CA1332943C - Process for preparing perhydrothiazepine derivatives - Google Patents

Abstract

Perhydrothiazepine derivatives of formula (I):

(I) (in which R1 represents an optionally substituted alkyl group, R2 represents a carboxy-protecting group or hydrogen and R4 and R5 are hydrogen, alkyl, cycloalkyl, aryl or heterocyclic) can be prepared by reacting together compounds of formulae (II) and (III):

(II)

Description

1 3 ~
-PROCESS FOR PREPARING PERHYDROTHIAZEPINE
DERIVATIVES

The present invention relates to a novel process for preparing a known class of perhydrothiazepine derivatives.

The perhydrothiazepine derivatives which may be prepared by the process of the present invention are those compounds of formula (I):

COOR2 S R~
R--CH HH ~N~ RS

in which:

R represents an alkyl group, an alkyl group having a cycloalkyl substituent or an aralkyl group:

R2 repre~ents a carboxy-protecting group or a hydrogen 1 ~3 3 2 ;~ ~;r ~3 atom; and R and R are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group.

Compounds of formula (I) are disclosed in European Patent Publication No. 161,801, which was published after the priority date, but before the filing date, hereof. This prior European Patent Publication describes the valuable activity of these compounds as inhibitors of the activity of angiotensin converting enzyme (hereinafter referred to, as is conventional, as "ACE"). As a result of their ACE inhibitory activity, these compounds are useful as antihypertensive agents and have shown considerable promise for such use.

We have now discovered a new and improved process for producing the compounds of formula (I).

Thus, in accordance with the present invention, the compounds of formula (I) and salts and esters thereof are prepared by reacting a compound of formula (II):

~L 3 ~ 3 cOOR2a Rl_CH--oS02R3 (II

(in which R is as defined above, R2 represents a carboxy-protecting group and R represents an aryl group or a haloalkyl group) with a compound of formula (III):

H2 N ~S X R 5 (in which R4 and R5 are as defined above), to give a compound of formula (IV):

j 1 3 ~ 2 - 1 ~ 3 cOOR2a ~ S \~ Rl Rl--CH--NH~ )~ 5 (IV~

o H

i hi h Rl R2a R4 and R5 are as defined above); reacting said compound of formula (IV) with a compound of formula (V):

XCH2COOR (V) (in which X represents a halogen atom and R
represents a carboxy-protecting group) in the presence of a base, to give a compound of formula (VI):

cOOR2a S R~
Rl- CH--NH~ 5 ( V I

(in which R , R , R , R and R6 are as ~ 33~3 s defined above); if necessary, removing the carboxy-protecting group R and optionally R to afford said compound of formula (I); and optionally salifying and/or esterifying the product.

It is a significant advantage of the present invention that the starting materials of formulae (IV) and notably (III) may be optically active and that the synthesis reactions of the present invention take place stereospecifically, so as to provide an optically active final product of formula (VI) or (I). It is well known that, where a compound can exist in the form of two or more stereoisomers (especially optical isomers), one of those isomers can normally be expected to have greater activity than the other(s). Furthermore, it is believed that the process of the present invention can give a higher final yield than the prior processes. A further advantage, as compared with the prior process, is that it enables the desired final product to be obtained from the starting material in fewer steps.

In the compounds of formulae (I), (II), (IV) and (VI), where Rl represents an alkyl group, this may be a straight or branched chain alkyl group which has from 1 to 10, preferably from 1 to 9, carbon atoms, and examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, -f~ ~3 s fJ ~ '~

neopentyl, hexyl, octyl and nonyl groups.

Where Rl represents an alkyl group having a cycloalkyl substituent, the alkyl part is preferably a Cl-C4, more preferably Cl or C2, alkyl group, whilst the cycloalkyl part may have from 3 to 8, more preferably from 5 to 7, ring carbon atoms. Examples of such cycloalkyl-substituted alkyl groups include the cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and 2-cycloheptylethyl groups. The cycloalkyl part of the cycloalkyl-substituted alkyl group may be unsubstituted or it may be substituted as defined below.

Where R represents an aralkyl group, the alkyl part is preferably a Cl-C4, more preferably Cl-C3 alkyl, group (e.g. methyl, ethyl or propyl), whilst the aryl part is a carbocyclic aryl group which preferably has from 6 to 10 ring carbon atoms and may comprise a single or multiple (fused) ring system.
Preferred examples of such aryl groups include the phenyl, l-naphthyl and 2-naphthyl groups. The aryl part of the aralkyl group may be attached to the alkyl part by a single bond or by two bonds, one to each of two carbon atoms of the alkyl part, to form a partially hydrogenated ring. Examples of such aralkyl groups include the benzyl, phenethyl, l-naphthylmethyl, ~ ~h~

2-(1-naphthyl)ethyl, 2-naphthylmethyl, 2-(2-naphthyl)ethyl and 2-indolyl groups. The aryl part of the aralkyl group may be unsubstituted or it may be substituted as defined below.

Where the aforementioned cycloalkyl part of the cycloalkyl-substituted alkyl group or the aryl part of the aralkyl group is substituted, it may have from 1 to 3 substituents selected from: Cl-C4 alkyl groups, such as the methyl, ethyl, propyl, isopropyl, butyl, iso-butyl and t-butyl groups; Cl-C4 alkoxy groups, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups; halogen atoms, such as the fluorine, chlorine and bromine atoms; and Cl-C4 alkylthio groups, particularly the methylthio or ethylthio groups. Where more than one substituent is present, these may be the same or different.

In the compounds of formulae (I), (II), (IV) and (VI), where R or R represents a carboxy-protecting group, the nature of such a group is not critical to the invention and any carboxy-protecting group, preferably ester-forming group, commonly known in the art may equally be employed in the present invention. The compound of formula (I), in which R2 represents a carboxy-protecting group, may be employed as such for therapeutic treatment, in which case it is ~. 3 ~

desirable that the protecting group should not have any adverse effect upon the compound, i.e. it should not increase the toxicity (or unacceptably increase the toxicity) or reduce the activity (or unacceptably reduce the activity) in vivo as compared with the free acid.
It is particularly desirable, in that case, that the carboxy-protecting group R2 should be hydrolizable in vivo to give the free acid. Alternatively, however, if the compound of formula (I) is not to be administered therapeutically as such, for example if the protecting group R is to be removed, so that the corresponding free acid (or a salt thereof) is to be administered, or if the compound of formula (I) is merely to serve as an intermediate in the preparation of other active compounds, then the nature of the protecting group R2 is even less critical and its nature can be dictated merely by considerations of convenience in the reaction.

However, it is particularly preferred that R2 should represent an ester group which is hydrolysable in vivo and that the other carboxylic acid group should be free, as almost all of the resulting monoesters can show remarkably improved bioavailability as a result of its conversion to the active dicarboxylic acid _ vivo.

Preferred groups which may be represented by R2 or R2a include: Cl-C10, preferably Cl-C6, alkyl 1 3 ~

groups, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl groups;
aralkyl groups in which the aryl part is a C6-C10 carbocyclic aryl group and the alkyl part is a Cl-C6 alkyl group, preferably a Cl-C4 alkyl group, such as the benzyl, diphenylmethyl, l-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl), 2-(1,2,3,4-tetrahydronaphthyl) and phthalidyl groups; a C6-C14, preferably C6-C10, carbocyclic aryl group, such as a phenyl, l-naphthyl or 2-naphthyl group; or a silyl group, particularly a trialkylsilyl group where each alkyl part is a Cl-C6, preferably Cl-C4, alkyl group, such as the trimethylsilyl and t-butyldimethyl-silyl groups. Any of the above groups may be substituted or unsubstituted.

Where the above groups are substituted, they preferably have from 1 to 3 substituents, which are preferably Cl-C4 alkyl groups, halogen atoms, hydroxy groups, Cl-C4 alkoxy groups, acyloxy groups (particularly aliphatic and carbocyclic aromatic carboxylic acyloxy groups), oxo groups, carboxyl groups, alkoxycarbonyl groups (particularly those where the alkoxy part is a Cl-C6 alkoxy group),`
alkoxycarbonyloxy groups (particularly those where the alkoxy part is a Cl-C6 alkoxy group), acylamino groups (particularly aliphatic and carbocyclic aromatic ~ 3 ~

carboxylic acylamino groups), nitro groups, cyano groups, amino groups, alkylamino groups (particularly where the alkyl group is a Cl-C6, preferably Cl-C4, alkyl group), dialkylamino groups (particularly those where the two alkyl groups, which may be the same or different, are each Cl-C6, preferably Cl-C4, alkyl groups), alkylthio groups (particularly those where the alkyl part is a Cl-C6, preferably Cl-C4, alkyl group), arylthio groups (where the aryl part is a C6-C10 carbocyclic aromatic group, which may be unsubstituted or substituted as defined herein), alkylsulphonyl groups (particularly those where the alkyl part is a Cl-C6, preferably Cl-C4, alkyl group), arylsulphonyl groups (where the aryl part is a C6-C10 carbocyclic aromatic group, which may be unsubstituted or substituted as defined herein) and 2-oxo-1,3-dioxolen-4-yl groups (which may be unsubstituted or substituted as defined herein, particularly by aryl, e.g. phenyl, or Cl-C6, preferably Cl-C4 and more preferably Cl or C2, alkyl groups).

Examples of such substituted protecting groups include the: haloalkyl groups, such as the 2,2,2-trichloroethyl and 2-iodoethyl groups;
hydroxyalkyl groups, such as the 2-hydroxyethyl and 2,3-dihydroxypropyl groups; alkoxyalkyl and alkoxyaralkyl groups, such as the methoxymethyl, (2-methoxyethoxy)methyl and ~-methoxybenzyl groups;
acyloxyalkyl groups, such as the acetoxymethyl, l-acetoxyethyl and pivaloyloxymethyl groups; the phenacyl group; alkoxycarbonylalkyl groups, such as the methoxycarbonylmethyl group; alkoxycarbonyloxyalkyl groups, such as the ethoxycarbonyloxymethyl and l-(ethoxycarbonyloxy)ethyl groups; nitroaralkyl groups, such as the P-nitrobenzyl group; cyanoalkyl groups, such as the l-cyanoethyl and 2-cyanoethyl groups;
alkylthioalkyl groups, such as the methylthiomethyl and ethylthiomethyl groups; arylthioalkyl groups, such as the phenylthiomethyl group; alkylsulphonylalkyl groups, such as the 2-methanesulphonylethyl and 2-ethanesulphonylethyl groups; arylsulphonylalkyl groups, such as the benzenesulphonylethyl group; and 2-oxo-1,3-dioxolen-4-ylalkyl groups, particularly 2-oxo-1,3-dioxolen-4-ylmethyl groups, such as the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl groups.

In the compounds of formula (II), the nature of the group represented by R3 is not critical to the invention, as the group is removed in the course of the reaction and thus does not appear in the final product.
R3 can be a haloalkyl group having from 1 to 4, more preferably 1 or 2 and most preferably 1, carbon atom.

