IE940214L - Perhydrothiazepine derivatives, their preparation and their¹therapeutic use - Google Patents

Description

T4 APPLICATION No. 80628 Perhydrothiazepine derivatives, their preparation and their therapeutic use.

The present invention relates to a series of perhydrothiazepine derivatives which have the valuable ability to lower blood pressure and hence which are of potential use in the treatment of humans and other animals suffering from elevated blood pressure.

There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) 20 can be caused by a variety of factors and a large number of drugs is available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension, as well as the degree of hypertension and the acceptance of the treatment by the patient. One of the known causes of hypertension is the presence in blood plasma of the polypeptide known as angiotensin II, and a reduction in the blood plasma levels of angiotensin II has been shown to reduce hypertension. The first step in the production of angiotensin II in the mammalian 35 body is the conversion of a blood protein, by the 80628 2 enzyme renin, to a polypeptide known as "angiotensin I". This angiotensin I is then converted by 5 angiotensin converting enzyme (hereinafter referredto, as is conventional, as "ACE") to angiotensin II.

Clearly, this preparative route provides several opportunities for reducing the plasma levels of angiotensin II, for example by inhibiting the activity of renin or of ACE. Certain polypeptides have been found to inhibit the activity of renin and have been proposed for use as hypotensive agents. Recently, it has also been discovered that certain perhydrothiazepine compounds are capable of inhibiting the activity of ACE and similarly have been proposed 2Q for use as hypotensive agents.

An advantage of inhibiting the activity of ACE, as compared with inhibiting the activity of renin, is 25 that ACE not only participates in the formation of angiotensin II, but also participates in the metabolism of bradykinin, converting it to an inert substance. Bradykinin is a natural vasodilator and . . its elimination would thus be a further positive factor in elevated blood pressure.

For example, certain perhydro-l,4-thiazepin-5-one derivatives (as well as their corresponding thiazocine analogs) are disclosed in European Patent Publication No. 68,173; these thiazepine derivatives differ from chose of the present invention principally in being unsubstituted at the 2- and 3-positions.

There is also a mention of certain 1,4-thiazepine derivatives similar to those of the present inventionin European Patent Publication No. 120,728 (published after the priority dates of the present application), but the 1,4-thiazepine derivatives disclosed therein differ from those of the present invention primarily in the nature of the substituent at the 6-position; additionally, those derivatives actually disclosed are unsubstituted at both the 2-and 3-positions.

The compounds of the present invention have the advantages over the prior art compounds of higher activity and a longer duration of activity, in general, than the prior art compounds, especially those of European Patent Publication No. 68,173. The compounds of the invention differ from the prior art compounds in that they possess at the 2- and/or 3-positions a group selected from certain specific groups which have an essentially hydrophobic (or lyophilic) nature. It is believed that the hydrophobic nature of such groups leads to enhanced binding of the compound to ACE (hence inhibiting the activity of ACE to a greater degree) and an increase in fat-solubility (which leads to enhanced retention in the tissues of the mammalian body and delayed excretion). These factors together lead to the expectation that the compounds of the invention will demonstrate a greater ability to lower blood pressure, coupled with a greater duration of activity.

The compounds of the invention are named herein as perhydro-1,4-thiazepine derivatives; an alternative nomenclature sometimes employed is as 1-thia-4-azacycloheptane derivatives.

