-1-oet enyl]-1-oxocyclopentane (1a) in 10 ml of ether/ethyl acetate (1:1 vol.), an excess of diazomethane in ether is added and the reaction mixture is kept at room temperature for 30 minutes . It is then evaporated to dryness under vacuum to give 2c\-(6-carbomethoxyhexyl)-3-C(3S)-hydroxy-trans-1-octenyl)-1-oxocyclopentane (Ila).

By similarly substituting a stoichiometrically equivalent amount of the other starting materials with formulas (la) [and (lb)], i.e. (3S )-hydroxy-trans-1-octenyl]-1-oxocyclopentane,

2* k-(6-carboxyhexyl)-3p- f (3S)-hydroxy-trans-1-octenyl]-4c*.-hydroxy-1-oxocyclopentane,

2oC-(6-carboxy-cis-2-hexenyl)-3p>- C(3S)-hydroxy-trans-1-oct enyl]-4oL- hydroxy- 1-oxocyclopentane,

2cL-(6-carboxyhexyl)-3p-C(3S)-hydroxy-trans-1-octenyl]-lcx,-hydroxycyclopentane,

2<x-(6-carboxyhexyl)-3β-C()-hydroxy-trans-1-octenyl]-1β-hydroxycyclopentane,

2oU (6-carboxy- cis -2-hexenyl)-3 p- C(3S )-hydroxy-tran- 1-oc t eny l] -1^.- hydroxy cyclopent an,

2W,-(6-carboxy-cis-2-hexenyl)-3 p- L(3S)-hydroxy-trans-1-octenyl]-lft-h<y>drox<y>c<y>clo<p> either,

2o<-(6-carboxyhexyl)-3f)- C(3S)-hydroxy-trans-1-octenylj-4^-hydroxy-loc-hydroxycyclopentane,

2^-(6-carboxyhexyl)-3lb- C(3S)-hydroxy-trans-1-octenylj -4oC-hydroxy- lp-hydroxy cy cio pen tan,

2<*-(6-carboxy-cis-2-hexenyl)-3β-L(^S)-hydroxy-trans-1-octenylj-4ok-hydroxy-1C\-hydroxycyclopentane and

2<X-(6-carboxy-cis-2-hexenyl)-3p-L(3S)-hydroxy-transl--oet enyl]-4o<-hydroxy-1p-hydroxy cyclopentan, for 2a-(6-carboxy -hexyl)-3P-L(3S)-hydroxy-trans-1-octenylj-1-oxo-cyclopentane, is prepared

2u-(6-carbomethoxy-cis-2-hexenyl)-3&-C(3S)-hydroxy-trans-1-octenyjf-1-oxocyclopentane,

2,3-(6-carbomethoxyhexyl)-3β-[(3S)-hydroxy-trans-1-oethene 1)-4β-hydroxy-1-oxocyclopentane,

2^-(6-carbomethoxy- cis -2-hexenyl)-3p- L(3S)-hydroxy- trans-l-octeny^^ -4ouhydroxy-l-oxocyclopentane which is an oil having an NMR: sSJS1} 0.88 ( 3H,t), 3/64 (3H,s), 5-35 (2H,m), 5.56 (2H,m); MS: m/e 3^8 (M-HgO), 330 (M-2H 2 O); [c*J ^3 -71.4°.

2«- (6-carbomethoxyhexyl)-3p- C(3S)-hydroxy- trans-1-octenylj -1C-hydroxycyclopentane,

2<-(6-carbomethoxyhexyl)-3f>- L(3S)-hydroxy-trans-1-octenylj-1p-hydroxycyclopentane,

2<\-(6-carbomethoxy-cis-2-hexenyl)-3β-L(3S)-hydroxy-trans-1-octenyl]-loc-hydroxy cyclopentan,

2c*,-(6-carbomethoxy-cis-2-hexenyl)-3ft-£(3S)-hydroxy-trans-1-oethenyl]-1p-hydroxycyclopentane,

