IL110820A - Imidazolin-5-one and 5,6-dihydropyrimidin-4-one derivatives and their preparation - Google Patents

Abstract

Heterocyclic N-substituted derivatives of formula (I) and their salts are new. R1, R2 = H, 1-6C alkyl, 1-4C alkoxy, NH2, NH2CH2-, COOH, (1-4C alkoxy)carbonyl, CN, tetrazolyl, methyltetrazolyl, methylsulphonylamino, trifluoromethyl sulphonylamino(methyl), N-cyanoacetamide, N-hydroxy- acetamide, N-((4-carboxy)-1, 3-thiazol-2-yl) acetamido, ureido, 2-cyanoguanidinocarbonyl, 2-cyano-guanidino-methyl, imidazol-1-yl-carbonyl, 3-cyano-2-methyl isothioureidomethyl, with the proviso that R1 and R2 are not both H. R3 = H, 1-6C alkyl (optionally substituted by one or more halogen, 2-6C alkenyl, 3-7C cycloalkyl, Ph, phenyl-(1-3C alkyl) or (2-3C alkenyl)phenyl; the Ph groups are optionally substituted by at least 1 halogen, 1-4C alkyl, halogen-(1-4C alkyl), polyhalogeno-(1-4C alkyl), OH or 1-4C alkoxy. R4, R5 = 1-6C alkyl, Ph, phenyl-(1-3C alkyl), the alkyl, phenyl and phenylalkyl groups being optionally substituted by one or more halogen, perfluoro-(1-4C alkyl), OH or 1-4C alkoxy. Or R4 and R5 together form =CR7R8, (CH2)n or (CH2)pY(CH2)q. R7 = H, 1-4C alkyl or Ph; R8 = 1-4C alkyl or Ph. Y = O, S, C (substituted by 1-4C alkyl, Ph or phenyl-(1-3C alkyl) or NR6. R6 = H, 1-4C alkyl, phenyl-(1-3C alkyl), 1-4C alkylcarbonyl, halogeno-(1-4C(alkyl)carbonyl, polyhalo-(1-4C alkyl)carbonyl, -COPh, alpha-aminoacyl or an N-protecting group. Or R4 and R5 together form indane or adamantane. p + q = m; n = 2-11; m = 2-5; X = O or S. z and t = 0 or one is 0 and the other is 1. Specifically claimed is 2-n-butyl-4- spirocyclopentane -1-((2'-(5-tetrazolyl) biphenyl-4-yl)methyl) -2-imidazolin-5-one.

Description

and derivatives and their preparation SANOFI 94623 This invention relates to and one derivatives and their The compounds described in the parent application 97612 from which the present application is divided are useful in the treatment of cardiovascular diseases like heart failure as well as in the treatment of the central nervous system and in the treatment of glaucoma and diabetic The described in the parent application relates to the compounds of and R2 are alike or different and each independently represents hydrogen or group selected a a amino an alkoxycarbonyl in which the alkoxy is a methyltetrazolyl with the proviso that at least one cf the Hi cr is differeat is a a alkyl which is tuted or by one or halogen atoms a a a a in which the alkyl is or a alkenyl in which the is said phenyl groups being unsubstituted or or by a halogen a a a polyhalogenoalkyl a or a and R5 each independently represents a a phenyl or a phenylalkyl in which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a a hydroxy1 and a or and together form a group of the formula in which is a alkyl or a phenyl and is a alkyl or a else and together are either a group or the formula or a group of the in which Y is oxygen or a sulfur or a carbon atom substituted by a grou a phenyl or a phenylalkyl in which the alkyl is or a group in which e is a a a phenylalkyl in which the alkyl a alk a a or and together with the carbon atom to which they are form an indane or an p a is an integer between 2 and is an integer between 2 and X is an oxygen or sulfur and z and are zero or one is zero and the other is and their When a compound of the invention has an asymmetric the invention includes the 2 optical isomers of this The salts of compounds of formula consist of those with organic or inorganic acids which permit appropriate separation or zation of compounds of formula such as pioric oxalic acid or an optionally active for example a mandelic acid or a camphosulphonic and those which form pharmaceutically acceptable salts such as the hydrogen dihydrogen methane methyl The salts of compounds of formula also consist of salts with organic or inorganic for example salts of alkali or alkaline earth metals like salts of the salts of sodium and potassium being or with a tertiary such as or even salts of or any physiologically acceptable According to this description and in the claims which a halogen atom is understood to be a chlorine or fluorine A group denoted by is understood to be a group classically used in peptide chemistry for temporary protection of the amine for example a Z or Fmoc group or a benzyl An esterified carboxy group is understood to be an ester which is labile under the appropriate like for example a benzyl or tertiary butyl means or branched aliphatic hydrocarbon Compounds of formula in which is in the ortho position and is a carboxy group or tetrazolyl and R2 is hydrogen are preferred of formula in and 5s linked together with the carbon to which they bonded constitute a cyclopsntane or are preferred compounds of formula in which is a group are preferred Compounds of formula in which X is an oxygen atom are likewise preferred compounds of formula in which z t 0 are The following abbreviations are used in the description ethyl tBu tetrahydrofuran dichloromethane dicylcohexylcarbodiimide d Ether ethyl ether triflucroacetic acid b zyloxycarbonyl bsnzotriazolyloxy trisdimethylamino The parent specification also relates to the method of preparation of compounds The said method comprises the following a heterocyclic derivative of which and Rs have the meanings indicated above for 0 is reacted with a derivative of of in which Hal is a halogen atom and and are either and cr a grouping which is a precursor of Rt and the compound thus obtained of is treated with s reagent the compound obtained from or of 2 is an sulfur is treated by groups into groups respectively in order to prepare compound compounds tie compounds as defined The present invention relates to compounds of which is a a alkyl which is tuted or substituted by one or halogen atoms a a a a in which the alkyl is or a alkenyl which the alkenyl is said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen a a a hydroxyi or a and Rs each independently represents a a phenyl or a phenylalkyl in which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a a hydroxyi and a and together form a group of the formula in which is a alkyl or a phenyl and is a or a else and together are either a group of the formula or a group of the in which Y is either an oxygen or a sulfur or a carbon atom substituted by a a phenyl or a phenylalkyl in which the alkyl is or a group which is a a a phenylalkyl which the alkyl is a a a polyhaiogenoaikylcarbonyl a an or an or and together with the carbon atom to which they are form an indane or an p q n is an integer between 2 and is an integer between 2 and 5 X is an oxygen atom or sulfur and and are zero or one is zero and the other is one with limitation that if z and t are zero and X is an oxygen and other than a a phenyl or a alkyl which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or halogen atoms or by a group selected from a perf luoroalkyl a and a or and together are other than in which Y i a group in which is a a alkyl or a alkyl which the alkyl is 2 to 5 is other than 6 or when represents a substituted phenyl and together are other a group in which n is between 3 and 5 and if z 1 and is a and are each other than a c z t 0 and R4 and together with the carbon to which they are bonded constitute a are preferred These compounds correspond to in which X is an oxygen or a atom and is a a which is unsubstituted or substituted by one or more halogen a a a a phenylalkyl in which the alkyl is a phenylalkenyl in which the alkenyl is said phenyl groups being stituted or onosubstituted or polysubstituted by a halogen a halogenoalkyl a C a hydroxy1 or a with the proviso that is other than a substituted phenyl group when X is Compounds in which z 0 and t 1 of formula in which R5 and X have the definitions given above for are preferred compounds in which z 1 and t 0 with in R3 is a which is or substituted by one or halogen atoms a a a a