Novel Cyclopentene and Cyclopentane Derivatives

The present invention relates to novel pharmacologically active compounds in particular to novel cyclopentene and cyclopentane derivatives.

In one compound aspect the present invention provides novel derivatives of the general formula I: ##SPC1##

wherein

R and R.sub.2 each individually represent a hydrogen

Atom or an alkyl group;

R.sub.1 represents an alkyl group;

R.sub.3 and R.sub.4 each individually represent an alkyl or aralkyl group, or, together with the adjoining nitrogen atom form a heterocyclic ring which may include further heteroatoms such as oxygen or nitrogen;

--OR.sub.5 is a functional group; and

X and X' represent hydrogen atoms or, when taken together, a double bond.

The novel compounds of formula I have pharmacological, such as analgesic anti-inflammatory activity. Additionally, they are intermediates in the production of other pharmacologically active compounds such as some prostagladin-type compounds sharing the same cyclic moiety.

As stated --OR.sub.5 is a functional group where R.sub.5 is for example, hydrogen, alkyl, acyl, carbamoyl and so on. The alkyl groups R.sub.1 to R.sub.5 which may be straight chain or branched, are preferably lower alkyl groups having 1 to 6 and especially 1 to 4 carbon atoms. Examples of such groups are methyl, ethyl, and the various propyl, butyl, pentyl and hexyl groups. The aralkyl group as R.sub.3 and R.sub.4 preferably has 1 to 6, especially 1 to 4 carbon atoms in the alkyl moiety, the aryl moiety including especially the phenyl group; acyl group R.sub.5 may have the formula alkyl--CO-- where alkyl is as defined above. Carbamoyl group R.sub.5 preferably has the formula:

where R.sub.6 is an alkyl group as defined above or an aryl group, for example, phenyl or a phenyl substituted by halogen, such as chlorine or bromine; nitro; or CF.sub.3.

It will be noted that formula I includes cyclopentene and cyclopentane derivatives. The cyclopentene derivatives of the present invention are generally of formula IIa or IIb: ##SPC2##

The cyclopentane derivatives of the present invention fall generally within one of the following formulae: ##SPC3##

In these formulae, symbols R.sub.1 to R.sub.5 are as defined above.

The various novel compounds represented by formula I may be prepared from a starting material which is a .gamma. -lactone of formula IV. ##SPC4##

wherein R.sub.1 to R.sub.4 are as defined above; and

Y is halogen such as chlorine or bromine; by opening the lactone ring thereof with a, preferably, strong base such as an alkoxide like sodium methoxide. Preferably one mole-equivalent of the base is used.

The directly formed compounds falling within formula I above, and in particular, within formula IIa, are then used to prepare the remaining compounds of the present invention. Ring opening of the lactone ring of the compound of formula IV produces the cis-syn epimer of formula IIa wherein R.sub.5 is hydrogen. The term "syn" throughout this specification always referring to the steric configuration of the --OR.sub.5 group.

This compound may be converted into compounds having other functional groups in the 5- position by susitable known procedures. For example, acetylation using for example, an acyl halide such as acetyl chloride, produces the 5-acyl, and in that particular case, the 5-acetyl derivative of the said 5-hydroxy-epimer; a suitable isocyanate, such as a phenyl or alkyl-isocyanate produces a 5-urethane derivative. Compounds having an ether function in the 5-position may be prepared by alkylating using an alkyl halide such as methyl iodide, or dimethyl sulphate, especially by reaction with the sodium salt of the 5-hydroxy epimer, the sodium salt being formed for example, by reacting the 5-hydroxy compound with sodium hydride. In some cases it may be advisable to protect the keto function in the molecule prior to alkylating. This may be effected by forming the corresponding ketal which grouping is removed subsequent to the ether formation by hydrolysis using, for example, an acid such as HCl.

The cis-syn epimer of formula IIa formed upon initial ring opening of the lactone of formula IV may be converted to the corresponding trans-syn epimer of formula IIb by any suitable method, such as treatment with a solution of an alkoxide, for example, sodium methoxide, in an alcohol such as methanol, optionally with protection of the keto group as described above.

The cyclopentane derivatives falling within formula I, i.e., those compounds of formulae IIIa, b and c may be produced from the cyclopentene derivatives by, for example, hydrogenation using hydrogen gas in the presence of a hydrogenation catalyst such as platinum or palladium on carbon.