2a-(6-carbomethoxyhexyl)-3p-L(3S)-hydroxy-trans-1-octenylj-4o(-hydroxy-1^,-hydroxycyclopentane,

2^-(6-carbomethoxyhexyl)-3(1- [(3S)-hydroxy-trans-1-octenyl]-4*<-h<y>drox<y>-1<p->hydroxycyclopentane,

2d.-(6-carbomethoxy-c is-2-hexenyl)-3p-!j3S)-hydroxy - t sans- 1-octenyl"(-4c*.-hydroxy- 1&C-hydroxy cyclopentan and

2<*-(6-Carbomethoxy-cis-2-hexenyl)-3β-L(3S)-hydroxy-trans-1-octenyl]-4β-hydroxy-1p-hydroxy cyclopent an.

In a similar way but by using diazoethane or diazopropane instead of diazomethane and by using the solid compounds with the formulas (la) [<p>g (lb)J in front of the corresponding ethyl and propyl esters.

Example 2.

Reaction (2).

To a solution of 70 mg (0.20/mmol) 2U-(6-carbomethoxyhexyl)-3β-[(3S)-hydroxy-tr^ns-1-octenyl)-1-oxocyclopentane (Ila) dissolved in 20 ml of dry diethyl ether containing 76 mg (0.75 mmol) of triethylamine is added to 40 mg (0.25 mmol) of freshly distilled p-toluenesulfenyl chloride. The reaction mixture is stirred at room temperature until the yellow color disappears (about 20 minutes) and it is monitored by thin layer chromatography. After the reaction has ended as judged by thin-layer chromatography, the formed precipitate is filtered off, and the filtrate that has been obtained is concentrated and purified by preparative thin-layer chromatography (elution with ethyl acetate:hexane::2:3) which gives 2x-(6-carbomethoxyhexyl) -3?-[(1-S)-p-tolylsulfinyl-trans-2-octenyl)-1-oxocyclopentane (IIIa) which is further purified by column chromatography (using ethyl acetate:hexane) or crystallization from ether:hexane.

In a similar manner using a stoichiometrically equivalent amount of other carbomethoxy compounds of formulas (Ila) and (IIb) in place of 2oc-(6-carbomethoxyhexyl)-3β-f_(3S)-hydroxy-trans-1-octenyl] -1-oxocyclopentanes that is

2<x-(6-carbomethoxy-cis-2-hexenyl)-3pr C(3S)-hydroxy-trans-1-oethenyl]-1-oxocyclopentane,

2ck-(6-carbomethoxyhexyl)-3p-f (3S)-hydroxy-trans-1-octenyl3~4cA-hydroxy-1-oxocyclopentane,

2o<-(6-carbomethoxy-cis-2-hexenyl)-3f>- [(3S)-hydroxy-trans-1-oethenyl]-4oU hydroxy-1-oxocyclopentane,

2oc-(6-carbomethoxyhexyl)-3p- [(3S)-hydroxy-trans-1-octenyl]-lcuhydroxycyclopent an,

2c*_ (6-carbomethoxyhexyl)-3f>- t(3S)-hydroxy-1rans-1-octenyl]-1p-hydroxycyclopentane,

2cx-(6-carbomethoxy-cis-2-hexenyl)-3p-C(3S)-hydroxy-trans-1-octeny l]-HK-hydroxy cyclopentan,

2«.-(6-carbomethoxy-cis-2-hexenyl)-3p-L(3S)-hydroxy-trans-1-octenylj-1p-hydroxycyclopentane,

2^-(6-carbomethoxyhexyl)-3β-[(3S)-hydroxy-trans-1-octenyl]-4^-hydroxy-1^-hydroxycyclopentane,

2oC-(6-carbomethoxyhexyl)-3p-L(3S)-hydroxy gtrans-1-octenylj-4c*-hydroxy-1p-hydroxy cyclopent an,

2&-(6-carbomethoxy-cis-2-hexenyl)-3p-[(3S)-hydroxy-trans--!-oet enyl]-4&L-hydroxy-K-hydroxycyclopentane and

