IE43816B1 - Substituted cyclopenta/b/furan compounds useful in the synthesis of prostaglandin analogues - Google Patents

Description

This invention relates to intermediate compounds useful for the preparation of ll-deoxy-15-substituted16,17,18,19,20-pentanorprostaglandins. The prostaglandin compounds of this invention are analogues of the naturally occurring prostaglandins and have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.

The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al, Acta Physiol Soand 64:332-33, 1965 and Bergstrom, et al. Life Sci 6:449-455, 1967) and lower systemic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc 23:327. 1964? Bergstrom, et al, 1965, op oit; 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 action for PGE^ and FGE2 is as a bronchodilator (Cuthbert, Brit Med J 4:723-726. 1969).

Still another important physiological role for prostaglandins is in connection with the reproductive cycle. PGE2 ^-s Known to possess the ability to induce labour (Karim, et al, J Obstet Gynaec Brit Cwlth 77:200-210 - 2 43816 1970), to induce therapeutic abortion (Bygdeman, et al. Contraception, 4, 293 91971) and to be effective for control of fertility (Karim, Contraception, 3_, 173 (1971)).

Several prostaglandins of the E and P series are known as inducers of labour in mammals, and PGn^, F2 and F^ are known for control of the reproductive cycle. It has been shown that luteolysis may take place as a result of administration of PGF2a - [Labhsetwar, Nature, 230, 528 (1971)] and hence prostaglandins have been used for fertility control by a process in which smooth muscle stimulation is not necessary.

Still other known physiological activities for PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, In: WorChester Symp on Prostaglandins, New York, Wiley, 1968, p 55-64) and also of platelet aggregation (Emmons, et al, Brit Med J 2:468-472, 1967).

It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. Evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by β-oxidation of the carboxylic acid side-chain and by oxidation of the 15a-hydroxy group (Anggard, et al, Acta Physiol Scand 81, 396 (1971) and references cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1., 3 816 319 (1972).

Accordingly, it has been considered desirable to prepare analogues of the prostaglandins which would have physiological activities equivalent to the natural compounds, i but in which the selectivity of action and the duration of the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side effects, particularly gastrointestinal side effects frequently Observed following systemic administration of the natural prostaglandins (Lancet, 536, 1971).

It has now been found that these needs may be met by certain ll-deoxy-16,17,18,19,20-pentanorprostaglandins and epimers thereof. These compounds are the subject of Patent Specification No. 43815.

This invention relates to certain substituted cyclopenta[b]furans which are useful as intermediates for the preparation of the prostaglandins of the above Patent Specification No: 2635/75. The present invention accordingly provides a compound of the general formulas and the C^g epimers and C^g epimeric mixtures thereof, wherein Ar is a- or β-thienyl? 5-phenyl-a- or β-thienyl? 5-lower alkyl-a- or β-thienyl? a- or β-naphthyl; tropyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylene- 4 dioxyphenyl; 3,4-dichlorophenyl; 3,5-dimethyIpheny1 or a monosubstituted phenyl group wherein the said substituent is a bromine, chlorine or fluorine atom or a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; and R is hydrogen or methyl; and wherein R is 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, Z is a single bond or trans double bond and Q is =0 or .OH or where Q is =0, R is hydrogen or the group OR'1 together 10 with the hydrogen atom and the C^g carbon atom together form a carbonyl group.

Preferred compounds include those of the formula; wherein R, Z and Ar are as defined above.

The terms lower alkyl and lower alkoxy used herein refer to groups having a to Οθ alkyl chain.

The compounds of this invention may be prepared from known compounds by steps described hereinafter and illustrated by Reaction Scheme A. The conversion of the compounds of the present invention into prostaglandin analogues is described in Patent Specification No. 43835 .

In the reaction scheme the symbols R and Ar are as defined above and is 2-tetrahydropyranyl or dimethyl-tert-butylsilyl, As shown in Scheme A, the first step (l·->2_) is a condensation between the known aldehyde 1 (Corey and Ravindranathan, Tetrahedron Lett, 1971, 4753 with an appropriate 3-oxophosphonate to produce enone 2. The oxophosphonate is usually produced by condensation of the appropriate carboxylic acid ester with a dialkyl methylphosphonate. Typically the desired methyl ester is condensed with dimethyl methylphosphonate.