phenylalkyl in which the is or a alkenyl in which the alkenyl is said phenyl groups being unsubs or monosubstituted or by a halogen a a halogenoalkyl a a hydroxy1 or a and are each independently a a phenyl or a phenylalkyl in which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or halogen atoms or by a group selected from a a and a and together form a group of the formula in which is hydrogen a alkyl or a phenyl and is a C alkyl or a Lor and together are either a group of the formula or a group of the formula in which Y is either an oxygen or a sulfur or a carbon atom substituted by a alkyl a phenyl or a phenylalkyl in which the alkyl is or a group in is a a a phenylalkyl in which the alkyl is a alkylcarbonyl a 1 a polyhalogenoalkylcarbonyl a an or an or together with the carbon atom to which they are form an indane or an are prefferred Passages of the description which are not within the scope of the claims do not constitute part of the The derivatives are prepared by known For the described by Jacquier et and by Brunken and Bach s be used by reacting an with an acid or its ester according to following reaction in which R is a is hydrogen or a and z and t are as defined previously for This reaction is performed in acid by heating in an inert solvent such as xylene or According to another of a compound be prepared by reacting in acid medium an aminoalkylamide on an alkyl according to the following reaction S 10 where R is a The compound also be prepared by using a of working described by Takenaka et by reacting the derivative with an acid of CO Hal 11 in which Hal is a preferably The reaction is carried out in a basic a compound in accord with another subject of this is prepared by method comprising reacting a compound of in which A is an an group or an being hydrogen or a with a compound of B 14 in which B a C grouping a grouping 5 a and Hal representing a halogen preferably then optionally the compound thus obtained is treated with reagent The derivative of is prepared in accord with a method described in patent application EP 324 The conversion of group into an group is carried cut using methods which are well to the specialist in the when the compound to be prepared has an Ea group is an esterified carboxy When the compound to be prepared has an group may be either a tetrazolyl protected for example by a or a cyano group which will then be replacsd by a tetrazolyl optionally protected by a Conversion of the cyano group into may be carried out by an for example tin or sodium groups such as cyano or acid chloride groups may also be used and these may then be converted using reactions which are to the specialist in the field in order to obtain Ea groups such as those described for compound when a it may be converted into an or eve into The 1 representing an acid chloride may be converted Ba representing ureido or representing a nitro may be converted into an amino from Ba such as may be representing a cyano say be converted into from which can be prepared methylisothioureidomethyl to Gordon et J or a accord with Stage is performed in an inert solvent such as in a basic for example in the presence of potassium a metal a metal calcium carbonate triethyla Stage is performed by heating under nitrogen in a solvent such as according to method described by Cava et The method comprising st ges and cl is called method 1 in the following compounds may be prepared according another method which is likewise a subject of this This method reacting an aminoacid of COOH in which z and Rs have the meanings indicated above for and whose amine function is protected with the Pr group with a cterivative of in which represent either and or a precursor of and after deprotacting the the compound thus obtained of is then treated with an alkyl of formula in which has the meaning indicated above for and E is a the compound thus obtained of is treated with reagent the compound thus obtained in b2 or in c2 of treated under approprtiate conditions to prepare compound by conversion of the groups into groups Compounds are known or prepared by known methods the Amino Greenstein and John Viley Compounds prepared according to Buropean patent application 32 Stage is carried out under the normal conditions couplin an acid and an for example in the presence of BOP and cf Stage which is the of compound in the presence of is performed according to Jacquier et and according to and Bach In the following description the method comprising stages a2 to is called method According to one variant of method in stage an intermediary of may optionally be isolated and then compound may be prepared by cyclisation in acid to another variant of method 2 and in to prepare a compound I in which is one group an amino acid of may be reacted in acid medium with an aldehyde or a ketone of and Rs have the meanings given above for then a of is obtained by action compound Cyclisation of this compound in acid medium leads to d In this to prepare a compound in which is a carboxy the substituent is preferentially a another alternative for the preparation of the compounds according to the invention in which z and t are is the method which is likewise a of this This last method reacting an imidazole derivative of RS have the indicated above for with a derivative of methyl of in which is a halogen atom and represents either and respectively or a precursor of and in the presence of oxygen and UV in a basic the compound thus obtained of is treated reagent diphosp etan the compound thus obtained b3 or c3 of is then treated under appropriate conditions to prepare compound by converting the groups into Si groups The imidazole derivative is either commercially or or prepared by known methods as indicated above for the preparation of Stage is performed in an inert solvent such as for To facilitate the a photosensitizing product such as methylene blue may be In the fallowing the method comprising stages to is called method Compounds according to tne invention in which and linked together represent a group of formula in which Y is an be prepared by catalytic hydrogenolysis of a corresponding compound in which Y is an being The affinity of products according to the invention for angiotensine II receptors was studied in a linkage test of II labelled with iodine 125 to membrane receptors in rat The method used was that described by et in 208 was This was the concentration which produced displacement of the labelled angiotensine linked specifically to the The CIso of the compounds according tothe invention is less than In the angiotensine II antagonistic effect of the products according to the invention has been confirmed in various animal species in which the system had been activated previously et 7 Comuounds according to the invention are active after administration by various particularly the oral sign of toxicity was observed with these compounds at pharmacologically active Thus the compounds according to invention may be used in the treatment of various cardiovascular particularly heart venous as well as in the treatment of diabetic and various diseases oi the central nervous memory disorders or for This invention also relates to the pharmaceutical containing an efficacious dose of a compound according to the invention or a pharmaceutically acceptable salt and appropriate The said are chosen according to pharmaceutical form and the desired method of In the pharmaceutical carpositions of this invention or rectal the active principles of I or optionally their may be administered in the form of administration mixed with classical pharmaceutical to animals and to humans for the prevention or treatment of the illnesses or diseases The appropriate forms of administration units include forms for the oral route such as granules and oral solutions or intranasal forms of intramuscular or intravenous forms of ad and rectal forms of adminstra For topical the