2ix-(6-carbonethoxy-cis-2-hexenyl)-3(b-£(3S)-hydroxy-trans-1-octenyl-4^-hydroxy-1|i)-hydroxycyclopentane is prepared

2o4-(6-carbomethoxy-cis-2-hexenyl)-3fr-C(iS)-p-tolyl-sulfinyl-trans-2-octenyl]-1-oxocyclopentane,

2<-(6-carbomethoxyhexyl)-3p- {_{IS )-p-tolylsulfinyl-trans-2-oet enyl]-4<X- hydroxy- 1-oxocyclopentane,

2oU (6-carbomethoxy-cis-2-hexenyl)-3p-L(IS)-p-tolyl-sulfinyl-trans-2-o-ctenyl]-4c-hydroxy-1-oxocyclopentane which is an oil having an NMR: S ^s52'* ^H,s), 3-64 (3H,s), 7-0-7.6 (4H,m); MS: m/e 452 (M -2H 2 O), Mp tetrahydrofuran +11°

2d.- (6-carbomethoxyhexyl)-3fb-£(1S)-p-tolylsulfinyl-trans-2-octenyl]-10C-hydroxy cyclopentane,

2oc-(6-carbomethoxyhexyl)3p-[(1S)-p-tolylsulfinyl-trans-2-octenyl]-1p-hycroxycyclopentane,

2&<r-(6-carbomethoxy-cis-2-hexenyl)-3p-r(1S)-p-tolyl-sulfinyl-trans-2-octenyl]-1^-hydroxycyclopentane,

2oL-(6-carbomethoxy-cis-2-hexenyl)-3p-[(1S)-p-to!yl-sulfinyl-trans-2-octenyl]-1p-hydroxycyclopentane,

2c^- (6-carbomethoxyhexyl )-3p>- C( IS )-p-tolylsulfinyl-trans-2-octenyl]-4oC- hydroxy-1=*- hydroxy cyclopentan,

2<\_ (6-carbomethoxyhexyl)-3p- L( IS )-p-toly lsulf iny 1-trans-2-octenyl]-4-oi-hydroxy- lp-hydroxy cyclopent an,

2c<-(6-carbomethoxy- cis-2-hexenyl )-3p>- L(1S)-p-tolylsulfinyl-trans-2»-octeny l]-4ok-hydroxy-l<|<.- hydroxycyclopehtan, and

2cx-(6-carbomethoxy-cis-2-hexenyl)-3p-H(1S)-p-tolylsulfinyl-trans-2-octenyl] -* £k- hydroxy- lp>-hydroxy cyclopent an.

In a similar way, but using ethyl and propyl esters with the formulas (Ila) [and (llb)l instead of the methyl esters described above, the corresponding ethyl and propyl esters of 3-(1S)-p-tolylsulfinyl-trans-2 are prepared -octe-nyl compounds of the formulas (illa) [and (lIIb)J .

Similarly using any of the other substituted sulfinyl chlorides of the formula C1SR where R is defined as above (except R - p-tolyl) instead of p-toluenesulfenyl chloride and using different compounds of the formulas. (Ila) [and (ilb)J the corresponding 3 - (IS )-substituted sulfinyl-trans-2-octenyl - compounds with the formulas (Illa) [and (illb)] are prepared.

Example 3-

Reaction (3)•

100 mg of 2*.-(6-carbomethoxyhexyl)-3|5- [(1S)-p-tolyl-sulfinyl-trans-2-octenyl]-1-oxocyclopentane (IIIa) is mixed with 20 ml pancreatic lipase preparation prepared according to preparation 1 by room temperature. The mixture is emulsified by ultrasound for five minutes and stirred at room temperature for thirty minutes. The mixture is poured over with 125 ml of acetone, filtered and evaporated under vacuum, after which the resulting residue is extracted with four 25 ml portions of ethyl acetate. The extracts are beaten

together and concentrated by vacuum evaporation. The concentrate is chromatographed on silica gel thin plates using a 9:1 mixture (parts by volume) of chloroform:methanol. The product is removed from the silica gel with 3:1 (parts by volume) ethyl acetate:methanol. After filtration and vacuum evaporation of the solvent, 2<x-(6-carboxyhexyl)-3β-L(1S)-p-tolylsulfinyl-trans-2-octenyl]-1-oxocyclopentane (IVa) is provided.