~ 3~3~3 The number of halogen atoms may vary widely, depending upon the number of available substitutable positions and may range from 1 to complete perhalogenation. Preferred examples of haloalkyl groups which may be represented by R include the trichloromethyl, trifluoromethyl and fluoromethyl groups. Where R represents an aryl group, this is a C6-C10 carbocyclic aromatic group which is unsubstituted or has one or more substituents (for example any of the substituents hereinbefore described in relation to aryl groups). Examples include the phenyl, l-naphthyl and 2-naphthyl groups and such groups having one or more (for example from 1 to 3) nitro, fluorine, chlorine or bromine substituents, for example the P-nitrophenyl, o-nitrophenyl, m-nitrophenyl, 2,4-dinitrophenyl, 4-chloro-3-nitrophenyl, ~-bromophenyl, P-fluorophenyl and 2,5-dichlorophenyl groups.

In the compounds of formulae (I), (III), (IV) and (VI), where R4 or R5 represents an alkyl group, this is preferably a Cl-C10, more preferably Cl-C8, alkyl group, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl or octyl group. Where R or R
represents a cycloalkyl group, this is preferably a C3-C8, more preferably C5-C7, cycloalkyl group, for example the cyclopentyl, cyclohexyl or cycloheptyl ~ ~2~3 group. Where R or R represents an aryl group, this is a C6-C10 carbocyclic aryl group, which may be unsubstituted or substituted as defined above in relation to any of the substituted aryl groups hereinbefore mentioned, for example the phenyl, l-naphthyl or 2-naphthyl group. Where R or R
represents a heterocyclic group, this has from 5 to 14, preferably from 5 to 10, ring atoms, of which from 1 to 5, preferably from 1 to 3, are nitrogen and/or oxygen and/or sulphur hetero-atoms and examples of such groups include the furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl, isoquinolyl and indolyl groups.

Any of these alkyl, cycloalkyl, aryl and heterocyclic groups represented by R4 and R5 may be unsubstituted or they may be substituted. Where they are substituted, there is no particular upper limit on the number of substituents, which will be dictated largely by the number of substitutable positions and possibly by steric constraints; in general, however, from 1 to 3 substituents are preferred. Examples of suitable substituents include: Cl-C6, preferably Cl-C4, alkyl groups, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl groups;
aralkyl groups (in which the aryl part is a C6-C10 carbocyclic aromatic group and the alkyl part is a 1 3 ~

Cl-C4, preferably Cl or C2, alkyl group), for example the benzyl or phenethyl groups; C6-C10 carbocyclic aryl groups, for example the phenyl, l-naphthyl or 2-naphthyl groups; hydroxy groups;
Cl-C6, preferably Cl-C4, alkoxy groups, for example the methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy groups; aralkyloxy groups (in which the aryl and alkyl parts are as defined above in relation to aralkyl groups), for example the benzyloxy group;
C6-C10 carbocyclic aryloxy groups, for example the phenoxy group; halogen atoms, for example the fluorine, chlorine or bromine atoms; the nitro group; the cyano group; the carboxy group; alkoxycarbonyl groups in which the alkoxy part is a Cl-C6, preferably C1-C3, alkoxy group, for example the methoxycarbonyl or ethoxycarbonyl groups; the amino group; alkylamino groups, in which the alkyl part is a Cl-C4 alkyl group, for example the methylamino or ethylamino groups;
dialkylamino groups, in which each alkyl part, which may be the same or different, is a Cl-C4 alkyl group, for example the dimethylamino or diethylamino groups;
acylamino groups (in which the acyl part is preferably an aliphatic or carbocyclic aromatic carboxylic acyl group), for example the acetamido or benzamido groups;
the carbamoyl group; mono- and di-alkylcarbamoyl groups, in which the or each alkyl part is a Cl-C4 alkyl group, for example the dimethylcarbamoyl or -- ~ 3 ~ ~ T~

diethylcarbamoyl groups; Cl-C6, preferably Cl-C4, alkylthio groups, for example the methylthio or ethylthio groups; C6-C10 carbocyclic arylthio groups, for example the phenylthio group; Cl-C6, preferably Cl-C4, alkylsulphonyl groups, for example the methanesulphonyl or ethanesulphonyl groups; and C6-C10 carbocyclic arylsulphonyl groups, for example the benzenesulphonyl group.

In the compounds of formulae (V) and (VI), the carboxy-protecting group represented by R may be any one of the groups hereinbefore described in relation to R2 and R . It is generally preferred that the two carboxy-protecting groups, R2, where it represents such a group, (or R ) and R , should be selected from different classes of such group, so that the two groups may, if desired, be removed independently.

In the compound of formula (V), the halogen atom represented by X is preferably a chlorine, bromine or iodine atom.

Any compound of formula (II) necessarily has at least one asymmetric carbon atom in its molecule. When this compound of formula (II) reacts with the compound of formula (III), a Walden inversion takes place at this asymmetric carbon atom. Since the corresponding carbon ~1 3 ~ w .~ ~r J

atom in the compound of formula (I) is preferably in the S-configuration, where the compound is to be used as an ACE inhibitor, we therefore prefer that the asymmetric carbon atom in the compound of formula (II) should be in the R-configuration.

Preferred examples of the compounds of formula (I), which may be prepared by the process of the present invention, are given in the following Table. The following abbreviations are used in this Table:

Bu Butyl iBu isobutyl Bz benzyl Et ethyl Fur furyl cHx cyclohexyl Np naphthyl Oc octyl Ph phenyl cPn cyclopentyl _Pr isopropyl Thi thienyl Thiz 1,3-thiazolyl -s l ~ 3 Table Cpd R1 R2 R4 R5 No.

1. 2 2 Et 2-Thi H
2PhCH2CH2 Bu 2-Thi H
3PhCH2CH2 _Bu 2-Thi H
4PhCH2CH2 Bz 2-Thi H
5PhCH2CH2 Et 3-Thi H
6 - 2 2 Bu 3-Thi H
7PhCH2CH2 _Bu 3-Thi H
8PhCH2CH2 Bz 3-Thi H
9PhCH2CH2 Et 2-Fur H
10 2 2 Bu 2-Fur H
11 2 2 _Bu 2-Fur H
12 2 2 Bz 2-Fur H
13 2 2 Et 3-Fur H
14 2 2 Bu 3-Fur H
15 2 2 Et 4-Thiz H
16 2 2 Bu 4-Thiz H
17 Oc Et 2-Thi H
18 Oc Et 3-Thi H
19 _Bu Et 2-Thi H
20 _Bu Et 3-Thi H

~ ~ 3 ~ ~ ~ J

Table (cont) Cpd. Rl R2 R4 R5 No 212-cHxEt Et 2-Thi H
222-cHxEt Et 3-Thi H
23 2 2 Et Ph H
24 2 2 Bu Ph H
25 2 2 Et _Pr H
26 2 2 Bu _Pr H
27 2 2 Et H 2-Thi 28 2 2 Bu H 2-Thi 29 2 2 _Bu H 2-Thi 30PhCH2CH2 Bz H 2-Thi 31 2 2 Et H 3-Thi 32 2 2 Bu H 3-Thi 33PhCH2CH2 Et H 2-Fur 34PhCH2CH2 Bu H 2-Fur 35PhCH2CH2 Et H cPn 36 2 2 Et H cHx 37PhCH2CH2 Et H Me 38 2 2 Et H _Pr 39PhCH2CH2 Et l-Np H
40PhCH2CH2 Bu 1-Np H
41 2 2 Bz l-Np H
42 2 2 Et 2-Np H

q ~

Table (cont) Cpd. R R2 R4 R5 No 43PhCH2CH2 Bu 2-Np H
44PhCH2CH2 Bz 2-Np H
45PhCH2CH2 Et H Ph 46 2 2 Bu H Ph The first stage in the process of the present invention comprises the condensation of the haloalkylsulphonyloxy or arylsulphonyloxy compound of formula (II) with the aminothiazepine of formula (III).
This reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it does not interfere with the reaction. Suitable solvents include, for example: hydrocarbons, which can be aliphatic, cycloaliphatic or aromatic, for example hexane or benzene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane; esters, such as ethyl acetate; ketones, such as acetone: amides, such as dimethylformamide, dimethylacetamide, hexamethyl-phosphoric triamide or _-methyl-2-pyrrolidine; and dimethyl sulphoxide.

The reaction can also be assisted by the presence of -~ 3 ~
J .~j '* ') a sulphonic acid scavenger. There is no particular restriction on the nature of the sulphonic acid scavenger employed and examples include: fluorides, such as potassium fluoride or cesium fluoride; alkali metal and alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate;
alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate; alkali metal hydrides, such as sodium hydride or lithium hydride; and organic bases, such as triethylamine, pyridine, picoline or tetraethylammonium hydroxide. If the reaction is to be effected in two phases, an aqueous phase and a phase comprising a water-immiscible solvent (such as methylene chloride or chloroform), an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, can also be employed as the sulphonic acid scavenger. Where a two-phase system is to be employed, a phase-transfer catalyst, such as tetrabutylammonium bromide or benzyltriethylammonium iodide should also be employed.

The reaction will take place over a wide range of temperatures and the precise temperature chosen is not critical to the invention. We generally prefer to carry out the reaction at a temperature within the range from -20C to +120C. The time required for the reaction may vary widely, depending upon many factor6, notably the reaction temperature, the solvent and the nature of the -~ 3 3 ~

sulphonic acid scavenger employed, but, at a temperature within the suggested range, a period of from 1 hour to 5 days will normally suffice.

After completion of the reaction, the resulting compound of formula (IV) can be separated from the reaction mixture by conventional means. For example, a suitable recovery technique comprises: adding an organic solvent, such as ethyl acetate, to the reaction mixture;
washing the organic layer with water and then drying it;
and evaporating off the solvent to give the desired product. If necessary, this product can be further purified by such conventional techniques as recrystallization or the various chromatography techniques, notably column chromatography.

As already mentioned, this reaction involves a Walden inversion at the asymmetric carbon atom (the carbon atom to which the sulphonyloxy group is attached) in the compound of formula (II). Accordingly, where the compound of formula (II) has the R-configuration, the product of formula (IV) has the S-configuration at this carbon atom. On the other hand, where the starting material of formula (II) has the S-configuration at this carbon atom, the product has the R-configuration at this carbon atom.

~ 3 ~ 2 ~ ~ ~

The next step in the process of the invention comprises the N-alkylation of the compound of formula (IV) with the haloacetic acid derivative of formula (V). This reaction is preferably effected in the presence of a solvent and also preferably in the presence of a base. The nature of the solvent employed is not critical to the invention, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example: hydrocarbons, which may be aliphatic, cycloaliphatic or aromatic, such as hexane or benzene; halogenated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane; esters, such as ethyl acetate; ketones, such as acetone; amides, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide;
and dimethyl sulphoxide. Suitable bases include, for example: alkali metal hydrides, such as sodium hydride, lithium hydride or potassium hydride; alkyl-alkali metals, such as butyllithium; alkali metal amides, such as lithium diisopropylamide, lithium dicyclohexylamide or lithium bis(trimethylsilyl)amide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and amines, such as triethylamine, triethylenediamine, 1,5-diazabicyclo[4.3.0]nonene-5 or 1,8-diazabicyclo[5.4.0]undecene-7. Where the reaction is carried out in a two-phase system comprising an aqueous phase and a phase comprising a water-immiscible solvent (such as methylene chloride or chloroform), an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, may also be employed as the base.
Where a two-phase system is used, a phase-transfer catalyst, such as tetrabutylammonium bromide or benzyltriethylammonium iodide is preferably also employed.