Enone 2 is then reduced to enol 3. with zinc borohydride or a kindred alkyl borohydride such as lithium triethylborohydride or potassium tri-sec-butvlborohvdride. This reduction produces a mixture of epimers both of which may be used as substrates for further reactions. The enol 3. is used to produce prostaglandin analogues having a α-hydroxyl at C^5· The epimer of 3. is used to produce prostaglandin analogues having a β-hydroxyl at c-j_g· in addition, the mixture of epimers may be used to produce ) 15-oxoprostaglandin analogues. The epimers produced in the hydride reduction can be separated by column, preparative thin layer, or preparative high pressure liquid chromatography. In the reaction ethers such as tetrahydro furan or 1,2-dimethoxyethane or acetonitrile are usually employed as solvents.

Enone 2. may be reduced catalytically with hydrogen to ketone 6, a suitable starting material for the preparation of 13,14-dihydroprostaglandin analogues. This reduction may be achieved with either a homogeneous catalyst such as tris-triphenylphosphinerhodium chloride or with a heterogeneous catalyst system such as platinum, palladium or rhodium. The stage at which the reduction is carried out is not critical as will be seen below. - 7 43816 Scheme A 3 8 16 Enone 2 may also be reduced with borohydride ion to produce alcohol 2 in a single step or alternatively, enol 2 may be catalytically reduced to produce alcohol 2 using conditions described above. (2-»4) involves the protection of the free hydroxyl group with 2-tetrahydropyranyl or dimethyl-tert-butylsilyl groups which can be incorporated in the molecule by treatment with dihydropyran and an acid catalyst, usually ptoluenesulfonic acid, in an anhydrous medium or dimethyl1° tert-butylsilyl chloride and imidazole respectively. (4—>2) is a reduction for the lactone 4 to hemiacetal 2 using a suitable reducing agent such as diisobutylaluminium hydride in an inert solvent. Low reaction temperatures are preferred and -60 to -80°C are usual. However, higher temperatures may be employed if over reduction does not occur. 2 is then purified if desired by column chromatography. As indicated in Scheme A, compounds 4 and 2 may be catalytically reduced to 2 ®nd 2. respectively, by the procedure outlined above.

The conversion of (2-+2J follows that already outlined by the conversion of (2_->5) .

In the foregoing procedures, where purification by column chromatography is desired, appropriate chromatographic supports include neutral alumina and silica gel and 60-200 mesh silica gel is generally preferred. The chromatography is suitably conducted in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the specific Examples. Where purification by high pressure liquid chromatography is desired, appropriate supports include Corasil, Porasil and Lichrosorb with inert solvents such as ether, chloroform, methylenechloride, cyclohexane and n-hexane being employed. (The ί words Porasil and Lichrosorb are Registered Trade Marks).

It will be seen that the foregoing formulae depict optically active compounds. It is intended that both optical antipodes, e.g. 8,12-nat and 8,12-ent (prostaglandin numbering), be embraced by the foregoing formulae herein and in the appended claims. The two optical antipodes ate readily prepared by the same methods by mere substitution of the appropriate optically active precursor aldehyde. It will be clear, however, that the corresponding racemates will be useful because the eventual product prostaglandin analogues will exhibit valuable biological activity by virtue of theit content of the above-mentioned biologically active optical isomers, and it is intended that such racemates also be embraced by the foregoing formulae herein and in the appended claims.