In a similar manner using a stoichiometrically equivalent amount of the other methyl esters of the formulas (Ila) Log (Hb)J instead of 2x-(6-carbomethoxyhexyl)-3p-ll(lS)-p-tolylsulfinyl l- t rans-2-octenyl]-1-oxocyclopentane det v il-.-sin i.

2k-(6-carbomethoxy-cis-2-hexenyl)-3p-L(1S)-p-tolylsulfinyl-trans-2-octenyl]-1-oxocyclopentane,

2oc-(6-carbomethoxyhexyl)-3 p>-[( IS )-p-tolylsulfiny 1-trans-2-octenyl]-4<-hydroxy-1-oxocyclopentane,

2c*-(6-carbomethoxy-cjLs-2-hexenyl)-3p- C( IS )-p-tolyl-sulfin<y>l- trans~2-octenyl]-4°<*>\-hydroxy-1- oxocyclopentane,

2x-(6-carbomethoxyhexyl)-3 (3- L( IS )-p-tolylsulfinyl-trans-2-pct enyl]-lcx-hydroxy cyclopentan,

2<K-(6-carbomethoxyhexyl )-3p- C(1S )-p-tolylsulfinyl-trans-2-octenyl]-1 p-hydroxycyclopentane, 2 tx-(6-carbomethoxy- c is-2-hexenyl )- 3|b- Q IS )-p-tolylsulf iny I-trans-2-octeny l|-loi-hydroxy cyclopent an,

2&n-(6-carbomethoxy-cis-2-hexenyl)-3p-H(1S)-p-tolyl-sulfinyl-trans-2-octenyl-1p-hydroxycyclopentane,

2tx-(6-carbomethoxyhexyl)-3p>-[ (1S)-p-tolylsulfiny 1-trans-2-octenyl]-4c\-hydroxy-lc^-hydroxycyclopentane,

2^-(6-carbomethoxyhexyl )-3/3>- L( IS )-p-t o ly lsulf iny 1-trans-2-octenyl]-4o(-hydroxy-lp-hydroxycyclopentane,

2 oy-(6-carbomethoxy-cis-2-hexenyl)-3p-[(IS)-p-tolylsulfinyl-trans-2-octenyl]-4cC-hydroxy-lcA-hydroxycyclopentane and

2^-(6-carbomethoxy-cis-2-hexenyl)-3p-[(IS)-p-tolylsulfinyl-trans-2-octeny lj-4cx-hydroxy-lp-hydroxy cyclopentane is prepared

2(X-(6-carboxy-els-2-hexenyl)-3p-[(1S)-p-tolylsul-phenyl-trans-2-octenyl]-1-pxocyclopentane,

2oc-(6-carboxyhexyl)-3p-L(IS)-p-t olylsulfinyl-trans-2-octenyl]-4c^-hydroxy-1-oxocyclopentane,

2<K-(6-carboxy-cis-2-hexenyl)-3 E>- £( IS )-p-tolylsulf inyl- trans °»2-oct enyl] -4<x- hydroxy- 1-oxo cyclopent an ,

2(X-(6-carboxyhexyl)-3β-β(1S)-p-tolylsulphinyl-trans-2-octenyl]-1α-hydroxycyclopentane,

2<\-(6-carboxyhexyl)-3β-C(1S)-p-tolylsu.lf inyl-trans-2-octenyl]-1p-hydroxycyclopentane,

2^-(6-carboxy-cis-2-hexenyl)-3p-L(1S)-p-tolylsulfinyl-trans-2-octeny li-lix-hydroxycyclopentane,

2c-(6-carboxy-_cis-2-hexenyl)-3p-£(1S)-p-tolyl-sulfinyl-trans-2-octenyl]-1p-hydroxycyclopentane,