The reaction will take place over a wide range of temperatures and the particular reaction temperature chosen is not critical to the present invention. We generally find it convenient to carry out the reaction at a temperature in the range from -20C to +100C. The time required for the reaction may also vary widely, depending upon many factors, notably the reaction temperature and the nature of the solvent and base employed, but a period of from 30 minutes to 24 hours will normally suffice.

After completion of the reaction, the desired compound of formula (VI) can be recovered from the reaction mixture by conventional means. For example, one suitable recovery technique comprises: adding an organic solvent, such as ethyl acetate, and water to the reaction mixture and then separating the organic layer;
washing the organic layer with water and drying it; and 1~2 ~J~

then evaporating off the solvent, to give the desired product. This product may, if necessary, be further purified by such conventional techniques as recrystallization or the various chromatography techniques, notably column chromatography.

The desired final product of formula (I), which has valuable ACE inhibitory activity, can then be prepared by selective deprotection of the carboxy-protecting group R6 in the compound of formula (VI). The precise deprotection reaction chosen will depend upon the nature of the protecting group employed, as well as the nature of the carboxy-protecting group R2 , which it may be desired to leave intact. Such deprotection reactions are well known to those skilled in the art. Examples of suitable deprotection reactions include the following:

When R6 represents a methyl or ethyl group, it may be removed by hydrolysis with an alkali, particularly an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide;

When R6 represents a methoxymethyl, methoxyethoxymethyl, t-butyl, diphenylmethyl, ~-methoxybenzyl, trimethylsilyl or t-butyldimethylsilyl group, deprotection is preferably effected by means of an acid, which can be a mineral acid, organic acid or s~

Lewis acid, for example hydrochloric acid, hydrobromic acid, trifluoroacetic acid or aluminium chloride;

When R6 represents a benzyl or D-nitrobenzyl group, deprotection is preferably effected by catalytic reduction in the presence of a suitably supported metal catalyst, e.g. platinum, palladium or Raney nickel;

When R represents a 2,2,2-trichloroethyl, 2-iodoethyl, phenacyl or P-bromophenacyl group, deprotection is preferably effected by reduction, preferably with zinc powder and an acid, such as acetic acid; and When R6 represents an allyl group, deprotection is preferably effected by catalytic means, for example with tetrakis(triphenylphosphine)palladium (O).

In order to achieve selective deprotection of R
by any of these deprotecting methods, it is necessary that the two protecting groups R and R should be so chosen that R is stable under the conditions under which R is deprotected. Such selective deprotection is, however, well known in the art and requires no further elucidation here. As an example, in a preferred embodiment, R may represent an alkyl group (for example a methyl, ethyl or butyl group, which l32~n ,JI ~.

is removable by alkaline hydrolysis), whilst R may represent a group removable by acid hydrolysis, such as a methoxymethyl, t-butyl, diphenylmethyl, p-methoxybenzyl or trimethylsilyl group.

The deprotection reactions are preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the deprotection reaction. Of course, preferred solvents will vary depending upon the precise deprotection method chosen, but examples of suitable solvents include: water; acids, particularly aliphatic carboxylic acids, such as acetic acid or formic acid;
alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran, dioxane or anisole; ketones, such as acetone or methyl ethyl ketone; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform;
and aromatic hydrocarbons, such as benzene or toluene.
The reactions will take place over a wide range of temperatures and, again, the preferred reaction temperature will depend upon the method of deprotection, but a temperature within the range from -10C to +100C
is generally suitable. The time required for the reaction may vary widely, depending upon the deprotection method and other factors, notably the reaction temperature, but a period of from 30 minutes to 24 hours will normally suffice.

13 3 2 9 ~7. r~

The resulting compound of formula (I) can be purified by conventional means, such as recrystallization or the various chromatography techniques, notably column chromatography.

If desired, the compound of formula (I) prepared by this reaction can be converted into a pharmaceutically acceptable salt by conventional treatment with an acid or with a base, since the compounds of formula (I) possess both basic nitrogen atoms and at least one car-boxylic acid group. Hence, the compounds can form both acid addition salts and salts with cations.
Examples of acid addition salts include salts with: such inorganic acids as the hydrohalic acids (e.g.
hydrochloric acid or hydrobromic acid), sulphuric acid, phosphoric acid or nitric acid; such organic carboxylic acids as oxalic acid, maleic acid, fumaric acid, tartaric acid or citric acid; and such organic sulphonic acids as methanesulphonic acid or benzenesulphonic acid. Examples of salts with cations include, for example: salts with alkali metals, such as sodium or potassium, which can be prepared by reacting the free acid with an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide; alkaline earth metal salts, such as calcium or magnesium salts, which can be prepared by reacting the free acid with the alkaline earth metal hydroxide, such as calcium hydroxide or 13~29~

magnesium hydroxide; the ammonium salts, which can be prepared by reacting the free acid with ammonium hydroxide; salts with other metals, such as aluminium, which can be prepared by reacting the free acid with the corresponding hydroxide, such as aluminium hydroxide;
salts with organic basis, such as triethylamine, dicyclohexylamine, cinchonine, guanidine or quinine, which can be prepared by reacting the free acid with the base itself; and salts with basic amino acids, such as lysine or arginine, which can be prepared by reacting the free acid with the basic amino acid.

The starting material of formula (II) employed in the process of the invention may be prepared stereospecifically by the synthetic route illustrated below for the compound where R represents a phenethyl group; other compounds of formula (II) may be prepared by corresponding methods.

Ph ~\COOH step 1 (VII~

Ph~ COO-e-Menth)~l step 2 (V~II ) H

Ph~COO-e-Menthyl step 3 (IXI

OH OH

Ph--~COOH step ~ Ph'~--~ COOEt (X~ ~XI~

oso2P3 step S ~COOEt (XII~

In the above formulae, R3 is as defined above, Et represents the ethyl group and Ph represents the phenyl group.

The starting material of formula (VII) ~described in 1~329~

the Journal of the American Chemical Society 74, 4392 (1952)] is refluxed, in step 1, in a suitable solvent, such as benzene, with Q-menthol in an amount equimolar to the compound of formula (VII). The reaction is preferably effected in the presence of a catalytic amount of ~-toluenesulphonic acid and gives the Q-menthyl ester (VIII) quantitatively.

This ester (VIII) is catalytically reduced in Step 2, preferably employing a palladium-on-carbon catalyst, and then the product is recrystallized from petroleum ether, easily giving the Q-menthyl a-hydroxy-carboxylate compound (IX) in which the carbon atom attached to the hydroxy group is in the R-configuration. This compound of formula (IX) has been reported in Annales de Chimie 20, 144 (1933), where it was synthesized by reaction of a racemic compound corresponding to the compound of formula (X) with a large excess of Q-menthol, by introducing hydrogen chloride gas for a long time. The process described above, however, as compared to the prior process, does not require such an excessive amount of expensive Q-menthol and can be carried out without difficulty.
In addition, the catalytic reduction of the compound of formula (VIII) to the compound of formula (IX) affords rather more of the compound in the R-configuration than in the -configuration; in general, the proportion of 1332~

compound (IX) in the _-configuration to that in the S-configuration ranges from 55:45 to 60:40.

In place of Q-menthol, other optically active alcohols may be used to equal effect, if desired.

The compound of formula (IX) is first converted, in Step 3, to the free carboxylic acid (X) and then this is converted, in Step 4, to the ethyl ester (XI), as described in Annales de Chimie 20, 144 (1933); this is a conventional synthetic reaction in organic chemistry.
The hydroxy group is then sulphonylated in Step 5 by reacting the ethyl ester of formula (XI) with a compound of formula R S02Y (in which R3 is as defined above and Y represents a halogen, preferably fluorine or chlorine, atom or a group of formula -OS02R , in which R is as defined above). The reaction of Step 5 preferably takes place in the presence of a base, for example triethylamine or pyridine. The product, the compound of formula (XII), corresponds to a compound of formula (II) in which R represents a phenethyl group and R represents an ethyl group.

The other starting material employed in the process of the present invention, that is to say the perhydrothiazepine derivative of formula (III), can, for example, be prepared as illustrated by the following reaction scheme:

\N~ + Rl'--CH=C~ step 6 (XIII) (XIV) RL Rl' R7 ~S~R5 step 7 R7 ~S--f RS

(XV) IXVI) R8/ ~ 5 (XVII) '' (IIII

~`:

In the above formulae, R4 and R are as defined above and R and R , which may be the same or different, each represents a hydrogen atom or an amino-protecting group.

The nature of the amino-protecting groups which may be represented by R and R are not critical to the present invention and any such group known in the field in the organic synthesis may be employed in this invention. Examples of such protecting groups include:
alkoxycarbonyl groups, and substituted derivatives thereof, such as the 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, trimethylsilylethoxycarbonyl, 2-(P-toluenesulphonyl)ethoxycarbonyl~ t-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or P-nitrobenzyloxycarbonyl groups; acyl groups, particularly aliphatic and aromatic carboxylic acyl groups, such as the formyl, acetyl, benzoyl, chloroacetyl or trifluoroacetyl groups; diacyl groups in which R and R together are represented by a single group, for example the phthaloyl group or the 2,3-diphenylmaleoyl group; substituted methyl groups, such as the methoxymethyl, benzyloxymethyl, benzyl, 3,4-dimethoxybenzyl or trityl groups; alkylidene and aralkylidene groups, such as the isopropylidene, benzylidene and salicylidene groups; acylvinyl groups, such as the l-methyl-2-acetylvinyl or -13329~3 l-methyl-2-benzoylvinyl groups; and silyl groups, such as the trimethylsilyl or t-butyldimethylsilyl groups.

The first step in this reaction, Step 6, consists of the Michael addition of the compound of formula (XIII), which is a cysteine derivative, to a nitroolefin derivative of formula (XIV). This reaction, which is well known, may be carried out in the presence of a base and in the presence of a solvent. The nature of the solvent is not critical and any solvent may be employed, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example:
aromatic hydrocarbons, such as benzene, xylene or toluene; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; amides, such as dimethylacetamide or dimethylformamide; esters, such as ethyl acetate;
dimethyl sulphoxide; and water. A single one of these solvents or a mixture of any two or more may be employed. There is also no criticality as to the base employed and examples include: amines, particularly tertiary amines, such as triethylamine, N-methylmorpholine, N,N-dicyclohexylamine or pyridine;
carbonates and bicarbonates, particularly those of the alkali metals, such as sodium bicarbonate, potassium 13329~3 bicarbonate, sodium carbonate or potassium carbonate;
metal hydroxides, particularly alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; and fluorides, particularly alkali metal fluorides, such as potassium fluoride or cesium fluoride.