The compounds of the present invention are those acids of formula (I): cooh , I r'-a-ch— nh wherein: cooh (I) .35 R1 represents a C^-C^ alkyl group, a Cj-Cg cycloalkyl group, a carbocyclic aryl group having from 6 to 14 ring carbon atoms, a partially hydrogenated carbocyclic aryl group having from 6 to 14 ring carbon atoms or a heterocyclic group having from 5 to 14 ring atoms, of which from l to 5 are hetero-atoms selected from the group consisting of nitrogen, sulphur and oxygen atoms, said groups represented by R1 being unsubstituted or having at least one substituent selected from the group consisting of: (a) oxo groups, C^-Cg alkyl groups, Cg-C10 carbocyclic aryl groups, aralkyl groups wherein the alkyl part is C1-Cg alkyl and the aryl part is cg"c1g carbocyclic aryl, hydroxy groups, C^-Cg alkoxy groups, alkoxyalkoxy groups where each alkoxy part is C1-Cg, aralkyloxy groups, wherein the alkoxy part is C^-Cg alkoxy and the aryl part is Cg-C1Q carbocyclic aryl, aryloxy groups wherein the aryl part is cg-c10 Gari30CYclic aryl, halogen atoms, nitro groups, cyano groups, carboxy groups, alkoxycarbonyl groups wherein the alkoxy part is C^-Cg alkoxy, amino groups, C^-Cg alkylamino groups, dialkylamino groups wherein each alkyl part is C^-Cg alkyl, aliphatic or carbocyclic aromatic carboxylic acylamino groups, carbamoyl groups, alkylcarbamoyl groups where the alkyl part is C1*Cg alkyl, dialkylcarbamoyl groups where each alkyl part is ^-Cg alkyl, C1-Cg alkylthio groups, Cg-C1Q carbocyclic arylthio groups, C^-Cg alkylsulphonyl groups and Cg-C10 carbocyclic arylsulphonyl groups wherein the aryl part is unsubstituted or has from l to 3 C1-Cg alkyl substituents; 2 4 R and R are the same or different and each represents a hydrogen atom, a alkyl group, a C3"CQ cycloalkyl group, an aralkyl group wherein the alkyl part is C2.'C6 an<* cke aryl part is C6~C10 carbocyclic arY1/ or a C6'Ci4 carbocyclic 2 4 aryl group, provided that R and R do not both represent hydrogen atoms, said groups represented by 2 4 R and R being unsubstituted or having at least one substituent selected from the group consisting of the substituents defined in (a) above; A represents a direct carbon-carbon bond, a methylene group, an ethylene group, an oxymethyl group or a thiomethyl group; B represents a alkylene or alkylidene group or a C3-Cg cycloalkylene or cycloalkylidene group; a is 0, 1 or 2; and pharmaceutically acceptable salts thereof; and carboxy protected esters thereof selected from carboxy protected esters of use as synthetic intermediates and carboxy protected esters of use as pharmaceuticals.

The invention also provides a pharmaceutical composition for the treatment of angiotensin-induced hypertension, which composition comprises a hypotensive agent in admixture with a pharmaceutically acceptable carrier or diluent, wherein said hypotensive agent is selected from the group consisting of acids of formula (I), pharmaceutically acceptable salts thereof and esters thereof, as defined above.

The invention also provides processes for preparing the compounds of the invention, which are described in more detail hereafter.

In the compounds of the invention, R1 may 20 represent an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group.

Where R1 represents an alkyl group, this may be a straight or branched chain alkyl group which has from 1 to 10, more preferably from 1 to 8, carbon atoms. Examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl and octyl groups.

Where R1 represents a cycloalkyl group, this has 35 from 3 to 8, more preferably from 5 to 7, ring carbon atoms and examples of such groups include the cyclopentyl, cyclohexyl and cycloheptyl groups. 8 Where R1 represents an aryl group, this is preferably a carbocyclic aryl group which 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, 1-naphthyl and 2-naphthyl groups.

Where R1 represents a partially hydrogenated carbocyclic aryl group, this is preferably a polycyclic (more preferably bicyclic) system having from 8 to 14, more preferably 9 to 14 and most preferably 9 or 10 ring carbon atoms. In particular, we prefer that it should consist of a fully aromatic ring fused to another ring, of which all carbon atoms other than those at the points of fusion are fully saturated. Accordingly, the most preferred such groups are the indanyl and 1,2,3,4-tetrahydronaphthyl groups. We prefer that the group should be attached to the bond or group represented by A via one of the saturated carbon atoms. Accordingly, preferred groups are the 2-indanyl, l-(1,2,3,4-tetrahydronaphthyl) and 2 - (1,2,3,4-tetrahydronaphthyl) groups.

Where R1 represents a heterocyclic group, this may be a saturated or unsaturated heterocyclic group and may be monocyclic or polycyclic (preferably bicyclic); it preferably has from 5 to 10 ring atoms, of which from 1 to 5, more preferably from 1 to 3, are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur atoms. Examples of such heterocyclic groups include the tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, morpholinyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl and indolyl groups.