The racemic mixtures are readily prepared by the same methods employed herein to synthesize the optically active species, by mere substitution of corresponding racemic precursors in place of optically starting materials. It will be seen, in addition, that the foregoing formulae include an optical centre at C-16 (prostaglandin numbering) whenever R is methyl. It is intended that both C-16 optical antipodes (e.g. R and S) be embraced by the foregoing formulae herein and in the appended claims. The - 10 4 38 1'6 glacial acetic acid, filtered, evaporated and combined with 250 ml ethyl acetate which was washed successively with 100 ml saturated sodium bicarbonate solution (2x), 150 ml water (lx), 150 ml saturated brine (lx), dried (Na^SO^) and evaporated to yield 2.51 g (nat.)-2-[5r/,-hydroxy-2p-(3-oxo~ 4-phenyl-i£aixs-l-butenyl)cyclopent~lct-yl] acetic acid, γlactone (2b) as a solid after column chromatography (Silica gel, Baker 60-200 mesh), m.p. 52-56° (a]^2^ = +35.0° (C = 0.8, CHClg).

The nmr spectrum (CDCl^) exhibited a doublet of doublets centered at 6.806 (IH, J = 7.16 cps) and a doublet centered at 6.276 (IH, J = 16 cps) for the olefinic protons, a broad singlet at 7.266 (5H) for a singlet at 3.826 (2H) for I C6H5-CH2-Cand multiplets at 4.78-5.186 (IH) and 1.2-2.86 (8H) for the remainder of the protons.

EXAMPLE III. (nat.) 2—Γ 5g-hvdroxv-2B-(3a-hydroxy-4-phenyl-trans-1butenyl)cyclopent-la-yl] acetic acid, γ-lactone (3b).

To a solution of 2.5 g (9.25 mmole) (nat.) 2-[5ahydroxy-2 β-(3-oxo-4-phenyl-trans-l-butenyl)cyclopent-laylj acetic acid, γ-lactone (3_) in 30 ml dry THF in a dry nitrogen atmosphere at -78° was added dropwise 9.25 ml of a 1.0M lithium triethylborohydride solution. After - n— 43816 . extracted with 100.ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc HgO), dried (MgSO^), and concentrated (water aspirator) to a crude residue and distilled, b.p. 134-5° ( <0.1 mm) to give 3.5 g (29%) dimethyl 2-oxo-3-phenylpropylphosphonate (2).

. . The nmr spectrum (CDClg) showed a doublet centered at 3.75 (J = 11.5 cps, 6H) for ·- - ... . ' - -. ' . o' ' / . (CH30)-P—, a triplet centered at 3.37 5 (2H) for CHg-O-CH^-C^-, a 10 singlet at 3.285 (3H) for CHg-O-CHg-, a doublet centered at 3.145 (J = 23 cps, 2H) ‘ ' - . '' 0 0 - -<· ii -Ml·-··· .· ·;.· ·.-.·· . · -c-ch2-p— ,a singlet at 3.95 (2H) for -. ' 0 ·. - I! . :.

.. : ,,-Ch2_c._ . . and.a broad singlet at 7.2 5'(6H) for ΟθΗ^-.

' · - ' . EXAMPLE II. (nat.)-2-[5 a-Hydroxy-2β-(3-oxo-4-phenyl-trans-1-butenyl) cyclopent-la] acetic acid, γ-lactone (2b); Dimethyl 2-oxo-3-phenylpropylphosphonate (6.93 g, 28.6 mmole) in 420 anhydrous THE was treated with 1.21 g - (28.6 mmole) 57% sodium hydride in a dry nitrogen atmosphere at room temperature. After 60 min. of stirring, 2-[5a-hydroXy-2β-formylcyclopent-la-yljacetic acid, γlactone (1) 'in 50 ml anhydrous THF was added. After 95 minutes the reaction mixture was quenched with 4.2 ml -12 43816 glacial acetic acid, filtered, evaporated and combined with 250 ml ethyl acetate which was washed successively with 100 ml saturated sodium bicarbonate solution (2x), 150 ml water (lx), 150 ml saturated brine (lx), dried (Na2SOJ) and evaporated to yield 2.51 g (nat.)-2-Γ5a-hydroxy-2B-(3-oxo4-phenyl-trans-1-butenyl)cvclopent-la-yl1 acetic acid, γlactone (2b) as a solid after column chromatography (Silica gel. Baker 60-200 mesh), m.p. 52-56° (a]^2^ = +35.0° (C = 0.8, CHC13).