The reaction will take place over a wide range of temperatures, although a temperature of from -20C to +120C is generally convenient. The time required for the reaction may vary widely, depending upon many factors, notably the reaction temperature, but a period of from 1 hour to 3 days will normally suffice.

After completion of this reaction, the resulting compound of formula (XV) may, if required, be collected from the reaction mixture by conventional means. For example, the compound of formula (XV) is normally produced in the form of a salt thereof. This is separated from the reaction mixture and then dissolved in water and washed with an organic solvent (such as benzene or toluene) to remove non-acidic substances with which it is contaminated. The aqueous layer containing the salt of the compound (XV) is then acidified to give the free compound (XV). This may be extracted from the aqueous reaction mixture with an organic solvent,-such as ethyl acetate, and then the organic solvent may be evaporated off to give the free compound (XV). If 13329g3 necessary, this can be purified by such conventional techniques as recrystallization or the various chromatography techniques, notably column chromatography.

In Step 7 of this reaction scheme, the resulting compound of formula (XV) is subjected to reduction, to reduce the nitro group to an amino group. Any reduction process capable of doing this without substantially affecting other parts of the molecule may be employed without any particular restriction. For example, suitable reduction processes include:

catalytic reduction, employing hydrogen in the presence of a metal catalyst, such as platinum, palladium, Raney nickel or rhodium, preferably on a suitable carrier, such as carbon in an appropriate form;

reduction with a metal hydride, such as lithium borohydride, sodium borohydride or potassium borohydride; or reduction with a metal (such as tin or zinc) and an acid (such as hydrochloric acid or acetic acid).

These reactions are normally and preferably effected in the presence of a solvent, the nature of which may vary depending upon the precise type of reduction 13329~3 process employed. However, the nature of the solvent is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include: water;
alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran, diethyl ether or dioxane; halogenated aliphatic hydrocarbons, such as methylene chloride;
esters, such as ethyl acetate; aromatic hydrocarbons, such as benzene or toluene; amides, such as dimethylformamide or dimethylacetamide; and organic acids, particularly lower aliphatic carboxylic acids, such as acetic acid or formic acid. The reactions will take place over a wide range of temperatures and, although the preferred temperature will vary depending upon the precise reduction reaction chosen, a temperature of from -20C to +100C will normally suffice. The reactions will take place under atmospheric pressure, although superatmospheric pressure may be preferred in some cases.

The resulting amino acid compound of formula (XVI) can, if desired, be separated and purified by such conventional means as precipitation at its isoelectric point, recrystallization or the various chromatography techniques, notably column chromatography.

In Step 8, the amino acid (XVI) is subjected to intramolecular condensation by dehydration to prepare the perhydrothiazepine derivative of formula (XVII).
This may be effected by condensation methods well known for the formation of amide bonds from amino groups and carboxyl groups in the field of peptide chemistry. In general, this reaction is achieved by contacting the compound of formula (XVI) with a dehydrating agent, such as N,NI-dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethyl cyanophosphate or phosphorus pentachloride. When the dehydrating agent is a carbodiimide, the addition of l-hydroxybenzotriazole, N-hydroxysuccinimide or the like to the reaction system can accelerate the rate of reaction. The reaction is preferably effected in the additional presence of a base, such as pyridine, picoline, triethylamine, N-methylmorpholine, sodium carbonate or sodium bicarbonate. The reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example:
amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide: ethers, such as tetrahydrofuran or di`oxane; alcohols, such as methanol or ethanol; ketones, such as acetone; halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; esters, such as ethyl acetate; and aromatic hydrocarbons, such as benzene or toluene. In some cases, the product will separate as crystals from the reaction mixture and may then simply be recovered by filtration or other such separation techniques; in other cases, the compound may, if required, be purified by, for example, column chromatography.

In the last step, Step 9, the amino-protecting groups represented by R and R8 are removed from the compound of formula (XVII) by conventional methods well known in the field of organic synthesis, to give the desired compound of formula (III). The precise reaction chosen to remove the amino-protecting group will, of course, depend upon the nature of the protecting group to be removed, for example:

when R and/or R8 represents a t-butoxycarbonyl, P-methoxybenzyloxycarbonyl~ benzyloxycarbonyl, trityl or t-butyldimethylsilyl group, it may be removed by treatment with an acid, which can be a mineral, organic or Lewis acid, for example hydrochloric acid, hydrobromic acid, trifluoroacetic acid or aluminium chloride;

when R and/or R represents a benzyloxycarbonyl or ~-nitrobenzyloxycarbonyl group, it can be removed by catalytic reduction, e.g. as described in relation to Step 7;

1~329~3 where R and/or R represents a 2,2,2-trichloro-ethoxycarbonyl or 2-iodoethoxycarbonyl group, it can be removed by reductive deprotection with zinc powder and an acid, e.g. acetic acid;

when R and/or R represents an allyloxycarbonyl group, it can be removed by catalytic deprotection with tetrakis(triphenylphosphine)palladium(O);

when R and R together represent a phthaloyl or 2,3-diphenylmaleoyl group, it can be removed by reaction with hydrazine or a derivative thereof; and when R and/or R8 represents a 2-(~-toluenesulphonyl)ethoxycarbonyl group, it can be removed by treatment with an alkali, such as sodium hydroxide.

All of these deprotecting reactions are preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Of course, the preferred solvent will vary depending upon the nature of the deprotecting reaction chosen, but examples of suitable solvents include: water; acids, particularly lower aliphatic carboxylic acids, such as acetic acid or formic acid; alcohols, such as methanol or ethanol;

-13329~3 ethers, such as tetrahydrofuran, dioxane or anisole;ketones, such as acetone; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; and aromatic hydrocarbons, such as benzene or toluene. These reactions will take place over a wide range of temperatures, although the preferred reaction temperature will depend upon the nature of the deprotecting reaction; however, in general, the reactions will be carried out at a temperature within the range from -10C to +100C. The time required for the reaction will vary, depending upon many factors, notably the nature of the deprotecting reaction and the reaction temperature, but a period from 30 minutes to 24 hours will normally suffice.

The compound of formula (III) obtained as described above can, if required, be purified by such conventional techniques as recrystallization or the various chromatography techniques, notably column chromatography.

An alternative synthetic route for the compounds of formula (III) is illustrated by the following reaction scheme:

_ 42 1332943 X

Rll IxvIII) IXIXl Rl' R~
R7 ~S~R5 step 11 R7 ~ ~R5 R COOR9 ~ R COOH

(XXJ IXVI) R~/ ~ÇN\~

IXVIIJ

S Rl' 1/ ~/
~N

\H
( III ) -In the above formulae, R , R , R and R are as defined above, R represents a hydrogen atom or a carboxy-protecting group, R and R are the same or different and each represents a hydrogen atom or an amino-protecting group, and Z represents a halogen atom or a sulphonyloxy group.

Examples of carboxy-protecting groups which may be represented by R are as given before in relation to R and R . Examples of amino-protecting groups which may be represented by R and R are as given before in relation to R7 and R8. Where Z represents a halogen atom, this is preferably a chlorine, bromine or iodine atom. Where Z represents a sulphonyloxy group, this may be a substituted or unsubstituted lower alkanesulphonyloxy group (for example a methanesulphonyloxy, ethanesulphonyloxy or trifluoromethanesulphonyloxy group) or a substituted or unsubstituted aromatic sulphonyloxy group (e.g. a benzenesulphonyloxy or ~-toluenesulphonyloxy group).

In Step 10, condensation of the cysteine derivative of formula (XVIII) with the compound of formula (XIX) can be carried out under conditions similar to those employed for the condensation reaction of the compound of formula (II) with the compound of formula (III) in accordance with the present invention, eliminating a sulphonic acid or hydrogen halide of formula HZ. After completion of this reaction, the resulting compound of formula (XX) can be separated from the reaction mixture by conventional means. For example, a suitable recovery procedure comprises: extracting the reaction mixture with an organic solvent, such as ethyl acetate;
separating the organic layer; washing the organic layer with water and then drying it; and evaporating off the solvent to give the desired product. If necessary, this product can be further purified by such conventional techniques as recrystallization or the various chromatography techniques, notably column chromatography.

Step 11 consists of the deprotection of the compound of formula (XX) by removing the carboxy-protecting group R and the amino-protecting groups R and R but without removing the amino-protecting groups R and R8 .

The carboxy-protecting group R9 may be removed in a similar manner to that described above in relation to the removal of the carboxy-protecting group R .

The amino-protecting groups R and R may be removed by those reactions described above in relation to the removal of the amino-protecting groups R and R from the compound of formula (XVII) in Step 9.

However, since R and R in the compound of formula (XX) are not to be removed, it is necessary that R
and Rll should represent amino-protecting groups chosen from a class of groups different from those represented by R and R,so that R and R
may be removed without interfering with R and R.
For example, if R and R together represent a phthaloyl group, R represents a t-butoxycarbonyl or ~-methoxycarbonyl group and Rll represents a hydrogen atom, the protecting group of R10 may be removed selectively by treatment with an acid.

As required, the carboxy-protecting group R9 may be removed before or after removal of the amino-protecting groups R and R . Alternatively, by appropriate choice of protecting groups, the carboxy-protecting group R may be removed simultaneously with the amino-protecting groups R
and Rll. For example, if R9 represents a t-butyl group, R represents a t-butoxycarbonyl group and R represents a hydrogen atom, deprotection with an acid gives the desired compound of formula (XVI) in a single step. Similarly, if R9 represents a 2,2,2-trichloroethyl group, R10 represents a 2,2,2-trichloroethoxycarbonyl group and Rll represents a hydrogen atom, reduction with zinc powderJacid gives the compound of formula (XVI) in one step.

Steps 12 and 13 of this reaction scheme are identical to Steps 8 and 9 of the previous reaction scheme and may be carried out in exactly the same way to give the desired compound of formula (III), which may, if required, be separated from the reaction mixture and purified as described above.

Since the compounds of formula (I~ prepared in accordance with the process of the present invention contain several asymmetric carbon atoms in their molecules, they can exist in the form of various optical isomers. These isomers can, if desired, be prepared individually by using the appropriate optical isomer of the starting material of formula (II) and/or (III) previously resolved. As already noted, the synthesis reactions of the process of the present invention are stereospecific. However, if one or both of the starting materials used is a mixture of isomers, e.g. a racemate, the compound of formula (I) will normally be obtained as a corresponding mixture of isomers. If desired, this mixture of isomers can be separated into the individual isomers by conventional resolution techniques, such as salt formation with an optically active base (for example cinchonine, cinchonidine, quinine or quinidine) or with an optically active organic acid (for example Q-camphorsulphonic acid or d-camphorsulphonic acid) or by various other conventional techniques. such as 13329~3 chromatography or fractional recrystallization.