It should be noted that the conversion of the initially formed hydroxyl in the 5-position into another reactive function may usually be effected at any stage in a reaction sequence although care should be taken to avoid a reaction sequence which utilizes a reaction step where deleterious effects on groups or moieties already present in the molecule may be expected.

The starting lactones of formula IV above are themselves novel and form a further compound aspect of the present invention. These lactones may be prepared via a Wagner-Meerwein rearrangement, by halogenating, especially chlorinating or brominating a salt derivative of formula V: ##SPC5##

wherein

R.sub.1 and R.sub.2 each individually represent hydrogen atoms or alkyl groups, preferably lower alkyl groups;

R.sub.3 and R.sub.4 each individually represent hydrogen atoms, alkyl groups or, together with the adjoining nitrogen atom form a heterocyclic ring which may include further heteroatoms such as oxygen, nitrogen; and

B.sup.+ represents an organic or inorganic cation, preferably in a polar solvent.

This invention further provides, in another of its composition of matter aspects, a pharmaceutical composition comprising as active ingredient at least one active compound of the general formula I in association with a pharmaceutically acceptable carrier therefor.

The compositions of the present invention are preferably administered either orally, parenterally or rectally. Advantageously, the composition is in a dosage unit form appropriate to the desired mode of administration. For example, the dosage unit may be a tablet, capsule, pill, powder, packet, granule, wafer, elixir, suppository, or a measured quantity of a suspension, solution, a syrup or segregated multiples of the foregoing. The term "dosage unit form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture, or otherwise in association, with a pharmaceutical carrier therefor, the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such as a half or a quarter of a severable unit is required for a single therapeutic adminstration.

The actual percentage of the active component in the composition may be varied, but advantageously is between about 2% and about 60%, or more, based on the total weight of the composition. Conveniently, the compositon of the invention when in dosage unit form contains 0.5 mg. to 1000 mg., and more conveniently form 5 mg. to 250 mg., of the active ingredient of the general formula I.

The compositions of the present invention will normally consist of at least one compound of formula I, admixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, catchet, paper or other container. A carrier which serves as a vehicle, excipient or diluent medium for the therapeutically acitve ingredient may be a solid, semisolid or a sterile liquid.

Some examples of the carriers which may be employed in the pharmaceutical compositions of the invention are lactose, dextrose, sorbitol, mannitol, starches such as wheat, corn, or potato starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxethylene sorbitan monolaurate, methyl and propyl hydroxybenzoates, pyrogen-free water and substantially isotonic saline solution. The choice of carrier is determined by the preferred form of administration, the solubility of the compound and standard pharmaceutical practice, all as more clearly set forth in "Remington's Practice of Pharmacy" by E. W. Martin and E. F. Cook, a wellknown reference text in this field.

In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose, there may be employed, for example, talc, aluminum, magnesium or calcium stearates or polyethylene glycols (Carbowaxes) of suitable molecular weight.

The pharmaceutical compositions of this invention may contain, in addition to the active ingredient of the general formula I, one or more other pharmacologically active ingredients which elicit desirable complementary effects.

An example of suitable pharmaceutical compositions according to this invention are presented below for the purpose of facilitating a better understanding of this aspect of the invention.

For oral administration, sugar coated tablets may have the following composition:

The present invention will be further described but not limited to the following specific examples.

Description of preparation of .gamma. lactones of Formula IV

The .gamma. -lactones of Formula IV defined in the following Table 1 were prepared in a similar manner to the procedure described in Step (ii) of Example 1, starting of course from the corresponding amine salt.

Preparation of .gamma. -lactone of 7-bromo-5-endocarboxy-6-endo-dimethylcarboxamido-3-endo-hydroxy-3-exomethy l-2-oxabicyclo-[2.2.1]heptane. (Formula IV where R.sub.1 =R.sub.3 =R.sub.4 =CH.sub.3 ; R.sub.2 =H; Y=Br)

i. From the dimethylamine salt of 3 exo-carboxy 2 exo-dimethylcarboxamino-4-methyl-7-oxabicyclo-[2.2.1]-5-heptene