2<x-(6-carboxyhexyl )-3P- C( IS)-p-tolylsulfinyl-trans-2-octenyl]-4<x-hydroxy-lo<v-hydroxycyclopentane, 2ou (6-carboxyhexyl)-3p- L ( IS )-p-tolylsulfinyl-trans-2-octenyl]-4cA-hydroxy-1p-hydroxycyclopentane,

2<*-(6-carboxy- c is-2-hexenyl)-3?-[(1)-p-tolylsulfinyl-trans-2-octenyl-4o<s-hydroxy-1a-hydroxycyclopentane and

2oc-(6-carboxy-cis-2-hexenyl)-3p-[(1S)-p-tolyl-sulfinyl-trans-2-octenyl]-4frv-hydroxy-1p-hydroxycyclopentane.

In a similar manner, the other [(IS)-su.bsti-tuertesulfinyl-trans-2-octenyl] methyl ester compounds of the formulas (illa) [and (illb)] are converted into their corresponding free acids.

In a similar way, the ethyl and propyl esters are converted

of (IS)-p-tolylsulfinyl-trans-2-octenyl and (IS)-substituted sulfinyl-trans-2-octenyl compounds to their corresponding free acids.

Example 4.

This example illustrates methods for producing salts according to the invention. 2.0 ml of 0.1 N aqueous sodium bicarbonate is added to a solution containing 92 mg of 2\- (6-carboxy-hexyl)-3p»-C(IS)-p-tolylsulfinyl-trans-2-octenylJ-1-oxocyclopentane (IVa ) in 5 ml of methanol and the resulting mixture is stirred at room temperature for one hour. The mixture is then evaporated to dryness under reduced pressure to give the sodium salt of 2<N (6-carboxyhexyl)-3P-L(1S)-p-tolylsul-phenyl-trans-2-octenyl]-1-oxocyclopentane.

In a similar way and by following the same procedure but using 1.0 molar equivalent of potassium bicarbonate

(in the form of an aqueous 0.1 N solution) instead of sodium bicarbonate, the potassium salt is prepared from 2*- (6.-carboxyhexyl)-3P-[(IS)-p-tolyl-sulfin<y>l- trans-2-octenyl]- 1-oxocyclopentane.

In a similar way and by the following same procedure, the corresponding sodium and potassium salts are prepared respectively from the free acids that were prepared in example

Biodata.

2<X-(6-carbomethoxy-cis-2-hexenyl)-3p-£( IS )-p-tolylsulfinyl-trans-2-octenyl]-4c<-hydroxy-1-oxocyclopentane is active as a bronchodilator as measured in Sample E<1>described below.

Sample E<1>.

I.V. Test for bronchodilator activity in mar<= pigs.

(I.V. histamine challenge).

Material and methods.

Female guinea pigs weighing 400-500 g were anesthetized with urethane (1 g/kg, IP) and both the trachea and the carotid artery were cannulated. The tracheal cannula (plastic tube) was connected to a Harvard ventilator and a pressure transducer to measure changes in

breath resistance. The cannula in the carotid artery (a 22 g needle) made it possible to inject IV materials. Readings were done at a Harvard biographer. A standard histamine challenge was given to determine the animal's sensitivity to histamine. Five minutes later, sample material was given followed by a new histamine challenge at the indicated time after dosing with sample material. Repeated histamine challenges were given as indicated to determine the duration of action of the test material. The histamine was given in a 0.2 ml buffered saline solution, while the test material was given in water.

End point.

The β-wise inhibition of the histamine response was determined by measuring the peaks in the respiratory resistance after the histamine administration without and with the test agent.

It is obvious that many modifications of the invention described above and in the claims can be made without departing from the basic principles and scope thereof.