The compounds of formula (I) prepared by the process of the present invention have the ability to inhibit the activity of the enzyme ACE, which converts angiotensin I
into angiotensin II. Angiotensin II is a pressor substance and is a possible cause of hypertension in mammals, including humans.

Hence, compounds of formula (I) and pharmaceutically acceptable salts and esters thereof are useful for the diagnosis, prevention and therapy of hypertension. When the compounds of formula (I) or salts or esters thereof are employed for medical use, they may be administered orally or parenterally in appropriate compositions, for `
example powders, granules, tablets, capsules or injections, either alone or in admixture with appropriate pharmaceutically acceptable carriers, vehicles or diluents. The dose will vary depending upon the nature and severity of the disorder, as well as upon the age, condition and body weight of the patient. For example, for the therapy of an adult human patient, the dose at each administration would preferably be from 0.5 to 1,000 mg, more preferably from 1 to 100 mg, for oral administration, whilst the preferred dose at each administration for intravenous injection would be from 0.1 to 100 mg, more preferably from O.2 to 10 mg. One 133294~

or more of these doses, preferably from 1 to 3 doses, may be administered daily.

The invention is further illustrated by the folowing Examples. The preparation of certain starting materials employed in these Examples is illustrated in the subsequent Preparations. The values for optical rotation were all measured with the sodium D-line, i.e.
all such values are [a]D.

6(R)-[l(S)-Ethoxycarbonyl-3-phenYlpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine 200 mg of 6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 15), 393 mg of ethyl 2(R)-(~-nitrobenzenesulphonyloxy)-4-phenylbutyrate (prepared as described in Preparation 5) and 840 mg of sodium bicarbonate were mixed with 3 ml of dimethylacetamide, and the mixture was stirred at room temperature for 66 hours. Ethyl acetate and water were then added to the reaction mixture. The ethyl acetate layer was separated, washed with water and concentrated by evaporation under reduced pressure, to give a residue, which was subjected to column chromatography through silica gel, eluted with a 1:5 by volume mixture of ethyl acetate and methylene chloride, to afford 295 mg of the title compound as crystals, melting at 104-105.

[a~25 +18.6~ (C=l.l, chloroform).

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.26 (3H, triplet, J=7Hz);
1.75-2.2 (2H, multiplet);
2.4-3.0 (5H, multiplet);
3.36 (lH, triplet, J=6.5Hz);
3.6-4.3 (4H, multiplet);

6.7-7.0 (3H, multiplet);

7.15 (5H, singlet);
around 7.15 (lH, multiplet).

6(R)-[l(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine In a similar manner to that described in Example 1, 6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 15) was condensed with ethyl 2(_)-(_-nitrobenzenesulphonyl-oxy)-4-phenylbutyrate (prepared as described in Preparation 7) in the presence of sodium bicarbonate to 13329~3 afford the title compound in 77% yield. The melting point, optical rotation and nuclear magnetic resonance spectrum of the compound were identical to those of the compound prepared as described in Example 1.

6(R)-[l(S)-EthoxycarbonYl-3-PhenYlProPYlamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine A mixture of 160 mg of 6(_)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 15), 336 mg of ethyl 2(_)-(P-nitro-benzenesulphonyloxy)-4-phenylbutyrate (prepared as described in Preparation 5) and 400 mg of anhydrous potassium fluoride in 2 ml of dimethylformamide was stirred at 50C for 9 hours. The reaction mixture was then mixed with a mixture of ethyl acetate and water.
The ethyl acetate layer was separated and concentrated by evaporation under reduced pressure, to give a residue, which was subjected to column chromatography through silica gel, eluted with a 5:1 by volume mixture of methylene chloride and ethyl acetate, to give 199 mg of the title compound as crystals. The melting point, optical rotation and nuclear magnetic resonance spectrum of the compound were identical with those of the compound prepared as described in Example 1.

-Using the same procedure as described above, thetitle compound was also obtained by using either ethyl 2(R)-(o-nitrobenzenesulphonyloxy)-4-phenylbutyrate, ethyl 2(R)-(_-nitrobenzenesulphonyloxy)-4-phenylbutyrate, ethyl 2(R)-(2,4-dinitrobenzenesulphonyl-oxy)-4-phenylbutyrate, ethyl 2(R)-(4-chloro-3-nitrobenzenesulphonyl)-4-phenylbutyrate or ethyl 2(R)-(P-bromobenzenesulphonyloxy)-4-phenylbutyrate (prepared as described in Preparations 6, 7, 9, 8 and 10, respectively), in place of ethyl 2(R)-(p-nitrobenzenesulphonyloxy)-4-phenylbutyrate.

E~AMPLE 4 6(R)-rl(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine 1.4 ml of triethylamine and 3.45 g of etnyl ~-~henyl-2(R)-trifluoromethanesulphonyloxybutyrate tprepared as described in Pre~aration 11) were added to a solution of 1.9 g of 6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 15) in 100 ml of methylene ~hloride at room temperature. The reaction mixture was then stirred for 15 hours, washed with water and concentrated by evaporation under reduced pressure. The cesidue was subje~ted to ~o~umn ~hromat~gcaphy through 133294~

silica gel, eluted with a 3:1 by volume mixture of methylene chloride and ethyl acetate, to afford 3.35 g of the title compound as crystals. The melting point, optical rotation and nuclear magnetic resonance spectrum of the compound were identical to those of the compound prepared as described in Example 1.

t-Butyl a-{6(R)-rl(S)-EthoxycarbonYl-3-Phenylpropyl-amino]-5-oxo-2(S)-(2-thienyl)perhYdro-1,4-thiazepin-4-yl}acetate 0.11 ml of t-butyl bromoacetate was added to a solution of 235 mg of 6(_)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in any of Examples 1-4) in dimethylformamide. 28 mg of sodium hydride as a 55% w/v dispersion in mineral oil were added to the mixture, whilst cooling with an ice-salt bath. The reaction mixture was then stirred at room temperature for 30 minutes. Ethyl acetate and water were added.
The ethyl acetate layer was separated, washed with water and concentrated by evaporation under reduced pressure.

The residue was subjected to column chromatography through silica gel, eluted with a 20:1 by volume mixture of methylene chloride and ethyl acetate, to give 281 g of the title compound as a syrup.

[a~25 +39.3 (C=l.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.26 (3H, triplet, J=7HZ);
1.48 (9H, singlet);
1.8-2.25 (2H, multiplet);
2.55-4.8 (12H, multiplet);
4.15 (2H, quartet, J=7.5Hz);
6.85-7.35 (3H, multiplet):
7.20 (5H, singlet).

a-{6(R)-[l(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetic acid hydrochloride 2.4 g of t-butyl a-{6(R)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 5) were dissolved in 20 ml of 4N solution of hydrochloric acid in dioxane, and the mixture was allowed to stand at room temperature for 15 hours. The solvent was distilled off and the residue was dissolved in 35 ml of ethyl acetate and then allowed to stand in a 13329~3 refrigerator, to yield 1.8 g of the title compound as crystals. The product was recrystallized from a mixture of ethanol and ethyl acetate to give crystals melting at 187C (with decomposition).

[a]25 +48 (C=l.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum [(CD3)2S0]
ppm:
1.32 (3H, triplet, J=7.5Hz);
2.0-3.4 (7H, multiplet);
3.7-5.2 (8H, multiplet);
6.9-7.5 (3H, multiplet);
7.28 (5H, singlet).

6(R)-[l(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(R)-(3-thienyl~perhydro-1,4-thiazepeine In the same manner as described in Example 4, the _-alkylation of 1.7 g of 6(R)-amino-5-oxo-2(R)-(3-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 23) with ethyl 4-phenyl-2(R)-trifluoromethanesulphonyloxybutyrate (prepared as described in Preparation 11) gave 2.9 g of the title compound as crystals, melting at 120.5-121C.

-- 13329~3 [a]25 +31.1 (C=l.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.22 (3H, triplet, J=7Hz);
1.7-2.1 (2H, multiplet);
2.5-2.8 (4H, multiplet);
3.25-4.2 (4H, multiplet);
3.33 (lH, triplet, J=6.5Hz);
4.11 (2H, quartet, J=7Hz);
7.26 (5H, singlet);
7.05-7.6 (3H, multiplet);
7.93 (lH, triplet, J=6Hz).

t-Butyl a-{6(R)-[l(S)-ethoxycarbonyl-3-phenylpropyl-amino]-5-oxo-2(R)-(3-thienyl)perhydro-1,4-thiazepin-4-yl}acetate In the same manner as described in Example 5, alkylation of 2.6 g of 6(_)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(R)-(3-thienyl)perhydro-1,4-thiazepine (prepared as described in Example 7) with 2.6 g of t-butyl bromoacetate gave 3.3 g of the title compound as a syrup.

[a] +43.9 (C=l.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.29 (3H, triplet, J=7.5Hz);
1.49 (9H, singlet);
1.85-2.2 (2H, multiplet);
2.48 (lH, broad singlet);
2.6-3.15 (4H, multiplet);
3.36 (lH, triplet, J=6.5Hz);
3.55-4.5 (6H, multiplet);
4.18 (2H, quartet, J=7.5Hz);
7.26 (5H, singlet);
7.0-7.4 (3H, multiplet).

a-[6(R)-[l(S)-EthoxycarbonYl-3-PhenylpropYlamino]-5-oxo-2(R)-(3-thienyl)Perhydro-1,4-thiazepin-4-yl}acetic acid hydrochloride In the same manner as described in Example 6, treatment of 3.0 g of t-butyl a-{6(R)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(_)-(3-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 8) with a 4N solution of hydrochloric acid in dioxane gave 2.6 g of the title compound as crystals, melting at 145-148C (with coloration at 140C).

133294~

[a]25 +48.9 (C=l.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum [(CD3)2S0]
ppm:
1.28 (3H, triplet, J=7.5Hz);
2.05-2.4 (2H, multiplet);
2.6-3.3 (5H, multiplet);
3.7-5.2 (8H, multiplet);
7.30 (5H, singlet);
7.1-7.65 (3H, multiplet).

6(R)-[l(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(R)-phenylperhydro-1,4-thiazepine In the same manner as described in Example 4, N-alkylation of 2.7 g of 6(R)-amino-5-oxo-2(_)-phenylperhydro-1,4-thiazepine (prepared as described in Preparation 27) with ethyl 4-phenyl-2(R)-trifluoro-methanesulphonyloxybutyrate (prepared as described in Preparation 11) gave 3.0 g of the title compound as crystals, melting at 118-119.5C.

[a] 5 +3.5 (C=l.0, dimethylformamide).

13329~3 Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.28 (3H, triplet, J=7.5Hz);
1.85-2.25 (2H, multiplet);
2.6-3.15 (4H, multiplet):
3.39 (lH, triplet, J=6.5Hz);
3.45-4.15 (4H, multiplet);
4.20 (2H, quartet, J=7.5Hz);
6.55 (lH, multiplet);
7.24 (SH, singlet);
7.33 (5H, singlet).

t-Butyl a-{6(R)-[l(S)-ethoxYcarbonyl-3-phenYlProPYl-amino]-5-oxo-2(R)-phenylperhydro-1~4-thiazepin-4-yl}-acetate In the same manner as described in Example 5, alkylation of 2.7 g of 6(_)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(_)-phenylperhydro-1,4-thiazepine (prepared as described in Example 10) gave 3.35 g of the title compound as a syrup.