compounds according to the invention may be used in ointments or In order to obtain the preventive or therapeutic effect the dose of active principle may vary between and 50 mg per body weight and per Each unit say contain to preferably from 1 to 500 active ingredients in combination with a pharmaceutical This unit may be administered 1 to 5 times per day in such a way as to administer a daily dosage of from to 5000 preferably from 1 to 2500 When a solid composition is prepared in the form of the principal active ingredient is mixed with a pharmaceutical vehicle such as magnesium arable gum and the The tablets may be coated with a cellulose or other appropriate material or again they may be treated in such a way that they have a prolonged retarded activity and they release a predetermined quantity of active principle preparation in capsules is obtained by mixing the active ingredient with a diluant and pouring the mixture obtained into soft or hard A preparation in the form of syrup or elixir or for the form of drops contain the active ingredient together with a preferably with no calorie methylparaben and propylparaben as as well as an agent to give a suitable taste and Powders or granules which can be dispersed in water contain the active ingredient mixed with dispersion or wetting or suspension agents like again with sweeteners taste For rectal suppositories which are prepared with binders melting at the rectal far example cacao butter or are For parenteral aqueous isotonic saline soutions or sterile and injectable solutions which contain pharmacologically compatible dispersion wetting for example propylenegiycol or are The active principle may also be formulated in the form optionally with one or several supports or addi The compos of this invention may alongside the products of formula I above or one of the pharmaceutically acceptable other active principles such for tranquillisers or other drugs which may be used the treatment of the illnesses diseases indicated this invention also relates to pharmaceutical compositions containing several active principles in one of which is a compound of the invention and the other may be a a calcium a a agent or a The fallowing examples illustrate the invention without limiting it in any In these the following abbreviations are d means TA means ambient means an aqueous solution containing g potassium bisulfate and g potassium sulfate per melting paints are given in degrees Celcius unless indicated to the they were measured without the Purity of the products was checked using thin layer chromatography or The products are characterised their MR spectra recorded at 200 in deuterated the internal reference being To interpret the the following were s for a singlet for a broadened singlet d a doublet t for a triplet q far a quadruplet quint for a quintuplet for a a very broad band or multiplet im means In the classic the hydrogen atoms are numbered on the biphenyl as shown in the following In the fallowing s and t are except when the compound prepared is a 1 Method carbaxylic acid was prepared according to the method described by et Peptide Protein 700 g of the product prepared in the precedin stage were dissolved in 3 ml and 576 970 mg BOP and enough to give a pH of 6 were added in After stirring for 1 the reaction medium was diluted with 100 ml ethyl acetate and 20 ml The organic phase was washed successively with a saturated sodium bicarbonate then with a solution and finally with a saturated sodium chloride After drying over sodium the solution was evaporated to An oil was obtained with The product obtained in the preceding stage was dissolved in 10 ml then 1 ml diethyiamine was added and the mixture stirred 14 hours at reaction medium was taken up with 100 ml ethyl acetate and 20 ml water and the organic phase was washed once with once with a saturated sodium chloride dried over sodium sulfate and evaporated to The residue was chramatographed on silica gel by eluting with an ethyl ammonia solution mixture mg expected product were 3350 H and 1700 C 0 1650 C 0 spectrum ppra s 9 H ppra 10 H d 2 H ra 8 H biphenyl t 1 H NH 394 mg of product prepared the preceding stage and 250 ethyl were mixed 2 ml 1 drop of acetic acid was added then the was heated to allowing the to After the reaction medium was taken up with 50 ethyl 10 ml water and 1 ml saturated sodium bicarbonate The organic phase was then washed with a saturated chloride dried over sodium sulfate and evaporated to The residue was on silica gel by eluting with an ethyl mixture 390 mg of the expected product was which 15 c C 0 and 1625 C spectrum ppm t 3 H ppm s 9 H ppm sext 2 H ppm quint 2 ppm m 8 H cyclopentane ppm t 2 H ppm s 2 H ppm 8 E H spectrum 461 mg of product prepared the preceding stage were treated with 4 ml TFA for 45 After evaporation under the residue was taken up with A white solid was obtained which was washed with ether and then dried under spectrum t 3 H ppm sext 2 H ppm quint 2 H 8 H cyclopentane ppm t 2 H ppm s 2 a S aromatic H mass spectrum 405 2 Xethod 1 The ethyl ester of carboxylic acid was prepared according to AD and 3ILLICA Ethyl valerianate was prepared to ELVAIff and then released from its hydrochloride by the action of potassium carbonate and The ethyl ester of carboxylic acid and ethyl valerimidate were dissolved in 12 ml xylene containing 6 drops of acetic After hours of heating under the reaction medium was concentrated under vacuum and the residue was then on silica gel by eluting with a acid mixture The fraction containing the expected product was evaporated several times in the presence of xylene and then of benzene to remove acetic the product was obtained in the form a 1720 C 0 1635 C N the fact that no band is visible between 1500 and 1600 indicates in chloroform the product is an spectrum ppm t 3 H CH3 ppm sext 2 H ppm m 10 H and cyclopentane ppm t 2 H ppm NH mass spectrum 195 The prepared in stage may also be obtained in accord with another described by using cyclopentanone as the starting is carried out in accord with g sodium cyanide was dissolved in ml water in a flask and a solution containing g ammonium chloride in ml water and ml ammonia solution was then 3 g cy lopentanone in ml methanol were added to the After hours the warmed to for 45 then the heating was turned off and the stirring continued for 45 minutes and the flask cooled to 25 The contents were extracted several with dried over sodium filtered and concentrated under 4 g expected product was obtained in an oily The obtained was dissolved 300 ml acetone and a solution of g oxalic acid dihydrate in 200 ml acetone was added with The precipitate which formed was washed with acetone and then g This compound is This stage was carried out in accord with Chemistry of New g of the oxalate obtained the preceding stage were treated with mi concentrated sulfuric acid for 45 minutes with A gas was evolved and the temperature increased to The mixture was cooled to and poured into a mixture of ice and concentrated ammonia solution The suspension which formed was extracted 6 times in succession with chloroform containing 3 ml ammonia solution were added to the aqueous phase and this was then extracted again with chloroform containing methanol The combined organic phases were dried over sodium filtered and The expected product was obtained in the form of a white m g The analysis results and the spectrum confirmed the This stage was carried out accord with et 3 g of the prepared in the preceding stage were placed in 70 ml anhydrous THF and ml triethylamine and 3 ml valeryl chloride in 10 ml anhydrous THF were added with A white suspension was The intermediate compound which was but not was 6 g potassium hydroxide in pellet 7 ml water and 16 ml methanol were Heating under was performed for two and a half hours and then 9 g ammonium chloride were After 15 minutes the was concentrated under The residue