The nmr spectrum (CDCl^) exhibited a doublet of doublets centered at 6.805 (1H, J = 7.16 Cps) and a doublet centered at 6.276 (1H, J = 16 cps) for the Olefinic protons, a broad singlet at 7.266 (5H) for O II C6H5~ CH2- C - a singlet at 3.826 (2H) for C6H5~ CH2- C ~ ' and multiplets at 4.78-5.186 (1H) and 1.2-2.86 (8H) for the remainder of the protons.

EXAMPLE III. (nat.) 2 - [ 5 a-hydroxy-2 β-(3 a-hydroxy-4-phenyl-trans-1butenyl)cyclopent-la-yl]acetic acid, γ-lactone (3b).

To a solution of 2.5 g (9.25 mmole) (nat.) 2-[5ahydroxy-2 β-(3-oxo-4-phenyl-trans-1-butenyl)cyclopent-1 ayl] acetic acid, γ-lactone (3.) in 30 ml dry THF in a dry nitrogen atmosphere at -78° was added dropwise 9.25 ml of a 1.0M lithium triethylborohydride solution. After stirring at -78° for 30 min, 20 ml of acetic acid/water (40:60 v/v) was added. After the reaction came to room temperature, 40 ml of water was added and the reaction was extracted with methylene chloride (3 x 50 ml), washed with > brine (2 x 5 ml), dried (Na^SO^) and concentrated (water aspirator). The resultant oil was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using cyclohexane and ether as eluents.

After elution of less polar impurities a fraction containing LO 365 mg (nat.) 2-Γ5a-hvdroxv-2S-(3a-hvdroxv-4-phenvl-transl-butenyl)cyclopent-la-yl]acetic acid, γ-lactone (3b), a 578 mg fraction of mixed 3b and epi-3b and finally a fraction (489 mg) of (nat.) 2-[5a-hydroxy-2p-(3p-hydroxy4-phenvl-trans-1-butenyl)cyclopent-la-yl]acetic acid, γ15 lactone epi 3b were obtained.

The (nat.) 3b had (α]ρ25 = +6.623° (C = 1.0 CHC13) and (nat.) epi-3b had [α]β25 = +24.305° (C = 1.69, CHC13). The 15-epi product of this example (epi-3b) can be converted into the 15-epi-11-deoxyprostaglandins of this invention by the procedures of Examples XVII-XXX and XXXII-XXXV of Patent Specification No. 43815. .

The products of this example (3b and epi-3b) may be converted into the 13,14-dihydro-ll-desoxyprostaglandin two-series analogues of this invention by the procedures of Examples XXXII, XVIII-XXI, XXIII, XXVI, XXVII-XXX and XXXIV-XXXV of Patent Specification No. 43815.

EXAMPLE IV. (nat.)-2-[5a-hydroxy-2p-(3a-(tetrahydropyran-2-yloxy)-4phenyltrans-l-butenyl)cyclopent-la-yl] acetic acid,Ύ 30 lactone (4b).

To a solution of 805 mg (2.95 mmole) (nat.)-2-[5ahydroxy-2 β-(3 a-hydroxy-4-phenyl-trans-1-butenyl)cyclopentla-yljacetic acid, γ-lactone (3b) in 20 ml anhydrous methylene chloride and 0.735 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 35.3 mg p-toluenesulfonic acid, monohydrate. After stirring for 35 minutes, the reaction mixture was combined with 150 ml ether, the ether solution washed with saturated sodium bicarbonate (2 x 100 ml) then saturated brine (1 x 100 ml), dried (Na^SO^) and concentrated to yield 1.2 g (>100%) crude (nat.) 2-[5a-hydroxy-2f3-(3a-(tetrahydropyran~2yloxy)-4-phenyl-trans-1-butenyl)cyclopent-1 α-yl]acetic acid, γ-lactone (4b).

The ir (CHCl^) spectrum had a medium adsorption at 957 cm 1 for the trans-double bond and a strong adsorption at 1770 cm 1 of the lactone carbonyl.