[a]25 +21.7 (C=l.0, dimethylformamide).

133294~

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.28 (3H, triplet, J=7.5Hz);
1.47 (9H, singlet);
1.8-2.3 (2H, multiplet);
2.5-3.1 (4H, multiplet);
3.37 (lH, triplet, J=6.5Hz);
3.45-4.65 (6H, multiplet);
4.18 (2H, quartet, J=7.5Hz);
7.24 (5H, singlet);
7.32 (5H, singlet).

a-{6(R)-[l(S)-Ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(R)-phenylperhydro-1,4-thiazepin-4-yl}acetic acid hydrochloride In the same manner as described in Example 6, treatment of 3.1 g of t-butyl a-{6(R)-[l(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2(R)-phenyl-perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 11) with a 4N solution of hydrochloric acid in dioxane gave 2.82 g of the title compound as a powder, melting at 112-115C (with softening from 96C).

[a]25 +25.9 (C=l.O, dimethylformamide).

13329~3 Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
1.28 (3H, triplet, J=7.5Hz);
2.0-2.35 (2H, multiplet);
2.5-3.4 (5H, multiplet);
3.7-5.15 (8H, multiplet);
7.30 (5H, singlet);
7.40 (5H, singlet).

Q-Menthyl benzYlidenepyruvate A mixture of 62 g of benzylidenepyruvic acid ~reported in The Journal of The American Chemical Society, 74, 4392 (1952)], 49.45 g of Q-menthol and 6.2 g of P-toluenesulphonic acid monohydrate in 300 ml of benzene was heated unde~ reflux for 5 hours in a flask fitted with a Dean-Stark dehydrator. The reaction mixture was cooled, washed with an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulphate. The solvent was then evaporated off under reduced pressure, to give 105.8 g of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
0.78 (3H, doublet, J=9.5Hz);
0.92 (6H, doublet, J=7.5Hz);
0.6-2.2 (9H, multiplet);
4.87 (lH, doublet of triplets, J=4 ~ 10HZ);
7.18 ~ 7.76 (2H, AB-quartet, ~=16HZ);
7.25 (5H, broad singlet).

Q-Menthyl 2(R)-hydroxy-4-phenylbutyrate 33.9 g of Q-menthyl benzylidenepyruvate (prepared as described in Preparation 1) dissolved in 250 ml of isopropanol were hydrogenated at 50C for 5 hours in the presence of 3.3 g of a 5% w/w palladium-on-carbon and hydrogen at 3 kg/cm . At the end of this time, the catalyst was removed and the solvent was stripped off.
The residue was dissolved in 30 ml of petroleum ether, the solution was seeded with crystals of the title compound, and the mixture was allowed to stand, to afford 11.6 g of the title compound as crude crystals.
The product was recrystallized from petroleum ether, to yield 9.8 g of a pure sample melting at 85-86C.

[a]25 -67 (C=1.0, chloroform).

13329~3 The melting point and optical rotation of the title compound were identical to those described in Annales de Chimie, 20, 144 (1933).

Nuclear Magnetic Resonance Spectrum tCDC13) ~ ppm:
0.74 (3H, doublet, J=9.SHz);
0.88 (6H, doublet, J=7.5Hz);
0.5-2.2 (llH, multiplet);
2.6-3.0 (3H, multiplet);
4.13 (lH, doublet of doublets, J=5 & llHz);
4.73 (lH, doublet of triplets, J=4 & lOHz);
7.13 (5H, singlet).

2(R)-Hydroxy-4-phenylbutyric acid 132.8 g of Q-menthyl 2(R)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 2) were added in portions to a solution of 46.8 g of potassium hydroxide in 320 ml of ethanol, whilst ice-cooling, and then the mixture was stirred at room temperature for 16 hours.
At the end of this time, the ethanol was removed by distillation in vacuo, and the residue was dissolved in a mixture of water and petroleum ether. The aqueous layer was separated, washed with petroleum ether, cooled with ice, mixed with 1 litre of ethyl acetate and then 1~3294~
-its pH was adjusted to a value of 2 by the addition of concentrated hydrochloric acid. The ethyl acetate layer was separated, washed twice with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure to give 70.9 g of the crystalline product.
This was recrystallized from toluene, to give 65 g of the pure title compound melting at 115-116C.

~~25 -8.6 (C=1.0, ethanol).

Nuclear Magnetic Resonance Spectrum [(CD3)2CO]
ppm:
1.75-2.3 (2H, multiplet);
2.6-2.95 (2H, multiplet);
4.12 (lH, doublet of doublets, J=5 & 7Hz);
5.92 (2H, broad singlet);
7.24 (5H, singlet).

Ethyl 2(R)-hYdroxy-4-phenylbutyrate 60 g of 2(R)-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 3) were dissolved in 1.8 litre of ethanol, and then 1.7 ml of concentrated sulphuric acid was added dropwise at 15C. The mixture 13329~3 was then maintained at room temperature for 16 hours.
At the end of this time, the ethanol was distilled off in vacuo, and the residual oil was dissolved in a mixture of 0.5 litre of ethyl acetate and 0.2 litre of water. The ethyl acetate layer was separated, washed twice with an aqueous solution of sodium chloride and once with an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulphate and then concentrated by evaporation in vacuo, to give 68.1 g of the title compound as an oil.

[a] -20.1 (C=1.5, chloroform).

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.21 (3H, triplet, J=7Hz);
1.7-2.2 (2H, multiplet);
2.6-2.9 (2H, multiplet);
3.32 (lH, singlet);
4.13 (2H, quartet, J=7Hz);
around 4.15 (lH, multiplet);
7.19 (5H, singlet).

Ethyl 2(R)-(P-nitrobenzenesulphonYloxY)-4-phenylbutyrate 0.167 ml of triethylamine was added to a solution of 133294~
_ 208 mg of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) and 221 mg of P-nitrobenzenesulphonyl chloride in 2.5 ml of methylene chloride, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was then distilled off. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to yield 336 mg of the title compound as a syrup, which was crystallized by allowing it to stand in a refrigerator, to give crystals melting at 36-38C.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.20 (3H, triplet, J=7Hz);
2.0-2.9 (4H, multiplet);
4.11 (2H, quartet, J=7Hz);
4.96 (lH, triplet, J=6Hz);
7.17 (5H, multiplet);

8.22 (4H, A2B2, ~=2.8 ppm, J=9.6Hz).

EthYl 2(R)-(o-nitrobenzenesulphonyloxY)-4-phenylbutyrate In a similar manner to that described in Preparation 5, 2.0 g of ethyl 2(R)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) were sulphonylated with 2.1 g of o-nitrobenzenesulphonyl fluoride, to give 2.35 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.18 (3H, triplet, J=7Hz);
2.0-2.9 (4H, multiplet);
4.12 (2H, quartet, J=7Hz);
5.06 (lH, triplet, J=6Hz);
7.14 (5H, singlet);
7.5-8.15 (4H, multiplet).

Ethyl 2(R)-(m-nitrobenzenesulphonYloxY)-4-PhenYlbutyrate In a similar manner to that described in Preparation 5, 2.45 g of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) were sulphonylated with 2.73 g of m-nitrobenzenesulphonyl chloride, to give 3.5 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.20 (3H, triplet, J=7Hz);
2.0-2.4 (2H, multiplet);
2.55-2.9 (2H, multiplet);
4.12 (2H, quartet, J=7Hz);
5.01 (lH, triplet, J=6Hz);
7.22 (5H, broad singlet);
7.78 (lH, triplet, J=8Hz);
8.2-8.9 (3H, multiplet).

Ethyl 2(R)-(4-chloro-3-nitrobenzenesulPhonyloxy)-4 phenylbutyrate In a similar manner to that described in Preparation 5, 2.22 g of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) were sulphonylated with 3 g of 4-chloro-3-nitrobenzene-sulphonyl chloride, to yield 3.0 g of the title compound as a syrup, which was crystallized by allowing it to stand in a refrigerator, to give crystals melting at 34.5-35.5C.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.21 (3H, triplet, J=7Hz);
2.0-2.9 (4H, multiplet);
4.13 (2H, quartet, J=7Hz):
--4.96 (lH, triplet, J=6Hz);
7.17 (5H, multiplet);
7.67 (lH, doublet, J=9Hz);
8.03 (lH, doublet of doublets, J=2 & 9Hz);
8.39 (lH, doublet, J=2Hz).

Ethyl 2(R)-(2,4-dinitrobenzenesulphonYloxY)-4-phenyl-butYrate In a similar manner to that described in Preparation 5, 1.04 g of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) was sulphonylated with 1.25 g of 2,4-dinitrobenzenesulphonyl fluoride, to give 1.47 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.21 (3H, triplet, J=7Hz);
2.0-2.95 (4H, multiplet);
4.12 (2H, quartet, J=7Hz);

5.17 (lH, triplet, J=6Hz);
7.21 (5H, multiplet);
8.2-8.7 (3H, multiplet).
-13329q~
6g Ethyl 2(R)-(p-bromobenzenesulphonyloxy)-4-phenylbutyrate In a similar manner to that described in Preparation 5, 1.1 g of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) was sulphonylated with 1.38 g of P-bromobenzenesulphonyl chloride, to give 1.2 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDCl3) ~ ppm:
1.21 (3H, triplet, J=7Hz);
1.9-2.85 (4H, multiplet);
4.12 (2H, quartet, J=7Hz);
4.89 (lH, triplet, J=6Hz);
7.22 (5H, multiplet);
7.77 (4H, A2B2, ~=0.2 ppm, J=8.5Hz).

PREPARATION ll EthYl 4-Phenyl-2(R)-trifluoromethanesulphonyloxybutyrate 6.2 ml of pyridine were added to 16 g of ethyl 2(_)-hydroxy-4-phenylbutyrate (prepared as described in Preparation 4) in 160 ml of methylene chloride, whilst cooling in an ice-salt bath. 14.9 ml of trifluoromethanesulphonic anhydride were then added -13~2943 dropwise to the reaction mixture over a period of one hour 20 minutes. At the end of this time, the reaction mixture was stirred for a further 30 minutes and then concentrated by evaporation under reduced pressure. The residue was mixed with 150 ml of a 1:1 by volume mixture of ethyl acetate and cyclohexane and filtered to remove insoluble material. The filtrate was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and cyclohexane as an eluent, to give 24.4 g of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.28 (3H, triplet, J=7Hz);
2.0-2.95 (4H, multiplet);
4.25 (2H, quartet, J=7Hz);
5.14 (lH, triplet, J=6Hz);
7.27 (5H, singlet).