Claims (28)

1. 3 - (IS)-substituted sulfinyl-trans-2-octenyl compounds with the formulas: characterized by that R<1> is hydrogen or alkyl containing from one 2 3 to three carbon atoms; R is hydrogen or hydroxyl; R is alkyl containing from one to six carbon atoms, cycloalkyl containing from five to seven carbon atoms, chloromethyl, trichloromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, (5-chloroethyl, <*-chloroethyl , c^ -chloro-p-trichloroethyl, phenyl, p-tolyl, p-chlorophenyl-,- p-fluorophenyl, 2,4-dichlorophenyl or 2,5-dichlorophenyl; W is a saturated bond or a cis-double bond and at the wavy line ( t,) represents c\ or p configuration and non-toxic, pharmaceutically acceptable salts of these compounds when R is hydrogen. 2. Compounds according to claim 1, characterized in that the formula (A). 3. Compounds according to claim 1, characterized in that it is 2a-(6-carboxyhexyl)-3p-[(IS)-p-tolyl-sulfinyl-trans-2-octenyl]-1-oxocyclopentane. 4. Compound according to claim 1, characterized in that it is 2<\-(6-carbomethoxyhexyl)-3P-C(1S)-p-tolylsulfinyl-trans-2-oethenyl]-1-oxocyclopentane. 5. Compound according to claim 2, characterized in that it is 2t-(6-carboxy-cis-2-hexenyl)-3&-C(1S)-p-tolylsulfinyl-trans-2-oethenyl]-1-oxocyclopentane. 6. Compound according to claim 2, characterized in that it is 21*-(6-carbomethoxy-cis-2-hexenyl)-3p-[(IS)-p-tolylsulfinyl-trans-2-octenyl]-1- oxocyclopentane. 7. Compound according to claim 2, characterized in that it is 2* (6-carboxyhexyl)-3β-1IS)-p-tolyl-sulfinyl-trans-2-octenyl]-4c*-hydroxy-1-oxocyclopentane. 8. Compound according to claim 2, characterized in that it is 2ol-(6-carbomethoxyhexyl)-3p-C(1S)-p-tolylsulfinyl-trans-2-octenyl]-4cx-hydroxy-1 -oxocyclopentane. 9. Compound according to claim 2, characterized in that it is 2-oc-(6-carboxy-cis-2-hexenyl)-3p-[(IS)-p-tolylsulfinyl-trans-2-octenyl]-4cx- hydroxy-1-oxocyclo-pentane. 10. Compound according to claim 2, characterized in that it is 2K-(6-carbomethoxy-cis-2-hexenyl)-3P-E(1S)-p-tolylsulfinyl-trans-2-octenyl)-4<\- hydroxy-1-oxocyclo-pentane. 11. Compounds according to claim 1, characterized in that they have the formula (B). 12. A compound according to claim 11, characterized in that it is 2't-(6-carboxyhexyl)-3p-t1IS)-p-tolylsulfinyl-trans-2-octenyl]-1'<-hydroxycyclopentane. 13. Compound according to claim 11, characterized in that it is 2<*-(6-carbometoxyhexyl)-3β>-ti IS)-p-toly lsulfinyl-trans-2-octeny lj-lcx-hydroxy cyclopent an. 14. Compound according to claim 11, characterized in that it is 2oc-(6-carboxy-cis-2-hexene 1 )-3p-L(is)-p-tolylsulfinyltrans-2-oct enyl] -l<x- hydroxy cyclopent an. 15- Compound according to claim 11, characterized in that it is 2°i-(6-carbomethoxy-cis-2-hexeny 1 )-3ft-[(IS)-p-tolylsulfinyl-trans-2-octenyl ] -1d-hydroxycyclopentane. 16. Compound according to claim 11, characterized in that it is 2<*-(6-carboxyhexyl)-3β-L(1S)-p-tolylsulfinyl-trans-2-octenyl)-4α-hydroxy-1β-hydroxycyclopentane. 17. Compound according to claim 11, characterized in that it is 2<*\-(6-carbomethoxyhexyl)-3β-L(1S)-p-toly lsulfinyl l-trans-2-octenyl]-4oc-hydroxy- lo*v-hydroxy cyclopent an. 18. Compound according to claim 11, characterized in that it is 2c-(6-carboxy-cis-2-hexenyl)-3β-L(IS)-p-t oly lsulfinyl l-trans-2-octenyl]-hydroxy - lol-hydroxy-cyclopentane. 