EXAMPLE V. (nat.)-2-[5a_hydroxy-2p-(3a-(tetrahydropyran-2-yloxy)-4phenyl-trans-butenyl)cyclopent-Ια-yl)acetaldehyde, γhemiacetal (5b).

A solution of 1.1 g (2.96 mmole) 2-[5-hydroxy-2p(3a-(tetrahydropyran-2-yloxy)-4-phenvl-trans-1-butenyl)cyclopent-Ια-yl]acetic acid, γ-lactone (4b) in 15 ml dry toluene was cooled to -78° in a dry nitrogen atmosphere.

To this cooled solution was added 4.05 ml of 20% diisobutylaluminium hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65° (15 minutes). After an additional 30 minutes of stirring at -78°, anhydrous methanol was added until gas 4381® evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 150 ml ether, washed with 50% w/v sodium potassium tartrate solution (2 x 50 ml), brine (1 x 75 ml), dried (Na^O^) and concentrated to yield 883 mg (nat. )-2[5 a-hydroxy-2β-(3 a- (tetrahydropyran-2-yloxy)-4-phenyltrans-1-butenvl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (5b) after column chromatography.

EXAMPLE VI. 2-[5 a-Hydroxy-2 β-(3-oxo-4-(m-tolyl)butyl)cyclopent-1 a-yl]acetic acid, γ-lactone (6c).

A heterogeneous mixture of 6.8 g of 2-[5a-hydroxy-2β(3-oxo-4-(m-tolyl)-trans-1-butenvl)cyclopent-1g-vll acetic acid, γ-lactone (2c) and 670 mg of 10% palladium on carbon in 55 ml of ethyl acetate was shaken in Parr Shaker for 30 minutes. The mixture was then filtered through a pad of Celite and was concentrated. Purification of the crude residue by silica gel chromatography using 10% ethyl acetate in benzene as eluent afforded the desired 2-[5a-hydroxy-2β(3-oxo-4-(m-tolyl)butyl)cyclopent-la-yl]acetic acid, γlactone (6c) as a solid melting at 60.5-62.5° and weighing 2.9 g.

The product of this Example (6c.) may be converted into the 13,14-dihydro-prostaglandin two-series analogues by the procedures of Examples XVI-XXI, XXIII, XXVI-XXX and XXXIV-XXXV of Patent Specification No. 43815. - 16 43816 EXAMPLE VII. 2-[5α-Rydroxy-2β-(3a-(tetrahydropyran-2-yloxy)-4-phenylbutyl) cyclopent -Ια-yl] acetic acid, γ-lactone (8b).

A heterogeneous mixture of 500 mg of 2-[5a-hydroxy-2P(3 a-(tetrahydropyran-2-yloxy)-4-phenvl-trans-1-butenyl) cyclopent-la-yl]acetic acid, (4b) and 50 mg of 5% rhodium on alumina in 5 ml of ethyl acetate is stirred under 1 atmosphere of hydrogen for 2 hours. The mixture then is filtered through a pad of Celite then is concentrated. Purification of the crude residue by silica gel chromatography affords the desired 2-[5a-hydroxy-2p-(3a-(tetrahydropyran-2-yloxy)-4-phenylbutyl)cyclopent-Ια-yl]acetic acid, γ-lactone (8b).

The product of this Example (8b) may be converted into the 13,14-dihydro-prostaglandin two-series analogues by the procedures of Examples XVIII-XXI, XXIII, XXVI-XXX, and XXXIV-XXXV of Patent Specification No. 43815.

EXAMPLE VIII. 2-(5 a-hydroxy-2 β-(3 a-dimethyl-tert-butylsilyloxyl-4-(3,5dimethylphenyl)-trans-1-butenyl)cyclopent-la-yl] acetic acid, γ-lactone (4d).

A solution of 1.47 g (4.95 mmoles) of 2-[5a-hydroxy-2β(3a-hydroxy-4-(3,5-dimethylphenyl)-trans-l-butenyl)cyclopentla-yl] acetic acid, γ-lactone (3d), 945 mg (6.3 mmoles) of dimethyl-tert-butylsilyl chloride, and 910 mg (13.4 mmoles) of imidazole in 2.5 ml of dimethylformamide was stirred under nitrogen at 37° for 18 hours. The solution was then concentrated, the residue was diluted with methylene chloride, and the organic layer was washed with water (3x), was dried (anhydrous magnesium sulfate), and was concentrated.