S-[2-nitro-1-(2-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine A mixture of 48.4 g of L-cysteine, 90 g of di-t-butyl pyrocarbonate and 70 g of sodium bicarbonate dissolved in a mixture of 500 ml of water and 200 ml of tetrahydrofuran was stirred at 55C for 2 hours in an atmosphere of nitrogen. The reaction mixture was 13~294~

cooled; it was then mixed with ice and 0.5 litre of ethyl acetate and adjusted with concentrated hydrochloric acid to a pH value of 3. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure, to give a syrupy _-t-butoxycarbonyl-L-cysteine. This was dissolved in 1 litre of toluene. 60 g of 1-nitro-2-(2-thienyl)-ethylene were added to the solution and subsequently 50 ml of N-methylmorpholine were added dropwise to the reaction mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 3 hours.
0.5 litre of water was added to the mixture and it was then stirred for a further 5 minutes. The aqueous layer was separated and the toluene layer was extracted 5 times, each time with 100 ml of a 5% v/v aqueous solution of _-methylmorpholine. Ice and 700 ml of ethyl acetate were added to the combined aqueous extracts and separated aqueous layer, and the mixture was adjusted with concentrated hydrochloric acid to a pH value of 3.
The ethyl acetate layer was separated, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure, to give 127 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.46 (9H, singlet);
2.7-3.1 (2H, multiplet);

4.2-5.7 (5H, multiplet);
6.75-7.05 (2H, multiplet);
7.1-7.3 (lH, multiplet).

S-[2-amino-1-(2-thienYl)ethyl]-N-t-butoxycarbonyl-L
cysteine 127 g of S-t2-nitro-1-(2-thienyl)ethyl]-N-t-butoxy-carbonyl-k-cysteine (prepared as described in Preparation 12) were dissolved in 1.3 litre of acetic acid. It was then hydrogenated at 70C for 5 hours in 35 g of 5% w/w palladium-on-carbon and hydrogen at 3 to 4 kg/cm . The catalyst was then removed by filtration and the filtrate was concentrated by evaporation under reduced pressure to give a syrup. The syrup was dissolved in a mixture of 50 ml of methanol and 50 ml of water, subjected to column chromatography through Diaion (trade mark) HP-20, using a column of 7 cm diameter and 35 cm length, and eluted successively with 2 litres of water, 0.5 litre of 20% v/v aqueous acetone and about 3 litres of 50~ v/v aqueous acetone. The fraction containing the title compound was concentrated by evaporation under reduced pressure, to give 75 g of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
1.37 (9H, singlet);
2.6-3.5 (4H, multiplet);
3.9 (lH, multiplet);
4.5 (lH, multiplet);
6.2 (lH, multiplet);
6.8-7.1 (2H, multiplet);
7.42 (lH, multiplet).

6(R)-t-Butoxycarbonylamino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepine A solution of 57 ml of _-methylmorpholine in 30 ml of dimethylformamide was added dropwise to a solution of 75 g of S-[2-amino-1-(2-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine (prepared as described in Preparation 13) and 56.5 ml of diphenylphosphoryl azide in 500 ml of dimethylformamide, whilst ice-cooling. The mixture was allowed to stand overnight at room temperature. 1 litre of ethyl acetate and 1 litre of water were added to the reaction mixture. The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were washed twice with water, dried over anhydrous magnesium sulphate and concentrated by evapQration under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 1:4 by volume mixture of ethyl acetate and methylene chloride, to give 49.4 g of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.45 (9H, singlet);
2.9 (2H, multiplet):
3.6-4.4 (3H, multiplet);
4.85 (lH, multiplet);
5.99 (lH, doublet, J=5Hz);
6.8-7.3 (3H, multiplet);
7.3 (lH, multiplet).

6(R)-Amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepine 47.4 g of 6(R)-t-butoxycarbonylamino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 14) were mixed with 148 ml of a 4N

solution of hydrogen chloride in dioxane, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated by evaporation under reduced pressure, after which diethyl ether was added. The crystals which precipitated were collected 133294~

by filtration, to yield 35.6 g of the hydrochloride of the diastereoisomers of the 2(R) and 2(S) compounds.

A solution of 33 g of potassium carbonate in 190 ml of water was added to a suspension of this hydrochloride in a mixture of 1 litre of methylene chloride and 50 ml of methanol, and the mixture was stirred for two hours.
The precipitates were filtered off and an organic layer was separated from the filtrate. The aqueous layer was combined with a solution of the precipitates dissolved in 80 ml of water and the combined aqueous solution was extracted twice, each time with 100 ml of a 10% v/v solution of methanol in methylene chloride. The combined methanol/methylene chloride extracts were dried over anhydrous magnesium sulphate, and then the solution was concentrated by evaporation under reduced pressure to a volume of about 150 ml. The concentrate was mixed with 250 ml of ethyl acetate, concentrated to a volume of about 200 ml and allowed to stand overnight to afford 12.4 g of a precipitate, which was collected by filtration, giving the title compound melting at 157C.

[a]23 +51.5 (C=1.36, dimethylformamide).

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
2.21 (2H, broad singlet);

2.6-2.9 (2H, multiplet);
3.4-4.4 (4H, multiplet~:
6.8 (2H, multiplet);
7.40 (lH, doublet of doublets, J=1.5 & 4.5Hz);
7.83 (lH, broad triplet, J=7Hz).

DiphenylmethYl s- r 2-t-butoxYcarbonylamino-l-(2-thienyl)ethYl]-N-phthaloylcysteinate (a) 2-t-Butoxycarbonylamino-1-(2-thienyl)ethanol A mixture of crude 2-amino-1-(2-thienyl)ethanol (prepared by the reduction, with lithium aluminium hydride, of 62 g of the cyanohydrin derivative of 2-thiophenecarboxaldehyde), 66 ml of triethylamine and 97 g of di-t-butyl pyrocarbonate in 440 ml of methanol was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 1:4 by volume mixture of ethyl acetate and 13329~3 methylene chloride, to give 45 g of the title compound as crystals, melting at 101-102C.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.43 (9H, singlet);
3.0-3.6 (3H, multiplet);
5.00 (lH, doublet of doublets, J=4 ~ 7.5Hz);
4.8-5.2 (lH, broad triplet);
6.94 (2H, multiplet);
7.18 (lH, multiplet).

(b~ 2-t-Butoxycarbonylamino-l-chloro-1-(2-thienyl)ethane A solution of 12.8 g of phosphorus pentachloride in 240 ml of methylene chloride was added dropwise to a solution of 15 g of 2-t-butoxycarbonylamino-1-(2-thienyl)ethanol [prepared as described in step (a) above] in 120 ml of methylene chloride at 0 to -5C.
When the addition was complete, the reaction mixture was stirred for 10 minutes, and 210 ml of a 4N aqueous solution of sodium hydroxide were added to it at once.
The mixture was stirred for a further 5 minutes. The methylene chloride layer was separated, washed with a large quantity of water, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure, to give 13.6 g of the title compound as crystals, melting at 40-43C. The product was used in 13329~3 the following reaction without further purification, because decomposition of the compound took place in contact with silica gel.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.43 (9H, singlet);
3.5-3.8 (2H, multiplet);
4.90 (lH, broad multiplet);
5.21 (lH, doublet of doublets, J=6 & 7Hz);
6.75-7.3 (3H, multiplet).

( c ) DiPhenylmethyl s- r 2-t-butoxYcarbonYlamino-l-(2-thienyl)ethyl]-N-phthaloylcysteinate 6.2 g of sodium bicarbonate were added to a solution of 10 g of L-cysteine p-toluenesulphonate and 7.5 g of _-carboethoxyphthalimide in 68 ml of dimethylformamide, and the mixture was stirred at 90 to 100C for 3.5 hours in an atmosphere of nitrogen. The reaction mixture was cooled and then dissolved in a mixture of ethyl acetate and an aqueous solution of potassium bisulphate, after which it was acidified. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulphate. 7.4 g of diphenyldiazomethane were added to the ethyl acetate solution, and the reaction mixture was stirred at room temperature for 1 hour in an atmosphere of nitrogen. The solvent was then evaporated 133294~

off under reduced pressure, and the residue was dissolved in 60 ml of dimethylformamide and then mixed with 10 g of 2-t-butoxycarbonylamino-1-chloro-1-(2-thienyl)ethane [prepared as described in step (b) above]. 8.6 g of sodium carbonate was added to the mixture. The reaction mixture was then stirred at 60C
for 16 hours in an atmosphere of nitrogen and dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 1:4 by volume mixture of ethyl acetate and cyclohexane, to give 7.3 g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.38 (9H, singlet):
3.0-3.7 (4H, multiplet);
4.31 (lH, broad triplet, J=7Hz);
4.75 (lH, broad multiplet);
4.92 (lH, doublet of doublets, J=6.5 ~ 7.5Hz);
6.7-7.3 (14H, multiplet);
7.5-7.85 (4H, multiplet).

13329~3 S-[2-Amino-l-(2-thienYl)ethyl]-N-phthaloYlcysteine 43 ml of trifluoroacetic acid were added to a solution of 9.3 g of diphenylmethyl S-[2-t-butoxy-carbonylamino-l-(2-thienyl)ethyl]-N-phthaloylcysteinate (prepared as described in Preparation 16) in 34 ml of anisole, and the reaction mixture was allowed to stand at room temperature for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure. 34 ml of ethyl acetate, 26 ml of water and 3.3 g of sodium bicarbonate were added to it, in turn.
The reaction mixture was then stirred and adjusted with a 3N solution of hydrochloric acid to a pH value of 5.8. The title compound precipitated on cooling and stirring the mixture. The compound was then collected by filtration and washed with a 1:1 by volume mixture of acetone and diethyl ether, to give 1.7 g of the title compound.

PR~PARATION 18 5-Oxo-6-phthalimido-2-(2-thienyl)perhydro-1~4-thiazepine 1.75 g of diphenylphosphoryl azide and 1.0 ml of _-methylmorpholine were added to a solution of 1.7 g of 13329~3 S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (prepared as described in Preparation 17) in 2g ml of dimethylformamide, and the reaction mixture was stirred at room temperature for 15 hours. About 50 ml of water and about 100 ml of ethyl acetate were added, and the mixture was stirred, which resulted in the precipitation of the title compound. This was collected and dried, to give 0.8 g of the title compound as crystals. The ethyl acetate layer of the filtrate was separated, concentrated by evaporation under reduced pressure and triturated with a small amount of ethyl acetate and diethyl ether to give more of the title compound, which was collected by filtration to yield a further 0.35 g.
The total yield was 1.15 g.

Melting point: 183-184C.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
2.95-3.95 (4H, multiplet);
4.46 (lH, doublet of doublets, J=4 ~ 8Hz):
5.33 (lH, doublet of doublets, J=5 & 8Hz);
6.9-7.5 (3H, multiplet);
7.87 (4H, singlet);
8.12 (lH, broad triplet, J=7Hz).