A well stirred solution of 15.75 g. of the dimethylamine salt of 3-exo-carboxy-2 exo-dimethylcarboxamido-4-methyl-7-oxabicyclo [2.2.1]-5-heptene in 200 ml. of water was cooled to about 1.degree.C. in an ice bath and 9.3 g. of bromine vapour was passed into said cooled solution over 30 minutes via a stream of nitrogen. The temperature of the solution during the bromine addition was maintained between 0.degree.-5.degree.C. The precipitated solid was separated by filtration, washed with cold water and whilst still wet, suspended in 75 ml. of cold acetone and subsequently refiltered. 13.2 G. of white crystalline crude product having a melting point of 126.degree.C. was obtained. The product was recrystallized using acetone (excess acetone being removed in vacuo at 30.degree.C.), the melting point of the recrystallized product being 131.degree.C. (dec.).

ii. From the amine salt as in (i) but which salt is prepared in situ from the anhydride of 2.3 exodicarboxy-4-methyl-7-oxabicyclo [2.2.1]-5-heptene and not isolated prior to its being converted to the desired lactone.

36 G. of the anhydride of 2,3 exo-dicarboxy-4-methyl-7-oxabicyclo [2.2.1]-5-heptene was added at room temperature to a stirred solution of 18 g of dimethylamine dissolved in 420 ml. of water, and the mixture stirred at that temperature for about twenty minutes, i.e. until all the solid dissolved. The mixture was then cooled to 0.degree. -1.degree.C. and 32 g. of bromine vapour passed thereinto via a stream of air or nitrogen. The temperature during the addition of the bromine was maintained at between 0.degree. and 5.degree.C. The addition of the bromine took about 45 minutes and the solid which precipitated was filtered using suction and washed with 100 ml. of cold water. The wet material was suspended in 175 ml. of cold methanol, refiltered using suction and washed with methanol. 46.5 G. of a creamy crystalline product comprising mainly the desired compound but contaminated with a small amount of isomer where R.sub.1 and R.sub.2 are interchanged was obtained. Upon recrystallizing the crude product by dissolving same in 1350 ml. of refluxing methanol and allowing to cool, 32.3 g. of the desired product was obtained in the form of white crystals - melting at 131.degree.C. (dec.). The structure was further confirmed by IR and NMR spectral analysis.

The following Examples 10 to 18 describe in detail the production of specific compounds of Formula I, both directly and indirectly, from the novel lactones of Formula IV. The various procedures described in these examples are applicable, obviously with appropriate changes of starting materials etc., to the preparation of the compounds of Formula I given in the following Tables 2 to 5.

Preparation of 2-acetyl-cis-syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclopen tene.

A solution of 27 g. of sodium methoxide in 200 ml. of abs. methanol was added dropwise to a stirred suspension of 152 g. of the .gamma. -lactone of Example 1 in 600 ml. of abs. methanol. The exothermic reaction was subjected to cooling with dry-ice/acetone bath at such a rate that the sodium methoxide addition took 4 - 5 minutes while the reaction temperature was maintained between 4.degree. and 10.degree.C. Upon completing the reaction the pH was then checked and if found to be basic, adjusted to neutral using a few drops of acetic acid. The methanol was removed in vacuo and the residue treated with chloroform. The insoluble sodium bromide was removed by filtration and the solvent removed by evaporation to dryness in vacuo. The residue was crystallized from ethyl acetate/ether, separated by filtration and washed with a small amount of cold ethyl acetate. 95 G. of the desired product having a melting point of 98.degree. - 102.degree.C. was obtained. Recrystallization from ethylacetate gave 90 g. of purified compound, melting point 105.degree. - 106.degree.C.

Preparation of 2-acetyl-trans-syn-3carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclope ntene.

A mixture of 30 g. of 2-acetyl-cis-syn-3 carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclopentene in 200 ml. of ethyl acetate was brought to reflux and a solution of 0.22 g. sodium methoxide in 2 ml. of methanol was added thereto at once and the reflux continued for six minutes. The reaction mixture was then rapidly cooled using an ice bath until its temperature was approximately 40.degree. - 45.degree.C. when about 100 ml. of the solvent was removed in vacuo. The resulting reaction mixture was cooled in an ice bath for 30 minutes resulting in the crystallization of the product which was collected by filtration and washed with cold ethyl acetate. 10.8 G. of this crude product melting at 135.degree. - 138.degree.C. was obtained. Upon recrystallization from hot ethyl acetate, 10.1 g. of refined product having a melting point of 141.degree. - 142.degree.C. was obtained.

The combined mother liquors from the above procedure were concentrated to 100 ml. volume, heated to reflux, and a solution of 0.11 g. sodium methoxide in 1 ml. of methanol was added. The above procedure was repeated but only 50 ml. of ethyl acetate was removed. In this way a further 4.1 g. of the crystallized desired product was obtained having a melting point of 140.degree. - 142.degree.C.