Purification of the crude residue by silica gel chromatography using chloroform as eluent provided the desired 2-[5a-hydroxy-2 β-(3 a-dimethyl-tert-butylsilyloxy-4-(3.5— dimethylphenyl)-trans-1-butenyl)cyclopent-la-vll acetic acid, γ-lactone (4d) as a viscous oil weighing 1.67 g.

The product of this Example (4d) may be converted into the corresponding 11-deoxyprostaglandins by the procedures of Examples XVIII-XXX, XXXII, and XXXIV-XXXV of Patent Specification No. 43815.

X X X X XX XX XX X X CM OJ 04 CN CN CN CN CN CN CN CN CN CN 04 CN CN CN CN CN CN CN 04 CN CN »w-' s—- -~s *—·** 04 m 00 o in rd Φ m io cn 10 O o O rd rd rd cn cn cn ~4 rd m m cn cn cn cn cn cn cn cn cn cn X X X X xx \ χ XX X X in in m tn in m in in m m m m rd rd rd rd rd rd rd rd rd rd rd rd l«d rd rd rd rd rd rd rd rd rd rd rd — m si4 in m <0 CO H CQ H ρ- CN r- Γ- r*» γ- Γ* Γ- Γ- > Γ- γ- ο- 00 m η cn οί Γη cn m cn γο cn γο cn Additional Compounds m m rd rd c: O o 0 EC EC •rl O o JJ CN <0 in cn -μ O ro Φ 0 CN CN 2 & + 1 O 1 1 0=4 01 3 3 1 g g S S 04 3 P 3 3 ffi rd rd rd rd g o g 0 >c 0 3ί 0 Eh 0 >1 g I 3 Ο XJ o j3 0 XJ 0 42 1 A ft £ < ft ft 04 0—0 >i (0 >i Id g >< m >ι Φ • £ o Λ P Λ 1-1 3 K 3 & p £ 1 \ Cn 0 0 tp CN tn tn X 5U 0 Π3 0 in t— Ό 0 • Ό 0 Ό 0 Cl cn ttJ — O 04 fl) 4J 10 M* 0) +1 o Φ 4-) Φ 4-) 00 • 10 •rl flj 1 1 •d (tf X •H nJ •id flj 00 p 1 A rd Md g in Ή g 1 6 rd X p e 1 •rd 0 Φ d 0 0_ ♦id 0 •rl 0 1 0 < X CO p P H H o P P P P m tf A in 3 3 A A 3 Λ CO 3 3 3 X! co r- Λ rd A 0 6 6 ft 0 rd A 0 A 0 rd rd 04 = O 1 04 EC Φ Φ O s 2 oi w EC UJ EC S3 S3 UJ i I O = o X rd H rd CQ >1 & 3 3 3 3 0 fl) rd fl) fl) 4-» fd •rl rd s XJ XJ 0 3 >. 3 & A P β rd •3 3 Φ 0 rd A Φ 1 Φ 3 P & 4X rd CN rd 3 A 0 XJ >1 A >c 1 >1 A rd rd 4-) X rd 3 rd 3 0 XJ fl) 0 >1 Φ >1 -P P •P 0 S 3 XJ ,3 3 3 0 3 rd rd •rl •rl 4-) 4-) A Φ A rd <3 >i >1 nJ Ό Φ CD •rl 3 nJ XJ 3 3 1 1 6 g rQ A 3 □ •Pi Φ Φ M· in 14 T 1 , 1 1 , 3 3 - «. < 61 ol in cn A A A A cn cn X Additional Compounds of the Structure double bond; S = single bond rd I ε ο ιΰ •Ρ (ΰ Ό Ο Ιο ω Ο ο Ο ο ο Ο 00 00 CO ο ο ο ο ο Ο σ σ σ ω <0 ω CD co ω ιη ΙΛ ιη ΡΊ ΡΊ ΡΊ ΡΊ ΡΊ ΡΊ ΡΊ ΡΊ ΡΊ ο ο ΙΠ ΙΓ) ιη ·» Ο Ο Ο Ο Γ* Γ- Γ Γ Γ- Γ- Γ- [*- Γ- cn cn <η cn cn <η σ σ σ ο Ο ό ό Ο Ο ό ο ό Γ- Γ- Γ- ο» > Γ- r- Γ- Γ- Γ- Γ* > Γ- Γ- Γ* r- Η rd ι—I γΗ rd Η Η rd rd Ο CN 4J W SL « Ο ο Ο CM OJ CM 44 +1 +> W Μ Η \ \ X Q Φ. & Κ Ο CM •μ § Additional Compounds rd Η Η £ Φ •Η rd & Φ Ή rd ϊΧι 44 44 >1 β β rd rd 4J •P β Φ Φ £>1 Ν 1 1 Φ 44 44 rd rd CM CM rd rd 44 04 Ά ί>1 >1 1 1 »>< >1 & rd β C rd rd X5 44 0 >1 >1 Φ (U >1 >1 •P P Ρ 44 44 44 x: β β 44 44 0 •Ρ dJ a a a) Φ & a rd Φ φ •id •rl Λ 44 iti Φ XJ e Φ ή* ? ? β 1 β | 0 1 έι εΐ Ol ol in in ca 01 Οί «Η I t 3 TO A P +> fl •fl 0 fl 0 fl rfl 05 0 fl fl 0 & 04 ε 0 fl □ rd fl fl 0 •fl P •fl Τ3 N 4 CO CO CO o O o o Q o o o <71 01 01 o O o o o o in in in m in 10 10 \0 10 10 Φ in w ro ro <0 ro CO ro <0 co Γ0 ro ro o O o o O O o n o’ in in b b b b b b b 10 10 b b 01 01 01 01 01 σι 01 σι σι 01 01 * * * o o o o o o o o o o u b b b b b b b 10 10 b b b b b b b b b b b b b rfl tfl «—I tfl rfl ifl ifl ifl ifl rfl rfl ο Ο] «Ρ « § Ρϊ S Φ C Φ Ν C Φ \ Ο φ β φ Ν fl Φ > rtj ο φ fl φ Ν β Φ § οι φ β φ Ν fl Φ CQ Ο Φ fl fl X φ Χί Ο Η ϋ P 4J P P u (4 H ω w 0 o P TA 03 H O O o o P ifl H CN CN w te »4 S >4 δ »4 ft tl ft tl Q Q o Q Q Q Q Q o A A a a a a a a te a a a a o I o o o o I o O o o I o o I 1 ca B tCL B 1 ¢0. B CEL B 1 ca 1 B 1 ca © Φ © Φ s a S3 a te a a a te a te _+ i 1 1 Η & φ XJ & Μ Ο rfl Χί υ άί & © Λ ft rfl >1 Ρ rfl & φ X! ft Η >ι ι Φ +1 G 0 £ Φ £ rfl tfl rfl tfl tfl r4 •a N >1 >1 >1 >1 >t Ό G fl fl fl G G 1 Φ Φ Φ Φ © Φ in x; Χί rfl Λ •G XJ ft 0t 04 04 ft ft to fl fl rfl Φ fl ε fl fl rfl ω Φ fl? >1 P •fl H •fl § E U g T3 C fl Φ 'Si fl •fl U5 •rl fl fl Φ fl •fl P fl fl fl 5r ω a φ ε •fl £ S’ &> o +) its ε o Λ rd fl m rfl & Φ χ! rfl 0 Φ Ό P G 05 © 03 >1 Xi fl 05 ft fl rfl M p >1 P a Λ φ P 05 > Φ •fl rfl & 0 •fl V a w 1 in z-*. fl 0 co 3 816 Additional Compounds Η T Ar T R z/ IR data cm m-methylphenyl a-OTHP H D 1770, 970 m-methylphenyl β-ΟΤΗΡ H D 1770, 970 o-biphenylyl a-OTHP H D 1770, 970 o-biphenylyl β-ΟΤΗΡ H D 1770, 970 5-phenyl-2-thienyl a-OTHP H D 1770, 970 5-phenyl-2-thienyl β-ΟΤΗΡ H D 1770, 970 β-naphthyl a-OTHP H D 1770, 970 β-naphthyl β-ΟΤΗΡ H D 1770, 970 p-chlorophenyl a-OTHP H D 1770, 970 p-chlorophenyl β-ΟΤΗΡ H D 1770, 970 p.-t.-butylphenyl a-OTHP H D 1770, 970 p-t-butylphenyl β-ΟΤΗΡ H D 1770, 970 phenyl a-OTHP (+)Me D 1770, 970 phenyl β-ΟΤΗΡ (+) Me D 1770, 970 phenyl a-OTHP (-)Me D 1770, 970 phenyl β-ΟΤΗΡ (-)Me D 1770, 970 phenyl(ent) a-OTHP H D 1760, 960 phenyl(ent) β-ΟΤΗΡ H D 1760, 960 3,5-dimethylphenyl a-ODMTBS H D 1760, 965 3,5-dimethylphenyl β-ODMTBS H D 1760, 965 / 0 is trans double bond; S is single bond.

I6 Additional Compounds Ar T R ζ/ IR data m-methylphenyl α-ΟΤΗΡ Η D 970 m-methylphenyl β-ΟΤΗΡ Η D 970 o-biphenylyl α-ΟΤΗΡ Η D 970 o-biphenylyl β-ΟΤΗΡ Η D 970 5-phenyl-2-thienyl α-ΟΤΗΡ Η D 970 5-phenyl-2-thienyl β-ΟΤΗΡ Η D 970 β-naphthyl α-ΟΤΗΡ Η D 970 β-naphthyl β-ΟΤΗΡ Η D 970 p-chlorophenyl α-ΟΤΗΡ Η D 970 p-chlorophenyl β-ΟΤΗΡ Η D 970 p-t-butylphenyl α-ΟΤΗΡ Η D 965 p-t-butylphenyl β-ΟΤΗΡ Η D 965 phenyl α-ΟΤΗΡ (+)Me D 975 phenyl β-ΟΤΗΡ (+)Me D 975 phenyl α-ΟΤΗΡ (-)Me D 975 phenyl β-ΟΤΗΡ (-)Me D 975 phenyl(ent) α-ΟΤΗΡ Η D 970 phenyl(ent) β-ΟΤΗΡ Η D 970 3,5-dimethylphenyl a-ODMTBS Η D 965 3,5-dimethylphenyl β-ODMTBS Η D 965 / D is trans double bond; S is single bond. 3 316

Claims (4)

1. CLAIMS:1. A compound of the general formula: and the epimers and epimeric mixtures thereof, 5 wherein Ar is a- or β-thienyl; 5-phenyl-a- or β-thienyl; 5-lower alkyl-a- or β-thienyl; a- or β-naphthyl; tropanyl, phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-dichlorophenyl; 3,5-dimethylphenyl or a mono-substituted phenyl group wherein the said substituent is a bromine, 10 chlorine or fluorine atom or a trifluoromethyl, phenyl, lower alkyl or lower alkoxy group; R is hydrogen or methyl; and wherein R is 2-tetrahydropyranyl or dimethyl-tertbutylsilyl, Z is a single bond or trans double bond and Q is =0 or or where Q is =0, R is hydrogen or the group OR together with the hydrogen atom and the carbon atom together form a carbonyl group.

2. A compound as claimed in claim 1 of the general 20 formula:25 wherein Ar, R and Z are as defined in claim 1.

3. Compounds as claimed in either claim 1 or claim 2 and substantially as hereinbefore described with reference 5 to the Examples II to VIII.

4. Processes for preparing compounds as claimed in any one of claims 1 to 3 substantially as hereinbefore described with reference to Reaction Scheme A or the Examples II to VIII.