GB2075503A - Prostanoid aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation - Google Patents

Prostanoid aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation Download PDF

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GB2075503A
GB2075503A GB8113239A GB8113239A GB2075503A GB 2075503 A GB2075503 A GB 2075503A GB 8113239 A GB8113239 A GB 8113239A GB 8113239 A GB8113239 A GB 8113239A GB 2075503 A GB2075503 A GB 2075503A
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Description

1 GB 2 075 503 A 1
SPECIFICATION Aminocyclopentane Alkenoic Acids and Esters and Their Preparation and Pharmaceutical Formulation
The endoperoxides prostaglandins G2 and H,, and thromboxane A 2 are naturally occurring, reactive metabolites of arachidonic acid in human platelets. They are not only potent aggregatory 5 agents but are also constrictors of vascular and bronchial smooth muscle, and therefore substances which antagonise their effects are of considerable interest in human medicine.
We have now found a new group of compounds which have shown endoperoxide and thromboxane antagonist activity, and are therefore of interest in the treatment of asthma and cardiovascular diseases. These compounds can broadly be described as cycl'opentanealkenoic acids 10 and esters in which the double bond is in the 3,4-position in relation to the cyclopentane ring and in which the ring is substituted by heterocyclic amino, oxo and alkanoyloxy or ether (particularly aralkoxy) groups. The invention thus provides compounds of the general formula (1) OR2 I CH 2)2XR1 wherein X is cis or trans -CH=CH-, R' is straight or branched Cl-, alkyl bearing as a terminal substituent - COOR 3 where R 3 is a hydrogen atom, Cl-, alkyl or C7-1. aralkyl (e.g. benzyi); (1) 15 Y represents a saturated heterocyclic amino group which has 5-8 ring members and (a) 20 optionally contains in the ring -0-, -S- ' -S02-1 -NIR 4 (where R 4 is a hydrogen atom, Cl-, alkyl or aralkyl having a Cl-4 alkyl portion); and/or (b) is optionally substituted by one or more Cl-4 alkyl groups; R2 is (j) C 2-4 alkanoyl; 00 C3_., alkenyi, optionally substituted by phenyl (the phenyl being optionally substituted byC,-4alkyl, Cl-, alkoxy, halogen, C.-7 cycloalkyl or phenyl (Cl-4) alkyl), 25 biphenyl (optionally substituted by Cl-4 alkyll Cl-4 alkoxy or halogen), or naphthyl; (ill) Cl-,, alkyl; (M Cl-, alkyl substituted by (a) phenyl loptionally substituted by halogen, hydroxy, Cl-, alkyl, Cl-, alkoxy, Cl-4 hydroxyalkoxy, trifluoromethyl, cyano, aryloxy (e.g. phenoxy), C.-7 cycloalkyl, aralkoxy (e.g.
benzyloxy), di methyl am inomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH,), C,-4 alkanoyi,-NRr2R6 (where R' and R' are the same or different and are each a hydrogen atom or C,-4 30 alkyl, or where -NR5R 6 is a saturated heterocyclic amino group as defined above for Y), Cl-3 alkylthio, Cl-, alkyisulphinyi, Cl-3 alkylsulphonyl, phenylalkyl having a Cl-, alkyl portion, aminosulphonyl, Cl-3 alkanoylaminosulphony], phenyisulphonyl (the phenyl portion being optionally substituted by Cl-3 alkyl or Cl-, alkoxy), nitro, or thienyll, (b) thienyl or furanyl [the thienyl and furanyl groups being optionally substituted by Cl-, alkyl, Cl-, alkoxy, aryl (e.g. phenyl) or phenyl (Cl- 3) alkyl or phenyl (Cl-3)-alkoxy (the 35 aryl or phenyl group in each case being optionally substituted by C,-, alkyl, C,-, alkoxy or halogen), aryloxy (e.g. phenoxy, C.-7 cycloalkyl, halogen, nitro or thienyll, (c) biphenyl (optionally substituted by phenyl or one or two Cl-4 alkyl, Cl-4 alkoxy or halogen substituents), or (d) naphthyl (optionally substituted by Cl4 alkyl, Cl-4 alkoxy or halogen); and the physiologically acceptable salts and the solvates (e.g. hydrates) thereof.
The structural formulae herein are to be understood to include the enantiomers of each of the compounds concerned as well as mixtures of the enantiomers, including racemates, even though the precise structure as set out only relates to one enantiomer.
The alkyl groups referred to above in the definition of the compounds of formula (1) may be.
straight or branched.
The alkyl portion of the group R' may for example contain 1-5 carbon atoms in a straight or branched chain, and is preferably -CH2CH-. Examples of suitable R 3 groups are Cl-3 alkyl (e.g.
methyl), but R 3 is preferably a hydrogen atom. R' is thus preferably (CHICOOH.
When R' is a hydrogen atom, the compounds are capable of salt formation with bases and the compounds are preferably used in the form of such salts. Examples of suitable salts are alkali metal so (e.g. sodium and potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium, substituted ammonium (e.g. tromethamine or dimethylaminoethanol), piperazine, N,N- dimethylpiperazine, morpholine, piperidine and tertiary amino (e.g. triethylamine) salts. Inorganic salts are preferred.
X is preferably a cis -CH=CH- group.
The heterocyclic amino group Y may for example have a 5, 6 or 7-membered ring, e.g.
2 GB 2 075 503 A 2 pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1 - dioxothiamorpholino, homomorpholino and hexamethyleneimino. Examples of the optional substituents which may be present in a second nitrogen atom in the ring are methyl, ethyl and benzyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl or ethyl. Y is preferably piperidino, morpholino, homomorpholino,thiamorpholino or 1-dioxothiamorpholino, and compounds in which Y is a morpholino or piperidino group are particularly preferred.
The amino group Y enables the compounds to form salts with organic acids, e.g. maleates.
R' may for example be C,-,, alkyl (e.g. pentyl or decyl); C3-, alkenyl (e. g. allyl, optionally substituted by phenyl); or C,-, alkyl (e.g. methyl or propyl) substituted by phenyl [optionally substituted by a C1-4 alkyl (e.g. tert butyl), C1-7 cycloalkyl (e.g. cyclohexyl), C1- 3 alkylthio (e.g. methylthio), phenyl 10 (C,j alkyl (e.g. benzyl) or thienyll, furanyl or thienyl (optionally substituted by a phenyl group), biphenyl [optionally substituted by C1-3 alkyl (e.g. methyl), C,_, alkoxy (e.g. methoxy), halogen (e.g. chlorine) or phenyl], or naphthy]. R' is preferably a phenylalkyl group in which the alkyl portion contains C,-, carbon atoms and the phenyl is substituted with one of the following groups: C1-3 alkylthio, thienyl or phenyl optionally 15 substituted by C1-3 alkyl, C1-3 alkoxy; halogen or phenyl; or is thienylalkyl in which the alkyl portion contains 1-3 carbon atoms and the thienyl group is substituted by a phenyl group; or cinnamyi.
Particularly preferred R' groups are phenylalkyl groups in which the alkyl portion is a C1-3 alkylene chain and the phenyl group carries a phenyl substituent, preferably in the paraposition (which phenyl substituent is optionally substituted by a C1-3 alkyl, C,-3 alkoxy or halogen, this additional 20 substituent preferably being in the meta or more particularly the para- position); or thienyimethyl group (particularly a 4-thienyimethyl group) substituted by a phenyl group, which substituent is preferably in the 2-position; or cinnamyl.
A particularly preferred group of compounds has the formula (1) in which:
X is cis -CH=CH-, R' is -CH2CH2COOH, Y is morphoiino or piperidino, and R 2 is phenyl (Cl-3) alkyl in which the phenyl group is substituted by phenyl (which phenyl substituent is optionally substituted by C1-3 alkyl, C1-3 alkoxy or halogen); ph enyithienyl m ethyl; or cinnamyi, and the physiologically acceptable salts and solvates (e.g. hydrates) thereof.
Particularly important compounds in this latter group are those in which Y is morpholino and R 2 is 1,1'-biphenyimethyi; 1, 1 '-biphenyl methyl substituted in the para- position by methyl, methoxy or chloro or in the meta-position by methoxy; 1,1'-biphenylpropyi; 2- pheny[thien-4-yimethyi; or cinnamyi; and those in which Y is piperidino and R 2 is 1,1 l_biphenyl methyl or 4'- methoxy-1,1 '-biphenyl methyl. 35 Especially important are:
[1 '-biphenyl)-4-yilmethoxy]-2-(4-morpholinyi)-3-oxycyclopentyll-4heptenolc acid; and [1 R41 a(Z),2p,5a]]-(-)-7-[5-[[(1,1 1-biphenyi)-4-yilmethoxy]-2-(4- morpholinyl)-3oxocyclopentyll-4-heptenoic acid; and the hydrates and salts thereof, particularly the calcium, 40 piperidine, piperazine and N,N-dimethylpiperazine salts. The calcium salts are particularly important.
In general, the compounds of formula (1) in which the carbon atom carrying the -(CH2)2XR' group is in the R-configuration (and mixtures containing this isomer) are preferred.
Compounds of formula (1) inhibit blood platiet aggregation and bronchoconstriction. The test for inhibition of platelet aggregation is as described by G. V. Born in Nature 194, 927-929 (1962) except 45 in that collagen is used instead of ADP as the pro-aggregatory agent. The test for potential inhibition of bronchoconstriction is as described by K. M. Lulich et al in British Journal of Pharmacology 58, 7 1 79, (1976) except guinea-pig lung is used instead cat lung.
The compounds are thus of interest in the treatment of asthma, and as inhibitors of platelet aggregation and thrombosis for use in renal dialysis and the treatment and prevention of occlusive 50 vascular diseases such as arteriosclerosis, atherosclerosis, peripheral vascular disease, cerebral vascular disease including transient ischaemic attacks, stroke, pulmonary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction. They may be formulation in conventional manner for use, with one or more pharmaceutical carriers.
For oral administration, the pharmaceutical composition may take the form of, for example, 55 tablets, capsules, powders, solutions, syrups, or suspensions prepared by conventional means with acceptable excipients.
The compounds may be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen-free water.
For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurised packs ora nebuliser, or as a cartridge from which the 65 j C.
3 GB 2 075 503 A 3 powdered composition may be inhaled with the aid of a suitable device. in the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
For use as antithrombotic agents, the compounds are preferably administered orally, for example in amounts of 0.05 to 10 mg/kg body weight, 1 to 4 times daily.
For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.05 to 10 mg/kg body weight, 1 to 4 times daily; preferably however they are administered by inhalation at doses varying from 0.3 to 30 mg, 1 to 4 times daily. The compounds may be used in combination with other antiasthmatic agents.
The precise dose administered will of course depend on the age and condition of the patent.
Suitable methods for preparing compounds of formula (1) are described below.
In the following discussion, the groups R', R 2, R 3, X and Y are as defined above except where otherwise indicated.
(a) Compounds of formula (1) may be prepared by oxidising a corresponding hydroxy compound, e.g. a compound of formula (2) OR2 1CH2)2XR NO Y (2) (wherein RIO is C,-., alkyi substituted by -COOR 3, -CH20H or -CHO).
Suitable methods of oxidation include using a CrIl oxidising reagent in a suitable solvent, e.g. chromic acid in acetone (e.g. Jones reagent, preferably used in the presence of a diatomaceous silica such as Celite) or Cr03 in pyridine. These reagents are for example used at temperatures of -201 to room temperature.
Other important methods include using an activated sulphur reagent, e.g. (i) Nchlorosuccinimidedimethyisulphide complex in a suitable solvent (e.g. toluene or dichloromethane) at temperatures of for example -25 to 251, preferably at 0-50, (H) a dimethyisulphide (e.g. dimethyisulphoxide) activated by a suitable electrophilic reagent (such as oxalyl chloride, acetyl bromide or thionyl chloride) in a suitable solvent (e.g. toluene or dichloromethane), e.g. at -70 to -201; dicyclohexylcarbodiimide can also be used as the electrophilic reagent (preferably in the presence of CF. COOH or its pyridinium salt) at for example -101 to room temperature, using the same solvents, or (iii) pyridine -S03 complex in dimethyisulphoxide, preferably at 01 to room temperature.
When R3 is a hydrogen atom, better yields are sometimes obtained by prior protection of the carboxyl group, for example in the form of a trialkyl (e.g. trimethyl, triethyl or dimethyl (11dimethylethyi))sily] ester.
CM oxidising agents are generally preferred. The choice of oxidation method however will depend on the nature of the starting material of formula (2). Thus when Ria is -CH,OH or -CHO, a Crvl oxidising agent will generally be used. When Y is in the a-configuration conditions should be chosen to effect epimerisation, either at the same time or after oxidation.
Any hydroxy or amino group present in the starting material and required in the end product should be suitably protected in this reaction.
(b) Compounds of formula (1) in which R3 is an alkyl or aralkyl group can be prepared by esterification of the corresponding carboxylic acid in which R 3 is a hydrogen atom, reaction with a diazoalkane being preferred.
Alternatively, the acid may be converted into an activated derivative (e. g. a corresponding mixed -anhydride) e.g. by reaction with an alkyl chloroformate (e.g. isobutyl chloroformate) in the presence of a suitable base, e.g. triethylamine or pyridine. The activated derivative can then be reacted with an appropriate alcohol, for example using a solvent such as acetone and temperatures of -10' to room temperature.
(c) Compounds of formula (1) in which R 2 is phenalkyl substituted by amino may be prepared by reduction of the corresponding azide, for example using zinc and sodium dihydrogen phosphate (e.g. in tetrahydrofuran).
(d) Compounds of formula (1) may also be prepared by selective reduction of a corresponding compound of formula (1) in which X is an acetylene group. These intermediates are also novel compounds. Suitable methods of reduction include using hydrogen in the presence of a catalyst, e.g. palladium on a support (e.g. CaC03 or BaS04) and poisoned for example by lead or pyridine. Suitable solvents include ethyl acetate or methanol.
(e) Where salts of compounds of formula (1) are desired such salts may be formed by conventional methods, for example by treating acids of formula (1) with appropriate bases. Salts may 55 also be formed with acids.
4 GB 2 075 503 A 4 The salts may be formed in conventional manner. For example, amine salts are conveniently prepared by adding the amine to a solution of an acid of formula (1) in a solvent such as ether. Salts of inorganic bases may be prepared by adding the base to a solution of the acid in an aqueous organic solvent. Certain salts may also be prepared by exchange of cation; for example, calcium salts may be prepared by addition of a calcium salt (e.g. the chloride or acetate) to a solution of a salt of a compound of formula (1), e.g. an amine or alkali metal salt.
The principal intermediates required for the reactions described above may be prepared by the following methods.
It will be appreciated that the following reactions will frequently require the use of, or will conveniently be applied to, starting materials having protected functional groups. It is to be understood 10 generally that the references below to specific starting materials are intended to include references to corresponding materials having protected functional groups.
It will also be appreciated that certain of the reactions described below are capable of affecting other groups in the starting material which are desired in the end product, and account must be taken of this when performing multi-stage reactions.
(f) Compounds of formula (3) 9R2 R NO' Y (where R' is as defined above for R' where R3 is a hydrogen atom) may be prepared by reacting a compound of formula (4) 9R2 I'VeNO NO' Y is (3) (4) 20 with an appropriate Wittig reagent, e.g. a phosphorane of formula R 7 P=CHR1 (where R 7 or 3 is C1-6 alkyl aryl, e.g. monocyclic aryl such as phenyl) or a salt thereof, e.g. the potassium salt. Suitable reaction solvents include hydrocarbons (e.g. benzene and toluene), ethers (e.g. tetrahydrofuran), dialkylsulphoxides (e.g. dimethylsulphoxide), alcohols and halogenated hydrocarbons. The reaction may be carried out at any suitable temperature from -700 to 500C, preferably at room temperature.25 The reaction is particularly suitable for the preparation of compounds in which RI is terminally substituted by -COOH (in salt form). Any hydroxy group present is preferably in a protected state prior to this reaction. Suitable hydroxyl protecting groups are described below. Any -NH2 group present should also be protected, e.g. by t-butoxycarbonyl.
If desired, the configuration of the group X and R1 and R2 may then be modified to provide other 30 compounds of formula (2) e.g. by methods (I)-(o) below or M or M above.
The starting materials of formula (4) may be prepared by the following sequence:
Y 0 H002 OR2 (5) OR2 OR8 0 ' Y H 16) (4) A lactol of formula (5) is treated with an appropriate Wittig reagent (e. g. R7p=CHOR8, where R 7 is 3 as defined above and RI'S C1-4 alkyl) to give the vinyl ether (6). The reactions maybe performed as 35 described for process (f). The vinyl ether (6) is then hydrolysed to give the aldehyde (4), for example using a dilute acid such as hydrochloric acid. Acetone is a suitable solvent.
9 GB 2 075 503 A 5 Lactols of the formula (7) Y 0 H 0,,r OR2 (7) may be prepared by the method described in British Patent Specification 2, 028,805A, using starting materials containing the appropriate R 2 group.
Lactols of formula (8) No-r-r- OR2 required as starting materials may be prepared by the following sequence:
Y Rho 3 0 19) Y 0 1 1 OR2 112) (8) Y Rho/ 4_ OH (10) Y R h onIC," R2 (11) (R h above represents a hydroxyl protecting group). Thus the norbornanone (9) is first reduced (e.g. with NaBH,) to the alcohol (10) into which the R' group is then introduced (e. g. by reaction with R 2 IL, where10 L is a leaving group, e.g. halogen or tosylate) to give the compound (11). The protecting group (R h) is then removed and the hydroxy group oxidised (e.g. as described for process (a)) to give the norbornanone (12). The latter can then be converted into the lactol (8) by Baeyer- Villiger oxidation followed by reduction (e.g. with di-isobutyl aluminium hydride).
(g) Compounds of formula (2) in which the groups Y and OH are both in the P-position may be 15 prepared by reducing the corresponding compound of formula (1), e.g. with lithium tri-sec-butyl - borohydride.
(h) Compounds of formula (2) in which R1a contains -CH20H may be prepared by reducing the corresponding acid or ester of formula (2) or (1), e.g. with LiAM, (j) Compounds of formula (2) in which R1a contains -CHO maybe prepared in the same manner 20 as generally described for process (f) by reacting a compound of formula (4) with a phosphorane of formula R 7 P=CHIRIa in which Ria is C alkyl substituted by a protected formyi group (e.g. acetal).
3 1-7 of the protecting group then gives the required formyl intermediate.
(k) Compounds of formula (2) in which Y is in the a-configuration and the ring hydroxy group is in the P-configuration may be prepared by epimerising the corresponding compound in which the ring 25 hydroxy group is in the a-position. This may for example be effected with triphenylphosphine in the presence of an acid (e.g. formic or benzoic acid) and (C,1H1,00C. M2 at a low temperature.
Tetrahydrofuran is a suitable solvent.
(1) The acetylenes required as starting materials for process (d) may be prepared by first reacting a compound of formula (7) with a Wittig reagent (R7p=CBrR'), as described above for process (f). The 30 3 product is then dehydrobrominated to form the side chain acetylene group, and the ring hydroxy group then oxidised, as described for process (a).
(m) Compounds of formula (2) in which X is trans -CH=CH- may be prepared by isomerising 6 GB 2 075 503 A 6 the corresponding cis compound. T he isomerisation may for example be effected by treatment with, for example, p-toluene sulphinic acid in dioxan (e.g. at reflux) or azobisisobutyronitrile and thiophenol, using for example a hydrocarbon solvent (e.g. benzene) and any suitable temperature up to reflux.
(n) Compounds of formula (2) in which R 2 is phenalkyl substituted by -CH, N(CHI)2 may be prepared by treatment of the corresponding formyl compound with dimethylamine in the presence of a reducing agent, e.g. sodium cyano borohydride. The starting materials for this reaction may be made by the general method (f).
(o) Compounds of formula (2) in which R 2 is phenalkyl substituted by CONH2 or -CSNH2 and R 3 is hydrogen may be prepared from the corresponding cyano compound by hydrolysis or hydrosulphidation, e.g. with sulphur in the presence of a reducing agent.
(p) Compounds of formula (2) in which R 2 is phenalkyl substituted by alkylsulphinyl or alkylsulphonyl may be prepared by oxidation of the corresponding alkylthio compound with a peracid, for example peracetic acid at room temperature.