Preparation of 2-acetyl-trans-, syn-3-carbomethoxy-4-dimethylcarboxamido-5-acetoxy-1-cyclopentene.

A mixture of 1.2 g. of 2-acetyl-trans, syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclopentene, 12 ml. of methylene chloride and 1.2 ml. of acetyl chloride were refluxed for 30 minutes under anhydrous conditions, atmospheric moisture being excluded from the apparatus by a calcium chloride drying tube. The volatile components of the reaction mixture were then removed in vacuo and the residue crystallized from ether and recrystallized from ethylacetate. The desired product was obtained in a yield of 1.1 g. and the white crystals had a melting point of 112.degree.-114.degree. C.

Conversion of "cis, syn" isomer to "trans, syn" isomer utilizing a protected keto group procedure.

ii. A mixture of 25.5 g. of 2-acetyl-cis, syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclopentene, 200 ml. of dry benzene, 15 ml. of ethylene glycol and 0.3 g. of p-toluenesulphonic acid monohydrate was gently refluxed for 17 hours and the water collected in a Dien-Stark apparatus. The reaction mixture was cooled to room temperature, 3 ml. of triethylamine was added and the mixture washed with 50 ml. of water which was subsequently saturated with sodium chloride and extracted twice with 50 ml. of methylene chloride. The benzene solution and methylene chloride extracts were combined, dried over sodium sulphate and evaporate when 21.8 g. of the desired ketal of the above cis, syn isomer was obtained as a white solid melting at 82.degree. - 83.degree.C.

ii. 0.55 G. of sodium methoxide was added to a solution comprising 16.5 g. of the ketal formed in (i) in 100 ml. of methanol. The mixture was rapidly heated to reflux which was continued for 3 minutes, after which it was cooled in an ice bath to room temperature and the pH adjusted to neutral with acetic acid. The methanol was then removed by evaporation, 25 ml. of water added and the mixture extracted with 100 ml. methylene chloride. The aqueous phase was saturated with sodium chloride and extracted twice with 50 ml. of methylene chloride, the combined organic phase then being dried over sodium sulphate and evaporated. The crude ethylene ketal of 2-acetyl-trans, syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclopentene was crystallized from ether and recrystallized from ethylacetate, the product then having a melting point of 87.degree. - 89.degree.C. Yield: 12 g.

iii. Removal of ketal group.

A solution comprising 10 g. of the ketal formed in (ii) in 100 ml. of methanol was added to 100 ml. of water containing 1 ml. of conc. hydrochloric acid. The combined solution was allowed to stand at room temperature for 3 days. The solution was then neutralized with sodium bicarbonate and evaporated, a minimum amount of water added and the solution extracted exhaustively with methylene chloride; dried over sodium sulphate, filtered and finally evaporated in vacuo. The product was obtained in the form of crystals from ether and subsequently recrystallized from ethyl acetate. The desired product, obtained in a yield of 6.1 g., had a melting point of 140.degree. - 142.degree.C. and its structure confirmed by NMR analysis.

Production of a urethane derivative

To a solution of 0.6 g. of 2-acetyl-trans-syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclop etene in 6 ml. of benzene was added 0.3 g. of phenylisocyanate, and the solution refluxed for 1.5 hours. The precipitate which formed was filtered off and washed with benzene. The yield was 0.6 g. and the product had a melting point of 183.degree. -185.degree.C.

Conversion of a cyclopentene derivative to a cyclopentane derivative by hydrogenation

0.1 G. amount of 5% palladium on carbon was added to a solution comprising 3 g. of 2-n-butyryl-cis-syn-3-carbomethoxy-4-dimethylcarboxamido-5-hydroxy-1-cyclo pentene in 50 ml. of absolute methanol. The mixture was hydrogenated at 50 lbs. per sq. inch pressure until take up of hydrogen ceased. The catalyst was removed by filtration. The methanol was evaporated in vacuo and the residue treated with ether. The resulting solid was filtered off and retreated with ether to produce crystals which were filtered off and washed with ether. The yield of the product, which has a melting point of 80.degree. - 81.degree.C. was 2.5 g.

Epimerization, at the ketone function, to convert cis-syn-cis compound to the corresponding trans-syn-cis compound.