These groups represented by R1 may be unsubstituted or may have at least one substituent selected from the following groups: except where the group represented by R1 is itself an alkyl group, ^-Cg, preferably alkyl groups, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups; Cg-C1Q carbocyclic aryl groups, which may be monocyclic or fused polycyclic (preferably bicyclic) groups and which may themselves be substituted as here defined, particularly the phenyl, 1-naphthyl or 2 -naphthyl groups; aralkyl groups in which the alkyl part is C^-Cg alkyl and the aryl part is Cg-C10 carbocyclic aryl, for example the benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl and 3-phenylpropyl groups; the hydroxy group; C1-Cg, preferably C1-C4, alkoxy groups, for example the methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy groups; aralkyloxy groups, in which the aryl part is Cc-C.n o 1U carbocyclic aryl, more preferably phenyl, and the alkyl part is C^-Cg alkyl, more preferably C1-C2 alkyl and most preferably methyl, for example the benzyloxy group; aryloxy groups, in which the aryl part is Cg-C1Q carbocyclic aryl, more preferably phenyl, for example the phenoxy group; halogen atoms, for example the fluorine, chlorine and bromine atoms; the nitro, cyano and carboxy groups; alkoxycarbonyl groups, in which the alkoxy part is C1-Cg, more preferably C1-C3, alkoxy, for example the methoxycarbonyl and ethoxycarbonyl groups; the amino group; alkylamino groups in which the alkyl part is C^-Cg, more preferably C]L-C4, alkyl, for example the methylamino and ethylamino groups; dialkylamino groups, in which each alkyl part is CVC6, preferably C1-C4' more preferably C^-C^, alkyl, for example the dimethylamino or diethylamino groups; acylamino groups, which can be aliphatic acylamino groups, preferably having from 1 to 7, more preferably from 1 to 4, carbon atoms or carbocyclic aromatic carboxylic acylamino groups in which the aromatic part is Cg-C10 carbocyclic aryl and is more preferably a phenyl group, for example the acetamido and benzamido groups; the carbamoyl group; the alkyl carbamoyl and dialkyl carbamoyl groups, in which the or each alkyl part is C1-Cg, more preferably C1-C4 and most preferably Cj/Cj, alkyl, for example the N-methylcarbamoyl, N-ethylcarbamoyl, dimethyl carbamoyl or diethyl carbamoyl groups; .

C1-Cg, more preferably alkylthio groups, for example the methylthio or ethylthio groups; aryl thio groups in which the aryl part is Cg-C^g carbocyclic aryl, more preferably phenyl, for example the phenylthio groups; 12 C1-Cg# more preferably C1-C4 alkylsulphonyl groups, for example the methanesulphonyl or ethanesulphonyl groups; arylsulphonyl groups in which the aryl part is Cg-CiQ carbocyclic aryl, more preferably phenyl, for example the benzenesulphonyl group.

Where the group represented by R1 is substituted, the maximum number of substituents will, of course, depend upon the size of the group to be substituted and the steric effects exerted by the substituents; if the group represented by R1 is small, for example a lower alkyl group, and the substituent bulky, then steric hindrance may limit the number of potential substituents; at the other extreme, if the substituent is small, the number of substituents may only be limited by the number of available valencies of the atoms in the group represented by R1. For example, where the substituent is a fluorine or chlorine atom, R1 could represent a perfluoroalkyl or perchloroalkyl group. However, in general, from 1 to 3 substituents are preferred, although it should be appreciated that more may be appropriate in specific cases, as is well recognized by those skilled in the chemical arts.

Where R2 or R4 represents an alkyl group, this 13 r is a C1-C10 alkyl group, which may be a straight or branched chain group, more preferably having from l to 8 carbon atoms. Examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl-, hexyl, heptyl and octyl groups. 2 4 Where R or R represents a cycloalkyl group, this has from 3 to 8, more preferably from 5 to 7, ring carbon atoms and preferred such groups include the cyclopentyl, cyclohexyl and cycloheptyl groups. 2 4 Where R or R represents an aralkyl group, the alkyl part is a C1-Cg alkyl group (examples being those C^-Cg alkyl groups included amongst the examples of alkyl groups which may be represented by R1) and the aryl part is a Cg-C10 carbocyclic aryl group (examples of which are those groups given as examples of aryl groups which may be represented by R1). Preferred aralkyl groups are the benzyl, phenethyl and 3-phenylpropyl groups.