19. Compound according to claim 11, characterized in that it is 2<*-(6-carbomethoxy-cis-2-hexenyl)-3?-[ (IS )-p-toly lsulfinyl-trans-2-octeny lJ-4^ ,- hydroxy-l<*r hydroxy-cyclopentane. 20. Compound according to claim 11, characterized in that it is 2**-(6-carboxyhexyl)-3β-L(IS)-p-tolylsulfinyl-trans-2-octenyl-1β-hydroxycyclopentane. 21. Compound according to claim 11, characterized in that it is 2<X-(6-carbomethoxyhexyl)-3β-L(1S)-p-tolylsulfin<y>1-trans-2-octenyl]-1p-hydroxycyclopentane. 22. Compound according to claim 11, characterized in that it is 20i-(6-carboxy-cis-2-hexenyl)-3P~ [(IS)-p-tolylsulfin<y>1-trans-2-octenyl]-lp -hydroxycyclopentane. 23- Compound according to claim 11, characterized in that it is 2^- (6-carbomethoxy-_cis-2-hexenyl)-3p-C(IS)-p-tolylsulfin <y>l - trans-2-octenyl-lp- hydroxycyclopentane. 24. Compound according to claim 11, characterized in that it is 2«- (6-carboxyhexyl )-3p-L( IS )-p-tolylsulfinyl- trans-2-octeny l]- 4^-- hydroxy- lp- hydroxy cyclopent an. 25. Compound according to claim 11, characterized in that it is 201-(6-carbomethoxyhexyl)-3 P~ L( IS)-p-toly lsulf iny l-trans-2-octenyl]-4<*-hydroxy- lp -hydroxy cyclopentan. 26. Compound according to claim 11, characterized in that it is 2<*-(6-carboxy-cis;-2-hexenyl)-3 p-C(IS)-p-tolylsulfinyl I-trans-2-octenyl ] -4<\- hydroxy- lp -hydroxycyclopentane. 27 • Compound according to claim 11, characterized in that it is 2^-(6-carbomethoxy-cis-2-hexeny1)-3p-[(IS)-p-t oly lsulfinyl-jtrans-2-octeny lJ-4oC- hydroxy-1p-hydroxy-cyclopentane. 28. Process and preparation of 3p-L(IS^substituted sulfinyl-trans-2-oethenyl] compounds with the formulas: where R is hydrogen or alkyl containing from one to three 2 3 carbon atoms; R is hydrogen or hydroxyl; R is alkyl containing from one to six carbon atoms, cycloalkyl containing from five to seven carbon atoms, chloromethyl, trichloromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, p-chloroethyl, o-chloroethyl, <*-chloro-p-trichloroethyl, phenyl, p -tolyl, p-chlorophenyl, p-fluorophenyl, 2,4-dichlorophenyl or 2,5-dichlorophenyl; W is a saturated bond or a cis double bond and the wavy line (£,) represents the <* or p configuration and non-toxic pharmaceutically acceptable salts of these compounds when R <1> is hydrogen, characterized by (a) that one treats a 3P~ T(3S)-hydroxy-trans-1-octenylJ for- bonds with the formulas where R , W and the wavy line (5) are defined as above and where R k is alkyl containing from one to three carbon atoms with a substituted sulfinyl chloride compound of the formula C1SR where R 1 is defined as above in the presence of an amine base to provide 3p-[_(IS )-substituted sulfinyl-trans-2-octenyl compounds with the formulas where R 2 , R "5 , R 4, W and the wave line ("§ ) are defined as above, (b) and biologically hydrolyzing the compounds of formulas (IIa) and (IIb) to provide 3p>-[(IS)-substituted sulfinyl- trans-2-octenyl compounds of the formulas where R 2 , R "5, W and the wavy line (5) are defined as above and (c) optionally converting the compounds of the formulas (.IVa.^oogl^IVb) into their corresponding non-toxic pharmaceutically acceptable salts.