A solution of 3.0 g. of cis-syn-cis-1-acetyl-2-carbomethoxy-3-dimethylcarboxamido-4-hydroxy-cyclop entane in 30 ml. of methanol containing 6.0 ml. of triethylamine was allowed to stand at room temperature overnight. The resulting solution was evaporated in vacuo and the residue treated with ether. The product, obtained in a yield of 2.0 g., had a melting point of 74.degree. - 77.degree.C. Upon recrystallization three times from ethyl acetate the melting point improved to 80.degree. - 82.degree.C.

Production of an acid derivative of Formula I, i.e. where R is hydrogen.

A solution comprising 0.48 g. of sodium hydroxide in 5 ml. of water was added to a solution of 2.55 g. transanti-cis-1-acetyl-2-carbomethyoxy-3-dimethylcarboxamido-4-hydroxycycl opentane in 10 ml. of water and maintained at room temperature for 3 hours. The resulting solution was poured onto 90 g. of Lowex 50 W-X8 ion exchange resin, which had previously been washed to neutrality with distilled water, and the mixture stirred well. An acidic mixture resulted which was filtered, washed with water and evaporated in vacuo. The residue was taken up in ether and the desired acid product obtained as crystals having a melting point of 118.degree. - 120.degree.C. in a yield of 1.8 g. The structure was confirmed by spectral analysis in the normal manner.

Etherification of the 5-position hydroxyl group utilizing a ketal protected ketone function.

15.7 G. of the ethylene ketal of trans-anti-cis-1 acetyl-2-carbomethoxy-3-dimethylcarboxamido-4-hydroxy-cyclopentane dissolved in 150 ml. of benzene was added slowly to a stirred suspension of 2.1 g. sodium hydride (57% oil dispersion) which had previously been washed with 2 .times. 10 ml. of benzene. Formation of the sodium salt was allowed to proceed for 5 minutes at room temperature or until hydrogen evolution ceased. 25 Ml. of methyl iodide was added and the reaction medium allowed to stand at room temperaure for 30 minutes; the reaction was completed by heating on a 60.degree.C. water bath for 3 minutes. The mixture was then cooled and 15 ml. of water added. The organic layer was separated and the aqueous layer extracted with 2 .times. 75 ml. of methylene chloride. The combined organic fractions were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was treated with minimum ether for dissolution and cooled in a refrigerator. The resulting product, containing a methoxy group in the 5-position and a ketal protected keto function was obtained in a yield of 9.7 g. and had a melting point of 85.degree. - 86.degree.C. This compound was treated in the manner described in Example 13 (iii) to remove the ketal group thereby regenerating the keto function. The keto product also had a melting point of 85.degree. to 86.degree.C.

As stated previously the following Tables contain further specific examples of compounds of the general formula I according to the present invention. The actual procedure used to produce each compound is indicated in each Table.

The following is a detailed disclosure of the novel derivatives of formula V and a process for their production.

The novel derivatives have the formula ##SPC6##

wherein

R.sub.1 and R.sub.2 each individually represent hydrogen atoms or alkyl groups, preferably lower alkyl groups;

R.sub.3 and R.sub.4 each individually represent hydrogen atoms, alkyl groups or, together with the adjoining nitrogen atom form a heterocyclic ring which may include further heteroatoms such as oxygen, and nitrogen; and

B represents an organic or inorganic cation.

The compounds of formula V are intermediates useful in the production of pharmacologically active compounds, in particular, they are useful in the preparation of pharmacologically active cyclo-pentane and pentene derivaives described in detail herein.

The term "lower alkyl" as used throughout this specification means alkyl groups containing from 1 to 6, preferably from 1 to 4, carbon atoms; for example, methyl, ethyl, propyl, isopropyl and the various butyl, pentyl and hexyl radicals. Alkyl groups R.sub.3 and R.sub.4 may also be substituted by a phenyl group.

The cyclic groups represented by ##EQU1## are typically of the formula: ##EQU2## wherein R.sub.3 and R.sub.4 are individually alkylene groups, preferably the same groups and containing 2 or 3 carbon atoms,

X is O or N, and

n is zero or 1.

Examples of such cyclic groups are:

piperazinyl (i.e., R.sub.3 =R.sub.4 =--C.sub.2 H.sub.4 --; X=N; n=1)

pyrrolidinyl (i.e., R.sub.3 +R.sub.4 =--(CH.sub.2).sub.4 --; n=0)

morpholinyl (i.e., R.sub.3 =R.sub.4 =--C.sub.2 H.sub.4 --; X=0; n=1) and

piperidinyl (i.e., R.sub.3 +R.sub.4 =--(CH.sub. 2).sub.5 ; n=0).