Where R2 or R4 represents a carbocyclic aryl group, this preferably has from 6 to 10 ring carbon atoms and may be a monocyclic or fused polycyclic (normally bicyclic) group. Preferred examples inlcude the phenyl, 1-naphthyl and 2-naphthyl groups. 14 Instead of the groups described above, R2 or R4 can represent a hydrogen atom, however, both of these symbols may not represent hydrogen atoms, in other words there must be 1 group other than hydrogen at the 2- or 3-, preferably the 2-, positions. Those compounds are 2 4 particularly preferred where one of R and R , 4 preferably R , represents a hydrogen atom and the 2 4 other of R and R represents one of the aforementioned groups. 2 4 The groups defined above for R and R may be unsubstituted or may have at least one substituent selected from those substituents defined in (a) above as substituents on the groups represented by R1. As with 1 2 4 R , where any group represented by R or R is substituted, the number of substituents is only limited by steric considerations, which, of course, vary depending upon the nature of the substituent and the substituted groups and so cannot be defined in general terms. Normally, however, it is convenient, where such groups are substituted, to have from 1 to 3 substituents, but it should be appreciated that this does not, in any sense, represent a practical limit.

The symbol A can represent a direct single bond between the group represented by R1 and the carbon atom of the group CH-NH- at the 6- position of the thiazepine ring; alternatively, it can represent a methylene group, an ethylene group, an oxymethyl (-OCH2") group or a thiomethyl (-SCH^-) group. We prefer that A should represent an ethylene group and more particularly prefer that the group represented by R1-A- should be: a straight or branched chain alkyl group having from 4 to 9 carbon atoms, for example a butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, octyl, isooctyl or nonyl group; a 2-cycloalkylethyl group, in which the cycloalkyl part has 5 or 6 ring carbon atoms, for example a 2-cyclopentylethyl or 2-cyclohexylethyl group; an aralkyl group having a total of from 7 to 12 carbon atoms, for example a benzyl, phenethyl, 1-naphthyl-methyl, 2 -naphthylmethyl, 2 -(1-naphthyl)ethyl or 2 -(2 -naphthyl)ethyl group; a phenoxymethyl or phenylthiomethyl group; or 30 a heterocyclic-substituted ethyl group, for example a 2 -(2 -thienyl)ethyl, 2 -(2-imidazolyl)ethyl or 2-(2-thiazolyl)ethyl group. n may be 0, 1 or 2, but is most preferably 0. 16 B may represent a C^-C4 alkylene or alkylidene group or a C3-Cg cycloalkylene or cycloalkylidene group. Examples of such alkylene groups which may be represented by B are the methylene, ethylene, trimethylene and tetramethylene groups. Where B represents an alkylidene group, this may be an ethylidene, propylidene or butylidene group, preferably an ethylidene group. Where B represents a C^-Cg cycloalkylene or cycloalkylidene group, these may be the cyclopropylene, cyclopropylidene, cyclobutylene, cyclobutylidene, cyclopentylene, cyclopentylidene,. cyclohexylene or eyelohexylidene groups, preferably the cyclopropylidene group. B most preferably represents a methylene group.

The compounds of formula (I) have two free carboxy groups and can thus form mono- or di- esters with appropriate ester-forming groups. There is no practical limitation upon the nature of the ester-forming groups employed in this invention, beyond the practical consideration that, if the resulting compounds-are in themselves to be used for the treatment of human beings or other animals, the resulting esters must be "pharmaceutically acceptable"; this, to the skilled man, means that the ester- forming groups must not, or must not to an unacceptable extent, reduce the activity or increase the toxicity of the compounds. Where the resulting compounds are not in themselves to be used as 17 medicines but, instead, are to be used as intermediates in the preparation of other compounds, even this practical restriction does not apply and any ester appropriate to the intended preparative route may be formed.