6-Amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepine 0.35 ml of N-methylhydrazine was added to a suspension of 0.50 g of 5-oxo-6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 18) in a mixture of 4 ml of methanol and 8 ml of methylene chloride. The mixture was stirred at room temperature for 2 days to give a homogeneous solution. The solution was then subjected to column chromatography through silica gel, eluted with a 1:9 by volume mixture of methanol and methylene chloride, to give 0.30 g of the title compound melting at 155-158C.

[a]25 O~ (C=l.O, dimethylformamide).

The optical rotation showed that the compound was a racemate of the compound described in Preparation 15.
The Rf value on thin-layer chromatography using a mixture of butanol, acetic acid and water (4:1:1 by volume) as the developing solvent and the NMR spectrum were identical with those of the compound prepared as described in Preparation 15.

13329~3 S-[2-Nitro-1-(3-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine In the same manner as described in Preparation 12, S-alkylation of _-t-butoxycarbonyl-L-cysteine with l-nitro-2-(3-thienyl)ethylene instead of l-nitro-2-(2-thienyl)ethylene gave the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.47 (9H, singlet);
2.7-3.4 (2H, multiplet);
4.1-5.7 (5H, multiplet);
7.0-7.45 (3H, multiplet).

S-[2-Amino-1-(3-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine In the same manner as described in Preparation 13, reduction of S-[2-nitro-1-(3-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine (prepared as described in Preparation 20) afforded the title compound as a powder.

Nuclear Magnetic Resonance Spectrum (D2O + NaOD) ppm:
1.90 (9H, singlet);
3.25-3.6 (4H, multiplet);
4.45-4.7 (2H, multiplet);
7.6-7.95 (3H, multiplet).

6(R)-t-Butoxycarbonylamino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepine In the same manner as described in Preparation 14, intramolecular condensation of S-[2-amino-1-(3-thienyl)-ethyl]-N-t-butoxycarbonyl-L-cysteine (prepared as described in Preparation 21) afforded the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
1.40 (9H, singlet);

2.6-2.85 (2H, multiplet);
3.7-4.3 (3H, multiplet);
4.60 (lH, multiplet);
6.59 (lH, broad doublet, J=6.5Hz);
7.14 (lH, multiplet);
7.4-7.6 (2H, multiplet);
-7.89 (lH, broad triplet, J=6.5Hz).

6(R)-Amino-5-oxo-2(R)-(3-thienYl)perhydro-1,4-thiazepine In the same manner as described in Preparation 15, deprotection of 6(R)-t-butoxycarbonylamino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepine (prepared as described in Preparation 22) followed by fractional crystallization gave the title compound as crystals, melting at 191.5-197C (with gradual decomposition from 173C) [a] +57.2 (C=l.O, dimethylformamide).

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
2.55-3.0 (2H, multiplet);

3.35-4.2 (4H, multiplet);
7.13 (lH, multiplet);
7.4-7.6 (2H, multiplet);
7.83 (lH, multiplet).

S-(2-Nitro-l-phenylethyl)-N-t-butoxycarbonyl-L-cysteine In the same manner as described in Preparation 12, S-alkylation of _-t-butoxycarbonyl-L-cysteine with ~-nitrostyrene instead of l-nitro-2-(2-thienyl)-ethylene gave the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDC13) ~ ppm:
1.46 (gH, singlet);
2.8-3.0 (2H, multiplet);
4.3-4.8 (4H, multiplet);
5.32 (lH, multiplet);
7.35 (5H, singlet);

9.43 (lH, singlet).

S-(2-Amino-l-phenylethyl)-N-t-butoxycarbonyl-L-cysteine In the same manner as described in Preparation 13, reduction of S-(2-nitro-1-phenylethyl)-_-t-butoxy-carbonyl-L-cysteine (prepared as described in Preparation 24) afforded the title compound as a powder.

Nuclear Magnetic Resonance Spectrum (D20 + NaOD) ppm:
1.89 & 1.93 (9H, each singlet);
3.2-3.6 (4H, multiplet);
4.3-4.65 (2H, multiplet);
7.94 (5H, singlet).

6(R)-t-Butoxycarbonylamino-5-oxo-2-phenYlPerhydro-l~4 thiazepine In the same manner as described in Preparation 14, intramolecular condensation of S-(2-amino-1-phenyl-ethyl)-N-t-butoxycarbonyl-L-cysteine (prepared as described in Preparation 25) gave the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO]
ppm:
1.41 (9H, singlet);
2.6-4.3 (5H, multiplet);

4.5-4.85 (lH, multiplet);
6.4-6.8 (lH, multiplet);
7.37 (5H, singlet);
7.75-8.15 (lH, multiplet).

6(R)-Amino-5-oxo-2~R)-phenylperhydro-1,4-thiazepine In the ~ame manner as described in Preparation 15, deprotection of 6(R~-t-butoxycarbonylamino-5-oxo-2-phenylperhydro-1,4-thiazepine (prepared as described in Preparation 26) followed by fractional crystallization gave the title compound as crystals, melting at 222-229C (with decomposition from 205C).

[a]25 +19.5 (C=1.0, dimethylformamide).

Nuclear Magnetic Resonance Spectrum ~(CD3)2SO]
ppm:
2.58 (lH, doublet of doublets, J=3 ~ 14Hz);
2.88 (lH, doublet of doublets, J=9 & 14Hz);
3.2-4.0 (3H, multiplet);
4.11 (lH, doublet of doublets, J=3 ~ 9Hz);
7.39 (5H, singlet).

Claims (8)

1. A process for preparing a compound of formula (I):
(I) (in which:

R1 represents an alkyl group, an alkyl group having a cycloalkyl substituent or an aralkyl group;

R2 represents a carboxy-protecting group or a hydrogen atom; and R4 and R5 are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group having from 5 to 14 ring atoms, of which from 1 to 5 are nitrogen and/or oxygen and/or sulphur hetero-atoms) or a salt or ester thereof, which process comprises:

reacting a compound of formula (II):

(II) (in which R1 is as defined above, R2a represents a carboxy-protecting group and R3 represents an aryl group or a haloalkyl group) with a compound of formula (III):

(III) (in which R4 and R5 are as defined above), to give a compound of formula (IV):

(IV) (in which R1, R2a, R4 and R5 are as defined above); reacting said compound of formula (IV) with a compound of formula (V):

XCH2COOR6 (V) (in which X represents a halogen atom and R6 represents a carboxy-protecting group) in the presence of a base, to give a compound of formula (VI):

(VI) (in which R1, R2a, R4, R5 and R6 are as defined above); if necessary, removing the carboxy-protecting group R6 and optionally R2a to afford said compound of formula (I); and optionally salifying and/or esterifying the product.

2. A process according to Claim 1, wherein R2 represents said carboxy-protecting group.

3. A process according to Claim 1, wherein, in said compound of formula (II):

R1 represents a C1-C9 alkyl group, a C1-C4 alkyl group having a C5-C7 cycloalkyl substituent, an aralkyl group in which the alkyl part is a C1-C4 alkyl group and the aryl part is a C6-C10 carbocyclic aryl group or said cycloalkyl-substituted alkyl group or aralkyl group having from 1 to 3 substituents selected from C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen atoms and C1-C4 alkylthio groups;

R2a represents a C1-C10 alkyl group, an aralkyl group in which the aryl part is a C6-C10 carbocyclic aryl group and the alkyl part is a C1-C4 alkyl group, a C6-C10 carbocyclic aryl group, a trialkylsilyl group or said alkyl, aralkyl, aryl or trialkylsilyl group having from 1 to 3 substituents selected from C1-C4 alkyl groups, halogen atoms, hydroxy groups, C1-C4 alkoxy groups, acyloxy groups, oxo groups, carboxyl groups, alkoxycarbonyl groups, alkoxycarbonyloxy groups, acylamino groups, nitro groups, cyano groups, amino groups, alkylamino groups, dialkylamino groups, alkylthio groups, arylthio groups, alkylsulphonyl groups, arylsulphonyl groups and 2-oxo-1,3-dioxolen-4-yl groups; and R3 represents a C1-C4 haloalkyl group, a C6-C10 carbocyclic aromatic group or a C6-C10 carbocyclic aromatic group having at least one substituent selected from nitro groups and halogen atoms.

4. A process according to Claim 1 or Claim 3, in which, in said compound of formula (III), R4 and R5 are the same or different and each represents a C1-C10 alkyl group, a C5-C7 cycloalkyl group, a C6-C10 carbocyclic aryl group or a heterocyclic group having from 5 to 10 ring atoms, of which from 1 to 3 are nitrogen and/or oxygen and/or sulphur hetero-atoms or said alkyl, cycloalkyl, aryl or heterocyclic group having at least one substituent selected from C1-C6 alkyl groups, aralkyl groups in which the aryl part is a C6-C10 carbocyclic aryl group and the alkyl part is a C1-C4 alkyl group, hydroxy groups, C1-C6 alkoxy groups, aralkyloxy groups in which the aryl part is a C6-C10 carbocyclic aryl group and the alkoxy group is a C1-C4 alkoxy group, C6-C10 carbocyclic aryloxy groups, halogen atoms, nitro groups, cyano groups, carboxy groups, alkoxycarbonyl groups in which the alkoxy part is a C1-C6 alkoxy group, amino groups, C1-C4 alkylamino groups, dialkylamino groups in which each alkyl part is a C1-C4 alkyl group, aliphatic and carbocyclic aromatic carboxylic acyl groups, alkylcarbamoyl groups in which the alkyl part is a C1-C4 alkyl group, dialkylcarbamoyl groups in which each alkyl part is a C1-C4 alkyl group, C1-C6 alkylthio groups, C6-C10 carbocyclic arylthio groups, C1-C6 alkylsulphonyl groups and C6-C10 carbocyclic arylsulphonyl groups.

5. A process according to Claim 1 or Claim 3, in which, in said compound of formula (V), R6 represents a C1-C10 alkyl group, an aralkyl group in which the aryl part is a C6-C10 carbocyclic aryl group and the alkyl part is a C1-C4 alkyl group, a C6-C10 carbocyclic aryl group, a trialkylsilyl group or said alkyl, aralkyl, aryl or trialkylsilyl group having from 1 to 3 substituents selected from C1-C4 alkyl groups, halogen atoms, hydroxy groups, C1-C4 alkoxy groups, acyloxy groups, oxo groups, carboxyl groups, alkoxycarbonyl groups, alkoxycarbonyloxy groups, acylamino groups, nitro groups, cyano groups, amino groups, alkylamino groups, dialkylamino groups, alkylthio groups, arylthio groups, alkylsulphonyl groups, arylsulphonyl groups and 2-oxo-1,3-dioxolen-4-yl groups.

6. A process according to Claim 1 or Claim 3, in which, in said compound of formula (II), the carbon atom to which said group represented by R1 is attached is in the R-configuration.

7. A process according to Claim 1 or Claim 3, in which said reaction of said compound of formula (II) with said compound of formula (III) is effected in the presence of a sulphonic acid scavenger.

8. A process according to Claim 1 or Claim 3, in which R4 and R5 are the same or different and each represents a furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl, isoquinolyl or indolyl group.