(q) Compounds of formula (3) in which -OR 2 is an ether group and Y is in the A-configuration maybe prepared byetherification of the corresponding hydroxy compound in which R 2 is a hydrogen, 15 atom. The reaction may for example be performed with an appropriate reagent R 2 L (L is as defined above), for example by reaction at room temperature in the presence of a suitable base (e.g. sodium hydride) in a suitable solvent (e.g. dimethy1formarnide).
W Compounds of formula (3) inwhich R2 is an alkanoyl group and Y is in the P-configuration may be prepared by acylation of the corresponding hydroxy compound, for example with the appropriate 20 alkanoic acid or an anhydride or halide thereof..
Any other hydroxy group present in the starting material used in process (q) or (r) should be protected in this reaction, as should the -COOH group in compounds in which R 3 is a hydrogen atom.
Suitable starting materials of formula (16) for processes (q) and (r) above may be prepared by the following sequence:
RH R 1 (13) 116) OH Rho', Y 114) Rho '. Y (15) A lactol of formula (13), in which -ORh is a protected hydroxy group is first treated with a Wittig reagent to give the vinyl ether (14), which is then converted into the aldehyde (15) by treatment with mercuric acetate. These steps are performed in the same general way as for the preparation of compounds of formula (4). The compound of formula (16) may then be formed from the aldehyde (15) 30 by method of process (f).
The preparation of the lactols (13) is described in British Patent Specification 2,028,805A.
As an alternative to the formation of the ether group by process (q), it may be formed at an earlier stage, by etherification of the compound of formula (14).
(s) Compounds of formula (2) may also be prepared by modifying the corresponding compound in. 35 which Y is -NH2.
This reaction may be performed by treating the starting material with a compound of the formula MIZ, where Z is a readily displaceable group (such as halo, e.g. iodo, or hydrocarbyisulphonyloxy, e.g.
p-toluenesulphonyloxy) and R' is the appropriate divalent group (e.g. (CH2)2S(CH2),7--). The reaction may be carried out in a solvent such as acetonitrile or methanol at reflux, in the presence of a suitable 40 base, e.g. potassium carbonate or sodium bicarbonate.
The amines required as starting materials for process (s) may be prepared by reduction of the corresponding azide, for example as described for process (c).
The azide starting materials may be prepared by methods analogous to those for preparing the compounds of formula (3), using reagents in which Y is an azido group. In particular, the preparations of lactols of formula (7) in which Y is azido is described in British Patent Specification 2,028,805A.
If desired, modification of the group R' or the configuration of the double bond may be effected before the formation of the group Y by process (s). The amino group may need to be protected in such transformations.
1 7 GB 2 075 503 A 7 In the preparation of the intermediates the ring hydroxy group will often be protected and the liberation of this (or any other hydroxy group present) will frequently be the last step in the preparation. Conventional methods of protection may be used, protection in the form of dimethyl-1,11 - d i methyl ethyl-si lyloxy or tetra hydropyra nyloxy groups being preferred. These groups may be removed by acid hydrolysis. Hydroxy groups may also be protected in the form of alkanoyloxy groups having up 5 to 7 carbon atoms, e.g. acetoxy. These groups may be removed by alkaline hydrolysis.
When a specific enantiomer of formula (1) is required, intermediates having the required stereochemical configuration should be used in the above processes. For example, enantiomeric bromohydrin (17) 0 / 'A\ Br ON (17) can be prepared by the method described by Newton et al in J.C.S. Chem. Comm., 1979, 908. This can then be converted into a compound of formula (1) in which the carbon atom carrying the -(CH,),XR' group is in the (R)- configu ration, via the appropriate enantiomer of the lactol (7), using the methods described above.
The following examples illustrate the invention. "Jones reagent" is a solution of chromic acid and 15 sulphuric acid in water. A 2.67M solution contains Cr03 (26.7 g) and concentrated H2S04 (23 mi) made up to 100 mi with water.
Temperatures are in 'C. The following abbreviations are used:
TILC-thin layer chromatography using SiO 2; PE-petroleum ether (boiling at 40-601 unless otherwise stated); DIBAL-diisobutylaluminium hydride;THF-tetrahydrofuran; DMF- dimethyiformamide; ER-ether; EA-ethyl acetate; DMSO-dimethyisulphoxide. Chromatography was carried out using silica gel unless otherwise stated. 'Dried' refers to drying with M9S04. 'Hyflo' is a filtration aid.
Intermediate 1 (endo, anti)-( )-5-hydroxy-7-(4-morpholinyl)bicyclo[2.2.llheptan-2-one A mixture of (endoantil-5-acetyi-7-(4-morpholinyi)bicyclo[2.2.1 1 heptan- 2-one (164 9) and 5N NaOH solution (750 m]) was stirrectfor 3 h and then extracted with CH2C12 (4x500 mi). The dried organic layers were evaporated in vacuo to give a semi-solid. Trituration with ER (500 mi) gave the title compound (83 g) as prisms, m.p. 119-121 0.
Intermediate 2 a) (endoanti)-( )-5-[[(1,1 1-biphenyl-4-Vllmethoxy]-7-(4morpholinyi)bicyclo[2.2.1]heptan-2one To a solution of Intermediate 1 (10.5 g), 1 -(bromo methyl)- 1, 1 '- biphenyl (13.6 g) and benzyitriethyl ammonium chloride (1.14 g) in CH2C12 (200 ml) was added 17N NaOH (100 m]) and the mixture stirred vigorously for 18 h. The layers were separated and the aqueous layer extracted with CHP2 (3 x 100 mi). The combined organic layers were washed with water (200 m]), dried and evaporated in vacuo. The residue was crystallised from iso-propyl acetate to give the title compound (15 g) as prisms, m.p. 149.5-151.50. The following compounds were prepared by a similar procedure.
b) (endoanti)-( )-5-[4-methoxy(phenyimethoxy)1-7-(4-morpholinyi)bicyclo[2. 2.1lhe ptan-2-one 40. m.p. 109-111 1, from Intermediate 1 and p-methoxybrnzyl bromide. Purification by chromatography 40 using 3:1 ER-PE through to 5:1 ER-methanol as eluent.
( )-4-[(endo,endo,anti)-2- [ Ull, V-1b iphenvi)-4-Vfl methoxy]-5- Rtetra hydro-2 H-pyra n-2 yi)oxylbicyclo[2.2.1 lheptan-7-yijmorpholine m.p. 109-1101 from Intermediate 27. Purification by chromatography using 7:3 ER-PE as eluent.
d)(endoanti)-( )-5-[[(1,11-biphenyi)-4-yi]methoxy]-7-(1piperidinyi)bicyclo[2.2.llheptan-2-one 45 m.p. 89-91 11 form Intermediate 57. Purification by chromatography using 3:2 PE-ER as eluent.
Intermediate 3 a) (endoanti)-( )-6-[[(1,11-biphenyl)-4yilmethoxy]-8-(4-morpholinyi)-2oxabicyc lo[3.2.lloctan- 3-one 38% Peracetic acid in acetic acid (20 m])was added dropwise over 10 min to a stirred solution of 50 Intermediate 2a (12.5 g) in CH2C12 (60 mi) maintained at 12-151. Stirring was continued at 15-200 8 GB 2 075 503 A 8 for 24 h, the mixture then cooled to 50 and treated with a solution of Na, SO, (25.1 9) in water (125 mO whilst maintaining the temperature below 200. Isopropyl acetate (90 ml) was added and the aqueous phase was separated. The organic phase was extracted with 1 N NaOH (60 mi) and water (2x60 mi), then dried and reduced in volume to about 35 mi. On cooling to 201 the title compound crystallised and was collected and dried (6.25 g), m.p. 137-1390.
The following compounds were prepared by a similar procedure:
b) (endoanti)-( )-6-[4-methoxy(phenyimethoxy]-8-(4-morpholinyl)-2oxabicyclo[3.2.lloctan-3one m.p. 158-1600, from Intermediate 2b. Purification from CH2CI--PE.
c)(endo,anti)-( )-6-[[(1,11-biphenyi)-4-yllmethoxyl-S-(1-piperidinyi)-2oxab icycio[3.2.1]octan-3- 10 one M.p. 88-900 from Intermediate 2d.
d) (endoanti)-( )-6-decyloxy-8-(4-morpholinyi)-2-oxabicyclo[3.2.lloctan-3one m.p. 59-610, from intermediate 80. Purification from PE.
- 15 Intermediate 4 a) (1 cv,2P.3a,5cr)-( )-5-[[(1,1 1-biphenyi)-4-yllmethoxy]-3-hydroxy-2-(4- morpholinyi)cyclopentane Acetaidehyde DIBAL in h-jxane (1.4 M; 6.9 mi) was added dropwise to a solution of Intermediate 3a) (1.9 g) in dry CH2C12 (30 mi) under nitrogen at -701. Stirring was continued for 2 h at -70' when methanol (50 m]) was cautiously added and the mixture then allowed to come to ambient temperature and 20 stirred for a further 3 h. The mixture was filtered through hyflo and the filtrate evaporated in vacuo. The residue was taken up into CH2C12 (50 mi), dried, filtered and concentrated to give the title compound as a glass (1.8 g)-.
I.R. (CHBr.) 3580,1718 cm-1.
The following compounds were prepared by a similar procedure:
b) - (11 a,2p,3a,5a)-( )-3-hydroxy-5-[4-methoxy(phonylrnethoxy)1-2-(4morpholinyl)cycl opentane Acetaldehyde from Intermediate 3b. Purification by chromatography using 98:2 CHC13-methanol as eluent.
TLC 95:5 CHC13-methanol Rf 0.8.
c)(1a,2a,3ce,5a)-( )-5-[[(1,11-biphenyi)-4-yilmethoxy]-3-hydroxy-2(4morpholinyl)cyclopentane Acetaldehyde m.p. 136-1380 from Intermediate 30.
d) (3aa,4a,5p,6aa)-( )-hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxyl-4-(4thiomorp holinyl)-2Hcyclopenta(b) furan-2-ol from Intermediate 55a.
TLC 9:1 Benzene-methanol Rf 0.25.
e) (11 a,2p,3a,5a)-( )-5-[[(1,1'-biphenyl)-4-yllmethoxyl-3-hydroxy-2-(1 piperidinyl)cyclopentane Acetaldehyde from Intermediate 3c. TLC 85:15 ERmethanol Rf 0.38.
f) (3aa,4a,5p,6aa)-( )-hexahydro-4-(hexahydro-1,4-oxazepin-4-yi)-5[(tetrahydro-2 H-pyran-2- 40 yl)oxyl-2H-cyclopenta(b)furan-2-oI from Intermediate 55b. TLC 9:1 ER-methanol Rf 0.3 1.
9) (1 a,2p,3a,5a)-( )-5-decyloxy-3-hydroxy-2-(4-morpholinyl)cyclopentane Acetaldehyde from intermediate 3d. TLC (S'02) EA Rf 0.2 1.
Intermediate 5 - a) (1 a,2p,3a,4a)-( )-4-[[(1,1 1-biphenyi)-4-yilmethoxyl-3-(3-methoxy-2- propenyi)-2-(4morpholinyi)cyclopentanol To a cold (00) stirred solution of potassium tert-butoxide (1.55 g) in dry THF (40 mi) under nitrogen, was added portionwise (methoxymethyi)triphenyl phosphonium chloride (4.72 g). The resulting suspension was stirred for 25 min whereupon a solution of Intermediate 4a) (1.82 g) in dry 50 THF (15 mi) was added dropwise. Stirring was continued at room temperature for 1.5 h. The reaction mixture was poured into brine, the pH adjusted to 6.6, and the mixture extracted with EA. The dried extracts were evaporated to leave a viscous oil. This crude material was flash chromatographed on silica. Eluting with 95:5 EA-methanol and recycling of the impure fractions gave the title compound as an oil (1.29 g). IR (CH13r) 3950 (br),3540,1668 cm-1.
The following compounds were prepared in a similar manner.
9 GB 2 075 503 A 9 b) (1 a.2a,3p,4a)-( )-2-(3-methoxy-2-propenyi)-4[(tetrahydro-2H-pyran-2- yi)oxy]-3-(4thiornorpholinyOcyclopentanol from Intermediate 4d. Purification by chromatography using ether as eluent. TLC ER Rf 0.28.
c) (1 a,2a,3p,4a)-( )-2-(3-methoxy-2-propenyi)-3-(1 -piperidinyi)-4[(tetrahydro-2H-pyran-2y1)oxylcyclopentanol from (3aa,4a,5p,6aa)-( )hexahydro-4-(1 -piperidinyi)-5-[(tetrahydro-2H-pyran-2-yi)oxy]2Hcyclopenta(b)furan-2-ol. TLC 4:1 EA-methanol Rf 0.22.
Intermediate 6 (1 a,2p,3a.5a)-( )-5-[[(1,1 1-biphenyi)-4-yilmethoxy]-3hydroxy-2-(4-morpholinyi)cyclopentane 10 Propanal, Hydrochloride Intermediate 5a (1.835 g) was dissolved in 1:1 acetone/0.5N H2S04 (65 mi) and was left standing overnight at room temperature. The acetone was evaporated and the residue treated with 8% NaHC03 solution and extracted with EA. The dried extracts were evaporated to give a foam (1.73 g) which was dissolved in ether and treated with ethereal hydrogen chloride. The title compound was filtered off and dried, m.p. 169-1721.
Intermediate 7 a) (1 a,2a,3p,4a)-( )-2-(3-methoxy-2-propenyl)-3-(4-morpholinyl)-4[(tetrahydro-2H-p yran-2- yl)oxylcyclopentanol, Acetate (Ester) To a cold (01) stirred solution of potassium tert-butoxide (2.15 g) in dry THF (40 m]) under nitrogen, was added portionwise (.methoxymethyi)triphenyl phosphonium chloride (6.57 g). The 20 suspension was stirred for 15 min, whereupon a solution of (3aa,4a,5p, 6aa)-hexahydro-4-(4 morpholinyi)-5-(tetrahydro-2H-pyran-2-yl)oxy-2H-cyclopenta(b)furan-2-oI (2 g) in dry THF (30 mi) was added dropwise. Stirring was continued at room temperature for 1 h, when methanol (30 mi) was added followed by evaporation of the mixture to dryness. The residue was treated with acetic anhydride (8 mi) and pyridine (10 mi) and left for 40 h. Evaporation in vacuo gave a residue which was 25 treated with 8% NaHCO, solution (50 m]) and extracted with CH2C12 (3x20 mi). The combined extracts were washed with brine (2x15 mi), dried and concentrated. Purification of the residue, initially by chromatography using 4:1 ER-methanol as eluent, and then by trituration with PE gave the title compound as an oil (13.23 g). IR (Neat) 1735,1655 cm-1.
The following compounds were prepared in a similar manner.
b) (1 a,2a,3p,4a)-( )-2-(3- methoxy-2-propenyi)-4-[(tetrahydro-2H-pyran-2yi)ocy1-3-(4thiomorpholinyi)cyclopentanol, Acetate (Ester), S-dioxide m.p. 131-1341 from Intermediate 63. Purification initially by chromatography using 1:1 EA-PE as eluent followed by crystallisation from isopropanol-ERisopentane.
c) (l a,2a,3p,4a)-(+)-3-(hexahydro-1,4-oxazepin-4-yi)-2-(3-methoxy-2propenyi)-4-[ (tetrahydro- 35 2H-pyran-2-yi)oxylcyclopentanol, Acetate (Ester) from Intermediate 4f. Purification by. chromatography using 95:5 ER-methanol as eluent. TLC 19:1 ER-methanol Rf 0.65.
Intermediate 8 (1 a,2a,3p,4a)-( )-2-(3-rnethoxy-2-propenyi)-3-(4-morpholinyi)-4[(tetrahydro-2H -pyran-- 40 y1)oxyjcyclopentanol A solution of intermediate 7a (0.3 g) in 0.5N NaOH (10 mi) was left to stand for 10 min, then extracted with ER (3 x20 mi). The combined extracts were dried, filtered and evaporated to give the title compound as an oil (0.25 g). IR (Neat) 3450, 1655 cm-1 Intermediate 9 a) (1 a,2p,3p,5p)-( )-4-[3-(2-naphthalenyimethoxy)-2-(3-methoxy-2propenyi)-5-[(tet rahydro- 2H-pyran-2-yi)oxylcyclopentyllmorpholine NaH (0.48 g, 80% dispersion in oil) was added to a solution of Intermediate 8 (2.2 g) and bromomethyi)naphthalene (3.56 g) in dry DMF (8 mi) at O1C. After stirring for 7 H, the suspension was pou'red into saturated NI-14C1 solution (75 mO and extracted into ER (3x50 mi). The combined extracts 50 were dried and concentrated, and the residue chromatographed on silica using ER as eluent to give the title compoundas an oil (2.1 g). IR (Neat) 1716, 1655 cm-1.
The following compounds were prepared by a similar procedure:
b) (1 a,20,30,50)-( )-4-[2-(3-methoxy-2-,propenyi)-3-[4-(1,1 -di methylethyl) phenyl methoxyl 5- [(tetra hyd ro-2H-pyra n-2-y1) oxyl cyclopentyll m orpholi ne from Intermediate 8 and 4-0,1 -dimethylethyi)phenyl methyl bromide. Purification by chromatography using ER as eluent.]R (Neat) 1650, 1120 cm- 1.
GB 2 075 503 A 10 c) (1 a,2p,3p,5p)-( )-4-[3-(4-cycioheXViPhenVimathoxy)-2-(3-methoxy-2propenyl)-5[(tetrahydro-2H-pyran-2-yi)ox.llcyciopentyllmorpholine from Intermediate 8 and 4-cyclohexyl phenyl methyl iodide. Purification by chromatography using ER as eluent.
d) (1a,2p,3p,5p)-(+)-4-[2-(3-methc,,,,1-2-propenyi)-3-(pentyloxy)-5[(tetrahydr o-2H-pyran-2- 5 yi)oxylcyclopentyll morpholine from Intermediate 8 and n-pentyl-tosylate. Purification by chromatography using EA as eluent.
e) (1 a,20,30,50)-( )-4-[2-(3-me-UhoxV-2-propc-nyl)-3-[4-(phenyI methyl)phenyl methoxy]-5 [(tetrahydro-2H-pyra n-2-y1) oxyl eye] opentjil morpholine from Intermediate 8 and 1 -(bromon-tethyi)-4-(phenyimethyi)benzene. Purification by chromatography 10 using ER as eluent.
f) (1 1-biphenyl)-4-yilmethoxy]-2-(3-methoxy-2-propenyi)-5- [(tetra hydro-2H-pyran-2-yi) oxy] cyclopentyll morphol ine from Intermediates 8 and 68. IR (Neat.) 1650, 1120 cm-1.
9)(1a,2P.3P,EP)- ;-!-[2-(2,-metilo.y-2-pvcp,(,,9ijl)-3-(2-propenyloxy)-5[ (tetrahydro-2H-pyran- 15 2-yi)oxylcyclopentyilinGrr,hc-linc- from Intermediate 8 and allyl bromide.
h) (1 a,2p,3p,5p)-( )-4-[2-(3-rnetboxy- 2-propenyi)-3-[4methyithio)phenyimethoxy)]-5- [(tetra hydro-2 H-pyran-2-!1) oxyl cyclopen-o.111 morpholine from Intermediate 8 and 1 -(bromo methyl)-4-(methy[thio) benzene. Purification by chromatography 20 using ER as eluent. IR (N1eat) 1650,1120 cm-1.
0 (1 a,2p,3p,5p)-(+)-LI,.-[2-(3-rnethcDxy-2-propeRiyl)-.1j--[(tetrahydro2H-pyra n-2-yi)oxy]-3-[(4-thien- 2-yl) phenyi niatho,.j] cy(j- morphoi iris from Intermediates 8 and 24a. PurNication by chromatography using ER as eluent.
j)(1a,2p,3p,5p)-(±4-[2-(3-meljhoxy-2-psopcDnyi)-3-[[(1,11:41,Ilfterphenyi)-4-yilmethoxy]-5- 25 [(tetrahydro-2H-pyran-2-yl)cDxylcyclopentyllmorpholine from Intermediates 8 and 24b. Purification by chromatography using ER as eluent. TLC ER Rf 0.18.
k) (1 a,20,30,5p)-( )-4-[2-(3-methox,1-2-F-,ropE.nyi)-3-(4-phenyithien-2yi)methox y]-5[(tetrahydro-2H-pyvan-2-yi)o,-ylcycic,,pantillrroovpholine from Intermediates 8 and 65. Purification by chromatography using EA as eluent.
1) [1 a,2p,30(E),5p]-( )-4- [2-(2--methexy-2-pr(Gpenyi)-3-[(3-phenyi-2propenyi)oxy]-5[(tetra hydro-2H-pyran-2-,11)oxyl cyclopentyll morpholine from Intermedaite 8 and cinnamyi bromide. Purification by chromatography using ether as eluent.
m) (l a,2p,3p,E-P)-'--)-,-4.,-12-[[(1,1'-biphc-nV1)-4--llmetboxy]-2-(3-n-, etho xy-2-propenyi)-5[(tetrahydro-2H-pyrai-2-2-yi)o,ylcyclopentyllthiomorpholine from Intermediate 5b and 1 -(bromortiethll)1,1'-biphenyl. Purification by chromatography using 3:2 ER-P E. TLC ER R 14 0.42.
n) (1 "-biphenyi)-4-yll methoxy]-2-(3-methoxy-2 propen'yi) -5-[-(tetrahydro-21-1-pyran-2-yi)oxyley-- lopentyllthiomorpholine, S-dioxide from Intermediate 59a and 4-(bromomethyi)-4'-methoxy(1,1'-biphenyi). Purification by chromatography using CH2C12 followed by ER as eluents. TLC ER Rf 0.41.
o) (1 a,2p,3p,5p)-( )-4-E2-(3-metho)cy-2-propenyi)-3-[[41-methyi(1,1 1biphenyi)-4-yilmethoxy]-5(tetrahydre-2H-pyran-2-yl)oxllcyclopentyllthlomo rpholine. S-dioxide from Intermediates 59a and 66. Purification by chromatography using CH2C12 followed by 4:1 ER-PE as eluent.
p) (1 a,2p,3fi,5p)-( )-4-E2-(3-motboxii-2-propenyl)-3-[4. -(phenyl methyl) phenyl methoxyl -5[(tetrahydro-2H-pyrarm-2-yi)o,,. flcyciopen'vll]thiomorpholine, S-dioxide from Intermediate 59a) and 1 (bromomethji)-4-(phenyl methyl) benzene. Purification by chromatography using CH2C12 followed by ER as eluents. TLC EA Rf 0.5.
q)(1a,2,3p,5A)-(+)-4-[S-[[(1,11-biphenyl)-4-ytlmethoxyl-2-(3-methoxy-2prop enyl)-5[(tetrahydro-2H-pyran-2-71)ox2llcyclopentyllthiomorpholine, Sdioxide from Intermediate 59a and 1-(bromomethyl)-1,1'-biphenyl. TLC 95:5 ER-methanol Rf 0.7.
11 GB 2 075 503 A 11 0 0 a,2A,3A.5AH )-4-[3-[(1,1 '-biphenyl)-4-yll methoxyl-2-(3-methoxy-2propenyl)-5L(tetrahydro-2H-pyran-2-yl)oxyjcyclopentyllhexahydro-1,4oxazepin from Intermediate 59b. TLC 97:3 ER-methanol Rf 0.68.
s) (1 a,2p,3p,5p)-( )-1 -[3-[[4"-methoxy(1,1'-biphenyi)-4-ylj methoxy]-2(3-methoxy-2-propenyl)5-[(tetrahydro-2H-pyran-2-yi)oxyleyclopentyllpiperidine from Intermediate 5c. Purification by chromatography using 98:2 CH2C12-methanol as eluent.
t) (1 1-biphenyi)-4-yllpropoxy]-2-(3-methoxy-2-propenyi)-5- [(tetra hydro-2 H-pyran-2-y1)oxyl cyclopentyll morpholine from Intermediates 8 and 60. Purification by chromatography using EA as eluent.
u)(1a,2p,3p,5p)-( )-4-[3-[[31-methoxy(1,1'-biphenyi)-4-yilmethoxy]-2-(3metho xy-2-propenyi)- 10 5-[(tetrahydro-2H-pyran-2yi)oxylcyclopentyllmorpholine Irom Intermediates 8 and 24c. Purification by chromatography using EA as eluent.
v) M a,20,30,5p)-( )-4-[3-[[41-methoxy(1,11-biphenyi)-3-yilmethoxy]-2-(3methoxy-2 -propenyi)5-[(tetrahydro-2H-pyran-2-yi)oxyleyclopentyllmorpholine from Intermediate 8 and 3-(bromomethyi)-4-methoxy(1,1'-biphenyi). Purification by chromatography 15 using EA as eluent.
Intermediate 10 a) (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-niorpholinyl)-5-(2naphthalenyimethoxy)cyclopentanepropanaI A solution of Intermediate 9a (2.1 g) in acetone (10 mi) containing 2N hydrochloric acid (5 mi) 20 was allowed to stand at room temperature for 1 h. After evaporation in vacuo the residue was neutralised with 8% NaHCO, solution and extracted with CHP2 (3x30 mi). The combined extracts were dried, filtered and concentrated to afford the title compound as a viscous oil (1.7 g). IR (Neat) 3420,1720 cm-1.
The following compounds were prepared by a similar procedure:
b) 0 a,2p,3a,5a)-( )-3-hydroxy-5-[4-(1,1 -dimethylethyl)phenylmethoxyl-2(4morpholinyl)cyclopentanepropanaI from Intermediate 9b. TLC 4:1 ERmethanol Rf 0.52.
c) (1 a,2P,3 a,5a)-( )-5-(4-cyclohexyl phenyl methoxy)-3-hydroxy-2-(4morpholinyl)cyclopentanepropanaI from Intermediate 9c. TILC 17:3 ERmethanol Rf 0.28.
d) (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyl)-5(pentyloxy)cyclopentanepropanal from Intermediate 9d. TLC 95:5 EAmethanol Rf 0.08.
e) (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyi)-5-[4- (phenyl methyl) phenyl methoxyl cyclopenta nepropanal from Intermediate 9e. Purification by chromatography using 9:1 ER-methanol as eluent.
f) (1 a,2p,3a,5a)-( )-5-[[4-chloro(1,1 1-biphenyi)-4-yllrnethoxyl-3hydroxy-2-(4morpholinyi)cyclopentanepropanaI from Intermediate 9f. Purification by chromatography using CHCI, through to 98:2 CI-IC13methanol as eluent.
g) (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyi)-5-(2propenyloxy)cyclopentaneprop anaI from Intermediate 99. Purification by chromatography using 4:1 ER-methanol as eluent.
h) (1 a,2p,3ce, 5a)-( )-3-hyd roxy-S-[4-rnethyithio (phenyl methoxy)1-2(4 morpholinyl)cyclopentanepropanaI from Intermediate gh. Purification by chromatography using 85:15 ERmethanol as eluent. TLC 85:15 45 ER-methanol Rf 0.28.
i) (11 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyl)-5-[(4-thien-2yl)phenylmethoxylcyclopentanepropanaI from Intermediate 9i. Purification by chromatography using CHCI, through to 98:2 CHC13-methanol as eluent. TLC 95:5 CHCI,-methanol Rf 0.3.
j) (1 cv,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyi)-4-[[(1.11:4',1 I'terphenyi)-4-yilmethoxylcyclopentanepropanaI m.p. 151-1531 from Intermediate 9j.
12 GB 2 075 503 A 12 k) (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyi)-5-[(4-phenyithien2yl)methoxylcyclopentanepropanal from Intermediate 9k. Purification by chromatography using 9:1 ER-methanol as eluent. [R (CHBr.) 3580-3540,2720, 1718 cm.
1) [l a,2p,3a,5a(E)]-( )-3-hydroxy-2-(4-morpholinyi)-5-[(3-phenyl2propenyi)oxylcyclopentanepropanaI from Intermediate 9 1. M (CHBr,) 3580, 3560,1720 cm-1.
m) (1 a,2p,3a,5a)-( )-5-[[(1,1 1-biphenyi)-4-yilmethoxy]-3-hydroxy-2(4thiomorpholinyi)cyclopentanepropanaI m.p. 109-1101 from intermediate 9m. Purification by chromatography using ER as eluent.
n) (1 a,2p,3a.5a).-( )-3-hydroxy-5-[[(4'-methoxy(1,1 '-biphenyi)-4yilmethoxy]-2-(4thiomorpholinyi)cyclopentanepropanal, S-dioxide from Intermediate 9n. IR (CH13r) 3580,2720,1720 cm-1.
o) (1 a,2p,3a,5a)-( )-3- hydroxy-5-[[4'-methyl(1,1 1-biphenyi)-4-yil methoxy]-2-(4thiomorpholinyi)cyclopentanepropanal, S-dioxide from Intermediate 9o. IR (CHBr,) 3580,2725,1720 cm-1.
p) (1 a,2P,3 a, 5a)-( )-3-hydroxy-5-[4-(ph enyl methyl) phenyl methoxy]2(4thiomorpholinyi)cyclopentanepropanal, S-dioxide from Intermediate 9p. IR (CHBr3) 3580,2720,1720 cm-1.
q)(1,,2p,3,,5,)-( )-5-[[(1,11-biphenyi)-4-yllmethoxy]-3-hydroxy-2(4thiomorpholinyi)cyclopentanepropanal, S-dioxide m.p. 152.5-1541 (dec.) from Intermediate 9q.
r) (1 [[1,1'-biphenyi)-4-yll methoxy]-2-hexahydro-1,4-oxazepin-4-yi)-3hydroxycyclopentane propanal from Intermediate gr. IR (CHBr,) 3580,2730,1720 cm- s) (1 a,2p,3a,5a)-( )-3-hydroxy-5-[[41-methoxy(l,1 1-biphenyi)-4-yil methoxy]-2-(1 piperidinyl)cyclopentanepropanaI from Intermediate 9s. IR (CHBr3) 3520,2730,1720 cm-1.
t) (1 1-biphenyi)-4-yllpropoxy]-3-hydroxy-2-(4morpholinyi)cyclopentanepropanaI from Intermediate 9t. IR (CHBr.) 3580, 2730, 1723 cm.
u) (1 a,2p,3a,5a)-( )-[3-hydroxy-5-[[31-methoxy(1,1 1-biphenyi)-4yllmethoxy]-2-(4morpholinyi)lcyclopentanepropanaI from Intermediate 9u. IR (CHBr3) 3580, 2720,1720 cm-1.
v)(1a,2p,3a,5a)-( )-[3-hydroxy-5-[[41-methoxy(1,11-biphenyi)-3yilmethoxy]-2-( 4morpholinyl)lcyclopentanepropanaI from Intermediate 9v. IR (CHBr3) 3560,2720,1720 cm-1.
Intermediate 11 (1 a,2p,3a,5a)-( )-3-hydroxy-5-[4-methoxy(phenyimethoxy)12-(4- morpholinyi)cyclopentanepropanaI Prepared as an oil from Intermediate 4b according to the methods described for Intermediates 5 and 6. 1 R (Neat) 3 3 80 (br.), 2 720, 1720, 118 cm-1 Intermediate 12 a) [1 a(Z),2P.3a,5a]- ( )-7-[5-[(1,1 1-biphenyi)-4-yil methoxy]-3-hydroxy-2-(4morpholinyl)cyclopentyll-4-heptenoic Acid To an intimate mixture of potassium tert-butoxide (1.29 g) and Qcarboxypropyi)triphenylphosphonium bromide (2.41 g) under nitrogen was added dry THF (50 mi). The suspension formed was stirred for 30 min whereupon a solution of the free base of Intermediate 6 (1.18 g) in dry THF (50 mi) was added dropwise. Stirring was maintained for 1.5 h whereupon water was added and all organic solvents were evaporated. The pH of the remaining suspension was adjusted 50 to 10 with 2N NaOH solution and the suspension was then extracted with EA to remove phosphorus contaminants. The pH was then adjusted to about 6.5 with phosphate buffer and the product extracted from the suspension with EA. The dried extracts were filtered and concentrated to give the title compound as a foam (0.93 g). IR (CHBr.) 3460,1710 cm-1 13 GB 2 075 503 A 13 Hydrochloride Salt To a solution of Intermediate 12a (0.25 g) in EA (5 m]) was added ethereal hydrogen chloride until no more cloudiness was produced. The solvents were decanted and the resulting oil repeatedly washed with dry ER to give a powder (0.13 g), m.p. 125.5-126.51.
Metha nesu I phonate Salt To a solution of Intermediate 12a (0.044 g) in EA (2 MI) was added methanesulphonic acid (0.01 g) at 201 and the mixture stirred for 1 h. The solid was filtered off, washed with EA and dried. Recrystallisation from ethanol gave material of m.p. 171-1741.
The following compounds were prepared by a similar procedure:
b) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-2-(4-morpholinyi)-5-(2naphthalenyimethoxy)cy clopentyll- 10 4-heptenoic Acid from Intermediate 1 Oa. Purification by chromatography using 85:15 ER-methanol as eluent. IR (Neat).3450-2300 (br.), 1715 cm-1.
c) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[4-methoxy(phenyirnethoxy)1-2-(4morpholinyl)cyclopentyll-4-heptenoic Acid from Intermediate 11. Purification by chromatography using 95:5 CHCl,-methanol as eluent. IR (CHBr3) 3580, 3500,1720,1710 cm-1.
d) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[4-(1,1 dimethylethyl)phenyimethoxy]-2-(4- morpholinyl)cyclopentyll-4-heptenoic Acid from Intermediate 1 Ob. Purification by chromatography using 9:1 ERmethanol as eluent. IR (CHBr3) 20 3500,1740,1710 cm e) [1 a(Z),2p,3a,5a]-( )-7-[5-(4-cyclohexylphenyimethoxy)-3-hydroxy-2(4morpholinyi)cyclopentyll-4-heptenoic Acid from Intermediate 10c. IR (CHBr,) 3500,1720,1708 cm-1.
f)[1a(Z),2p,3a,5a]-( )-7-[3hydroxy-2-(4-morpholinyi)-5(pentyloxy)cyclopenty l1-4-heptenoic 25 Acid from Intermediate 1 Od. Purification by chromatography using acetone as eluent.
9) [1 a(Z),2p,3a,Sal-( )-7-[3-hydroxy-2-(4-rnorpholinyl)5-[4(phenyl methyl) phenyl methoxyl cycl opentyll-4-heptenoic Acid from Intermediate 10e. Purification -by chromatography using 4:1 ER- methanol as eluent.
h) [1 a(Z),2p,3a,5a]-( )-7-[5-[[41-chloro(1,1 '-biphenyi)-4-yilmethoxy]-3hydroxy-2-(4morpholinyi)cyclopentyll-4-heptenoic Acid from Intermediate 1 Of. Purification by chromatography using CHC13 through to 96:4 CHC13methanol as eluent. IR (CHBr,) 3500, 1710 cm-1.
ill [l a(Z),2p,3a,5a]-( )-7-[3-hydroxy-2-(4-morpholinyi)-5-(2propenyloxy)cyclopenty ll-4- 35 heptenoic Acid from Intermediate 1 Og. Purification by chromatography using 9:1 ER- methanol as eluent. IR (CHBr 3) 3500,1740-1710 (br.) em-'.
j) [1 a(Z),2P.3a,Sal-( )-7-[3-hydroxy-5-[4-methyithio(phenyimethoxy)1-2(4- morpholinyi)cyclopentyll-4-heptenoic Acid from Intermediate 1 Oh. Purification by chromatography using 9:1 ER-methanol as eluent. [R (CHBr, ) 3 600-3400 (br.), 1730 (sh.), 1710 cm-1.
k) [1 M4,2P,3 a, Sal -W-7- [3-hydroxy-2-(4-mo rphol inyi)-5-[(4-thien-2 _yi) phenyl methoxyl cyclopentyll -4-heptenoic Acid from Intermediate 101 Purification by chromatography using CHCI, through to 94:6 CHCl.-methanol as 45 eluent. IR (CHBr,) 3500,1738, 1710 em.
1) [1 a(Z),2p,3a,5crl-( )-7- [3-hydroxy-2-(4-morpholinyi)-5-[[(1,1 1:4,1 "'-terphenyi)-4yilrnethoxylcyclopentyll-4-heptenoic Acid from Intermediate 1 Oj. IR (CHBr.) 3500, 1720 cm-1.
m)[1a(Z),2p,3a,5a]-( )-9-[5-[[(1,11-biphenyi)-4-yllmethoxy]-3-hydroxy-2(4morpholinyl)cyclopentyll-6-nonenoic Acid from Intermediate 6 and (5carboxypentyi)triphenylphosphonium bromide. [R (CHBr.), 3510, 1730 (Sh.), 1710 em-' 14 GB 2 075 503 A 14 n) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-2-(4-morpholinyl)-5-[(4-phenyithien2yl)methoxylcyclopentyll-4-heptenoic Acid from Intermediate 1 Ok.
o) [1 a(Z),2p,3a,5a(E)]-( )-7-[3-hydroxy-2-(4-morpholinyi)-5-[(3-phenyi2propenyi)oxyleyclopentyll-4-heptenoic Acid from Intermediate 101. Purification by chromatography using 9:1 ether-methanol as eluent. IR (CHBr3) 3500,1720 cm-1.
p) [1 '-biphenyi)-4-yll methoxy]-3-hydroxy-2-(4 thiomorpholinyl)cyclopentyi-4-heptenoic Acid 10from Intermediate 10m.IR(CHBr,)3500,1730,1710cm-1 q) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[[4'-rnethoxy(l, 1 1-biphenyi)-4- yil methoxy]-2-(4thiomorpholinyi)cyclopentyll-4-heptenoic Acid, S-dioxide m.p. 113-1151 from Intermediate 1 On. Purification by chromatography using 98:2 through to 96:4 ER-methanol as eluent.
15r)[1a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[[41-methyl(1,11-biphenyi)-4Yllmeth oxyl-2-(4- thiomorpholinyl)cyclopentyll-4-heptenoic Acid, S-dioxide m.p. 119.5-1121. 5 0 from Intermediate 1 Oo.
s) [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[4-(phenylmethyl)phenylmethoxyl-2(4- thiomorpholinyl)cyclopent-ill-4-heptenoic Acid, S-dioxide m.p. 127.5-128.51 from Intermediate 1 Op. Purification by chromatography using 96:4 ER-methanol 20 as eluent.
t) [1 1-biphenyl)-4-yllmethoxy]-3-hydroxy-2-(4thiomorpholinyl)cyclopentyll-4-heptenoic Acid, S-dioxide m.p. 109.5-111.5c' from Intermediate 1 Oq. Purification by chromatography using 98:2 ER-methanol as eluent.
u) fla(Z),2p,3a,5a]-(+)-7-[5-[[(1,11-biphenyl)-4-yllrnethoxyl-2(hexahydro-l,4-o xazepin-4-yi)-3hydroxycyclopentyll-4-heptenoic Acid from Intermediate 1 Or. TLC (S'02) 3:1 ER-methanol Rf 0.29.
v) [1 a(Z),2P.3a,5a]-( )-7-[3-hydroxy-5-[[41-methoxy(1,1 1-biphenyi)-4yil methoxy]-2-(1 - piperidinyi)cyclopentyll-4-heptenoic Acid, Compound with Piperazine (21) m.p. 106-1121 from Intermediate 1 Os. The title compound crystallised from a solution of the acid and piperazine in 2:1 EA-ER.
w) [11 a(Z),2P,3a,5a1-( )-7- [54340,11 1-biphenyl)-4-yllpropoxyl-3hydroxy-2-(4- morpholinyl)cyclopentyll-4-heptenoic Acid from Intermediate 1 Ot. Purification by chromatography using 5:1 EA- methanol as eluent. TLC 5:1 EA- 35 methanol Rf 0.3.
x) [1 a(Z),2p,3a,Sal-( )-7-[3-hydroxy-5-[[3"-methoxy(l,1 1-biphenyi)-4yil methoxy]-2-(4morpholinyi)cyclopentyll-4-heptenoic Acid from Intermediate 1 Ou. IR (CHI3r) 3500, 1725 (sh.), 1710 cm-1.
y)[1a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[[4'-methoxy(1,1"-biphenyi)-3yilmethox y]-2-(4- -40 morpholinyl)cyclopentyll-4-heptenoic Acid from Intermediate 1Ov. IR (CHBr,) 3500,1735 (sh.), 1710 cm-1 z) [1 a(Z),2p,3a,5a]-( '#-7-[5-decyloxy-3-hydroxy-2-(4morpholinyi)cyclopentyl1-4-h eptenoic Acid from Intermediate 17d.IR(CHBr,)3500,1735 (sh.), 1710cm-1.
Intermediate 13 [1 a(Z),2p,3a,5a]-( )-8-[5-[[(1,1 1-biphenyl)-4-yilmethoxy]-3-hydroxy-2- (4rnorpholinyl)cyclopentyll-5-octenoic Acid Prepared from Intermediate 6 (1 g) and (4- carboxybutyi)triphenylphosphonium bromide (3.17 g) in an analogous manner to that described for Intermediate 12a. The title compound was isolated as a 50 foam (0.92 g). IR (CH13r) 3500,1740,1705 cm-1.
GB 2 075 503 A 15 Intermediate 14 [1 M4,2P,3 a, 5a] -(+)-methyl 7-[5-[[1,1'-biphenyi)-4-yllmethoxy]-3- hydroxy-2-(4morpholinyl)cyclopentyll-4-heptenoate A solution of Intermediate 12a (0.7 g) in 9:1 methanol-H2S04 (20 mi) was stirred at room temperature for 2 h. Solid Nal-IC03 was added until pH 7.5-8, followed by water and extraction with 5 ER. The combined extracts were dried, filtered and evaporated to give the title compound as an oil (0.54 g). IR (CHBr3) 3580-3510,1730 cm-1 Intermediate 15 (endo, anti)-( )-6-[[4'-m ethyl (1, 1 1-biphenyi)-4yllmethoxy]-8-(4-morpholinyi)-2- oxabicyclo[3.2.lloctan-3-one Zinc bromide (27 g) in dry THF (180 m]) was stirred under nitrogen at 15- 201 during the addition of p-methylphenyimagnesium bromide [prepared in ether (160 mi) from Mg (3.24 g) and 4 bromotoluene (20.52 gfl. The mixture was stirred at 201 for 2 h.
Nickel acetylacetonate (1.8 g) and triphenylphosphine (7.34 g) were taken into THF (40 mi) and stirred under nitrogen during the addition of DIBAL (1M in hexane, 7 mi). After 5 min Intermediate 72 15 (4.75 g) in THF (65 mi) was added followed, after a further 5 min by the organozinc reagent. The mixture was then stirred at 221 for 30 h, whereupon saturated NH 4C1 solution (500 mi) and EA (300 ni) were added. The aqueous solution was adjusted to pH 5-6 with 2N hydrochloric acid and the layers separated. The aqueous solution was extracted with EA and the combined extracts dried and evaporated. The residue was chromatographed on silica using 7:3 through to 9:1 EA-PE (b.p. 60- 20 801) as eluent to give the title compound (3.1 g) as prisms, m.p. 141- 1440.
Intermediate 16 (1 a,2p,3(Y,5a)-( )-3-hydroxy-5-[[4'-methyi(1,1 1-biphenyi)-4-yi]methoxy]- 2-(4 morpholinyl)cyclopentane Acetaldehyde A stirred solution of Intermediate 15 (4.5 g) in dry CH2C12 (75 mi) at - 751 under nitrogen was treated with DIBAL (1.43M in hexane, 17.4 mi). Stirring was continued for 1 h, whereupon methanol (75 mi) was carefully added and the temperature allowed to rise to ambient. After 17 h, the mixture was filtered and the filtrate evaporated to give the title compound as a foam (4.63 g). TLC 9:1 EA methanol Rf 0.35.
Intermediate 17 a) 0 a.2P.3a,5a)-( )-3-hydroxy-5-[[41-methyl(1,11-biphenyl)-4-yllmethoxy]2-(4- morpholinyl)cyclopentanepropanaI To a stirred solution of potassium t-butoxide (3.89 9) in dry THF (110 mi) at -5l> was added (methoxym ethyi)tri phenyl phosphoni u m chloride (11.89 g) portionwise over 15 min. After stirring for min at -51 to 01 a solution of Intermediate 16 (4.03 g) in dry THF (35 mi) was added. The mixture 35 was stirred at 51 for 15 min and then at 201 for 1.7 5 h, quenched with water (7 mi) and the solvents removed in vacuo. The residue was then treated with 2N hydrochloric acid (20 m]) in acetone (50 m]) at 201 for 3.5 h. Aqueous Na2C03 was added to give a solution of pH 8 which was then diluted with water (100 mi) and extracted with EA (3x75 mO. The combined extracts were dried and evaporated and the residue chromatographed on silica (400 g) using 97:3through to 9:1 EA-methanol as eluent to 40 give the title compound as an oil (4.33 g). IR (Neat) 3400 (br.), 1720 cm- 1 The following compounds were prepared by a similar procedure:
b) (l ct,2a,3a,5a)-( )-5-[[1,1'-biphenyi)-4-yilmethoxy]-3-hydroxy-2-(4morpholinyi)cyclopentanepropanaI m.p. 114-1161 from Intermediate 4c.
c) 0 a,2p,3a,5a)-( )-5-[[1,11-biphenyi)-4-yilrnethoxy]-3-hydroxy-2-(1- piperidinyl)cyclopentanepropanaI from Intermediate 4e. M (CHBr,) 35003400 (br.), 1718 cm- od) (1 a,2p,3a,5a)-( )-5-decyloxy-3-hydroxy-2-(4morpholinyi)cyclopentanepropanaI from Intermediate 4g. Purification by chromatography using EA through to 95:5 EA-methanol as 50 eluents. M (Neat) 3530, 1723 cm-1.
Intermediate 18 [1 a(Z),2p,3a,5a]-( )-7-[3-hydroxy-5-[[41-methyi(1,1 1-biphenyl)-4- yllmethoxy]-2-(4 morpholinyl)cyclopentyll-4-heptenoic Acid (3-ca rboxypropyl)tri phenyl phosphoni u m bromide (12.9 g) was added to a solution of potassium 55 t-butoxide (6.73 g) in dry THF (170 mi) and the resultant suspension stirred at 201 for 35 min. A solution of Intermediate 17a (4.23 g) in THF (40 m]) was added and stirring continued at 201 for 2 h.
Water (5 mi) was then added, the solvent removed in vacuo and the residue taken into water (300 mi) and adjusted to pH 12 with 2N NaOH. Non-acidic material was extracted with EA (2x 100 mi) and the 16 GB 2 075 503 A 16 aqueous solution then re-adjusted to pH 6.5 with 2N hydrochloric acid. This solution was extracted with EA (3 x 100 mi) and the combined extracts dried and evaporated to give the title compound as an oil (3.97 g). IR (CHBr,) 3580, 3500, 1720, 1710 em-'.
Intermediate 19 (1 a,2p,3p,5p)-( )-4-[3-[[4'-methoxy(1,1 1-biphenyl)-4-yilmethoxy]-2-(3- methoxy-2-propenyi)-5[(tetrahydro-2H-pyran-2-yi)oxylcyclopentyllmorpholine NaH (74% dispersion in oil, 316 mq) was added to a solution of Intermediate 8 (1.11 g) and 4 (bromomethyi)-4'-methoxy(1,1 '-biphenyi) (2.86 g) in dry DMF (15 mi) under nitrogen at 01. The mixture was stirred at room temperature for 2 h whereupon NaH (74%, 52 mg) was added and the stirring continued for 1 h. The mixture was poured into aqueous NH4C1 (150 m]) and extracted with 10 CHCI, (4x 60 m]). The dried organic layers were evaporated and the residue chromatographed on silica (400 g) using 8:2 ER-PE (b.p. 60-800) through to ER as eluent to give the title compound as an oil (1. 17 g). IR (CHBr,) 1675, 1245 em-'.
Intermediate 20 (la,2p,3a,5a)-( )-[3-hydroxy-5-[[41-methoxy(1,11-biphenyi)-4-yilmethoxy]2-(4 - morpholinyi)cyclopentanepropanaI A solution of Intermediate 19 (2.99 g) in 2N hydrochloric acid (25 mi), acetone (50 mi) and CH2C12 (7 mi) was stirred for 30 min. The mixture was poured into 8% NaHC03 solution (200 mi) and extracted with CH2C12 (3x85 mi). The dried organic layers were evaporated and the residue io chromatographed on silica (100 g) using ER through to 4:1 ER-methanol as eluent to give the title 20 compound as an oil (2.09 g). iR (CHBr3) 3600-3500 (br.), 2725,1720 em-'.
Intermediate 21 [1 a(Z),2p,3a,5ctl-( )-7-[3-hydroxy-5-[[4'methoxy(1,1 '-biphenyi)-4- yilmethoxy]-2-(4 morpholinyi)cyclopentyll-4-heptenoic Acid (4-carboxypropyi)triphenylphosphonium bromide (3.9 g) and potassium tbutoxide (2.04 g) in dry 25 THF (90 mi) were stirred at room temperature for 15 min. A solution of Intermediate 20 (2 9) in dry THF (40 mO was added and the mixture stirred for 2 h. Water (30 mi) was added and the solvent evaporated. The residue was poured into 0.3N NaOH (150 mi) and washed with EA. The basic layer was neutralised by the dropwise addition of 5N hydrochloric acid and then extracted with CH2C12 (70 mi). The pH was adjusted to 6.5 and the aqueous layer re-extracted with CH2C12 (70 mi). The combined 30 CHP2 layers were dried and evaporated to give the title compound as a foam (1.66 g) IR (CHBr3) -1 3590,3500,1720 em.
Intermediate 22 ' a) Methyl 4-(thien-2-yi)benzoate The Grignard reagent from 2-bromothiophene (17.5 g) and Mg (2.7 g) in dry ER (200 mi) was 35 added to a stirred solution of anhydrous ZnBr2 (22.5 g) in dry THF (200 m]) at 51.
Simultaneously a solution of bis(triphenylphosphine)pailadium (11) dichloride (1 g) in THF (200 m[) was treated with DIBAL in hexane (1.43M, 2 mi) at room temperature under nitrogen. After 5 min a solution of methyl p-bromobenzoate (5 g) in ER (50 mi) was added followed after a further 5 min by the organozinc reagent described above. The mixture was stirred at room temperature for 18 hand then 40 poured into NH4C1 solution and extracted with EA. The combined extracts were dried and evaporated, and the residue chromatographed on silica using 1:20 through to 1 A EA-PE as eluent. The title compound was further purified by crystallisation from PE (b.p. 60-800) (2. 8 g), m.p. 141-1421.
The following compound was prepared in a similar manner:
b) Methyl 31-methoxy(1,1 1-biphenyl)-4-carboxylate m.p. 52-541) from 3bromoanisole and methyl p-bromobenzoate using the catalyst prepared from DIBAL, nickel acetylacetonate and triphenylphosphine. The product was purified by chromatography using 1:4 EA-PE (b.p. 60-800) as eluent.
Intermediate 23 a) 4-(thien-2-yi)benzene Methanol To a stirred suspension of LiAll---14 (2.28 g) in THF (200 m[) at room temperature was added dropwise a solution of Intermediate 22a) (6.6 g) in THF (50 mi). The mixture was heated under reflux for 2 h and then stirred at room temperature for 16 h. EA (10 m[) was carefully added, followed by 2N hydrochloric acid (100 mi). The THF was removed in vacuo and the residue extracted with ER. The combined extracts were dried, filtered and concentrated. Crystallisation of the residue from cyclohexane gave the title compound (4.5 g) as plates, m.p. 1151.
The following compounds were prepared in a similar manner:
b) 34(1,11 1-biphenyl)-4-yllpropanol m.p. 73-740 from 3-[(1,1'-biphenyi)4-yllpropanoic acid.
so 17 GB 2 075 503 A 17 c) [31-methoxy(l,l 1-biphenyl)-4-yi] methanol from Intermediate 22b. TLC EA Rf 0.6.
Intermediate 24 a) 2-(4-bro mo methyl phenyi)thiophene A solution of Intermediate 23a (4.3 g) in dry CH2C12 (80 mO was treated with a solution of P13r3 5 (2.15 mO in CH2C1. (20 mi) and the mixture stirred for 1 h. 10% Nal-IC03 solution (100 mi) was added, the organic phase separated, and the aqueous phase further extracted with CH2C12. The combined organic phase was dried, filtered and concentrated to give the title compound (4.6 g) as a solid, m.p.
80-1000.
The following compounds were prepared by a similar procedure:
b) 4-bromomethyi(1,1 1:41,1 ")terphenyl m.p. 213-2151 from 4-[(1,1'A', 1 ")terphenyll methanol.
- c) 4-bromomethy]-31-methoxy(1,1 '-biphenyi) from Intermediate 23c. TLC ER Rf 0.58.
l 5 Intermediate 25 a) [1 a,(E),2p,3a,5a]-,( )-7-[3-hydroxy-5-[[41methyl(1,1 "-biphenyl)-4-yilmethoxyl-2-(4morpholinyl)cyclopentyll-4heptenoic Acid A solution of Intermediate 18 (1.32 g) and p-toluene sulphinic acid (0.63 g) in dry 1,4-dioxan (60 mi) was heated under reflux in a nitrogen atmosphere for 3.5 h. The mixture was diluted with EA (80 mi), washed with pH 6 phosphate buffer (50 mi), dried and evaporated. The residue was chromatographed on silica using 9:1 EA-methanol as eluent to give the title compound as an oil, which on trituration with ER crystallised (0.63 g) m.p. 108-1110.
The following compounds was prepared in a similar manner:
b) [11 a(E),2p,3a,5a]-( )-7-[5-[[(1,1'-biphenyl)-4-yllmethoxyl-3-hydroxy2-(4- morpholinyl)cyclopentyll-4-heptenoic Acid from Intermediate 12a. Purification by chromatography using 9:1 EA-methanol as eluent. TLC 85:15 ER-methanol Rf 0.24.
Intermediate 26 [1 a(Z),2P.3a.5a]-( )-7-[5-[[1,1 1-biphenyl)-4yilmethoxy]-3-hydroxy-2-(430 morpholinyi)cyclopentyll-4-heptenoI A solution of Intermediate 12a (1 g) in dry THF (10 mi) was added dropwise under nitrogen to a stirred suspension of LiAM, (0.16 g) in dry THF (10 m]) and the mixture heated under reflux for 2 h. After cooling 1:1 water in THF (10 mi) was added followed by 5N NaOH (10 mi) and the mixture extracted with EA (3x20 mi). The combined extracts were dried, concentrated and the residue ch;omatographed on silica using 95:5 ERmethanol as eluent to give an oil which slowly crystallised (0.71 g). Recrystallisation from ER-isopentane gave the title compound of m.p. 7071.51.
Intermediate 27 (anti, endoendo)-( )-7-(4-morpholinyi)-5-[(tetrahydro2H-pyran-2- yi)oxylbicyclo[2.2.11 heptan-2-ol NaBH4 (2.2 g) was added in portions to a stirred solution of Intermediate 69 (17 g) in dry 40 methanol (250 mi) at 01. After 30 min the mixture was poured into saturated NH4C1 solution (350 mi) and extracted with ER (3x200 mO. The combined extracts were dried, filtered and concentrated to give the title compound as a foam (17.5 g). IR (Neat) 3440 (br.), 1120 cm.
Intermediate 28 (endoSYnendo)-( )-5-[[(1,1'-biphenyl)-4-yllmethoxy]-7-(4morpholinyl)bicyclo[ 2.2.11 45 heptan-2-ol A solution of Intermediate 2c (20.1 9) in 10% concentrated H2S04 in methanol (60 mi) was stood at room temperature for 1 h. The solution was neutralised with solid NaHC03 and extracted with CH2C12 (3 x200 mi). The combined extracts were dried, filtered and concentrated to give the title compound as a solid (17 g), m.p. 138-1400.
Intermediate 29 (endo,syn)-( )-5-11(1,1 1-biphenyi)-4-yilmethoxy]-7-(4morpholinyl)bicyclo[2.2.1 1heptan-2-one A mixture of dry dimethyisulphoxide (13.5 mi) and dry CH2C12 (50 mi) was added under nitrogen to a solution of oxalyl chloride (15.2 mi) in dry CH2C12 (25 mi) at -780 and the resultant activated complex stirred for 15 min. A solution of Intermediate 28 (15 g) in dry CH2C12 (50 mi) was added 55 dropwise and stirring continued for 5H. Triethylamine (55.1 mi) in dry CH, Cl, (50 mi) was added dropwise and the mixture was then allowed to reach room temperature with further stirring for 1.5 h.
18 GB 2 075 503 A 18 Water (350 mi) was added and the solution extracted with CH,Cl, (3x200 mi). The combined extracts were dried, filtered and evaporated and the residue chromatographed on silica using ER as eluent. The title compound was obtained as a solid which was further purified by crystallisation from EA-PE (b.p. 60-801) to give material (6.67 g) of m.p. 164-1650.
Intermediate 30 (endo, syn)-( )-6-[[(1,1'-biphenyl)-4-yllmethoxy]-8-(4morpholinyl)-2-oxabicyclo[3.2.lloctan-3one Peracetic acid (4.33 m], 6.12 M) was added dropwise to a mixture of Intermediate 29 (2 g), sodium acetate (2.17 g), acetic acid (20 mi) and water (10 mi) at 01. After stirring for 6 days a further quantity of peracetic acid (0.87 mi) was added and stirring continued for 24 h. Na2S01 was added to destroy excess oxidising agent and the mixture was then evaporated to dryness. The residue was neutralised with 8% NaHCO, solution and extracted with EA (3 X 75 mi). The combined extracts were dried, filtered and evaporated and the residue chromatographed on silica using 1:1 ER- CH2C12 as eluent to give the title compound as a solid (1.5 g), m.p. 244- 2460.
Intermediate 31 [1 a(Z),2a,3a,5a]-( )-methyl 7-[5-[[1,1'-biphenyl)-4yi]methoxy]-3-hydroxy-2-(4morpholinyi)cyclopentyll-4-heptenoate Prepared as an oil from Intermediate 1 7a according to the methods described for Intermediates 12a and 14. IR (Neat) 3440 (br.), 1730 cm-1.
Intermediate 32 [1 a(Z),2a.3a,5a]-( )-methyl 7-[3-(acetyloxy)-5-[[(1.1 1-biphenyi)-4-yil methoxy]-2-(4 morpholinyi)cyclopentyll-4-heptenoate A solution of Intermediate 31 (1.2 g) and acetic anhydride (2 m]) in pyridine (10 m]) was heated at 451 for 18 h. The mixture was diluted with ER (50 mi) and then washed with 8% Nal-IC03 solution (150 mi). The aqueous solution was re-extracted with ER (100 mi) and the combined organic phase 25 dried and concentrated. The residue was chromatographed on silica using ER as eluent to give the title compoundas an oil (0.85 g). IR (CHBr) 1742 cm-1 Intermediate 33 a) [1 a(Z),2a,3a,5a]-( )-7-[5-[[(1,1 1-biphenyi)-4yllmethoxy]-3-hydroxy-2-(4- morpholinyi)cyclopentyll-4-heptenoic Acid A solution of Intermediate 32 (0.83 g) in methanol (30 mi) containing 2N NaOH (5 ml) was allowed to stand at room temperature for 2 days. pH 6.5 buffer (made from 2:3 KI-12P04M,HPO,) (30 mi) was added and the solution extracted with CH2C12 (2 x 50 mi). The combined extracts were dfled and concentrated and the residue purified from CH2C127PE hp. 60- 801) to give the title compound(O.61 g), m.p. 163-1650.
The following compound was prepared in a similar manner:
b) [l a(Z),2p,3a.5a]-( )-7-[5-[[(1.1"-biphenyi)-4-yilmethoxy]-3-hydroxy-2(1piperidinyi)cyclopentyll-4-heptenoic Acid from Intermediate 58. IR (CHBr,) 3500,1700,1598 cm-1 Intermediate 34 [1 '-biphenyi)-4-yllmethoxy]-3-hydroxy-2-(4morpholinyi)cyclopentyll-4-heptenoic Acid a stirred solution of lithium tri-sec-butyl borohydride in THF (12 mi, 1 M) under nitrogen at -28' was treated slowly dropwise with a solution of Example 1 a (0.6 g) in dry THF (12 mi). After 3 h the mixture was poured into 2N H2S04 (20 mO and pH 6.5 phosphate buffer (50 mi) and washed with ER (1 x 150 45 mi, 1 x 50 m]). The aqueous layer was adjusted to pH 6.5 with 2N NaOH and extracted with EA (2x 100 mi). The combined extracts were dried and evaporated, and the residue chromatographed on silica using 4:1 EA-methanol as eluent to give the title compound as a foam (0. 35 g). TLC (S'02) 1:20:79 acetic acid-methanol-EA Rf 0.17.
Intermediates 35 and 36 (1 S,endo)-(+)-bicyclo[3.2.Olhept-2-en-B-oI (35) and (1 R,exo)-(-)- bicyclo[3.2.Olhept-2-en-6-oI (36) Bakers yeast (6 kg) and glucose (2.5 kg) in water (24 1) was stirred at 251 for 2 h. W bicyclo[3.2.Olhept-2-en-6-one (120 g. was added dropwise over 30 min. Stirring was maintained for 2.5 h whereupon a further quantity of glucose (3.5 kg) and water (4 1) was added. This addition was 55 repeated after 20 h and 26 h, glucose (4.5 kg) and water (5 1) being added on each occasion.
The reaction mixture was distilled at atmospheric pressure to give about 11 1 of aqueous ethanol containing starting material and some product-Fraction A. Then a steam distillation of the remaining reaction mixture gave 36 1 of aqueous distillate which was salted (7.25 kg) and extracted with CH2C12 4 19 GB 2 075 503 A 19 (3x10 1). The CH2C12 was distilled at atmospheric pressure through a helix filled column (93x5 cm) to leave a residue (about 400 mO-Fraction B. Fraction A was concentrated by distilling off most of the solvent through a helix filled column (50x3 cm). The residue was salted and extracted into CH2C12Fraction C.
Fractions B and C were combined, dried and the solvent was removed at atmospheric pressure to 5 leave a residue (55 g) which was distilled at 1201C and 15 mm Hg pressure to give an oil (39.8 g). This material was chromatographed on silica using 1:4 ethenisopentane as eluent to give the title compound as ethereal solutions after removal of most of the solvent.
Intermediate 35 (26.8 g) 64.5% w/w in ether.
Intermediate 36 (33.4 g) 30.4% w/w in ether.
The bulk of the material was used as above for the next stage. However 2 mi portions of the solutions were taken and distilled at atmospheric pressure in a micro distillation apparatus to give:
Intermediate 35 TLC 4:1 PE-ER Rf 0.3 [a] 26=+46.1 0 (CHCI,). D 26= Intermediate 36 TLC 4:1 PE-ER Rf 0.2 alD -73.9> (CHCU iintermediate 37 [1 R-(exoendo)]-(-)-2-bromo-3-hydroxybicyclo[3.2.Olheptan-6-one To a stirred solution of Intermediate 35 (6.64 g) in acetone (220 mi) and water (55 m]) was 9dded glacial acetic acid (0.65 mO and N-bromosuccinimide (43.22 g) and stirring was maintained for 18 h. The mixture was poured into sodium thiosulphate solution (250 m]) and extracted with ER (2x 175 mi). The organic layer was washed with 8% NaHC03 solution (150 mi), dried and evaporated 20 and the residue chromatographed on silica using 1:1 ER-PE as eluent. The title compound was obtained as a solid which crystallised from CC14 as needles (4.16 g), m.p. 90-92'. [a] 10=-60.8' D (MeOH).
Intermediate 41 [1 R-(endo, antifl -( )-5-hydroxy-7(4-morpholinyi)bicyclo [2.2.11 heptan-2-one A solution of Intermediate 37 (8.82 g) in CH2C12 (85 mi) containing morpholine (15 mi) was stirred at room temperature for 20 h. The precipitate was filtered off and washed with CH2C12 (100 MO The combined filtrates were washed with NaHC03 solution and water (75 m] each) dried and evaporated to give a semi-solid which was chromatographed on silica using EA as eluent. The title compoundwas obtained as a solid which crystallised from 1:1 EA-PE (b.p. 60-80'1) to give material 30 (6.1 g) of m.p. 137-1391. [a]20=+55.730 (MeOH).
D Intermediate 43 [1 R-(endoanti)]-(+)-5-[[(1,1 1-biphenyi)-4-yilmethoxy]-7- (4-morpholinyi)bicyclo[2.2.llheptan-2one A mixture of Intermediate 41 (10.45 g), benzy] triethylammonium chloride (1.5 g) and biphenyimethyl bromide(l 5.3 g) in CH2C12 (50 MI) was cooled to 01 whilst NaOH (12 g) in water (20 mi) was added. The two phases were stirred vigorously for 24 h at 201. The mixture was diluted with water (120 mi) and extracted with CH2C12 (3x 100 mi). The combined extracts were washed with brine (2 x 50 mi), dried and evaporated, and the residue triturated with ER (100 m]) to give a solid (16 g).
The solid was crystallised from isopropyl acetate (120 ml) to give the title compound (9.6 g) as 40 platelets m.p. 138-1400. [a] 21 =+22.120 (CHC13).
D Intermediate 44 [1 R-(endoanti)]-(-)-6-[[(1,1'-biphenyi)-4-yllmethoxy]-8(4-morpholiny]-2oxabicyclo[3.2.11 joctan-3-one Peracetic acid (8.7 mi, 6.12 M) was added dropwise to a stirred solution of Intermediate 43 (5 g) 45 in CH2C12 (25 mi) at 00. The mixture was stirred for 24 h while allowing the temperature to rise to ambient. 20% w/w Na2SO, in water (60 mO was added dropwise at 01 and the mixture was stirred at room temperature for 0.75 h. Iso-propyl acetate (25 mi) was added and the layers were separated. The aqueous layer was extracted with (1:1) isopropyl acetate-CH2C12 (2x25 mi), and the combined organic layers were washed with 1N Na01-1 (2x50 mO and brine (50 mO then dried and evaporated to give a so solid (3.3 g). The solid was crystallised from 1:1 EA-PE (80 mi) to give the title compound as prisms (6.9 g), m.p. 147-1481. [a] 21.5=-26.441 (CHCl D Intermediate 45 [1 R-0 a.2p,3a,5a)1-5-[[(1,1'-biphenyi)-4-yllmethoxy]-3hydroxy-2-(4-morpholinyi)cy clopentane Acetaidehyde A solution of Intermediate 44 (3 g) in dry CH2C12 (60 mi) was cooled (- 781) and stirred under nitrogen whilst a solution of DIBAL in hexane (10.7 mI, 1.43 M) was added dropwise. Methanol (60 mi) was added dropwise at -780 and the cooling bath was removed. After stirring at room temperature for 2 h the precipitate was filtered off and was washed well with methanol. The combined filtrates were evaporated in vacuo and the residue was dissolved in CH2C12 (100 mi), dried, filtered and 60 evaporated to give the title compound as a foam (2.95 g). IR (CHBr,) 3580, 1718 cm-1.
GB 2 075 503 A 20 Intermediate 46 [111-0 a,2P.3a,5a)1-5-[[1,1 1-biphenyi)-4-yilmethoxy]-3-hydroxy-2-(4- morpholinyi)cyclopentanepropanaI (Methoxymethyl)tri phenyl phosphoni u m chloride (7.15 g) was added to a stirred solution of potassium tert.-butoxide (2.35 g) in dry THF (40 mi) under nitrogen. After 15 mina solution of Intermediate 45 (2.75 g) in dry THF (20 mi) was added dropwise and stirring continued for 30 min.
The reaction mixture was poured into 2N hydrochloric acid (50 mi) at 00 and was stirred at 10 151 for 1.5 h. The mixture was adjusted to about pH 10 with saturated K2C03 Solution and extracted with CH2C12 (3 x 100 mi). The combined extracts were washed with brine (100 mi)., dried and evaporated and the residue chromatographed on silica using 9:1 EAmethanol as eluent to give the 10 title compound as a foam (2.47 g). TLC 9:1 EA-methanol Rf 0.3.
Intermediate 47 [1 R-[1 a(Z),2p,3a.5a]]-(+)-7-[5-[[(1,1 1-biphenyi)-4yllmethoxy]-3-hydroxy-2-(4morpholinyi)cyclopentyll-4-heptenoic Acid, Hydrochloride Dry THF (90 mi) was added to a stirred mixture of potassium tert-butoxide (2.46 g) and 3- z 15 (carboxypropyi)triphenylphosphonium bromide (4.6 g) under nitrogen. After about 30 min Intermediate 46 (2.25 g) in dry THF (50 mO was added dropwise and stirring continued for 2.5 h. Water (25 mO was added and most of the THF was removed in vacuo. The residue in water (50 0 and 2N NaOH (20 mi) was extracted with EA (2x50 mi). The aqueous layer was adjusted to pH 6 with buffer (1 M KH2P04 3 parts, 1 M Na2HP04 1 part) and was extracted with CH2C12 (3 x50 mi). The combined extracts were washed with brine, dried and evaporated to give a foam (2.7 g). This material was dissolved in EA (100 mi) and treated with an excess of ethereal hydrogen chloride. After cooling at 0' for 16 h the salt was collected and washed with 1:1 ER-EA (25 mi) followed by ER (40 ml).
* Crystallisation from 5:1 EA-methanol gave the title compound (1.6 g) as prisms, m.p. 152-1531.
[a] 2 D1=+5411 (CHCl).
Intermediate 48 (1 a,2p,3p,5p)-(+)-4-[2-(3-methoxy-2-propenyi)-3-[(2-phenyithien-4yi)methoxyl-5 -[(tetrahydro- 2H-pyran-2-yi)oxylcyclopentyllmorpholine NaH (0.952 9, 50% in oil) was added to a stirred solution of Intermediate 76 (5.38 g) and Intermediate 8 (2.6 g) in DMF (15 mO at 011. Stirring at room temperature was continued for 2 h 30 whereupon saturated M4C1 solution (50 mi) was added and the mixture extracted with ER (3x50 mi).
The combined extracts were washed with water (2x 100 mi), brine (100 mi) and then dried.
Evaporation gave an oil which was chromatographed on silica using 19:1 ERmethanol as eluent to give the title compound (2.87 g).
Analysis Found: C, 68.1; H, 7.8; N, 2.7 35 C2.1---13.NO.S requires: C, 68.0; H, 7.4; N, 2.7% Intermediate 49 (1 a,2p,3a,5a)-( )-3-hydroxy-2-(4-morpholinyl)-5-[(2-phenyithien-4yi)methoxylcyclopentanepropanal A solution of Intermediate 48 (2.75 g) in acetone (20 mi) was treated with 2N hydrochloric acid 40 (10 mi) for 2 h. 2N Na2CO, solution (10 mi) was then added and the acetone removed in vacuo. The remaining solution was basified by adding more Na2C03 solution and the mixture was extracted with ER (3 x30 mi). The combined organic layers were washed with brine (20 mi), dried and concentrated.
The residue was chromatographed on silica using 9:1 ER-methanol as eluent to give the title compoundas a foam (2 g).
Analysis Found:
C231---12,1\104S requires:
C, 66.3; H, 7.0; N, 3.3 C, 66.5; H, 7.0;N, 3.4% Intermediate 50 [1 a(Z),2p,3a.5a]-( )-7-[3-hydroxy-2-(4-morpholinyi)-5- [(2-phenylthien-450 yl)methoxylcyclopentyll-4-heptenoic Acid To an intimate mixture of potassium t-butoxide (1.89 g) and (3- carboxypropyi)triphenylphosphonium bromide (3.62 g) under nitrogen was added dry THF (50 mi). The suspension formed was stirred for 30 min whereupon a solution of intermediate 49 (1.75 g) in dry THF (10 mi) was added in one portion. Stirring was maintained for 1 h whereupon water (40 mi) and Nal---1C03 solution (10 mi) were added and the mixture extracted with ER (3x50 mi). The extracts were discarded and the aqueous phase acidified to pH 6.5 with KH2P04 solution and extracted with ER (3x75 mO. The combined ethereal extracts were washed with water (50 mi), brine (50 mi) and then dried. After evaporation the residue was chromatographed on silica using 4:1 ER-methanol as eluent to give the title compound as a foam (1. 15 g).
so 21 GB 2 075 503 A 21 Analysis Found:
C27HAO..S requires:
C, 66.8; H, 7.3; N, 3.0 C, 66.8; H, 7.3;N, 2.9% Intermediate 51 (endo,anti)-( )-7-azido-5-hydroxybicyclo[2.2.1]heptan-2-one A solution of (exoendo)-( )3-acetoxy-2-bromobicyclo[3.2.Olheptan-6-one (50 g) and potassium t-butoxide (27.25 g) in THF (1.5 1) was stirred at -750 for 1 h. The solution was allowed to warm to 01 and a solution of sodium azide (16.45 9) in water (600 mi was added and stirring continued at 201 for 18 h.
The two layers were separated and ether was added to the organic layer which was washed with water (2x250 m[). The combined aqueous layers were extracted with ER (2x250 ml) The combined 10 organic layers were dried and evaporated to give a gum (28.1 g). A solution of the gum in methanol (225 mi) was stirred with K2C01 (18.37 g) for 3.5 h at room temperature. The mixture was filtered and the filtrate was evaporated in vacuo to give a solid which was then taken into ER (150 mi) and washed with water (150 mi). The aqueous layer was extracted with ER (3x 125 m]) and the combined organic "layers were dried and evaporated to give an oil (24.5 g) which was chromatographed on silica. Elution 15 with 2:1 ER-PE gave an oil (18.7 g) which was triturated with ER to give the title compound as a solid (14.6 g), m.p. 72-740.
ntermediate 52 (3aa,4p,5a,6aa)-( )-4-azido-hexahydro-5-hydroxy-2H-cyclopenta(b)furan-2one 40% Peracetic acid (64.35 mi) was added to a cooled (01) stirred solution of Intermediate 51 20 (12.9 g) and sodium acetate (31.2 g) in acetic acid (155 m]) and water (15.5 mi) and the resulting solution then stirred at ambient temperature for 24 h. Excess NA2S03 solution was added to the cooled solution and stirring continued for 1 h. After evaporation in vacuo the residue was dissolved in 5N NaOH solution (400 mO with cooling and the solution stirred for 0.5 h. Concentrated hydrochloric acid (30 mi) was added with cooling and the solution was continuously extracted with CH2C12 (600 mi) for 25 18 h. The organic extracts were washed with 2N Na2C03 solution (100 mO and brine (100 mi), dried and evaporated to give a solid (3.5 g). A portion (1 g) was recrystallised from ER-PE (b.p. 60-800) to give the title compound(816 mg), m.p. 73-741.
Intermediate 53 (3aa,4p,5a6aa)-( )-4-azido-hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2Hcyc lopenta(b) 30 furan-2-one Dihydropyran (6.1 m]) was added to a cold (-201) stirred solution of p- toluenesulphonic acid (0.685 g) and Intermediate 52 (6.63 g) in CH2C12 (35 mO. After 2 h at - 201 the mixture was poured into 8% Nal-IC03 solution (300 mi). The organic layer was separated and the aqueous layer extracted with CH2C12 (3 x 100 mi). The combined extracts were washed with brine (200 mO, dried and evaporated in vacuo to give an oil (13.23 g) which was purified by chromatography on silica. Elution with 2:1 ER-PE (b.p. 60-800) gave the title compound as an oil (5.39 g). IR (Neat) 2100, 1780 cm-1 Intermediate 54 (3aa,4p,5a,6aa)-( )-4-amino-hexahydro-5-[(tetrahydro-2Hpyran-2-yi)oxy]-2H- cyclopenta(b)furan-2-one A solution of Intermefflate 53 (28.4 g) in ethanol (175 mO was hydrogenated at atmospheric pressure over pre-reduced 10% palladium oxide on charcoal (5.3 g) at 201 for 24 h. The mixture was filtered ('Hyfio') and the filtrate evaporated to give an oil (24.1 g). [R (CHBr,) 3370, 3300, 1762 cm-1.
Intermediate 55 a) (3aa,4a.SA,6aa)-( )-hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-(4thiomorp holinyi)-2H- 45 cyclopenta(b)furan-2-one A mixture of Intermediate 54 (6 g), anhydrous NaHCO, (5.2 g), Nal (9.72 g) and bis(2 chloroethyi)sulphide (5.15 g) in acetonitrile (250 mi) was heated under reflux for 18 h. The solvent was removed in vacuo and the residue in water (200 mi) was extracted with EA (4x200 m[). The combined extracts were washed with brine (200 mi), dried and evaporated to give an oil (10.2 g) which 50 was purified by chromatography on silica. Elution with ER and then 3:97 methanol-ER gave a solid (4.8 h). A portion was crystallised from ER-PE to give the title compound, m.p. 83-840 The following compound was prepared in a similar manner:
b) (3aa,4a,5p,6aa)-( )-4-(hexahydro-1,4-oxazepin-4-yi)-5-[(tetrahydro2Hpyran-2 -yl)oxy]-2H- cyclopenta(b)furan-2-one m.p. 68.5-72.5' from Intermediate 54. Purification by chromatography using 85.15 ER-methanol as eluent.
Intermediate 56 (anti, endo)-( )-7-(1 pi perid inyl)-5-[(tetra hydro -2Hpyran-2-yl)oxylbicyclo[2.2.llheptan-2-one Piperidine (64.1 mi) was added dropwise to a solution of (exoendo)-( )-2- bromo-3-[(tetra hydro2H-pyran-2-yi)oxylbicyclo[3.2.Olheptan-6-one (75 9) in high purity acetone (250 mi) at 011. The 22 GB 2 075 503 A 22 mixture was stirred in the dark for 24 h and then filtered. The filtrate was washed with water (2 x 150 m]), and the aqueous solution extracted with ER (3x200 mi). The combined organic layers were dried, filtered and evaporated to give the title compound as an oil (77.2 g). TLC 7:3 ER-PE Rf 0.18. Intermediate 57 (endo,anti)-( )-5-hydroxy-7-(1-piperidinyl)bicyclo[2.2.
1]heptan-2-one, Hydrochloride Ethereal hydrogen chloride (20 mi) was added dropwise to a solution of intermediate 56 (77.2 g) in methanol (300 mO at 01. After stirring for 1. 5 h at room temperature the solvent was removed in vacuo, and the residue triturated with iso-propanol to give the title compound as a solid (52 g), m.p. 246-2481.
Intermediate 58 [l a(Z),2p,3a,5a]-( )-methyl 7-[5-[[(1,11-biphenyi)-4-yilmethoxy]-3hydroxy-2-(1piperidinyi)cyclopentyll-4-heptenoate Prepared as an oil from Intermediate 17c according to the methods described for Intermediates 12a and 14. Purification by chromatography using 9:1 EA-methanol as eluent. IR (CHBr,) 3520, 1725, 15 em-'.
Intermediate 59 a) (1 a,2a,3p,4a)-( )-2-(3-metboxy-2-propenyi)-4-[(tetrahydro-2H-pyran-2yi)oxy]-3-( 4- thiomorphoinyi)cyclopeii-tanol, S-dioxide A solution ol Intermediate 7b (12.1 g) in methanol (80 mi) containing 1 N NaOH (60 mi) was stirred at room temperature for 5 h. The mixture was poured into brine (650 mi) and extracted with 20 CH2C12 (5x 150 m[). The combined extracts were dried, filtered and concentrated to give an oil, which was chromatographed on silica using 13:7 EA-PE (b.p. 60-801) through to EA as eluent to give the title compound as an oil (8.38 g). IR (Neat) 3510 (br.), 1650 em-'.
The following compound was prepared by a similar procedure:
b) (l a,2a,3p,4a)-( )-3-(hexahydro-1,4-oxazepin-4-yi)-2-(3-methoxy-2propenyi)-4-[( tetrahydro- 25 2H-pyran-2-yi)oxylcyclopentanol from Intermediate 7c IR (CHBr) 3500,1655 em-'.
Intermediate 60 3-[(11,1 1-biphenyi)-4-yilpropanol, 4-methy[benzenesulphonate A stirred solution ol Intermediate 23b (4.28 g) in pyridine (40 m]) at 00 was treated portionwise 30 with p-toluene sulphonyl chloride (7.71 g) over 1 h. Stirring was continued at 00 for 7 h when water (20 mi) was added and the mixture allowed to warm to room temperature with stirring for a further 1 h.
The mixture was partitioned between 2NA2S04 (250 mi) and ER (250 mi), the layers separated and the organic phase washed with a further quantity of 2N.H2SC)4 (2x250 m[). The organic phase was then washed with 2N.NaOH (3x100 m[), water (2x 100 mi) and dried. Evaporation of the solvent gave 35 the title compound as a solid (4.95 g), m.p. 86-871.
Intermediate 61 (3ao,,,4a,5p,6aa)-( )-hexahydro-5-hydroxy-4-(4-thiomorpholinyi)-2Hcyclopent a(b)furan-2-one, S-dioxide, Hydrochloride A solution of (endoantil-( )-6-(phenylmethoxy)-8-(4-thiomorpholinyl)-2oxabicyclo[3.2.ljoct an- 40 3-one, S-dioxide (10 g) in ethanol (60 ml) and water (40 ml) containing concentrated hydrochloric acid (40 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (5 g, 50% dispersion in water) in ethanol (40 ml). The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as a solid (8.55 g), m.p. above 2300 (dec.) (from water-ethanol).
Intermediate 62 (3aa,4a,5p,6aa)-( )-hexahydro-5-[(tetrahydro-2H-pyran-2-yi)oxy1-4-(4thiomor pholinyi)-2H- cyclopenta(b)furan-2-one, S-dioxide Dihydropyran (3.1 mi) was added to a stirred solution of the free base of Intermediate 61 (1.56 g) and p-toluene sulphonic acid monohydrate (1.17 g) in dry DIVIF (30 mi) at -101. The mixture was allowed to reach ambient temperature and stirring continued for 18 h, whereupon it was poured into 50 saturated aqueous Nal-IC03 solution (50 mi), extracted with EA (4x 100 mO, washed with water, dried, filtered and concentrated. The residue was chromatographed using 19:1 ER- methanol as eluent to give the title compound as a viscous oil (1.89 g. IR (CHBr,) 1762 em.
Intermediate 63 (3aa,4a,5p,6aa)-( )-hexahydro-5-[(tetrahydro-2H-pyran-2-yi)oxy]-4-(4thiomorp holinyi)-2H- 55 cyclopenta(b)furan-2-ol, S-dioxide A solution of Intermediate 62 (1 g) in CH2C12 (25 mi) at -70' under dry nitrogen was stirred during the additon of DIBAL (1 M in hexane, 8.7 mi). After 1.5 h at -701, methanol (25 mi) was 23 GB 2 075 503 A 23 carefully added and the mixture was then allowed to rise to ambient temperature whereupon stirring was continued for 1 8h. The mixture was filtered through 'Hyfio' and the filtrate evaporated to give the title compound as an oil (0.95 g).
Analysis Found: C, 53.2; H, 7.15; N, 3.5 C161-12,1\10,S requires: C, 53.2; H, 7.5; N, 3.9% 5 Intermediate 64 4-phenyl-2-thiophenemethanol A stirred suspension of 4-phenyl-2-thiophenecarboxaldehyde (4.32 g) in absolute ethanol (85 ml) was cooled in an ice-bath and treated with NaBH, 0.06 g). After 20 min the mixture was allowed to 10attain ambient temperature when stirring was continued for 6 h. Saturated aqueous NH4CI (30 ml) was 10 then carefully added to the vigorously stirred mixture, and the resulting suspension extracted with ER (2 x 200 ml). The combined extracts were dried (Na2SO,/K2CO3), filtered and evaporated to give the. title compound (4-2 g) as crystals, m.p. 112-113 0.
Intermediate 65 2-(bromomethyi)-4-phenyithiophene A cooled, stirred suspension of Intermediate 64 (3.86 g) in dry CH,Cl, (60 m[) was treated dropwise with a solution of PBr, (1.27 mO in dry CH2C12 (20 mi), and stirring continued for 30 min. The mixture was treated with 8% aqueous Nal-IC03 (100 mi), stirred for 20 min, extracted with ER (1 x 150 mi, 1 x 50 mi), and the extracts dried (M9S04), filtered and evaporated to give the title compound (5.01 g) as a solid, m.p. 87-88.51 Intermediate 66 [4'-methyi(l,l-biphenyi)-4-yilrnethanoI 4-methyi(1,1'-biphenyi)-4-carboxylic acid, methyl ester (1.43 g) in ER (25 mi) and THF (25 mi) was added over 5 min to LiAll-14 (420 mg) in ER (25 mO. The mixture was stirred at room temperature for 1 h and then cooled in ice. Aqueous NaOH (1 M, 2.1 mi) was added and after stirring (15 min) excess anhydrous Na2S04 was added. The mixture was filtered and the filtrate evaporated to give a solid.
Crystallisation from cyclohexane-methanol gave the title compound (1.04 g) m.p. 128-311.
Intermediate 67 4-bromomethyl-41-methyl (1,1 1-biphenyl) To a cold (01) solution of Intermediate 66 (0.917 g) in dry CH2C12 (14 mi) was added PBr, (0.29 30 mO.
After stirring for 1 h at 01, 8%-NaHCO, solution (30 mi) was added and the layers separated. The aqueous layer was extracted with CH.Cl, (2x30 mi), dried.and evaporated to give a solid (0.99 g). Crystallisation from PE (b.p. 60-801) afforded the title compound(O.91 9) m.p. 100-102'.
Intermediate 68 4-bromomethyl-41-chloro-1,1'-biphenyI 4'-chloroO, 1 1-biphenyi)-4-methanol (5.8 g) was converted into the title compound (6.8 g), m.p.
64-660 by the method for the preparation of Intermediate 67.
Intermediate 69 ( )-7-anti-(4-rnorpholinyl)-5-endo-[tetrahydro-2H-pyran-2yi)oxylbicyclo[2.2. 1lheptan-2-one 40 Morpholine (76 m]) was added dropwise over 15 mins to a stirred solution of 2-exo-bromo-3 endo-[(tetrahydro-2H-pyran-2-yi)oxy]bicyclo[3.2.Olheptan-6-one (100.8 g) in acetone (500 mi) at 00.
After 2 h at 51 the mixtures was stirred at 201 for 18 h and then filtered. Evaporation of the filtrate gav( an oil which was taken into ER (350 mi), filtered and washed (water, 2x 100 mi). The ethereal solution 45. was dried, filtered and evaporated to give the title compound as a solid. Purification from PE gate 45 material (85.5 g) of m.p. 86-881.
Intermediate 70 ( )-5-endo-hydroxy-7-anti-(4-morpholinyi)bicyclo[2.2.llheptan-2-one, Hydrochloride To a stirred solution of Intermediate 69 (96.4 9) in methanol (600 mO was added an ethereal solution of HCI (240 mO and the mixture stirred at 201 for 2.5 h (PH 1.5- 2). Filtration followed by so evaporation of the filtrate gave an oil which solidified on trituration with EA (2x200 mi). Coloured impurities were removed by extraction with boiling isopropanol to leave the title compound as a solid (70.6 g), m.p. 181-1820 Intermediate 71 ( )-5-endo-(4-bromophenyimethoxy)-7-anti-(4-morpholinyi)bicyclo[2.2. 1]heptan-2 -one 55 Aqueous NaOH solution (10 N; 200 mi) was added to a solution of the free base of Intermediate (21.1 g), benzyitriethylammonium chloride (4 g) and 4-bromobenzyi bromide (27.5 g) in CH2C12 24 GB 2 075 503 A 24 (400 mi) and the mixture stirred vigorously for 4 h. A further portion of 4-bromobenzyibromide (9 g) was then added and stirring continued for 68 h. Water (200 mi) was added and the layers separated.
The aqueous layer was extracted with EA (2x75 ffil), washed with water, dried and evaporated to give an oil (48 g) which solidified on standing. Excess alkylating agent was removed by triturtion with PE (b.p. 60-800) and crystallisation from EA-PE (b.p. 60-800) then gave the title compound (34.1 g) as 5 a solid, m.p. 130-131 11 Intermediate 72 ( )-6-endo-(4-bromophenyimethoxy)-8-anti-(4-rnorpholinyl)-2-oxabicyclo[3. 2.1 loctan-3-one Intermediate 71 (13.2 g) in acetic acid (110 mi) and water (55 mi) containing CH3COONa. 3H20 (23.7 g) was cooled (ca. 5-100) and stirred during the dropwise addition of peracetic acid (6.1 M; 10 28.5 mi). The resulting solution was stirred at 200 for 48 h when 10% Na2SO, solution (200 mi), was added, maintaining the temperature of the mixture at 10-151. After 1.5 h solvents were removed in vacuo at 3511, the residue taken into water (150 mi) and basified to pH 9 with Na2C03 Solution.
Extraction with EA (3x200 mi) followed by drying and evaporation gave a solid which crystallised from EAto give the title compound (5.49 g), m.p. 154-1561.
Intermediate 73 4-(1,3-dioxolan-2-y])-2-phenyithiophene A solution of 5-bromo-3-thiophenecarboxaldehyde (32.5 g) in benzene (500 mi) was treated with p-toluenesulphonic acid monohydrate (0.323 g) and ethylene glycol (21.1 g), and the mixture heated iO under reflux in a Dean and Stark apparatus until the theoretical volume of water had been removed. 20 After cooling the mixture was washed with water, (2 x) then brine, dried, filtered and concentrated, and the residue distilled (b.p. 96-1000 at 0.4 mm) to give the title compound as an oil (24 g).
Analysis Found: C7H713r02S required:_ C, 35.8; H, 3.0 C, 353;H, 3.0% Intermediate 74 5-phenyi-3-thiophenecarboxaldehyde A solution of phenyimagnesium chloride in THF (82.94 mI, 2.39 M) was added to a stirred solution of ZnBr2 (44.6 g) in dry THF (350 mi) under nitrogen. The mixture was stirred at room temperature for 15 min.
DIBAL (9.91 mI, 1 M) in hexane solution was added dropwise to a stirred mixture of triphenylphosphine (10.39 g) and nickel acetoacetonate (2.55 g) in dry THF (160 mi) under nitrogen. A solution of Intediate 73 (23.3 g) in dry THF (150 m[) was added after 10 min. The solution containing the organozinc reagent was then added dropwise and the mixture was stirred for 1 h.
2N hydrochloric acid (400 m[) was added at 01 and the mixture was stirred at room temperature for 0.5 h. The two layers were separated and the aqueous layer was extracted with ER (2x400 ml), 35 washed with Nal-IC03 solution and brine and then dried. Solvent removal in vacuo gave a solid (32.8 9) which was chromatographed using 9:1 PE (b.p. 60-801)-EA or eluent to give the title compound (13.35 g), m.p. 64-650 (from PE (b.p. 60-8011)).
Intermediate 75 5-phenyi-3-thiophenemethanol A stirred solution of Intermediate 74 (12 g) in methanol (120 mi) was treated with NaBH4 (1.82 g) at room temperature for 15 min. The mixture was cooled to 01 and treated with M4C1 solution (200 mi), followed by water (200 mi) and ER (400 m]). The ER extract was separated and the aqueous phase further extracted with ER (400 mi), washed with brine, dried, filtered and evaporated to afford the title compound as a solid (11.5 g), m.p. 92-931.
Intermediate 76 4-(bromomethyi)-2-phenyithiophene Intermediate 75 was converted into the title compound by the method for the preparation of Intermediate 65. TLC (ER) Rf 0.58.
- 40 Intermediate 77 [1 a(Z/E),2p,3a,5a]-( )-7-[5-[[(1,1 1-biphenyi)-4-yllmethoxy]-3-hydroxy-2- (4morpholinyi)cyclopentyll-4-bromo-4-heptenoic Acid To a stirred solution of potassium tert-butoxide (6.06 g) in dry THF (140 mi) at -701 was added (4-carbethoxypropyi)triphenylphosphonium bromide (22.16 g). After 0.5 h at -701 a solution of bromine in CH2C12 (25% v/v, 6.7 mi) was added dropwise and then stirring maintained for 0.9 h. A 55 solution of Intermediate 6 (4.09 g) in THF (30 ml) was then added and, after 0.5 h, the temperature of the mixture allowed to rise to 0' over 1 h. 2N NaOH (60 mi) and methanol (60 mi) were added and stirring continued at 201 for 4 h. After evaporation in vacuo the residue was taken into water (200 mi) and adjusted to pH 12 with 2N NaOH. Non-acidic material was removed by extraction with EA (1 x 100 GB 2 075 503 A 25 m], 2x50 mi), and the aqueous phase then re-adjusted to pH 6 with 2N hydrochloric acid. Extraction with EA (4x60 mi), drying and concentration gave the title compounds as a foam (5.23 g). iR (CHBr,) 3500,1725,1710 cm.
Intermediate 78 (1 1-biphenyi)-4-yilmethoxy]-3-hydroxy-2-(4morpholinyi)cyciopentyll-4-heptynoic Acid, Hydrochloride To a stirred solution of Intermediate 77 (2 g) in THF (15 mi) at 00 was added potassium tert.butoxide (2.4 g) in DMSO (15 mi). The mixture was stirred at 01 for 0.5 h and at 201 for 1.5 h whereupon water (200 mi) was added and the mixture extracted with EA (1 x 50 m]). The aqueous solution was adjusted to pH 6 with 2N hydrochloric acid and extracted with EA (3x60 mi). The combined extracts were washed with water (3 x 60 ml), dried and evaporated to give an oil, which was purified by chromatography on silica (130 g) using 4:1 EAmethanol as eluent to give a foam (0.65 g). A sample ws treated with ethereal hydrogen chloride to give the title compound. Crystallisation from - EA gave material of m.p. 162-163.5.
Intermediate 79 (1 a,2p,Sa)-( )-15-[[(1,1'-biphenyi)-4-yilmethoxy]-2-(4morpholinyi)-3-oxo-cyclo pentyll-4heptynoic Acid Prepared from the free base of Intermediate 78 according to the procedure described for Example 3a. Purification by chromatography using ER through to 98:2 ER-methanol as eluent. Crystallisation from ER-PE (b.p. 60-800) gave material of m.p. 90-930.
Intermediate 80 (endo,anti)-( )-5-decyloxy-7-(4-morpholinyi)bicyclo[2.2.llheptan-2-one Sodium hydride (46% dispersion in oil, 0.522 g) was added portionwise over 10 min to a stirred solution of Intermediate 1 (1.06 g) and decyl tosylate (2.34 g) in dry DIVIF (10 mi) under dry nitrogen at room temperature. The mixture was stirred for 5 h, poured into water (50 mi) and extracted with ER 25 (50 m], 2x25 mi). The combined extracts were washed with water (25 mi), dried and concentrated to give a solid. Crystallisation from PE gave the title compound (0.59 g), m. p. 64-650.
Example 1 a) [l a(Z),2p,Sal-( )-7-[5-[[(1,1'-biphenyi)-4-yilmethoxy]-2-(4morpholinyl)-3-oxoc yclopentyll- 4-heptenoic Acid Method 1 To a cold (-110) stirred solution of Intermediate 12a) (920 mg) and triethylamine (2.14 mi) in CH2C12 (10 mO and DIVISO (10 mi) was added pyridine-sulphur trioxide complex (915 mg) in DMSO (10 mi). Stirring was maintained at 251C for 3 h whereupon water (1 G mi) was added and the CH2C12 evaporated. To the resulting suspension a solution of citric acid (1.07 9) in water (10 mi) was added. 35 The mixture was extracted with EA, the combined extracts dried and concentrated. The residual oil was chromatographed on silica using ER as eluent to give the title compound as an oil which slowly crystallised (0.37 g). Recrystallisation of a sample from ER-iso-pentane at 01 gave material of m.p.
77.5-801,]R (Nujol) 3350-2400 (br.), 1735, 1705 cm-l; whereas recrystallisation above 50 gave a different polymorphic form of m.p. 98-100.51, IR (Nujol) 3400-2300 (br.), 1735,1702, 1250, 40 1005 cm-1.
Analysis Found: C2.1---1.5NO., requires:
Method 2 C, 72.9; H, 7.4; N, 2.9 C, 72.9; H, 7.4;N, 2.9% Jones reagent (0.54 m], 2.67 M) was added to a mixture of Intermediate 26 (0.25 g) and 'Hyflo' 45 - (1 g) in acetone (10 ml) and stirred for 1 H. Isopropanol (1 mi) was added, the mixture filtered and the filtrate washed with pH 5 buffer (2x 10 m]). After drying and evaporation the residue was purified by chromatography on silica using ER as eluent to give the title compound (0. 024 g).
Method 3 From Intermediate 33a) by the procedure described under Method 2.
Method 4 Method 5 so From Intermediate 34 by the procedure described under Method 2.
A suspension of 5% I'd on CaCO, poisoned with lead (70 mg) in EA (5 m]) containing triethylamine (0.2 mi) was hydrogenated at 21 'and atmospheric pressure for 0.5 h. A solution of 55 Intermediate 79 (36 mg) in EA (4 mi) was added and the hydrogenation continued for 2 h. The mixture was filtered, diluted with ER (20 mO and washed with pH 6 phosphate buffer solution (30 mi).
26 GB 2 075 503 A 26 Evaporation of the dried ethereal solution gave a solid (35 mg) which crystallised from ER-PE (b.p. 60-801) to give the title compound (23 mg), m.p. 95-980.
The following compounds were prepared by the procedure described for Method 1.
b) [l a(Z),2P.5a]-(±)-8-[5-[[(1,11-biphenyl)-4-yllmethoxy]-2(4morpholinyl)-3-ox ocyclopentyll-5 5 octenoic Acid m.p. 118-1200 from Intermediate 13.
Analysis Found:
C,.1---137NO, requires:
C, 7 3.6; H, 7.7; N, 2.9 C, 73.3; H, 7.6;N, 2.9%.
c) [1 a(Z),2p,5a]-( )-7-[2-(4-morpholinyl)-5-(2-naphthalenyimethoxy)-3oxocyclopent y11-410 heptenoicAcid from Intermediate 12b. Purification by chromatography using ER as eluent. ]R (CHBr.) 3600-2300 10 (br.), 1735, 1702 cm-1 Analysis Found: C271-1,,,,NO, requires:
C, 7 1. 1; H, 7.5;N, 3.2 C 71.8; H, 7.4;N, 3.1% d)[1a(Z),2p,5a]-( )-7-[5-[4-(1,1-dimethylethyi)phenyimethoxy]-2-(4morpholiny i)-3- oxocyclopentyl]-4-heptenoic Acid from Intermediate 12d. Purification by chromatography using ER as eluent. [R (CH13r) 3500, 1738, 1705 cm. TLC 95:5 ER-methanol Rf 0.53.
e) [1 a(Z),2p,5a]-( )-7-[5-[4-methy[thiophenyimethoxy)1-2-(4-morpholinyi)3-oxocycl opentyll- 4-heptenoic Acid, Compound with Piperazine (2:1), from Intermediate 12j. The acid was purified by chromatography using ER as eluent. The title compound (106 mg) crystallised from a solution of the acid (168 mg) and piperazine (25 mg) in ER (5 m]) to give material of m.p. 75-76.51'. IR (CHBr) 1735,1590 em-'.
f) [11 1-biphenyl)-4-yll methoxy]-3-oxo-2-(4thiomorpholinyl)cycl-opentyll-4-heptenoic Acid from Intermediate 12p. Purification by chromatography using 7:3 ER-isopentane as eluent. IR (CHBr3) 3500,1740,1705 cm-1. TLC ER Rf 0.45.
9) [l a(Z),2p,5a]-(+)-7-[5-[[4"-methoxy(l.11-biphenyi)-3-yllmethoxy]-2-(4rnorphol inyi)-3- oxocyclopentyll-4-heptenoic Acid from Intermediate 12y. Purification by chromatography using 4:1 EA-PE (b. p. 60-800) as eluent. IR 30 (CHBr.) 3500,1740,1710 cm-1. TLC 4:1 EA-PE (b.p. 60-801) Rf 0.44.
Example 2 [1 a(Z),2p,5a]-( )-methyl 7-[5-[[(1,1'biphenyl)-4-yil methoxy]-2-(4- morpholinyi)-3 oxocyclopentyll-4-heptenoate To a cold (-60'), stirred solution of oxalyl chloride (0.144 m]) in dry CH2C12 (20 mO was added 35 DMSO (0.133 mO. The solution was stirred for 15 min, when a solution of Intermediate 14 (0.37 g) in dry CH.C12 (20 mi) was added. After stirring for 2 h, triethylamine (1.04 mi) in dry CH2C12 (5 mO was added and the temperature then allowed to rise to ambient over 0.75 h. ER was then added and the mixture washed with 8% NaHCO, solution. The organic phase was separated, dried and concentrated, and the residue chromatographed on silica. Elution with 3:1 ER-isopentane gave the title compound as 40 an oil (0.23 g). IR (CHBr.) 1730 cm-1.
Analysis Found: C3.1---137NO, requires:
Q 73.1; H, 7.0; N, 2.8 Cl 73.3; H, 7.6;N, 2.9% Example 3 a) [l a(Z).2p,5a]-( )-7-[5-[4-methoxy(phenyimethoxy)1-2-(4-morpholinyi)-3oxocyclop entyll-4- 45 heptenoic Acid, Compound with Chloroform (31) To a solution of Intermediate 12c) (0.18 g) in acetone (10 mi) at -51 was added'hyflo' (0.7 g) followed by Jones reagent (2.67 M, 0.36 m[). The temperature was allowed to rise to 50 during 45 min when isopropanol (1 mi) was added. After 5 min the mixture was filtered and the solid washed 5() thoroughly with ER. The combined organic layers were washed with pH 6. 5 phosphate buffer (2x20 50 mi), dried and concentrated. Purification by chromatography using 98:2 CI- IC13-methanol as eluent gave the title compound as an oil (0.06 g). IR (CHBr3) 3500,1740,1710 cm- 1. TLC 98:2 CHC13 methanol. Rf 0.4.
The following compounds were prepared using a similar procedure:
27 GB 2 075 503 A 27 b) [1 a(Z),2p,5a]-( )-7 -[5-[[41-chloro(1,1 1-biphenyi)-4-yil methoxy]-2- (4-morpholinyi)-3oxocyclopentyll-4-heptenoic Acid from Intermediate 12h. Purification by chromatography using 99:1 CHC13-methanol as eluent. M (CHBr3) 3490,1740,1705 cm-1.
Analysis Found: C, 6 73; H, 6.6; N, 2.8 C29H34CIN05 requires: C, 68.0; H, 6.7, N, 2.8% c) [11 a(Z),20,5a]-( )-7-[2-(4-morpholinyl)-3-oxo-5-(2propenyloxy)cyclopentyll-4-he ptenoic Acid from Intermediate 12i. Purification by chromatography using 4:1 ER-PE (b.p. 60-8001 as eluent. IR (CHBr3) 3500,1735,1705 cm-1. TLC 4:1 ER-PE (b.p. 60-800) Rf 0.28.
d) [1 a(Z),2P, 5al -( )-7-[2-(4-morpho 1 inyi)-3-oxo-5-[(4-thien-2-yi) phenyl methoxyl cycl opentyll -4- 10 heptenoic Acid, Compound with Piperazine (21).from Intermediate 12k. The acid was purified by chromatography using 1:99 methanol-CHCI, as eluent. The title compound (140 mg) precipitated from a solution of the acid (200 mg) and piperazine (100 mg) in ER. Crystallisation from EA gave material of m.p. 1150 (dec). IR (CHBr,) 1740 cm-1. TLC ?R Rf 0.7.
e) [1 a(Z),2,5a]-( )-7-[2-(4-morpholinyl)-3-oxo-5-[[(1,11:41,1 uterphenyl)-4yllrnethoxylcyclopentyll-4-heptenoic Acid m.p. 1051 (dec.) from Intermediate 121). Purification initially by chromatography using ether as eluent and then by crystallisation from ER-isopentane at 00. TLC 9:1 ER-methanol Rf 0.23.
is f)[1a(E),2P.5a]-( )-7-[5-[[41-methyl(1,11-biphenyi)-4-yilmethoxy]-2-(4morpho linyl)-3- 20 oxocyclopentyll-4-heptenoic Acid m.p. 80-851 from Intermediate 25a. Purification initially by chromatography using ER as eluent and then by crystallisation from ER-isopentane at -201.
Analysis Found: C, 7 3. 1; H, 73; N, 2.8 C3,H37NO, requires: C, 733; H, 7.6; N, 2.9%. 25 g) [1 1-biphenyi)-4-yllmethoxy]-2-(4-morpholinyl)-3-oxocyclopentyll- 4-heptenoic Acid m.p. 103-1050 from Intermediate 25b. Purification initially by chromatography using ER as eluent and then by crystallisation from ER at -201.
Analysis Found: C, 72.8; H, 7.7; N, 3.0 30 C2.HAO, requires: C, 72.9; H, 7.4; N, 2.9% h) [l a(Z),2p,5a]-( )-9-[5-[[(1,11-biphenyl)-4-yilmethoxy]-2-(4morpholinyi)-3-oxoc yclopentyll6-nonenoic Acid m.p. 83-841 from Intermediate 12m. Purification initially by chromatography using ER as eluent and then by crystallisation from ER-isopentane.
Analysis Found:
C,,H3,NO, requires:
C, 7 3.3; H, 73; N, 2.8 C, 73.6; H, 7.8;N, 2.8% 0 [1 a(Z),2p,5a(E)]-( )-7-[2-(4-morpholinyi)-3-oxo-5-[(3-phenyi-2propenyi)oxylcyc lopentyll-4- heptenoic Acid m.p. 74.5-761 from Intermediate 12o. Purification by chromatography using ER as eluent.
Analysis Found: C2,H,,NO, requires:
C, 7 0.21; H, 7.9; N, 3.3 C, 70.2; H, 7.8;N, 3.3% j) [la(Z),2p,5a]-( )-7-[5-[[41-methyl(1,11-biphenyl)-4-yllmethoxyl-3-oxo2-(4- thiomorpholinyl)cyclopentyll-4-heptenoic Acid, S-dioxide from Intermediate 12r. Purification by chromatography using 98:2 ER- methanol as eluent. IR (CHBr3) 45 3 500, 1740, 1710 cm-1.
Analysis Found: C301-1,ffl,,S requires:
C, 6 6.5; H, 7. 1; N, 2.2 C, 66.8; H, 6.9;N, 2.6% k) [1 a(Z),2P, 5al -W-7[3-oxo-5-[4-(phenyl methyl) phenyl methoxy]-2- (450 thiomorpholinyi)cyclopentyll-4-heptenoic Acid, S-dioxide m.p. 126.5- 1281 (dec.) from Intermediate 12s. Purification by chromatography using ER as eluent. TLC 95:5 ER-methanol Rf 0.46.
so 28 G13.2 075 503 A 28 1) [l a(Z).2p,5a]-( )-7-[5-[[(1,1'-biphenyi)-4-yilmethoxy]-3-oxo-2(4thiomorpholinyi)cyclopentyll-4-heptenoic Acid, S-dioxide from Intermediate 12t. Purification by chromatography using 98:2 ER-methanol as eluent. IR (CHBr,) 3480,1743,1710 em-' Analysis Found: C, 66.0; H, 6.7; N, 2.6 5 C2.1---13.NO,,S requires: Q 66.3; H, 6.7; N, 2.7% m) [1 a(Z),2p,5a]-(+)-7-[5-[[(1,1 1-biphenyl)-4-yllmethoxy]-2-(hexahydro1,4-oxazepin-4-yl-3oxocyclopentyil4-heptenoic Acid from Intermediate 12u. Purification by chromatography using ER as eluent. [R (Neat) 3500-2500 (br.),1740,1710cm-1.TLCERRfO.47.
n) [l a(Z),2P.5a]-( )-7-[5-[3-[(1,11-biphenyi)-4-yllpropoxy]-2-(4morpholinyi)-3-ox ocyclopentyll4-heptenoic Acid from Intermediate 12w. Purification by chromatography using ER as eluent. IR (Neat) 3700-2200 (br.), 1740,1712 ern'. TILC ER Rf 0.25.
0)[1a(Z),2p,5a]-(+)-7-[5-[[3-methoxy(1,11-biphenyi)-4-yilmethoxy]-2-(4morph olinyi)-3- 15 oxocyclopentyll-4-heptenoic Acid from Intermediate 12x. Purification by chromatography using ER as eluent. IR (CHBr) 3500, 1740, 1710 em-'. TLC ER Rf 0.2.
p) [1 a(Z),2p,5a]-( )-7-[5-decyloxy-2-(4-morpholinyi)-3-oxocyclopentyll-4heptenoic Acid from Intermediate 12z. Purification by chromatography using 4:1 ER-PE as eluent,]R (CHBr,) 3500, 20 1740,1710 em-'. TILC (S'02) 4:1 ER-PE Rf 0.21.
Example 4 a) [l a(Z),2p,5a]-( )-7-[5-(4-cyclohexylphenyimethoxy)-2-(4-morpholinyi)3-oxocyclo pentyll-4- heptenoic Acid A stirred solution of oxalyl chloride (0.612 mi) in dry toluene (5 ml) under nitrogen at -601 was 25 treated dropwise with a solution of dry DIVISO (0.5 ml) in dry toluene (5 mi) and the mixture stirred for min. Simultaneously chlorotrimethyisilane (0.24 m[) was added dropwise to a solution of Intermediate 12e, (0.84 g) and triethylamine (0.264 mi) in dry toluene (10 mi) under nitrogen. This mixture was swirled for 5 min before being added dropwise to the above reaction mixture. The resulting solution was stirred at -601 for 15 min and then quenched with triethyla mine (2.8 mi). The 30 mixture was allowed to warm to 00, poured into aqueous KH2P04 (3.5 g in 200 mi water) and extracted with EA (4x50 mi). The combined organic extracts were washed with pH 6.5 phosphate buffer (2x20 mi), dried and concentrated. The residue was purified by chromatography on silica using 3.1 ER-PE as eluent to give the title compound as a gum (56 mg). IR (CHBr3) 3500,1740,1710 em-, TILC 80:1 ER-acetic acid Rf 0.39.
The following compounds were prepared using a similar procedure:
b) 11 a(Z),2P.5a]-( )-7-[2-(4-morpholinyl)-3-oxo-5(pentyloxy)cyclopentyl]4-hepteno ic Acid, Compound With Piperazine (21) from Intermediate 12f. Purification of the acid by chromatography using ER as eluent. The title compound (212 mg) crystallised from a solution of the acid (271 mg) and piperazine (45 mg) in ER (10 m]) to give material of m.p. 99-102.51 (dec.).
Analysis Found: C231-14.1\120. requires:
64.9; H, 9.5; N, 6.8 65.11; H, 9.5;N, 6.6% c) [1 a(Z),2p,5a]-( )-7-[2-(4-morphol inyi)-3-oxo-5-[4-(phenyl methyl) phenyl methoxyl cycl o45 pentyll-4-heptenoic Acid, Compound With Piperazine (21) m.p. 107-108 from Intermediate 12g.
Analysis Found: C,^21\120. requires:
C, 71.6; H, 7.9; N, 5.2 C, 71.9; H, 7.9;N, 5.2% d) [1 a(Z),2p,5a]-( )-7-[2-(4-morpholinyi)-3-oxo-5-[(4-phenylthien-2yl)methoxylcyc lopentyll-450 heptenoic Acid m.p. 86-880 from Intermediate 12n.
Analysis Found: C27H33NO5S requires:
6 6.8; H, 6.8; N, 2.8 67.11; H, 6.9;N, 2.9% 29 GB 2 075 503 A 29 e) [1 1-biphenyi)-4-yll methoxy]-3-oxo-2-(1 -piperidinyi)cyclopentyll-4 heptenoic Acid, Compound With Piperazine (21) m.p. 91-940 (dec.) from intermediate 33b. IR (CHBr3) 1738 cm.
f) [la(Z),2p,5a]-( )-7-[5-[[41-methoxy(1,11-biphenyl)-4-yllmethoxyl-3-oxo2-(4- thiomorpholinyl)cyclopentyll-4-heptenoic Acid, S-dioxide from Intermediate 12q. Purification by chromatography using 98:2 ER-methanol as eluent. TLC 95:5 ER-methanol Rf 0.46. IR (CHBr3) 3480,1740,1710 cm-1 g) [1 et(Z),2p,Sal-( )-7-[5-[[4'-methoxy(1,1 '-biPhenyl)-4-yilmethoxy]-3oxo-2-(1 piperidinyi)cyclopentyll-4-heptenoic Acid, Compound With Piperazine (21) 10m.p. 68-760 (dec.) from Intermediate 12v. IR (CHBr3) 1740 em-'.
Example 5.
[1 a(Z),2p,5a]-( )-7-[5-[[41-methyi(1,1 1-biphenyi)-4-yllmethoxy]-2-(4morpholinyl)-3- oxocyclopentyll-4-heptenoic Acid A solution of Intermediate 18 (928 mg) in acetone (30 mi) was stirred with Jones reagent (2.67 M; 1.5 m[) at -51 to -31' for 40 min. Isopropanol (1.5 mi) was addedand after stirring for 5 min, the 15 mixture was poured into pH 6 phosphate buffer (100 m[) and extracted with ER (3 x 50 mi). The combined extracts were evaporated and the residue taken into ER and dried; evaporation of this ethereal solution gave a foam (840 mg) which was purified by chromatography on acid-washed silica gel (85 g) using ER as eluent. Crystallisation from ER-isopentane at 00 gave the title compound (0.26 g)ofm.p.98-1021.1R(CHBr3)3500,1740,1710cm-1.
Analysis Found:
C3,1-1.7NO5 requires:
C, 72.9; H, 7.6; N, 2.9 C, 73.3; H, 7.6;N, 2.9% Example 6 [1 a(Z),2p,5a]-(±)-7-[5-[[41-methoxy(1,1 1-biphenyi)-4yilmethoxy]-2-(4-morpholinyl)-3- oxocyclopentyll-4-heptenoic Acid, Compound With Piperazine (21) Jones reagent (0.883 mi, 2.7 M) was added to Intermediate 21 (600 mg) in acetone (25 mi) at -101 and stirred for 45 min at 100. The mixture was neutralised by (25 ml) dropwise addition of 2N aqueous Na2CO, and then poured into Na2HP04/K1-12P04 buffer solution (pH 6). The mixture was extracted with CH2C12 (3x50 mO and the combined extracts dried, filtered and evaporated. The residue was chromatographed on acid washed silica using 1:1 through to 3:1 ER-PE (b.p. 60-800) as eluent 30 to give an oil, which was dissolved in ER and treated with an excess of piperazine in ER to give the title compound as a solid (0. 12 g), m.p. 116-1171 (dec.).
Analysis Found: C.2H42N20, requires:
Q 6 93; H, 7.6;N, 5.2 C, 69.8; H, 73;N, 5.1 % Example 7 [1 '-biphenyl)-4-yllmethoxy]-2-(4-morpholinyi)-3-oxocyclopentyi]-4heptenoic Acid, Compound With Piperazine (21), Hernihydrate To a solution of Example 1 a (0.37 g) in dry ER (20 mi) was added piperazine (0.037 9) in dry ER (4 mO. The ER was decanted off and the residue crystallised from CH2C12- ISOpentane to give the title corrpound(O.2g)m.p.113-1140.
Analysis Found: C, 7 0.9; H, 73; N, 5.4 C311-14,1\1205 1/4 H20 requires: C, 70.9; H, 73;N, 5.4% Example 8 [1 a(Z),2p,5a]-( )-7-[5-[[(1,1 1-biphenyi)-4-yllmethoxy]-2-(4- morpholinyi)-3-oxocyclopentyll-445 'heptenoic Acid, Calcium (2+) (21), Monohydrate Aqueous 0.2N.NaOH (2 m]) was added dropwise with stirring to a solution of Example 1 a (0.25 9) in aqueous acetone (M), (10 mO at room temperature until the pH reached 7.8. 7.2% w/v CaCI, (1 mO was then added followed by water (10 m]) and stirring continued for 2 h. The solid was filtered off, washed with water (5 mi) followed by ER (10 m]) and dried (351/0.05 mm Hg/7 h) to afford the title 50 coirpound(O.163g),m.p.132- 1341.
Analysis Found: C, 69.1; H, 6.8; N, 2.6; Ca, 3.9 C5.HUNA.Ca. H20 requires: C, 68.9; H, 7.0; N, 2.8;Ca, 4.0% Example 9 [11 a(Z),2A,5cr1-( )-7-[5-[[(1,1 1-biphenyl)-4-yllmethoxyl-2-(4morpholinyl)-3-oxocyclopentyll-455 heptenoic Acid, Calcium (2+) (2:1), Trihydrate Aqueous calcium acetate solution (0.17 g in 12 ml) was added dropwise with stirring to a solution of Example 1 a) (0.6 g) and Na HCO, (0.106 g) in aqueous ethanol (1:1, 24 ml). The mixture so GB 2 075 503 A 30 was stirred for 30 min when the solid was filtered off, washed with water (10 mi) followed by ER (5 m]) and dried (451/200 mm Hg/4 h) to afford the title compound (0.56 g), m.p. 1351 (dec.).
Analysis Found: C, 66.2; H, 6.9; N, 2.6; Ca, 3.6 C HWN201.Ca. 3H20 requires: C, 66.5; H, 6.9; N, 23; Ca, 3.8% Example 10 [1 a(Z).20.5a]-( )-7-[5-[[(1,1'-biphenyi)-4-yllmethoxy]-2-(4morpholinyi)-3-oxoc yclopentyll-4heptenoic Acid, Compound With N,Ndimethylpiperazine (21) A solution of Example 1 a) (0.35 g) in ER (25 mi) was treated with a solution of N,Ndimethylpiperazine (0.084 g) in ER (5 m]) and the mixture was allowed to stand in the cold. The title compound was filtered off and dried (0.33 g), m.p. 106-1080.
Analysis Found:
C32H42N20, requires:
Q 71.9; H, 7.9; N, 5.1 C, 71.9; H, 7.9;N, 5.2% Example 11 a) [1 RA11 1-biphenyi)-4-yilmethoxy]-2-(4-morpholinyi)-3- oxocyclopentyll-4-heptenoic Acid Janes reagent (1.83 m], 2.67 M) was added to a stirred mixture of 'hyfio' (4.8 g) and the free base of Intermediate 47 a) (1.2 g) in acetone (40 mi) at 51 and stirring was continued for 40 min.
Isopropanol (1.8 m[) was added dropwise and after 10 min the hyflo was removed by filtration and was washed with acetone (30 mi) and pH 5 buffer (50 m[, KH2P04 and Na2HP04 in water). The combined filtrates were evaporated in vacuo at 10-151 to remove most of the acetone. The residue was diluted 20 with pH 5 buffer (25 mi) and extracted with ER (4x50 m]). The combined extracts were eashed with pH buffer (20 mi) and brine (20 mO, then dried and evaporated to give an oil. The oil was chromatographed on silica using ER as eluent to give a solid (0.58 9) which was recrystallised from2:1 ER-isopentane (15 mO to give the title compound (0.484 g), m.p. 86-881. [a] 21.5=-13.660 (CHCI D Analysis Found: C29HAO, requires:
C, 72.5; H, 7.5; N, 2.7 C, 72.9; H, 7.4;N, 2.9% The following compound was prepared starting from Intermediate 35, in a similar manner to the preparation of the 1 R compound:
b) [1S-[1a(Z),2p,5a]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yllmethoxy]-2-(4morpholinyl)-330 oxocyclopentyll-4-heptenoic Acid m.p. 81-84'.
Analysis Found: C2.HA05 requires:
C, 72.8; H, 7.3; N, 2.7 C, 72.9; H, 7.4;N, 2.9% Example 12 [la(Z),2p,5a]-( )-7-[2-(4-morpholinyi)-3-oxo-5-[(2-phenyithien-4yi)methoxyIc yclopentyll-4- 35 heptenoic Acid A solution of DMSO in dry toluene (1.46 mi, 1.41 M) was added dropwise to a solution of oxalyl chloride in dry toluene (1.8 mi, 1.15 M) at -701 under nitrogen and the mixture stirred for 15 min.
Simultaneously, a solution of Intermediate 50 (0.4 9) in dry toluene (4 mi) was treated with a solution of triethylamine in dry toluene (1.13 m], 0.8 M) followed by a solution of trimethylsilyl chloride in dry 40 toluene (1.07 mi, 0.085 M). After stirring at room temperature for 10 min the mixture was added to the above prepared solution of activated DMSO and stirring continued for 30 min. Triethylamine (2 mi) in toluene (5 mi) was added and after a further 30 min the mixture was treated with 1 M aqueous KH2P04 (20 mi) and extracted with ether (3x20 mO. The combined extracts were washed with water (50 mO, brine (30 mi) and then dried. After evaporation in vacuo the residue was chromatographed on silica 45 using 2:1 EA-PE (b.p. 60-80') as eluent to give the title compound as a solid (0.27 g). Crystallisation from ER-isopentane at -100 gave material of m.p. 52-550. IR (CHBr3) 3500, 1735, 1703 cm-1.
Example 13 [1 RAII a(Z),2p,5a]]-(-)-7[5-[[1,1 '-biphenyi)-4-yllmethoxy]-2-(4- morpholinyi)-3-oxocyclopentyll4-heptenoic Acid, Calcium (2+) (21), Dihydrate Aqueous calcium acetate solution (0.083 g in 4.8 mO was added dropwise with stirring to a solution of Example 11 (0.25 g) and NaHCO, (40 mg) in aqueous ethanol (1A, 9.6 mi). The mixture was stirred at room temperature for 2 h when the solid was filtered off, washed with water and dried (200/0.1 mm Hg/20 h) to afford the title compound (0.23 g), m.p. 129-1310. [a] 2'=-28.47' D (CHQ,).
so 31 GB 2 075 503 A 31 Analysis Found: C, 67.4; H, 6.8; N, 2.7; Ca, 3.5 C.,^,N2o,Ca.21-1,0 requires: C, 67.7; H, 7.0; N, 2.7;Ca, 3.9% Pharmaceutical Examples Tablets
These may be prepared by direct compression or wet granulation. The direct compression 5 method is preferred but may not be suitable in all cases as it is dependent upon the dose level and physical characteristics of the active ingredient.
A. Direct Compression mg1Tablet Active ingredient 100.00 Microcrystalline cellulose B.P.C. 298.00 10 Magnesium stearate 2.00 Compression weight 400.00 The active ingredient is sieved through a 250 m-6 sieve, blended with the excipients and qompressed using 10.0 mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.
8. Wet Granulation Active ingredient Lactose B.P. Starch B.P. Pregelatinised maize starch B. P. Magnesium stearate B.P.
Compressed weight mg1Tablet 100.00 238.00 40.00 20.00 2.00 400.00 The active ingredient is sieved through a 250 m-G sieve and blended with the lactose, starch and pregelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed into 25 tablets as described for the direct compression formulae.
The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxylpropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.
Capsules mgICapsule 30 Active ingredient 100.00 STA-RX 1500 99.00 Magnesium stearate B.P. 1.00 Fill weight 200.00 mg A form of directly compressible starch supplied by Colorcom Ltd., Orpington, Kent.
The active ingredient is sieved through a 250 M-6 sieve and blended with the other materials. The mix is filled into No. 2 hard gelatin capsules using a suitable filling machine. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.
Inhalation Cartridges 1Cartridge Active ingredient (micronised) 3 mg 40 Lactose B.P. to 25 mg The active ingredient is micronised so that the majority of the particles are between 1 m-6 and 5 m-' in longest dimensions and none are greater than 10 m-'. The active ingredient is then blended with the lactose and the mix is filled into No. 3 hard gelatin capsules using a suitable filling machine.
Suspensions mg15 mI Dose 45 Active ingredient 100.0 Aluminium monostearate 75.0 Sucrose (powdered) 125.0 Flavour 1 as required Colour J 50 Fractionated coconut oil to 5.00 ml 32 GB 2 075 503 A 32 The aluminium monostearate is dispersed in about 90% of the fractionated coconut oil. The resulting suspension is heated to 11 5'C while stirring and then cooled. The flavour and colour are added and the active ingredient and sucrose are suitably dispersed. The suspension is made up to volume with the remaining fractionated coconut oil and mixed.
Injection for Intravenous Administration Active ingredient Suitable vehicle to mg 5 mI A sterile presentation of the active ingredient in an ampoule or vial together with an ampoule containing a suitable vehicle. The former may be prepared by (a) filling sterile material into vials under aseptic conditions (b) freeze drying a sterile solution of the active ingredient under aseptic conditions.10 The vehicle may be (a) Water for Injections B.P. (b) Water for Injections 13.P. containing: (1) Sodium chloride to adjust the tonicity of the solution and/or (2) buffer salts or dilute acid or alkali to facilitate solution of the active ingredient.
The vehicle is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The vehicle is sterilised by heating in an autoclave using one of the acceptable cycles.

Claims (17)

  1. Claims wherein 1. Compounds of the general formula (1) OR2 1 1 ..' 1 CH 2)
    2Xl 0 11) ' Y X is cis or trans -CH=CH-; RI is straight or branched Cl-7 alkyl bearing as a terminal substituent - COOR 3 where R 3 is a hydrogen atom, Cl-, alkyl or C7_1, aralkyl; Y represents a saturated heterocyclic amino group which has 5 to 8 ring members and (a) optionally contains in the ring -0-, -S-, -SO-, -NIR1 (where R' is a hydrogen atom, C,-7 alkyl or aralkyl having a Cl-4 alkyl portion; and/or (b) is optionally substituted by one or more C,-4 alkyl 25 groups; R 2 is (i) C2-4 alkanoyl; (H) C,-, alkenyl, optionally substituted by phenyl (the phenyl being optionally substituted by Cl-4 alkyl, Cl-4 alkoxy, halogen, C.-7 cycloalkyl or phenyl (Cl-4) alkyl), biphenyl (optionally substituted by C,-, alkyl, C,-, alkoxy or halogen), or naphthyl; (iii) C,_,2 alkyl; (R) Cl-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, Cl-, alkyl, Cl-, alkoxy, 30 Cl-4 hydroxyalkoxy, trifluoromethyl, cyano, aryloxy, C.-7 cycloalkyl, aralkoxy, dimethylaminomethyl, carboxamido (-CONH,), thiocarboxamido (-CSNH2), Cl-4 alkanoyi, -NIR5R 6 (where R' and R' are the same or different and are each a hydrogen atom or Cl-4 alkyl, or where NRIR 6 is a saturated heterocyclic amino group as defined above for Y), Cl_, alkylthio, Cl-, alkyisulphinyl, C,-3 alkylsulphonyl, phenylalkyl having a C,_3 alkyl portion, aminosulphonyl, C,_,3 alkanoylaminosulphonyl, 35 phenyIsulphonyl (the phenyl portion being optionally substituted by Cl-3 alkyl or Cl-3 alkoxy), nitro, or thienyll, (b) thiqnyl or furanyl (the thienyl and furanyl groups being optionally substituted by Cl-, alkyl, Cl-6 alkoxy, aryl or phenyl (Cl-3) alkyl or phenyl (C,J alkoxy (the aryl or phenyl group in each case being optionally substituted by Cl-3 alkyl, Cl-3 alkoxy or halogen), aryloxy, C5-7 cycloalkyl, halogen, nitro or thienyll, (c) biphenyi (optionally substituted by phenyl or one or two Cl-4 alkyl, Cl4 alkoxy, halogen substituents), or (d) naphthyl (optionally substituted by Cl-4 alkyl, Cl-4 alkoxy or halogen); and the physiologically acceptable salts and the solvates thereof.
  2. 2. Compounds as claimed in Claim 1 in which Y is morpholino, dioxothiamorpholino, homomorpholino, thiamorpholino or piperidino.
  3. 3. Compounds as claimed in Claim 1 or Claim 2 in which X is cis -CH=CH-.
  4. 4. Compounds as claimed in any one of the preceding claims in which R' is -(CH2)2COOR 3 where R 3 is a hydrogen atom or Cl-3 alky].
  5. 5. Compounds as claimed in any one of the preceding claims in which R 2 is phenyl (Cl-3) alkyl in which the phenyl group is substituted by Cl-3 alkylthio, thieny], or phenyl (optionally substituted by Cl-3 alkyl, Cl-3 alkoxy, halogen or phenyl); phenylthienyl (Cl-3) alky]; or cinnamyl.
  6. 6. Compounds as claimed in Claim 5 in which R 2 is phenyl (Cl-3) alkyl in which the phenyl group is substituted by phenyl, Cl-, alkylphenyl, Cl_, alkoxyphenyl or halophenyl; phenylthienyl (Cl-3) alkyl; or cinnamyi.
    1 11 ? 40 33 GB 2 075 503 A 33
  7. 7. Compounds as claimed in Claim 1 in which:
    X is cis -CH=CH-; R' is -(CH,),C001-1; Y is morpholino or piperidino; R' is phenyl (C,J alkyi in which the phenyl group is substituted by phenyl, C1-3 alkylphenyl, C,-21 5 alkoxyphenyl or halopheny]; phenylthienyl (Cl-3) alkyl; or cinnamyi; and the physiologically acceptable salts and solvates thereof.
  8. 8. Compounds as claimed in any of the preceding claims in which the carbon atom carrying the -(CH2)2XR' group is in the R-configu ration.
  9. 9. Compounds as claimed in Claim 1, said compounds being [1 a(Z),2p,5a]( )-7-[5-[[(1,1 1- 10 biphenyi)-4-yilmethoxy]-2-(4-morpholinyi)-3-oxocyclopentyll-4-heptenoic acid and the physiologically acceptable salts and solvates thereof.
  10. 10. C9mpounds as claimed in Claim 1, said compounds being [1 R-[ 1 a(Z), 2p,5a]]-(-)-7-[5[[(1,1'-biphenyi-4-yilmethoxy]-2-(4-morpholinyl)-3-oxoc yclopentyll-4-heptenoic acid and the - physiologically acceptable salts and solvates thereof.
  11. 11. The calcium salts of the compounds claimed in Claims 9 and 10.
  12. 12. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims together with one or more pharmaceutical carriers.
  13. 13. A process for the preparation of a compound as claimed in Claim 1 which comprises:
    (a) oxidising a compound of formula (2) OR2 ICH2)2XR'tl NO 12) Y in which R1a is a straight or branched alkyl group substituted by -COORI, -CH201-1 or -CHO; (b) in the preparation of a compound in which R 3 is alkyl or aralky], esterifying the corresponding compound in which R' is a hydrogen atom; 25 (d) reducing a corresponding compound in which X is an acetylene group; or (e) in the preparation of a salt, treating a compound as claimed in Claim 1 with an acid or (where R' is a hydrogen atom) with a base,_or converting one salt into another by exchange of cation.
  14. 14. Compounds as claimed in Claim 1, said compounds being the title compounds of any one of the Examples herein.
  15. 15. A pharmaceutical composition comprising a compound as claimed in any one of Claims 9 to 30 11 together with one or more pharmaceutical carriers.
  16. 16. A pharmaceutical composition as claimed in Claim 15 in unit dosage form.
  17. 17. A pharmaceutical composition substantially as described in any one of the pharmaceutical examples herein in which the active ingredient is a compound as claimed in any one of Claims 9 to 11.
    Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, Southampton Buildings, London, WC2A I AY, from which copies may be obtained.
GB8113239A 1980-04-30 1981-04-29 Prostanoid aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation Expired GB2075503B (en)

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EP0069447A2 (en) * 1981-04-29 1983-01-12 Glaxo Group Limited Aminocyclopentanol acids and esters and their preparation and pharmaceutical formulation
EP0074861A1 (en) * 1981-09-16 1983-03-23 Glaxo Group Limited Aminocyclopentane esters and their preparation and pharmaceutical formulation
EP0078668A1 (en) * 1981-10-29 1983-05-11 Glaxo Group Limited Preparation of aminocyclopentanealkenoic acids
FR2533213A1 (en) * 1982-09-16 1984-03-23 Glaxo Group Ltd Bi:phenyl-methoxy hydroxy-piperidino cyclopentyl heptenoic acid salt
GB2127406A (en) * 1982-09-16 1984-04-11 Glaxo Group Ltd Piperidinylcyclopentanolheptenoic acid salt
DE3339019A1 (en) * 1982-10-28 1984-05-03 Glaxo Group Ltd., London PRODUCTION OF AMINOCYCLOPENTANE ACIDS
GB2146023A (en) * 1983-09-06 1985-04-11 Glaxo Group Ltd Aminocyclopentanes and their preparation and pharmaceutical formulation
GB2167404A (en) * 1984-10-26 1986-05-29 Glaxo Group Ltd Prostanoid aminocyclopentane alkenoic acids and esters, their preparation and pharmaceutical formulation
US4837234A (en) * 1981-12-23 1989-06-06 National Research Development Corporation Prostaglandins
US5006539A (en) * 1981-12-23 1991-04-09 National Research Development Corporation Prostaglandins
GB2330307A (en) * 1998-02-07 1999-04-21 Glaxo Group Ltd EP4 Receptor antagonists as bone resorption inhibitors
EP2281813A1 (en) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses

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US4438111A (en) 1980-01-09 1984-03-20 Glaxo Group Limited Prostanoid compounds and pharmaceutical formulations
ZA81114B (en) 1980-01-09 1982-01-27 Glaxo Group Ltd Prostanoid compounds and their preparation and pharmaceutical formalation
US4410521A (en) * 1981-09-16 1983-10-18 Glaxo Group Limited Aminocyclopentane esters and pharmaceutical formulations
IL67041A (en) * 1981-10-29 1988-03-31 Glaxo Group Ltd 2-aminocyclopentane alkanoic and alkenoic acid esters,process for their preparation and pharmaceutical compositions containing them
GB8307099D0 (en) * 1983-03-15 1983-04-20 Glaxo Group Ltd Carbocyclic compounds
GB8601985D0 (en) * 1986-01-28 1986-03-05 Glaxo Group Ltd Chemical process
GB8625326D0 (en) * 1986-10-22 1986-11-26 Glaxo Group Ltd Medicaments
GB8715333D0 (en) * 1987-06-30 1987-08-05 Glaxo Group Ltd Process
GB9720270D0 (en) * 1997-09-25 1997-11-26 Pharmagene Lab Limited Medicaments for the treatment of migraine
US6414006B1 (en) 1998-10-15 2002-07-02 Merck Frosst Canada & Co. Methods for inhibiting bone resorption
AU6836200A (en) 1999-08-10 2001-03-05 Glaxo Group Limited Use of ep4 receptor ligands in the treatment of, inter alia, neuropathic pain and colon cancer
GB0124124D0 (en) * 2001-10-08 2001-11-28 Medical Res Council Methods of treatment
GB0208785D0 (en) * 2002-04-17 2002-05-29 Medical Res Council Treatment methtods
US20060166872A1 (en) * 2002-04-17 2006-07-27 Jabbour Henry N Fp receptor antagonists or pgf2 alpha antagonists for treating menorrhagia
WO2004071508A1 (en) * 2003-02-14 2004-08-26 Medical Research Council Ip receptor antagonists for the treatment of pathological uterine conditions
JP2008193940A (en) * 2007-02-13 2008-08-28 Honda Motor Co Ltd Method for purifying polyhydroxybutyrate
US9523045B2 (en) 2013-01-30 2016-12-20 Ecolab Usa Inc. Hydrogen sulfide scavengers
EP3286175B1 (en) 2015-04-22 2020-12-02 Ecolab USA Inc. Development of a high temperature stable scavenger for removal of hydrogen sulfide
EP3347440A4 (en) 2015-09-08 2019-05-08 Ecolab USA Inc. Hydrogen sulfide scavengers
EP3347441B1 (en) 2015-09-08 2020-06-10 Ecolab USA Inc. Hydrocarbon soluble/dispersible hemiformals as hydrogen sulfide scavengers
CA3031535A1 (en) 2016-07-29 2018-02-01 Ecolab Usa Inc. Antifouling and hydrogen sulfide scavenging compositions
WO2019014415A1 (en) 2017-07-13 2019-01-17 Ecolab USA, Inc. Method of removing a sulfur containing compound by adding a composition
US11499108B2 (en) 2019-01-23 2022-11-15 Championx Usa Inc. Complete removal of solids during hydrogen sulfide scavenging operations using a scavenger and a Michael acceptor

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GB1553293A (en) 1976-02-23 1979-09-26 Lepetit Spa Azaprostaglandins
GB2028805B (en) * 1978-07-11 1982-11-03 Glaxo Group Ltd Prostanoid compounds
CH648286A5 (en) * 1978-07-11 1985-03-15 Glaxo Group Ltd PROSTAGLAND DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVES.
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Cited By (15)

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Publication number Priority date Publication date Assignee Title
EP0069447A3 (en) * 1981-04-29 1983-03-16 Glaxo Group Limited Aminocyclopentanol acids and esters and their preparation and pharmaceutical formulation
EP0069447A2 (en) * 1981-04-29 1983-01-12 Glaxo Group Limited Aminocyclopentanol acids and esters and their preparation and pharmaceutical formulation
EP0074861A1 (en) * 1981-09-16 1983-03-23 Glaxo Group Limited Aminocyclopentane esters and their preparation and pharmaceutical formulation
EP0078668A1 (en) * 1981-10-29 1983-05-11 Glaxo Group Limited Preparation of aminocyclopentanealkenoic acids
US4837234A (en) * 1981-12-23 1989-06-06 National Research Development Corporation Prostaglandins
US5006539A (en) * 1981-12-23 1991-04-09 National Research Development Corporation Prostaglandins
FR2533213A1 (en) * 1982-09-16 1984-03-23 Glaxo Group Ltd Bi:phenyl-methoxy hydroxy-piperidino cyclopentyl heptenoic acid salt
GB2127406A (en) * 1982-09-16 1984-04-11 Glaxo Group Ltd Piperidinylcyclopentanolheptenoic acid salt
DE3339019A1 (en) * 1982-10-28 1984-05-03 Glaxo Group Ltd., London PRODUCTION OF AMINOCYCLOPENTANE ACIDS
AT387220B (en) * 1982-10-28 1988-12-27 Glaxo Group Ltd METHOD FOR PRODUCING AMINOCYCLOPENTANE ACIDS
FR2535322A1 (en) * 1982-10-28 1984-05-04 Glaxo Group Ltd PREPARATION OF AMINOCYCLOPENTANIC ACIDS
GB2146023A (en) * 1983-09-06 1985-04-11 Glaxo Group Ltd Aminocyclopentanes and their preparation and pharmaceutical formulation
GB2167404A (en) * 1984-10-26 1986-05-29 Glaxo Group Ltd Prostanoid aminocyclopentane alkenoic acids and esters, their preparation and pharmaceutical formulation
GB2330307A (en) * 1998-02-07 1999-04-21 Glaxo Group Ltd EP4 Receptor antagonists as bone resorption inhibitors
EP2281813A1 (en) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses

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JPS5882723A (en) 1983-05-18
SE8102731L (en) 1981-12-21
US4327092A (en) 1982-04-27
FR2481703A1 (en) 1981-11-06
FR2481703B1 (en) 1985-08-02
AU6995781A (en) 1981-11-05
JPH0263054B2 (en) 1990-12-27
DE3117087A1 (en) 1982-03-11
CH646965A5 (en) 1984-12-28
FI811350L (en) 1981-10-31
IT1170929B (en) 1987-06-03
ES501740A0 (en) 1982-09-16
ES8303386A1 (en) 1983-02-01
FI78293C (en) 1989-07-10
KR830005187A (en) 1983-08-03
BE888645A (en) 1981-10-30
JPH0314028B2 (en) 1991-02-25
ES510838A0 (en) 1983-02-01
ATA191781A (en) 1985-11-15
IL62734A (en) 1985-10-31
FI78293B (en) 1989-03-31
DK189881A (en) 1981-10-31
IE51241B1 (en) 1986-11-12
IT8148367A0 (en) 1981-04-29
KR850000214B1 (en) 1985-03-06
NL8102116A (en) 1981-11-16
US4342756A (en) 1982-08-03
NZ196966A (en) 1984-05-31
PT72951B (en) 1983-06-15
NO811470L (en) 1981-11-02
IE810957L (en) 1981-10-30
IL62734A0 (en) 1981-06-29
JPS5718671A (en) 1982-01-30
GB2075503B (en) 1984-03-28
AU540147B2 (en) 1984-11-01
PT72951A (en) 1981-05-01

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