obtained was absorbed in 40 ml water and extracted with 10 ml ethyl acetate and then twice with 5 ml ethyl The combined organic phases were dried over sodium sulfate and The filtrate was concentrated to g expected product were The spectrum ilar to that described The hydrochloride of this may be prepared by addition of concentrated hydrochloric The hydrochloride melts at while 970 mg product obtained in stage were dissolved in ml 270 mg sodium methylate were added and left at TA for 15 minutes with g biphenyl added to the suspension after 30 the mixture was heated at 3 hours under The reaction medium was taken up with a mixture of 100 ml ethyl 10 ml water and 1 ml saturated sodium bicarbonate The organic phase was washed with a saturated sodium chloride dried over sodium sulfate and evaporated to The residue was chromatcgraphed on silica gel by eluting with an ethyl mixture expected product which crystallized was The MR and mass spectra as well as the Rf were identical with those obtained in stage of example g product obtained in the preceding stage were stirred for 40 minutes in a solution containing 6 ml DCM and 8 ml After concentration under the residue was absorbed in ethyl the white precipitate which was washed with ether and then dried under g expected product was The and mass spectra identical to those obtained in example the Rf measured in was 3 Xethod 3 was prepared in accord with POOL and then was prepared in accord with and spectrum ppm t 3 H CH3 ppm sext 2 H ppm 2 H ppm s 4 H ppm 4 H H7 ppm t 2 ppm ra NH mass spectrum 178 1 g product prepared preceding stage was dissolved in 45 ml D F with 303 mg sodium methylate and a few mg methylene Oxygen into the reaction medium which was illuminated with a UV After 15 g was added and after 1 the reaction medium was taken up with 300 ml ethyl acetate containing 50 ml water and 5 ml saturated sodium bicarbonate The organic phase was then washed with a saturated sodium chloride dried over sodium sulfate and evaporated to The residue was on silica gel by eluting with an ethyl mixture 610 mg expected product which crystallized was The and mass spectra as well as the were identical to those obtained previously for the same This compound was obtained by treatment in acid medium as described in the last stage of example 1 and example The data identical to those obtained the same prepared using methods 1 or 4 and The ethyl ester of acid was prepared to Jacquier et 650 mg of this compound and mg ethyl valeri idate were dissolved in δ ml xylene containing 4 drops of acetic acid and heated under reflux for 7 The reaction was then concentrated under vacuua and the residue chromatographed on silica gel by eluting with a acid mixture After several evaporations of xylene and then of to remove the acetic 560 mg expected product which crystallised were IE c 0 1635 C N the absence of a signal between 1500 and 1600 confirms that the compound present in chloroform solution was a spectrum t 3 H s 6 H C ppm sext 2 H ppm quint 2 H t 2 H m 1 H spectrum 169 520 mg product prepared in the preceding stage were dissolved in 10 ml 167 mg sodium was added and stirred for 15 minutes under Then g was added and the mix was stirred for hours at 4 The reaction medium was taken up with 150 mi ethyl acetate and then 20 ml water and 2 ml saturated sodium bicarbonate The organic phase was washed with a saturated sodium chloride dried over sodium sulfate and evaporated to The residue was chromatographed on silica gel by with an ethyl mixture mg expected product which crystallized were IS C C 0 1625 C N spectrum ppm t 3 H ppm s 9 ppm s C and ppm ppm quint 2 H ppm t 2 H ppm s 2 H ppm aromatic A Effect study canfirned the position of the and substitutions on the mass spectrum 435 460 mg product prepared in the preceding stage were treated with 3 ml and 4 ml TFA for 45 After concentration under the residue was taken up with ether and the precipitate which formed was washed with ether and dried 450 mg product were obtained in the form of a white spectrum ppm t 3 H CH3 ppm quint 2 H ppm t 2 H ppm s 2 H ppm 8H mass spectrum 379 EXAMPLE 5 Method A mixture containing 250 sodium hydride dispersion in mineral and 5 ml DMF was prepared under an atmosphere of nitrogen and a solution containing g as in example stage in 10 ml DMF was added This was stirred for 30 minutes at TA and then solution of g in 10 ml was After stirring for 1 hour at the DMF was evaporated off under reduced pressure and the residue was absorbed in ethyl The organic phase was washed water and then dried over sodium filtered and The residue was on silica gel by with a acetate mixture g expected product was tetrazolyl g preceding g tributyltin aside and 30 ml xylene were heated under for 65 The xylene was then evaporated off and the residue was dissolved in 20 ml and 5 ml while adding ml hydroxide after 30 minutes g trityl chloride and then the mix was stirred 26 After evaporating off the the residue was taken up with ethyl acetate and washed well with a solution of potassium hydrogen sulfate and This was dried and The residue was chromatography alumina by eluting with a acetate mixture g expected product was g product prepared in the preceding stage dissolved in 10 ml methanol 10 ml After cooling the reaction medium to hydrochloric acid were added and the nix was stirred for 3 hours at TA and 30 After evaporation of the the residue was taken up with water and adjusted to pH 12 by adding sodium The aqueous phase was extracted with toluene and then ether The aqueous phase was acidified to 2 by the addition of hydrochloric acid and then extracted into ethyl dried and The white solid which was obtained was dried at under a reduced pressure of mm 840 expected product was spectrum ppm t 3 H CH3 ppm sext 2 H quint 2 H ppm ra 8 H ppm t 2 H ppm s 2H ppm 4H aromatic A Qvsrhauser Effect study confirmed the position of the substitution on the Potassium salt of mg of the compound obtained in the preceding stage were dissolved in 40 ml of an mixture and the pH was adjusted to pH 12 by adding an potassium hydroxide solution in a mixture This was the residue was taken up with isopropanol and evaporated The residue was dissolved in 20 ml isopropanol by heating gently and then left to return to ambient The mix was the filtrate evaporated and then the residue taken up with After grinding the product It was filtered washed again with heptane and dried under 945 mg the expected potassiun salt was Elemental C 61 95 H 6 03 N 6 13 17 14 EXAMPLE 6 and acid was prepared starting from in accord with the method described in the German patent DE 2 215 g compound from stage A was placed in 12 ml water and treated at with ml diisopropylethylaaine and then g in 12 ml After the reaction medium was diluted with 70 ml ethyl acetate and 10 ml water and adjusted to pH 2 using a saturated solution of potassium After the organic phase was washed with a saturated sodium chloride dried aver sodium sulfate and evaporated under The residue was diluted in 60 ml ether and then 7 mmole dicycohexylamine was The precipitate which formed was filtered and washed with It was then dissolved in a mixture of ethyl acetate and water and adjusted to pH with a saturated solution of potassium The organic phase was decanted washed with a saturated solution of sodium evaporated under vacuum and g of a white solid was 850 mg af t e prepared in stage B were dissolved in 15 ml and amounts of DIPEA and BOP were er 40 the medium was taken up with 200 ml ethyl acetate and 200 ml The organic phase was decanted and washed twice with a saturated solution of sodium bicarbonate and then once with a saturated solution of sodium After drying over sodium the organic phase was evaporated off under g expected product was The product obtained in stage C was dissolved in 30 ml 400 ag palladium on charcoal were added and hydrogen was passed through at atmospheric After 1 the catalyst was