B.sup.+ represents an inorganic or organic cation, preferably a monovalent cation. Examples of inorganic monovalent cations include the alkali metal anions such as lithium, potassium and sodium, especially the latter.

Possible polyvalent inorganic cations are barium and calcium. Examples of monovalent amine residues include those residues of amines of the formula: ##EQU3## where R.sub.3 and R.sub.4 are defined above.

Possible polyvalent organic cations include those obtained from diamines such as ethylenediamine.

The process for the production of the derivatives of formula V defined above, comprising reacting an adduct of the formula VI: ##SPC7##

wherein

R.sub.1 and R.sub.2 are as defined for formula V, with at least two moles of an amine of the general formula VII: ##EQU4## wherein R.sub.3 and R.sub.4 are as defined for formula V, and, if desired, converting the amine salt so formed into an organic salt by known methods.

Generally, conversion from an amine to an organic salt is effected by simple exchange such as treatment with an inorganic base for example, an alkali metal alkoxide, hydroxide, carbonate, etc., such as the potassium and sodium compounds, the alkoxides being preferred.

It will be noted that formula VII includes within its scope ammonia and for the purposes of this specification ammonia is deemed to be an amine.

In the above compounds, R.sub.1 and R.sub. 2 may be the same or different. If R.sub.1 and R.sub.2 are the same, the starting adduct of formula VI is symetric and upon opening the anhydride ring only one enantiometric pair is obtained. The possible enantiomers, are of formulae Va and Vb. ##SPC8##

wherein

R.sub.1 to R.sub.4 and B.sup.+ are as defined above, and R.sub.1 = R.sub.2.

However, when R.sub.1 is not the same as R.sub.2 in the starting adduct, opening of the anhydride ring results theoretically in two enantiomeric pairs. It is not felt necessary to draw out the actual structures of the four possible isomers since one skilled in the art would have little difficulty in doing so, if desired, espcially in view of the provision of formulae Va and Vb above. Of the joint possible compounds however, due to various factors and in particular steric hindrance, the two compounds where the amine group is on the opposite side of the molecule to the more bulky substituent R.sub.1 or R.sub.2 will predominate. It has been found that up to 90% of the product is a mixture of the two isomers where the above condition is met.

The various racemic mixtures can be resolved at appropriate stages by methods known in the art to the corresponding optically pure stereoisomers. Therefore, included within the scope of the present invention are the various possible isomers individually as well as the said racemic mixtures.

The present process may advantageously be carried out in a protic solvent and preferred are water or a lower alcohol such as methanol or ethanol. However, aprotic solvents, for example, ethers, such as ethyl ether, and aromatic solvents such as benzene and toluene, may be used.

The following examples are provided for further illustration, but not limitation.

Dimethylene salt of 3-exo-carboxy-2-exo-dimethylcarboxamido-4-methyl-7-oxabicyclo-[2.2.1]-5-he ptene (i.e., formula Va above where R.sub.1 =R.sub.3 =R.sub.4 =CH.sub.3 ; R.sub. 2 =H) 14.4 g. of the anhydride of 2,3-exo-dicarboxy-4-methyl-7-oxabicyclo-[2.2.1]-5-heptene were added en mass to a stirred solution comprising 18 ml. of 40% by volume aqueous dimethylamine and 100 ml. of methanol.

The reaction is slightly exothermic and the resulting mixture was stirred at the resulting temperature for a further 15 minutes or until a homogeneous solution was obtained. The solvents were removed in vacuo and the residue recrystallized from acetone. The desired compound was obtained after filtration as white crystals which were washed with acetone. 17.85 g. of the desired compound was obtained, having a melting point of 112.degree.C. (dec.) and was characterized further by IR and NMR data.

The mother liquors were found to contain a small amount of a mixture of the desired compound of formula Va with Vb.

The compounds defined in following Table 7 were prepared in an analogous manner to that described in Example 19 above, the various symbols used being referred to formula Va above.

The inorganic salt compound of Example 23 was formed by the exchange of an initially formed dimethyl-ammonium ion for the sodium ion. This was effected by treatment of the product of Example 19 with exactly one molar equivalent of sodium methoxide in methanol. The resulting solution was evaporated and the residue crystalized in the usual manner.

Further specific novel salts of formula Va according to the present invention are contained in the following Table 8: