GB2088876A

GB2088876A - Protected Phosphorus containing Peptide Derivatives

Info

Publication number: GB2088876A
Application number: GB8115480A
Authority: GB
Original assignee: Roche Products Ltd
Current assignee: Roche Products Ltd
Priority date: 1977-12-20
Filing date: 1979-03-20
Publication date: 1982-06-16
Also published as: GB2088876B

Abstract

Compounds of the formula <IMAGE> wherein R<10> represents a hydrogen atom, the methyl or hydroxymethyl group, a protected hydroxymethyl group or a mono-, di- or trihalomethyl group; R<20> represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an alpha -amino acid of the type normally found in proteins or a protected hydroxy-(lower alkyl) or protected guanidino-(lower alkyl) group; R<3> and R<4> each represent a hydrogen atom or a lower alkyl group; R<5> represents a protected amino group; the configuration at the carbon atom designated as (a) is (R) when R<10> represents other than a hydrogen atom and the configuration at the carbon atom designated as (b) is (L), are useful intermediates in the manufacture of therapeutically valuable phosphorus-containing peptide derivatives.

Description

SPECIFICATION Protected Phosphorus-Containing Peptide Derivatives The present invention is concerned with protected phosphorus-containing peptide derivatives.

The protected phosphorus-containing peptide derivatives provided by the present invention are compounds of the general formula

wherein R10 represents a hydrogen atom, the methyl or hydroxymethyl group, a protected hydroxymethyl group or a mono-, di- or trihalomethyl group; R20 represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an aamino acid of the type normally found in proteins or a protected hydroxy-(lower alkyl) or protected guanidino-(lower alkyl) group; R3 and R4 each represent a hydrogen atom or a lower alkyl group; R5 represents a protected amino group; the configuration at the carbon atom designated as (a) is (R) when R10 represents other than a hydrogen atom and the configuration at the carbon atom designated as (b) is (L).

The compounds of formula I are useful intermediates in the manufacture of the therapeutically valuable phosphorus-containing peptide derivatives which form the subject matter of our copening Application No. 7909676 (Serial No. 2 027 433 A).

The term "lower alkyl" is used in this Specification to mean a straight-chain or branched-chain alkyl group which preferably contains up to 8 carbon atoms. Examples of such lower alkyl groups are ethyl, propyl, butyl, tert.butyl, pentyl, hexyl etc. Examples of hydroxy (lower alkyl) groups denoted by R20 are 2hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like. The term "halo" means fluoro, chloro, bromo or iodo, examples of the aforementioned halomethyl groups being chloromethyl, dichloromethyl, trifluoromethyl etc.

When R'O in formula I represents other than a hydrogen atom, the configuration at the carbon atom designated as (a) is (R); that is to say, the configuration which would be obtained by replacing the carboxyl group of a naturally occurring amino acid by a phosphorus moiety.

A preferred class of compounds of formula I comprises those in which R' represents a hydrogen atom or the methyl group. Also preferred are compounds of formula I in which R2 represents a lower alkyl group, especially the ethyl, n-propyl or n-butyi group.

Examples of compounds of formula I hereinbefore are: (1 R)-1-[(N-Benzyloxycarbonyl-L-a- aminobutyryl)amino]-ethylphosphonic acid, (1R)-l -[(N-benzyloxycarbonyl-L norva lyl)amino]-ethylphosphonic acid, (1 R)-i -[(N-benzyloxycarbonyl-L- norleucyl)amino]-ethylphosphonic acid, [(N-benzyloxyca rbonyl-L-a- aminobutyryl)amino]-methyl-phosphonic acid, [(N-benzyloxycarbonyl-L-norleucyl)amino]methyl-phosphonic acid, [(N-benzyloxycarbonyl-L-norvalyl)amino]- methylphosphonic acid, (1R)-l -[(N-benzyloxycarbonyl-w-nitro- L-homoarginyl)-aminoj-ethylphosphonic acid and [(N-benxyloxycarbonyl-w-nitro-L- homoarginyl)amino]-methylphosphonic acid.

The compounds of formula I hereinbefore can be prepared by condensing a compound of the general formula

wherein R10, R3 and R4 have the significance given earlier and the configuration at the carbon atom designated as (a) is (R) when R'O represents other than a hydrogen atom; with a protected amino acid of the general formula

wherein R5 represents a protected amino group; R20 has the significance given earlier and the configuration at the carbon atom designated as (b) is (L).

The protected amino group denoted by R5 in a protected a-amino acid starting material of formula 111 hereinbefore can be any protected amino group which is well-known in peptide chemistry. The amino group is preferably protected with an aralkoxycarbonyl group, particularly the benzyloxycarbonyl group, or the tert.butoxycarbonyl group. However, the amino group can also be protected with, for example, a formyl, trityl, trifluoroacetyl or 2-(biphenylyl)isopropyloxycarbonyl group or can be in the form of a phthalimido group.The protecting group present in a protected hydroxymethyl group R'O or a protected hydroxy-(lower alkyl) group R20 can be any conventional hydroxy protecting group; for example, an aralkoxycarbonyl group (e.g. the benzyloxycarbonyl group), a lower alkanoyl group (e.g. the acetyl, propionyl and like groups), an aroyl group (e.g. the benzoyl group), a lower alkyl group (e.g. the tert.butyl group) or a lower aralkyl group (e.g. the benzyl group).

The condensation of a compound of formula II with a protected a-amino acid of formula Ill can be carried out according to methods known per se in peptide chemistry; for example, according to the mixed anhydride, azide, activated ester, acid chloride, carbodiimide or EEDQ (1ethoxycarbonyl-2-ethoxy-1 2-dihydroquinoline) method.

In one method, a compound of formula II can be condensed with a protected amino acid of formula Ill in which the carboxy group is a mixed anhydride residue formed with an organic or inorganic acid. Suitably, such a protected aamino acid of formula Ill is treated with a tertiary base such as a tri(lower alkyl)amine (e.g.

triethylamine) or N-ethylmorpholine in an inert organic solvent (e.g. tetrahydrofuran, 1,2,dimethoxythane, dichloromethane, toluene, petroleum ether or the like) and the salt obtained is reacted with an appropriate chloroformate (e.g.

a lower alkyl chlorofomate such as ethyl chloroformate or isobutyl chloroformate) at a low temperature. The mixed anhydride thus obtained is then suitably condensed in situ with a compound of formula II.

In another method, a compound of formula Il can be condensed with a protected a-amino acid of formula Ill in which the carboxy group is in the form of an acid azide. This condensation is preferably carried out in an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.

In yet another method, a compound of formula II can be condensed with a protected a-amino acid of formula Ill in which the carboxy group is in the form of an active ester group (e.g. the 4nitrophenyl, 2,4,5-trichlorophenyl or Nhydroxysuccinimide ester group). This condensation is suitably carried out in an inert solvent such as aqueous dimethylformamide or, wherein R3 and R4 in a compound of formula III both represent a lower alkoxy group, also in a lower alkanol such as aqueous ethanol.

In a further method, a compound of formula II can be condensed with a protected amino acid of formula Ill in which the carboxy group is in the form of an acid chloride. This condensation is preferably carried out in the presence of a base and at a low temperature.

In yet a further method, a compound of formula II can be condensed with a protected amino acid of formula Ill in the presence of a carbodiimide (e.g. dicyclohexyicarbodiimide) or EEDQ. This condensation can be carried out in an inert organic solvent (e.g. methylene chloride or a lower alkanol such as methanol, ethanol etc) at room temperature or at a temperature below room temperature.

The starting materials of formulae II and Ill are known compounds or can be prepared in analogy to the preparation of known compounds.

The following Examples illustrate the manner in which the compounds of formula I provided by the present invention can be prepared: Example 1 (i) 5.0 g (48 mmol) or L-a-aminobutyric acid were dissolved in 24 ml of 2-N sodium hydroxide and the solution was cooled to OOC. 12.3 g (72 mmol) of benzyl chloroformate and 18 ml (72 mmol) of 4-N sodium hydroxide were added alternately and portionwise while stirring over a period of 0.5 hour in such a manner that the temperature did not exceed 1 00C and that the pH was maintained at ca 11. The mixture was allowed to reach room temperature slowly and was then stirred overnight. The mixture was extracted with 50 ml of diethyl ether and the organic and aqueous phases were separated.The aqueous phase was acidified to pH 2 with 5-N hydrochloric acid to give an oily mixture. This mixture was extracted with two 75 ml portions of diethyl ether. The extracts were dried over sodium sulphate and evaporated to give 9.6 g of a colourless oil. This oil was dissolved in 10 ml of ethyl acetate and 100 ml of petroleum ether (boiling point 400--600C) were added to give an oily solution which was left to stand at OOC. There was obtained a white crystalline precipitate which was filtered off, washed with petroleum ether and dried to give 8.40 g t73%) of N benzyloxycarbonyl-L-a-aminobutyric acid of melting point 760--780C; [(g]20=~10.9 ; [cz]3 65=20.3 (c=1 % in ethanol).

(ii) 8.30 g (35 mmol) of N-benzyloxycarbonyl L-cz-amino-butyric acid and 4.02 g (35 mmol) of N-hydroxysuccinimide were dissolved in 75 ml of dimethoxyethane while stirring and the solution was cooled to OOC. 7.94 g (38.5 mmol) of dicyclohexylcarbodiimide were added and the mixture was stirred at OOC for 2 hours and then left to stand at OOC overnight. The solid byproduct was filtered off. The filtrate was evaporated to give N-benzyloxycarbonyl-L-a-a m inobutyric acid N-hydroxysuccinimide ester in the form of a stiff gum which was used without further purification.

(iii) 4.38 g (35 mmol) of (1 R)-1aminoethylphosphonic acid were dissolved in a mixture of 40 ml of water, 7.07 g (70 mmol) of triethylamine and 40 ml of dimethylformamide while stirring. The resulting solution was cooled to OOC and a solution of 35 mmol of N benzyloxycarbonyl-L-a-aminobutyric acid Nhydroxysuccinimide ester in 40 ml of dimethylformamide was rapidly added dropwise.

The mixture was stirred at OOC and was then allowed to come to room temperature while stirring overnight. The mixture was filtered to remove a small amount of solid. The filtrate was evaporated under an oil-pump vacuum. The residue was dissolved in a mixture of 30 ml of methanol and 10 ml of water and passed down a column of cation exchange resin (B.D.H., Zerolit 225,SRC 13,RS03H; 150 g; freshly regenerated in the acid cycle), elution being carried out with the same solvent. The acid eluate was collected and evaporated to give a slightly gummy white solid. This solid was triturated with 100 ml of diethyl ether and the diethyl ether was decanted off. The residual solid was dissolved in a mixture of 100 ml of methanol and 50 ml of water and the resulting solution was titrated to pH 4.5 with 4-N aqueous benzylamine (titre 8.0 ml; theory 8.75 ml). The mixture solidified towards the end of the titration, and the precipitate was filtered off, washed with water and dried to give 8.84 g of the monobenzylamine salt of (1 R)-1-[(N benzyloxycarbonyl-L-α-aminobutyryl)amino]- ethylphosphonic acid of melting point 228 - 231 C (decomposition); [a]20=-3l 30; [a]328%=-1 050 (c=1 % in glacial acetic acid).

Example 2 (i) 5.0 g (42.5 mmol) of L-norvaline were treated with 10.2 g (60 mmol) of benzyl chloroformate and sodium hydroxide in the manner described in Example 1(i). The crude oily product was crystallised from a mixture of 10 ml of diethyl ether and 20 ml of petroleum ether (boiling point 400--600C) to give 8.2 g (77% of N-benzyloxycarbonyl-L-norvaline of melting point 850--870C; [a]20--9 90; [a]230= 26.50 (c=1% in ethanol).

(ii) In a manner analogous to that described in Example 1 (ii), from 8.1 g (32 mmol) of N benzyloxycarbonyl-L-norvaline, 3.68 g (32 mmol) of N-hydroxysuccinimide and 7.21 g (35 mmol) of dichlorohexylcarbodiimide there was obtained, after trituration of the oily product with 25 ml of ethanol, a white crystalline product. Addition of 25 ml of petroelum ether (boiling point 400-- 600C) and filtration gave 9.82 g of nbenzyloxyca rbonyl-L-norvaline Nhydroxysuccinimide ester which was used directly in the next step. A purified sample melted at 950-970C and showed an optical rotation [aC]D0=35.1 (c=1% in ethanol).

(iii) In a manner analogous to that described in Example 1 (iii), from 9.82 g (28 mmol) of N benzyloxycarbonyl-L-norvaline Nhydroxysuccinimide ester and 3.75 g (30 mmol) of (1 R)-1-aminoethylphosphonic acid, but carrying out the titration with a mixture of 150 ml of methanol and 30 ml of water in place of diethyl ether, there were obtained 7.61 g of the monobenzylamine salt of (1 Fl)-1-[(N- benzyloxycarbonyl-L-norvalyl)a mino]ethylphosphonic acid of melting point 2250-- 2300C (decomposition); [α]D20=-29.9 ; [a]32065=-98 .80 (c=1 % in acetic acid).Evaporation of the filtrate and trituration of the residue with 100 ml of hot water followed by filtration and washing with ethanol and then with diethyl ether gave a second crop of 1.99 g of the monobenzylamine salt of (1R)-1-[(N- benzyloxycarbonyl-L-norvalyl)amino]- ethylphosphonic acid of melting point 2312340C (decomposition); [α]D20=-29.7 ; [a]326%=-99.20 (c=1% in acetic acid). The total yield was 9.60 g (73%).

Example 3 (i) 5.0 g (38 mmol) of L-norleucine were treated with 9.7 g (57 mmol) of benzyl chloroformate and sodium hydroxide in a manner analogous to that described in Example 1(i). The product, N-benzyloxycarbonyl-L-norleucine, was isolated in the form of an oil which was used in the process without crystallisation.

(ii) In a manner analogous to that described in Example 1 (ii), from ca 38 mmol of N benzyloxycarbonyl-L-norleucine, 4.38 g (38 mmol) of N-hydroxysuccinimide and 8.65 g (42 mmol) of dicyclohexylcarbodiimide there were obtained, after trituration of the crude oily product with 100 ml of diethyl ether, 7.47 g of Nbenzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester in the form of a crystalline solid of melting point 82 -84 C [a] D20=20 .7 (c=1 % in acetone).

(iii) In a manner analogous to that described in Example 1 (iii), from 7.40 g (20.5 mmol) of Nbenzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester and 2.56 g (20.5 mmol) of (1 Fl)-1 -aminoethylphosphonic acid, but carrying out the ion exchange step in methanol/water (5:1) instead of methanol/water (3:1), there was obtained, after evaporation and trituration of the crude product with ether, a solid which was digested with 1 50 ml of hot water, cooled and filtered to give 5.64 g (74%) of (1 R)-1 [(N-benzyloxycarbonyl-L-norleucyl)-amino]- ethylphosphonic acid of melting point 192 - 1 940C (decomposition); [α]D20=-37.8 ; [a [a]32065=-1 26.50 (c=0.5% in acetic acid).

Example 4 In a manner analogous to Example 1 (ii) and Example 2(iii), from 17.4 g (50 mmol) of Nbenzyloxycarbonyl-L-norvaline Nhydroxysuccinimide ester and 5.55 g (50 mmol) of amino-methylphosphonic acid, but carrying out the titration with benzylamine in a mixture of 250 ml of methanol and 50 ml of water, there were obtained 17.3 g of the crude monobenzylamine salt of the desired product, of melting point 195198 (decomp) (Crop 1). Evaporation of the filtrate and recrystallisation of the residue from a mixture of methanol (80 ml) and water (20 ml) gave a further 2.19 g of essentially pure product (tlc), having a melting point of 1 80- 1850 (dec). The total yield was 19.5 g (86%).

Recrystallisation of a 0.5 9 sample of Crop 1 from 10 ml of hot water gave a crop of 0.39 g of the pure monobenzylamine salt of (N benzyloxycarbonyl-L- norvalyl)aminomethylphosphonic acid of melting point 203205 (dec); [α]D20=-8.2 ; [a]23085=-21 30 (c=0.5%, in acetic acid).

Example 5 N-Benzyloxycarbonyl-L-norvaline (45.4 g 0.181 m) was stirred in methylene dichloride solution (200 mls) as dimethyl aminomethylphosphonate hydrochloride (31.76 g, 0.181 m) was added. The resulting suspension was cooled to -12 C as dry triethylamine (25.3 ml 0.181 m) was added dropwise. After the addition was complete, the cold mixture was stirred for 15 minutes before E.E.D.Q. (56.8 g 0.23 m) in methylene dichloride (100 ml) was added rapidly. This mixture was stirred cold for 2 hours, and then stirred at room temperature over the weekend.

The mixture was washed with water (100 ml) then with 1 N hydrochloric acid (4 times, with 100 mi each time). The total acid wash was backextracted with methylene dichloride (2x50 ml).

The combined organic solution was washed again with water (100 ml) and finally with 15% KHCO3 solution (3x 100 ml), then dried over anhydrous sodium sulphate. The solution was filtered and evaporated down. The residual oil was reevaporated down with benzene, to give a residue weighing 78.139.

The first signs of crystallisation were seen at this time. The oil was triturated with anhydrous ether (200 ml) in which it dissolved. Very soon crystallisation spread throughout the solution. The solution was refrigerated for 1 hour, the solid was filtered off, washed with ether and dried to constant weight in vacuo. There was obtained 58.2 g of a material having a melting point of 77--800C.

This was taken up in hot ethyl acetate (200 ml) and the solution filtered. To the cooled filtrate was added ether (200 ml). The mixture was seeded and refrigerated overnight. The solid was filtered off, washed with ether and dried in vacuo to give 50.64 g of a residue of m.p. 82--840C. This was [(N-benzyloxycarbonyl-L-norvalyl-amino] dimethylphosphonate.

Example 6 (a) L-Nitro-homoarginine (2.33 9, 10 mmol, m.p. 227--2300 (dec)) was treated with 3.41 g (20 mmol) of benzyl chloroformate and sodium hydroxide in the manner described in Example 1(i). The crude oily product was extracted from the acidified solution with ethyl acetate (twice with 100 ml) instead of with diethyl ether. The crude oily product, N-benzyloxycarbonyl-w-nitro- L-homoarginine, obtained after drying over sodium sulphate and evaporation, was obtained as a gum which was used in the following step without further purification.

(b) In a manner analogous to that described in Example 1 (ii), but using dimethyl formamide (50 ml) as solvent from ca 4.2 9 (approx. 10 mmol) of the crude N-benzyloxycarbonyl-w-nitro-L- homoarginine (obtained as above), 1.15 g (10 mmol) of N-hydroxysuccinimide and 2.27 9 (11 mmol) of dicyclohexylcarbodiimide there was obtained after removal of 1.73 g of dicyclohexylene and evaporation of the filtrate, the crude product N-benzyloxycarbonyl-w-nitro- L-homoarginine N-hydroxysuccinimide ester as a yellow oil was used in the next step without further purification.

(c) In a manner analogous to that described in Example 1 (iii) from ca 10 mmol of N benzyloxycarbonyl-c.)-nitro-L-homoarginine Nhydroxysuccinimide ester and 1.25 9 (10 mmol) of (1R)-1-aminoethylphosphonic acid, but carrying out the treatment with ion exchange resin RSO3H in 5:1 MeOH:H2O instead of 3:1. The acid eluate was evaporated and partitioned between water (300 ml) and ethyl acetate (150 ml) when some insoluble material was obtained.

This was filtered off and dried to give 1.36 9 of crude product having a m.p. of 190193 (dec), as characterised by tic and N.M.R. (Crop 1).

The filtrate solvent layers were separated, the aqueous layer was evaporated to dryness and the residue was triturated with acetone (50 ml) to give a white precipitate. This precipitate was filtered off and washed with acetone, and dried to give a further 1.43 (m.p. 1 84--80 (dec)) of the product, (1 R)- 1 -[(N-benzyloxycarbonyl-w-nitro-L- homoarginyl)amino]-ethylphosphonic acid (Crop 2).

Example 7 (i) In a manner analogous to that described in Example 1 (iii), from a solution of 45 mmol of N benzyloxycarbonyl-L-a:-aminobutyric acid Nhydroxysuccinimide ester in 40 ml dimethylformamide and 4.44 9 (40 mmol) of aminomethyl-phosphonic acid, but using methanol:water of 4:1 instead of 2:1, there were obtained 14.1 9 of the monobenzylamine salt of [(N-benzyloxycarbonyl-L-a-a m inobutyryl)amino]- methylphosphonic acid of m.p. 185--1950 (dec).

Evaporation of the filtrate and recrystallisation of the residue from a mixture of 50 ml of water and 50 ml of methanol gave as a white crystalline precipitate a further 1.6 9 of product of m.p.

205208 (dec). [a]020=-6.1 0; [a]23065=-21 .10 (C=0.51 %, CH3COOH).

Example 8 (i) In a manner analogous to that described in Example 3(iii), from 2.52 g (7 mmol) of N benzyloxycarbonyl-L-norleucine Nhydroxysuccinimide ester and 0.78 9 (7 mmol) of aminomethylphosphonic acid, but carrying out the ion exchange step in methanol/water of 2:1 instead of 5:1 and titrating the acid eluate directly with benzylamine (omitting evaporation and trituration with ether followed by dissolving in methanol/water again), there were obtained, after stirring with 100 ml of acetone, 0.56 9 of the monobenzylamine salt of [(N-benzyloxycarbonyl-L norleucyl)amino]-methylphosphonic acid having a m.p. of 185189 (dec). Evaporation of the filtrate and trituration with 50 ml of diethyl ether gave a further 1.9 g of product, m.p. 170--1800 (dec).

Claims

1. Compounds of the general formula

wherein R10 represents a hydrogen atom, the methyl or hydroxymethyl group, a protected hydroxymethyl group or a mono-, di- or trihalomethyl group; R20 represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an aamino acid of the type normally found in proteins or a protected hydroxy-(lower alkyi) or protected guanidino-(lower alkyl) group; R3 and R4 each represent a hydrogen atom or a lower alkyl group; R5 represents a protected amino group; the configuration at the carbon atom designated as (a) is (R) when R10 represents other than a hydrogen atom and the configuration at the carbon atom designated as (b) and (L).

2. compounds as claimed in claim 1, wherein R1 represents a hydrogen atom or the methyl group.

3. Compounds as claimed in claim 1 or claim 2, wherein R2 represents a lower alkyl group.

4. Compounds as claimed in claim 3, wherein R20 represents the ethyl, n-propyl or n-butyl group.

4. Compounds as claimed in claim 3, wherein R3 represents the ethyl, n-propyl or n-butyl group.

5. (1R)-l -[(N-Benzyloxycarbonyl-L-a- aminobutyryl)amino]-ethylphosphonic acid.

6. (1R)-l-[(B-Benzyloxycarbonyl-l- norvalyl)amino]-ethylphosphonic acid.

7. (1 Fl)-1-[(N-Benzyloxycarbonyl-L- norleucyl)amino]-ethylphosphonic acid.

8. [(N-Benzyloxycarbonyl-L-a- aminobutyryl)amino]-methylphosphonic acid.

9. [(N-Benzyloxycarbonyl-L-norleucyl)amino]methylphosphonic acid.

10. [(N-Benzyloxycarbonyl-L-norvalyl)amino]methylphosphonic acid.

11.(1R)-l -[(N-Benzyloxycarbonyl-co-nitro-L- homoarginyl)-amino]-ethylphosphonic acid.

12. [(N-Benzyloxycarbonyl-cl)-nitro-L- homoarginyl)amino]-methylphosphonic acid.

New Claims or Amendments to Claims filed on 23-12-81 Superseded Claims New or Amended Claims: Claims 1--4 as attached.

1. Compounds of the general formula

where R'O represents a hydrogen atom, the methyl or hydroxymethyl group, a protected hydroxymethyl group or a mono-, di- or trihalomethyl group; R20 represents a lower alkyl, hydroxy-(lower alkyl) or guanidino-(lower alkyl) group other than the characterising group of an aamino acid of the type normally found in proteins or a protected hydroxy-(lower alkyl) or protected guanidino-(lower alkyl group; R3 and R4 each represent a hydrogen atom or a lower alkyl group; R5 represents a protected amino group; the configuration at the carbon atom designated as (a) is (R) when R'O represents other than a hydrogen atom and the configuration at the carbon atom designated as (b) is (L).

2. Compounds as claimed in claim 1, wherein R'O represents a hydrogen atom or the methyl group.

3. Compounds as claimed in claim 1 or claim 2, wherein R20 represents a lower alkyl group.