filtered off and the filtrate was concentrated under The residue was chromatographed on silica by eluting with an ethyl ammonia solution mixture g expected product was obtained in the form of a white spectrum t 1 H H amide ppm 8 H H aromatiq ppm d 2 H ppm 4 H CH2 in 2 and 6 of tetrahydropyran ppm 4 H in and 5 of pom s 9 H tBu A mixture containing g of the compound obtained in stage 327 mg methyl and 2 drops of acetic acid were for 3 hours at reaction medium was taken up with 100 ethyl acetate and then washed with a saturated solution of sodium a saturated solution of sodium chloride and then dried over sodium sulfate and the ethyl acetate evaporated the residue which was obtained was chromatographed on silica by eluting with an ethyl mixture 550 mg expected product was obtained in the form of a HUE spectrum ppm m 8 H H ppm s 2 H CH2 ppm 4 in 2 and 6 of ppm t 2 H ppm 8 H and in 3 and5 of ppm s 9 H ppm t 3 H IE C C 0 1625 C N 530 mg of the product obtained in the preceding stage were treated with 4 ml dichlorcmethane and 5 ml TFA for 45 After evaporation under the residue was taken up with the precipitate which was farmed was washed with ether and then dried under 510 mg expected product was IMS spectrum ppm m 8 H H aromatic ppm s 2 H ppm m CH2 in 2 and6 of tetrahydropyran ppm t 2 H C3H7 ppm 6 and in 3 and 5 tetrahydropyran ppm sext 2 H C ppm t 3 H EXAMPLE 7 spiro and spira Method acid was prepared from in accord with the described in the German patent DE 2 215 Ethyl g of the compound prepared in stage A were added to a solution of 13 g hydrochloric acid in 50 ml ethanol at and then heated under reflux for 5 After concentration under the residue was washed with ether and dissolved in am mixture to which was added a saturated solution of potassium carbonate until 9 was The ethereal phase was washed with a saturated solution of sodium dried over sodium sulfate and then evaporated to g expected product was obtained in the form of an spectrum ppm m 5 H H ppm q 2 H ppm s 2 H of ppm 4 H 2 and6 of piperidine ppm ra 2 H CH2 3 and 5 of piperidine ppm a 2 H ppm t 3 H spira Ethyl valerimidate prepared as in example stage g ethyl g of the compound prepared in stage and 8 drops of acetic in 15 ml were mixed and heated under reflux for 6 After concentration under the residue was chromatographed on silica gel by eluting with a acid mixture g expected product was obtained after extraction with chloroform at pH 9 to remove acetic 1725 C 0 1640 C N spectrum ppm 5 H H aromatic s 2 H ppm 5 14 H piperidine and ppm t 3 H 513 g sodium methylate were added to g of the compound prepared in stage C dissolved in 25 ml and after 15 g mixture was heated at for 5 hours and then the reaction was taken up with300 ml ethyl 50 water and 5 saturated solution of sodium The organic phase was decanted off washed once with a saturated solution of sodium dried over sodium sulfate and evarorated under The residue was chromatographed on silica by eluting with an mixture g expected product was obtained C C 0 1630 C ppm 13 H H ppm s H ppm s 2 H ppm m 14 H of the piperidine and ppm s 9 H ppm t 3 H 350 at the obtained in stage D were dissolved in 4 and 5 After 45 the was concentrated under vacuus and the residue taken up with an precipitate which was foraed was filtered washed with ether and dried under 350 expected product was spectrun ppm 13 H ppm s 2 H ppm s 2 H ppm m 4 H in 2 and of the piperidine ppm t 2 H ppm 3 unresolved in 3 and 5 of the and ppm 2 H ppm t 3 H EXAMPLE and 300 mg of the compound from example stage were dissolved in 10 ml 180 mg palladium on charcoal were added and hydrogen was passed through for 3 hours at atmospheric The catalyst was filtered off and the filtrate was concentrated under 200 mg expected product was spectrum ppm m 8 H H ppm s 2 H CH 3 unresolved multiplets the 4 of the piperidine ppm t 2 H ppm 2 H 35 ppm sext 2 H ppm s 9 H tBu ppm t 3 H 160 product obtained in stage A were stirred in 3 ml dichlorome thane and 4 ml trif luoroacetic acid for 45 This was concentrated under vacuum and the residue was taken up with A gum was obtained which turned a drying under vacuum spectrum ppm m 8 H H ppm s 2 H 3 unresolved multiplets far the 4 of the piperidine ppm t 2 H ppm quint 2 H ppm sext 2 H ppm t 3 H EXAMPLE 9 msthyl trifluoroacetate and Method Valerimidine hydrochloride g ethyl valerimidate hydrochloride were added to a solution of g ammonia in 80 ml methanol at After the reaction medium was concentrated under vacuum and the expected product was obtained in the form a of a white This compound was prepared in accord with the working method described by and in starting with benzil and valerimidine IE 1725 C 0 1640 C spectrum ppm m 10 H H ppm t 2 H ppm 2 H ppm sext 2 H ppm t 3 H 11 ppm NH This compound was prepared in accord with the usual procedure by the reaction of carbonylbi henyl on the compound prepared in stage B in in the presence of sodium me IS C C 0 1635 cm C N spectrum ppm m 18 H aromatic ppm s 2 H ppm t 2 H ppm quint 2 H ppm sext 2 H ppm s 9 H t 3 H CH of 500 of the product prepared in stage C were treated wit ml ml acid at 20 far 20 After under the residue was taken up vdth an the precipitate which formed was washed with hexane and 440 mg expected product was ppm m 18 H H aromatic ppm s 2 H ppm t 2 H ppm quint 2 H ppm sext 2 H ppm t 3 H CH3 butyl EXAMPLE 10 acid acid was prepared in accord with and 740 mg of this acid and 5 ml ammonia solution were placed in an autoclave and heated at for 24 evaporation of the the residue was on a silica by eluting with a mixture aqueous ammonia solution 330 g expected acid was Ethyl 330 of the acid were dissolved in 10 ml This was cooled on an ice bath and saturated with gaseous hydrochloric After 24 hours under the reaction medium was evaporated down and the residue taken up vath a solution of sodium carbonate and extracted into ethyl then dried over sodium filtered and 312 mg expected ester was A mixture containing 310 mg of the compound obtained in stage 248 ethyl 10 ml xylene and S drops of acatic acid heated under After 2 hours and another 343 mg ethyl vaieri idate were and after 24 hours total under reflux the reaction was evaporated down and then chromatographed on silica by eluting a mixture 153 mg expected product was A mixture of 10 ml and 40 sodium hydride as an mix in was preoared undar an atmosphere of 144 sg of the compound preoared in stage dissolved in 5 ml added at ambient After 30 minutes with butoxycarbanyibiphenyl dissolved in 5 ml were The mix was with stirring for 2 hours and then evaporated the residua absorbed in water and extracted into ethyl This was sodium filtered and then purified by column chromatography by eluting with a acetate mixture 174 expected product was 10 al trifiuoroacetic acid was coaled on an and 161 mg of the compound prepared in stage were This was left for 30 minutes with and then evaporated The residue taken up ether and then evaporated down This operation was repeated and then the residue was dried under 140 mg expected compound was in the form of an amorphous spectrum ppm t 3 H a m 12 H c ppm t 2 H ppm s 2 H ppm s 2 H a 7 ppm m 8 H aromatic EXAMPLE 11 and g of the compound prepared in example stage were dissolved in 40 al toluene and reacted with 3 g of reagent under nitrogen at After 6 the reaction medium was filtered and The residue was chro atographed silica by eluting with a mixture The expected product was obtained in the form of an oil which crystallized in the m JIMS spectrum ppm t 3 H CH3 s 9 H tBu ppm 2 H ppm quint 2 H 10 ppm m H cyclopentane ppm t 2 H ppm s 2 H ppm 8 H H aromatic 225 mg of tie compound obtained in stage A were treated with 5 and 5 ml TFA for 30 After the residue was taken up with The expected compound was obtained in the form of a yellow powder which was centrifuged and then rinsed with n 160 spectrum spectrum 421 ppm t 3 GH3 ppm sext 2 H ppm quint 2 H ppm 8 H cyclopentane ppm t 2 H ppm s 2 H ppm 8 H H aromatic 12 and Xathod acid was prepared in accord with Che 892 and the corresponding ethyl ester was then prepared in accord with cited in example 2 g of the ethyl ester prepared in stage A and g ethyl valerimidate were dissolved in 20 ml xylene the presence of 60 acetic acid and heated under reflux for 3 500 Eg ethyl valerimidate were added again and the reflux maintained 3 additional The reaction medium was concentrated and then chro atcgraphed on silica by eluting with a acid mixture The pure fractions were combined and evaporated from g expected product was obtained in the form of a white MR spectrum ppra t 3 H CH3 ppm m 4 H ppm q 4 H ppm 2 H ppm m 4 H H The compound obtained in the preceding stage was dissolved in 20 ml anhydrous and treated with 450 mg sodium under After 20 minutes at ambient g were added and the mix was left with stirring at 40 6 The reaction medium was concentrated and then the normal washings were carried and the product was on silica by eluting with a acetate mixture The expected compound was obtained in the form of a spectrum ppra t 3 Η CH3 ppm s 9 H ppm 4 H ppm t 2 H ppm q 4 H ppm s 2 H ppm 12 H H aromatic g of the ccmpaund obtained in the preceding stage was dissolved in 15 ml and treated with 20 ml After the reaction medium was concentrated and absorbed in After grinding the solid obtained was rinsed with ether and g expected product was spectrum ppra t 3 ppm 4 ppm t 2 H ppm q 4 H Λ ppm s 2 H ppm m 12 H H aromatic Other compounds in accord with the invention have been prepared in accord with one of the methods described They are summarised in table The structure of each of thes compounds is in accordance with their EXAMPLE 13 CR4R5 X A mixture containing 404 mg of the compound prepared in example stage 15 ml and 260 was stirred for 72 hours at ambient The reaction medium was taken up ethyl acetate and washed with water and then a solution of sodium 420 mg product were obtained which were purified by chromatography on silica by eluting with a acetate mixture to obtain the expected 230 mg 120 SXAXPLE 14 SCH3 t R3 R5 X This compound was obtained by hydrogenation of the compound prepared in example 1 g of the compound prepared in example 5 stage A was placed in 15 ml absolute methanol and ml in the presence of palladium on charcoal and hydrogen was passed through at ambient temperature for 24 After 730 mg expected product was obtained in an oily A mixture containing 300 mg compound prepared in the preceding stage and 113 mg in 3 ml ethanol was refluxed far 24 the usual the reaction was purified by chromatography silica by eluting with a acetate mixture The expected product was isolated in the form of a white 307 EXAMPLE 15 Rl R2 R3 CR4R5 X This compound was obtained by starting with the prepared in the preceding 200 mg of the compound were placed in mi absolute saturated with ammonia at about and then heated in an autoclave at for 1 After concentration the reaction medium to chromatography was performed on silica by eluting with a mixture 130 mg expected product was EXAMPLE triiluoromethylsulfonate X and 15 g were mixed heated to and left at this temperature with stirring for After cooling to ambient the mix was taken up and The warm solution was on and the was evaporated g at mm A mixture containing g g 118 g and 500 ml tetrachioromethane were The mix was cooled to and the filtrate concentrated to obtain 9 g of an oily product which was used as such in the next A mixture containing 260 mg sodium in 5 ml was made up and 500 prepared as in example stage A was added at ambient temperature and under After 15 minutes with 901 in 5 ml were added and left for 24 hours with The reaction medium was concentrated to and taken up with a acetate The organic phase was decanted dried over sodium filtered and then the ethyl acetate evaporated The product which was obtained was on silica by eluting with a acetate mixture 500 mg expected product was 450 mg of product obtained in the preceding stage were placed in 10 ml in the presence of palladium on at ambient to be After filtration of the catalyst and 240 mg expected product was 225 product obtained the preceding stage and ml were mixed in 4 ml and to this was added ml acid under at and then left to return to ambient The reaction medium was washed with water and a solution of sodium bicarbonate and then dried and 150 of an amorphous white solid was spectrum ppm 7 H ppm 10 H and cyclopentane ppm system ppm 8 H ppm 1 H 10 ppm 1 H CF3SO3H EXAXPLE 17 trifluaromethylsulfonate CH2NHSO2CF3 R2 R3 X The preparation took place starting with aminc et yIbip prepared in example stage 322 mg of this compound and ml triethylamine were placed in ml DCX at and to this was added ml acid This was allowed to return to ambient poured into dilute acetic acid and extracted with The solution was dried over sodium filtered and the DCX evaporated The residue was c twice on silica by with acetate then 90 mg was spectrum 7 H ppm 10 H cyclopentane ppm 4 H ppm 8 H H aromatic ppm 1 H EXAMPLE 18 R2 R3 X The compound prepared in example 2 was released its trifluaroacetic acid salt by taking up this with an ethyl and by adjusting the of the solution to 6 by adding a saturated solution of sodium The organic phase was washed with a saturated solution of sodium dried over sodium filtered and concentrated to give the free base in form of a white 450 g of this compound were dissolved in 860 ml thionyl chloride was added at and the mix left with stirring at ambient temperature 2 The solution was concentrated and traces of thionyl chloride removed by azeotropic distillation with The acid chloride thus obtained was added dropwise to a solution containing 200 mg hydroxy1ami e hydrochloride and 700 in 10 ml After 2 hours at the reaction medium was concentrated and taken up with 100 ml and 50 ml The pH was adjusted to 7 and the organic phase extracted and dried over sodium After the solution was The product obtained was recrystallized from an ethyl 360 EXAMPLE 19 ί R3 CR4R5 X was prepared by using the method described by et in 52 starting with prepared in example 14 stage 1 the latter was dissolved in 50 hydrochloric acid and treated with potassium isocyanate for 1 hour at The reaction medium was ccncentratedi up with ethyl washed with sodium bicarbonate and then with a saturated solution of sodium After drying over sodium sulfate and the solution was concentrated and the oil was purified by chromatography on silica by eluting with a mixture 600 spectrum 3 H ppm 2 H ppm 2 H 8 H cyclopentane ppm 2 H ppm 2 ppm 2 H ppm 9 H 8 H aromatic NHCO EXAMPLES 20 and 21 and ethyl butyrimidate hydrochloride CH3 CH2 HC1 This was prepared in accord with 23 were added to a solution of g gaseous hydrogen chloride in 20 ml anhydrous ethanol and left for 4 days at Then the mixture was with into 200 ml anhydrous ether at The precipitate which formed was washed with ether and then dried under g expected product was Ethyl butyrimidate 16 i idate obtained in stage A were dissolved in 100 ml dichlorosethane and 50 ml water and 15 g potassium carbonate were After the dichloromethane was dried over potassium carbonate and then evaporated to dryness bein The ethyl ester of carboxylic carboxylic acid is available 15 g of this a inoacid were added to a solution of 23 g gaseous hydrogen chloride in 150 ml anhydrous ethanol at This was heated under reflux for 5 then the reaction medium was concentrated to dryness and absorbed in The white solid which was obtained was washed with ether and then dissolved in a mixture of 300 ml ether and 100 ml solution of potassium carbonate was added to adjust the pH to The organic phase was decanted washed with a saturated solution of sodium dried over sodium sulfate and then evaporated to 14 g expected product was obtained in the form of an 14 g of the product obtained in stage C were dissolved in 200 ml xylene containing ml acetic Half the imidate obtained in stage B was added and the mix was heated under After half of the remaining imidate was added and then the last quarter was added after 4 After a total of 7 hours the medium was evaporated The solid which was obtained was taken up with washed in ether and then g expected was 1715 C 1635 C N The compound present in solution is actually an from the positions of the IS 970 obtained in stage D was added to g of sodium hydride in oil in suspension in 10 After stirring for 20 g prepared according European patent 324 was added over 5 After 1 the medium was cancetrated under vaccum and half ws taken up with ethyl acetate and then in 20 ml The organic phase was decanted washed with a saturated solution of sodium dried over sodium sulfate and then concentrated under The residue was chromatographed on silica by eluting with an ethyl g expected product was obtained in the of a IS C C 0 1635 C N Analysis of the spectrum confirmed the g tertiarybutyl ester in stage E were stirred for 45 minutes in a mixture of 11 ml dichlaromethane and 15 ml trifluoroacetic After concentration under the residue was taken up with The solid which farmed was washed with ether and then g of white said was spectrum aromatic ppm 2 H ppm 2 H ppm 12 H spirocyclohexane ppm 3 H g obtained as above were dissolved in 150 ml ethyl acetate plus 20 ml hydroxide solrtion was added to obtain The organic phase was decanted washed with a saturated solution of sodium dried over sodium sulfate and then evaporated to The residue obtained was absorbed in ethyl filtered and g To 300 ag of compound prepared in the preceding in suspension in 5 ml were added mi After the reaction medium was concentrated under then evaporated twice The acid chloride thus obtained was dissolved in 2 ml and added to 42 nsr cyanamide ia solution in 1 ml dioxan containing ml sodium hydroxide After the reaction medium was diluted with ml ethyl acetate and 20 ml water and adjusted to pH 5 with acetic The organic phase was washed with a saturated solution of sodium dried over sodium sulfate and then evaporated to The residue was chro atographed an silica by eluting with a acid mixture 160 expected product was obtained as a 2150 C mass spectrum 429 spectrum 7 70 ppm 8 H aromati ppm 2 H ppm 2 H ppm 12 H and spirocyclohexane ppm 3 H EXAMPLE 22 N I R2 R3 CR4R5 X 0 This compound was prepared from the compound obtained in example The was prepared in accord with Plouvier et To a solution of 404 mg of compound prepared in example 20 and 190 rag of the thiazale derivative in 4 ml and 1 ml were added 500 mg BOP and ml triethyla This was stirred for 40 hours at temperature and then for 7 hours at The reaction medium was taken up with 50 ml ethyl acetate and washed twice with a then twice with a saturated solution sodium bicarbonate and then once with a saturated solution of sodium After drying over sodium the organic phase was concentrated under vacuum and the residue was chromatographed on silica by eluting with an ethyl 120 mg expected product was To 110 of product obtained in the preceding dissolved in 1 ml methanol and 1 ml was added ml hydroxide After 35 minutes the reaction medium was diluted with 10 ml water and 60 ml ethyl acetate and adjusted to 5 by the addition of hydrochloric The organic phase was washed with a saturatedd solution of sodium dried over sodium sulfate the The residue was taken up with filtered and 100 mg spectrum 1 H H 5 of thiazole ppm 8 H H ppm 2 H ppm 2 H ppm 12 H cyclohexane and ppm 3 H EXAMPLE 23 NH2 R3 CR4R5 X The acid chloride of A obtained in example 2 was 1 g this compound was placed in 20 DCM in the presence of mi chloride and stirred at ambient temperature for 2 After concentration of the it was absorbed in benzene and then concentrated The crude product which was isolated was than It was mixed with 417 mg sodium hydroxide ml water and 10 ml and left with stirring 5 The reaction medium was taken up with water and ethyl potassium carbonate was added and then it was The residue obtained was chroaatographed silica by eluting with a mixture 100 g expected product was 24 R3 X Starting from the of was prepared in accord with Jacquier et Tetrahedron To 430 mg of this compound in solution in 5 ml were added 644 mg This was stirred for 2 hours at ambient temperature and then 1 ml methyl orthovalerate was added and the mixture evaporated to under vacuum without external The residue was heated for 3 hours at concentrated under vacuum and then chromatographed on silica by eluting with a acetate mixture 580 mg of a white solid was 154 spectrum ppm 9 H 3 H 2 ppm 2 H ppm 1 H ppm 1 H CH 440 mg of compound obtained in stage A were dissolved in ml acetic acid and heated for 30 minutes at 100 The mix was evaporated to dryness under vacuum and the residue was chromatographed on silica by eluting with a acetate mixture 130 mg of expected product was obtained in an oily spectrum ppm 2 H i 100 mg compound obtained in the preceding stage were dissolved in 1 ml and 1 ml trifluoroacetic acid was added and then left with stirring for 40 minutes at ambient temperature and evaporated under residue was taken up with and then evaporated several On the addition of ethyl a white solid 101 Mass spectrum 439 spectrum ppm 3 H CH3 ppm 2 H ppm 2 H ppm 2 H ppm 2 H 1 ppm 13 aromatic EXAMPLE 25 R4R5 X g hippuric acid and g potassium bicarbonate were dissolved in 4 ml acetic anhydride and heated for a few minutes at then cooled to ambient temperature and z benzaldehyde After 1 hour at ambient 20 ml distilled water at were solid which precipitaed was washed with water and then with ethanol and g expected product in the form of a yellow solid was spectrum ppm 1 H ppm 10 H aromatic butylcarboxylate A mixture 500 mg of the compound obtained in the preceding 570 mg butylcarborylate and pyridine was heated at for 3 It was then evaporated under taken up with chloroform and then evaporated The residue was chromatographed on silica by eluting with a acetate mixture and then 106 mg expected product was obtained in the form of a yellow spectrum ppm 9 H ppm 2 H ppm H H aromatic ppm 1 H ppm 1 H A mixture of g compound obtained in the preceding stage and g freshly melted sodium acetate in 5 ml acetic acid were heated under reflux for 6 This was allowed to cool and then an insoluble material was precipitated by the addition of The filtrate was evaporated and the residue was chromatographed on silica by eluting with a mixture The solid which was obtained was recrystallized from ethyl a 692 120 spectrum ppm 2 H 19 H H aromatic EXAMPLES 26 and 27 and 500 mg of the compound prepared in example 5 and 58 mg sodium hydride were mixed in ml DMF and stirred for 30 minutes before adding 179 mg methyl iodide and 2 ml DMF and leaving with stirring at ambient temperature for 4 The reaction medium was taken up with water and then extracted with ethyl This was dried over sodium filtered and the solvent evaporated The residue was chromatographed on silica by eluting with a acetate mixture 2 fractions were 90 mg compound example 26 and 1S4 mg compound in example 27 spectra Example 26 ppm 3 H ppm 2 H ppm 2 H ppm 8 H cyclopentane ppm 2 H ppm 3 H ppm 2 H 7 system 4 H ppm 4 H 27 ppm 3 H CH3 ppm 2 H ppm 2 H ppm 8 H cyclopentane ppm 2 H ppm 3 H ppm 2 H 7 ppm 4 ppm 4 H 28 ethyl cyclopentylidenacetate 6 g of sodium hydride was placed in 40 ml benzene and ml ethyl triethylphosphonoacetate were added dropwise at a temperature below After 1 hour at ambient ml cyclopentahone added The mixture was thenheated to for 15 minutes and then cooled to ambient temperature and the supernatant liquid decanted 25 ml benzene were heated to for 15 coaled down and then the supernatant liquid was The operation was repeated once By evaporation of the 42 g expected product was obtained and this was at 11 mm Hg g 150 ml gaseous ammonia was added to 20 g ethyl cyclopentylideneacetate prepared in the preceding stage and heated to 72 The product obtained after evaporation was purified by chromatography on silica by eluting with a ammonia mixture The product obtained was dissolved in and dried over sodium It was then filtered and the evaporated to obtain g expected A mixture containing g acetamide prepared 25 ml methyl orthovalerate and a few drops of acetic acid was heated for 18 hours at After evaporation of excess the residue was taken up with ethyl bicarbonate and washed with an aqueous solution of sodium over sodium sulfate and then purified by chromatography on silica by eluting with a mixture 5 g spectrum ppm 3 H ppm 2 10 H 2 2 H ppm 2 H ppm 1 H NH This compound is that obtained in example stage 2 327 mg sodium hydride were mixed under nitrogen for 30 minutes in 30 ml with g of the preceding and g were After 4 hours with stirring at ambient the solvents were the residue was taken up ethyl acetate and dried over sodium sulfate and The product obtained was by chromatography on silica by eluting with an ethyl mixture a g methyl1 3 g of the compound obtained in the preceding stage were placed in methanol and cooled on a ml HC1 were added and left for 5 hours at ambient Afte evaporation the residue was taken up with ethyl acetate and water and hydroxide solution was added until the pH reached The mixture was decanted and the aqueous phase washed with ethyl ether and toluene and then again with This phase was adjusted to 6 pH 5 by the addition of dilute hydrochloric acid and then extracted with ethyl dried and The product obtained was purified an silica by eluting with a mixture 800 mg expected product was spectrum ppm 3 H ppm 2 H ppm 10 H cyclopentane ppm 2 H ppm 2 H ppm 2 H ppm 4 H ppm 4 H 29 e trifluoroacetate ethyl This compound was prepared in accord with g sodium were dissolved 200 ml absolute Half of the solution of sodium ethylate formed was poured into an To the remainder were added ethyl cyanoacetate and the mixture was Into another ampoule were poured g and then the sodium ethylate and were added simultaneously and dropwise to the reaction When the addition had reflux was maintained for 2 Then it was taken up with an ethyl ether water washed with a saturated solution of sodium chloride and then The product obtained distilled at at 11 a 24 ethyl This coapound was prepared by catalytic hydrogenation of the ethyl s 20 g of the ethyl yclopenanecarboxylate were placed in 200 al ethanol with and hydrogenated for 72 hours at 60 under a pressure of 100 bars in the presence of rhodium on After filtration on and the residue was chromatographed on silica by eluting with a ammonia mixture g A mixture containing g of the compound obtained in the preceding stage and g ethyl valerimidate in 100 al xylene containing a few drops of acetic acid was refluxed for 13 The reaction medium was taken up with ethyl acetate and a sodium carbonate solution and then dried and 14 spectrum 3 H CH3 12 H and cyclopentane ppm 2 H ppm 2 H 10 ppm 1 s 500 mg af product obtained in the preceding stage were placed in 40 ml in the presence of ag of sodium hydride in under and stirred at aabient temperature half an g carbonylbiphenyl were added and the was stirred another 2 After the residue was absorbed in an ethyl acetate water washed with a saturated solution of sodiun concentrated and on silica by eluting with an ethyl mixture a 280 mg trifluoroacetate 250 ml of the tertiarybutyl ester prepared in the preceding stage were dissolved in 10 ml This was cooled in an iced water bath and then 5 ml cold acid wereadded and left for one hour with stirring the then for 1 hour at ambient The mix was evaporated under reduced The residue was taken up with ethyl ether and then The operation was repeated times and then the residue from evaporation was taken up with ground up and the hexane The product was taken up ethyl ether and the precipitate was a 190 spectrum ppm 3 H CH3 ppm 2 H ppm 10 H and cyclopentane ppm 2 H ppm 2 H CH2 ppm 2 H ppm 8 H aromatic Table R4 cyclohexane 130 cyclohexane 141 CO2H cyclopen cyclopentane TFA CO2H cyclopentane TFA 151 cyclopentane TFA 88 CO2H H cyclopentane 230 CO2H cyclobutane TFA 178 cyclododecane TFA TFA CO2H TFA cyclohexane CO2H TFA cyclohexane CO2H TFA CO2H cyclopentane TFA 105 H et C02H have isolated in the of a mixture of optical insufficientOCRQuality

Claims (1)

1. A compound of the is a a alkyl which is or substituted by one or more halogen a a a a in which the alkyl is or a alkenyl in which the alkenyl said phenyl groups being unsubstituted or or polysubstituted by a halogen a a a polyhalogenoalkyl a hydroxyl or a R4 and each independently represents a a phenyl or a phenylalkyl in which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a a hydroxyl and a or and together a group of the in which 7 is a alkyl or a phenyl and is a alkyl or a else and together are either a group of the formula or a group of the in which Y is either an oxygen or a sulfur or a carbon atom substituted by a alkyl a phenyl or a phenylalkyl in which the alkyl is or a group i which Re is a a a phenylalkyl in which the alkyl is a a a an or an or and together with the carbon atom to which they are form an indane or an p q m n is an integer between 2 and or n 7 to 11 is an integer between 2 and 5 X is an oxygen atom or sulfur and z and are zero or one is zero and the other is for with limitation that if z and t are zero and X is an oxygen other than a a phenyl or a alkyl in which the alkyl is said phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a perf a hydroxyl and a or and together other than in which Y a group in which is a a alkyl or a phenyl alkyl which the alkyl is is 2 to 5 n is other 6 or when represents a substituted phenyl and together other than a group in which n is between 3 and 5 and if z 1 and is a and are each other than a compound according to claim 1 of the formula in which X is an oxygen atom or a sulfur atom and is a a alkyl which is unsubstituted or substituted by one or more halogen a a a phenylalkyl in which the alkyl is or a phenylalkenyl in which the alkenyl is said phenyl groups being stituted or monosubstituted or polysubstituted by a halogen a halogenoalkyl a polyhalogenoalkyl a hydroxyl or a A with the proviso that is other than a substituted phenyl group X is 1 of the formula efined above for of the formula in is a a alkyl which is tuted or substituted by one or more halogen a a a a phenylalkyl in which the is or a alkenyl in which the alkenyl is phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen a a halogenoalkyl a polyhalogenoalkyl a hydroxyl or a R4 and each independently represents a a phenyl or a phenylalkyl in which the alkyl is said alkyl phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen or by a group selected from a alkyl a hydroxyl and a and together a group of the formula which is a alkyl or a phenyl and is a alkyl or a Lor and together are either group of the formula a group the formula in which Y is either an oxygen or a sulfur or a carbon atom substituted by a alkyl a phenyl or a phenylalkyl in which the alkyl is or a group in which Re is a a a phenylalkyl in which the alkyl is a alkylcarbonyl a 1 genoalkylcarbonyl a C a an or an or together with the carbon atom to which they are form an indane or an p q n is an integer between 2 and o is an integer between 2 and and X is an oxygen atom or a sulfur with the limitation is other a phenyl if and R3 are each a A method of preparing a compound according to any one of claims 1 which comprises reacting a pound of the formula in which has the definition indicated claims to and B is a group a group c OH a group R being a and Hal denoting a halogen preferably with a compound of the formula in which and are as defined above for in claim 10 and is an OH an group or a group being hydrogen or a and if treating the resulting compound with reagent A according to claim 4 wherein s and X is insufficientOCRQuality