The resulting compounds of the invention may be represented by the formula (la): coor6 R1—A-CH—HH n (0) I R 2 0 8 I , coor' (la) - 1 4 (wherein R -R , A, B and rj are as defined above and 6 7 R and R , which are the same or different, each represents a hydrogen atom or a C1-C10 alkyl group, an aralkyl group in which the aryl part is a C6"C10 carbocyclic aryl group which is unsubstituted or substituted as defined in (b) below and the alkyl part is C^/Cg alkyl, a Cg-C14 carbocyclic aryl group, a partially hydrogenated Cg-C14 carbocyclic aryl group, a phthalidyl group or a trialkylsilyl group where each alkyl part is C1-Cg alkyl, said groups 18 6 7 represented by R and R being unsubstituted or having at least one substituent selected from the group consisting of: (b) halogen atoms, hydroxy groups, C -Cc alkoxy X o groups, (C^-Cg alkoxy) - (C^-C^ alkoxy) groups, aliphatic and carbocyclic aromatic carboxylic acyloxy groups, oxo groups, carboxy groups, alkoxycarbonyl groups where the alkoxy part is C1~Cg alkoxy, alkoxycarbonyloxy groups where the alkoxy part is C^-Cg alkoxy, aliphatic and carbocyclic aromatic carboxylic acylamino groups, nitro groups, cyano groups, amino groups, C^-Cg alkylamino groups, dialkylamino groups where each alkyl part is C1-Cg alkyl, Cg-C10 carbocyclic arylamino groups, C1-Cg alkylthio groups, cg"C1Q carbocyclic arylthio groups, C1*Cg alkylsulphonyl groups, cg_c10 carbocyclic arylsulphonyl groups and heterocyclic groups having from 5 to 14 ring atoms, of, which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, sulphur and oxygen atoms, said heterocyclic groups being unsubstituted or having at least one substituent selected from the group consisting of the substituents defined in (a) above.

Examples of such groups which may be represented by G 7 R and R inciude: 19 C1-Cg alkyl groups, such as Che methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl groups; aralkyl and diarylalkyl groups, such as the benzyl and benzhydryl (diphenylmethyl) groups; partially hydrogenated Cg"c10 carbocyclic aryl groups, such as the 1-indanyl, 2-indanyl, l - (1,2,3,4-tetrahydronaphthyl) and 2 -(1,2,3,4-tetrahydronaphthyl) groups; the phthalidyl group; Cg-C^g carbocyclic aryl groups, particularly the phenyl group; trialkylsilyl groups, particularly the trimethylsilyl and t-butyldimethylsilyl groups; and such groups listed above having one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, alkoxyalkoxy, acyloxy, oxo, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, acylamino, nitro, cyano, amino, alkylamino, dialkylamino, arylamino, alkylthio, arylthio, alkylsulphonyl, arylsulphonyl and 2-oxo-l,3-dioxolen-4-yl (which may itself be substituted) substituents.

Where substituents are present, their number is only limited by steric considerations, which depend upon the size of the substituent and of the substituted group; however, in general, from 1 to 3 substituents would be present.

Examples of such substituted groups which may be 6 7 represented by R or R include the 2,2,2-trichloroethyl, 2-iodoethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, methoxymethyl, 2-methoxy-ethoxymethyl, £-methoxybenzyl, acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl, phenacyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyloxy)ethyl, g-nitrobenzyl, 2-cyanoethyl, methylthiomethyl, ethylthiomethyl, phenylthiomethyl, 2 - methanesulphonylethyl, 2-benzenesulphonylethy1, (5-methyl-2-oxo-l, 3-dioxolen-4-yl)methyl and (5-phenyl- 2-oxo-l,3-dioxolen-4-yl)methyl groups.

Preferred classes of compounds of the present invention are those compounds of formula (la) in which the substituents are defined as follows: (A) Compounds in which: 21 R1 represents a phenyl group or a C2-C? alkyl group; 3 2 4 R and R are the same or different and each represents a hydrogen atom, a alkyl group, a phenyl group, a naphthyl group, a C^-Cg cycloalkyl jq group or a heterocyclic group having from 5 to 10 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur atoms; provided that they do not both represent a hydrogen atom; A represents an ethylene group; B represents a methylene group; and n is 0; 2 4 (A') R and R are the same or different and each represents a hydrogen atom, a C1-C10 alkyl group, a phenyl group, a naphthyl group, a C3-Cg cycloalkyl group or a heterocyclic group having 5 or 6 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulphur atoms; and R1, A, B and ri are as defined in (A) above; provided that R2 and R4 do not both represent a hydrogen atom; 22 (B) Compounds as defined in (A) above in which R6 represents a hydrogen atom, a C1-C1Q alkyl group or an aralkyl group in which the aryl part is a C^-C 6 10 carbocyclic aryl group and the alkyl part is a C -Cc 1 6 alkyl group; (C) Compounds in which: R1 represents a phenyl group or a C2*C7 alkyl group; 2 R represents a alkyl group, a phenyl group, a naphthyl group or a C3-C0 cycloalkyl group; 4 R represents a hydrogen atom; 6 R represents a hydrogen atom, a C^-C^ alkyl group or an aralkyl group of which the aryl part is a Cg-C1(3 carbocyclic aryl group and the alkyl part is a C^-Cg alkyl group; 7 R represents a hydrogen atom, a (C1-C4 alkoxy)carbonyloxy(C1-C4 alkyl) group, a (C2"cs alkanoyl)oxy(C1-C4 alkyl) group, a (5-alkyl-2-oxo-l,3-dioxolen-4-yl)alkyl group in which each alkyl group has from 1 to 4 carbon atoms, a (5 -phenyl-2 -oxo-1,3-dioxolen-4 -y1)alkyl group in which the alkyl part has from 1 to 4 carbon atoms, or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0; (D) Compounds in which: R1 represents a phenyl group or a C2*C7 alkyl group; 2 R represents a phenyl group, a naphthyl group, a C^-Cg alkyl group or a C3-C3 cycloalkyl group; 4 R represents a hydrogen atom; R6 represents a hydrogen atom, a C^Cg alkyl group or an aralkyl group of which the aryl part is. a Cg-C1Q carbocyclic aryl group and the alkyl part is a Cx-C4 alkyl group; R7 represents a hydrogen atom, an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a (2-oxo-l,3-dioxolen- 4-yl)alkyl group where the alkyl group is Cx-C4 and which has a Cx-C4 alkyl or phenyl substituent at the -position, or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0; (E) Compounds in which: R1 represents a phenyl group or a Cj-C-y alkyl group; 2 R represents a naphthyl group; 4 R represents a hydrogen atom; R^ represents a hydrogen atom, a C^-Cg alkyl group or an aralkyl group of which the aryl part is a Cg-C1Q carbocyclic aryl group and the alkyl part is a alkyl group; 7 R represents a hydrogen atom, an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a (2 -oxo-1,3-dioxolen- 4-yl)alkyl group where the alkyl group is C1~C4 and which has a alkyl or phenyl substituent at the -position, or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0; (F) Compounds in which: R1 represents a phenyl group or a C2~C7 alkyl group; 1 c 2 R represents a hydrogen atom; 4 R represents a C1-Cg alkyl group, a phenyl group, a naphthyl group or a C0-Ca cycloalkyl group; 3 8 R6 represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group or a phenylethyl group; 7 R represents a hydrogen atom, a (C2-C5 alkcuioyl) oxy (C1-C3 alkyl) group, a (Cx-C4 alkoxy)carbonyloxy(C1-C3 alkyl) group, a 30 (5-alkyl-2-oxo-l,3-dioxolen-4-yl)alkyl group in which each alkyl part is C1-C3, a (5-phenyl-2-oxo-l,3-dioxolen-4-yl)alkyl group in which the alkyl part is C1-C3 or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0. 6 7 Where R or R represents an ester-forming group, these are preferably either carboxy-protecting groups which are commonly used in organic chemical synthesis, such as the t-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, E-methoxybenzyl or benzhydryl groups, or a protecting group which is easily convertible to a free carboxy group in vivo, such as the acetoxymethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)-ethyl, phthalidyl or (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl groups.

Where the compounds of the invention contain one or two free carboxy groups, these compounds may also form salts with bases; the nature of the cation of the resulting salt is not critical to the present invention and, where the resulting compounds are for use as medicines, is only limited to the extent that the resulting salt must be pharmaceutically acceptable; where the compound is subsequently to be used as an intermediate for the production of another compound, even this restriction is not applicable. Of course, there are practical constraints, such as cost and availability of the bases used to form the salts, but these constraints vary from time to time and are irrelevant to the essence of the present invention. Examples of suitable salts include: alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; ammonium salts; salts with organic bases, for example triethylamine, dicyclohexylamine, cinchonine, guanidine or quinine salts; and salts with basic amino acids, for example lysine or arginine salts.

The compounds of the invention also contain a nitrogen atom which can potentially exert a basic effect and the compounds can thus also form acid addition salts. Where the compounds are to be used as medicines, the nature of such salts is only limited to the extent that the resulting compound should be pharmaceutically acceptable; where the compound is to be used as an intermediate, this criterion does not apply and any acid may be employed. Examples of suitable acids include inorganic acids, such as hydrogen halides, (for example hydrochloric acid or hydrobromic acid), sulphuric acid, phosphoric acid or nitric acid; organic carboxylic acids, for example oxalic acid, maleic acid, fumaric acid, tartaric acid or citric acid; and organic sulphonic acids, such as methanesulphonic acid or benzenesulphonic acid.

Examples of certain compounds of the present invention are given in the following list: 28 1. a-[6-(1-ethoxycarbonylnonylamino)- 5-oxo-3-phenyl-perhydro-1,4-thiazepin-4-yl]acetic acid 2. a-[6-(1-carboxynonylamino)- 5-oxo-3-phenyl-perhydro-1,4-thiazepin-4-yl]acetic acid 3 . a - [6 -(3 -cyclohexy1-1-ethoxycarbonylpropyl-amino)- 5 -oxo-3 -phenylperhydro-1,4-thiazepin-4 -yl]-acetic acid 4. a - [6-(1-carboxy-3-cyclohexylpropylamino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetic acid . 2 -[6-(1-ethoxycarbonylnonylamino)-5 -oxo- 3 -phenyl-perhydro-1,4-thiazepin-4-yl]propionic acid 6. 2 -[6 -(1-carboxynonylamino)- 5 -oxo-3 -phenyl-perhydro-1,4-thiazepin-4-yl]propionic acid 7. 2-[6-(1-ethoxycarbonyl-3 -phenylpropylamino)- 3 -isopropyl-5-oxoperhydro-l,4-thiazepin-4-yl]propionic ac 8. 2 -[6 -(1-carboxy-3-phenylpropylamino)- 3 -isopropy1-5-oxoperhydro-l,4-thiazepin-4-yl]propionic acid 9. 2-[3-sec-butyl-6-(1-ethoxycarbonyl- 3-phenylpropyl-amino)-5-oxoperhydro-l,4-thiazepin-4-yl]propionic acid 29 . 2 -[3 - sec -butyl- 6 -(l-carboxy- 3 -phenylpropyl-amino)-5-oxoperhydro-l,4-thiazepin-4-yl]propionic acid 11. a-[6-(1-ethoxycarbonyl- 3-phenylpropylamino) -3-isobutyl-5-oxoperhydro-1,4-thiazepin-4-yl]-acetic acid 12. a-[6-(1-carboxy-3-phenylpropylamino)-3-isobutyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 13. a-[6-(1-ethoxycarbonyl-3-phenylpropylamino)- 3-(2-methylthioethyl)- 5-oxoperhydro-1,4-thiazepin- 4-yl]acetic acid 14. a-[6-(1-carboxy-3-phenylpropylamino)-3-(2-methyl-thioethyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid . a-[3-cyclohexyl-6-(1-ethoxycarbonyl-3-phenylpropylamino) -5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 16. a-[3-cyclohexyl-6-(1-carboxy-3-phenylpropylamino) -5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 17. a-[3-benzyl-6-(1-ethoxycarbonyl- 3-phenylpropylamino) -5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 18. a -[3 -benzyl- 6 -(1-carboxy- 3 -phenylpropylamino)- -oxoperhydro-1,4-thiazepin-4-yl]acetic acid 19 . -a - [3-benzyl-6 - (1-echoxycarbonyl-3-phenylpropylamino) -1,5-dioxoperhydro-l,4-thiazepin-4-yl]acetic acid . a-[3-benzyl-6-(1-ethoxycarbonyl-3-phenylpropyl-amino)-1,l,5-trioxoperhydro-l,4-thiazepin-4-yl]acetic acid 21. a -[3 -benzyl-6 -(1-butoxycarbonyl-3 -phenyl-propylamino)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 22. 2-[3-benzyl-6-(1-ethoxycarbonyl-3-phenylpropylamino) - 5-oxoperhydro-1,4-thiazepin-4-yl]propionic acid 23. a -[2 -benzyl- 6-(1-ethoxycarbonyl- 3 -phenyl-propylamino)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 24. a-[2-benzyl-6-(l-carboxy-3-phenylpropylamino)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid . a-[6-(1-ethoxycarbonyl- 3 -phenylpropyl- amino)- 3-e-hydroxybenzyl-5 -oxoperhydro-1,4-thiazepin-4-yl]acetic acid 26. a - [6-(l-carboxy-3-phenylpropylamino)-3-£-hydroxy-benzyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 31 27. a -[6 -(1-ethoxycarbonyl- 3 -phenylpropyl-amino)- 5-oxo-3-phenylperhydro-1,4 -thiazepin-4-yl]-acetic acid 2 8. a -[6 -(1-carboxy- 3 -phenylpropylamino)- 5 -oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 29. a-[6-(1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]-acetic acid . a-[6-(l-carboxy-3-phenylpropylamino)-5-oxo- 2-phenylperhydro-l,4-thiazepin-4-yl]acetic acid 31. o-[6 -(1-ethoxycarbonyl- 3 -phenylpropylamino)- 3-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 32. a-[6-(1-carboxy-3-phenylpropylamino)-3-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 33. a-[6-(1-ethoxycarbonyl- 3 -phenylpropylamino)- 3- (1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 34. a-[6-(l-carboxy-3-phenylpropylamino)-3-(l-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 32 55. 1-[6-(1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-3-phenylperhydro-l,4-thiazepin-4-yl]-cyclopropanecarboxylic acid 56. a -{3 -benzyl- 6 -[1-ethoxycarbonyl- 2 -(1- naphthyl)ethylamino]-5-oxoperhydro-l,4-thiazepin-4-yl}-acetic acid 57. a-{3-benzyl-6-[l-carboxy-2-(1-naphthyl)ethylamino] -5-oxoperhydro-l,4-thiazepin-4-yl}acetic acid 58. a -{6 -[1-ethoxycarbonyl- 3 -(2 -naphthyl)propyl-amino]- 5 -oxo-3 -phenylperhydro-1,4-thiazepin- 4 - y 1} -acetic acid 59. a -{6-[1-carboxy-3 -(2 -naphthyl)propylamino]- -oxo- 3 -phenylperhydro-1,4-thiazepin-4 -yl}acetic acid 60. a-{6-[1-ethoxycarbonyl-3-(2-thienyl)propyl-amino] -5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl}-acetic acid 61. a -(6 - [1- carboxy- 3 - (2 - thienyl) propylamino] - - oxo- 3 -phenylperhydro-1,4-1hiazepin-4-yl}acetic acid 62. a - {6-[1-ethoxycarbonyl-3-(2-imidazolyl)propyl-amino]- 5 -oxo- 3 -phenylperhydro-1,4-thiazep in-4-y1}-acetic acid 33 63. a -{6 -[1-carboxy-3 -(2 -imidazolyl)propyl - amino] -5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl}-acetic acid 64. a-{6-[1-ethoxycarbonyl-3 -(1,3-thiazol-2-yl) - , • , propylamino]-5-oxo-3-phenylperhydro-l/4-thiazepm-4-yl}- acetic acid 65. a-{6-[1-carboxy-3 -(1,3-thiazol- 2 -yl)-propylamino]- 5 -oxo- 3 -phenylperhydro-1,4-thiazepin- 4 -y1}-acetic acid 66. a-[6-(1-ethoxycarbonyl- 2-phenoxyethyl- amino)- 5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]-acetic acid 67. a-[6-(1-carboxy-2-phenoxyethylamino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 68. a - [6- (l-ethoxycarbonyl-2-phenylthioethyl-. amino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]-acetic acid 69. a-[6-(l-carboxy-2-phenylthioethylamino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 70. pivaloyloxymethyl a -[6-<1-ethoxycarbonyl- 3 -phenylpropylamino)- 5 -oxo- 3 -phenylperhydro-1,4-thiazepin-4-yl]acetate 71. l-(ethoxycarbonyloxy)ethyl a-[6-(1-ethoxy-carbonyl- 3-phenylpropylamino)- 5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetate 72. (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl a-[6- (1-ethoxycarbonyl- 3 -phenylpropylamino)- 5 -oxo-3 -phenyl-perhydro-1,4-thiazepin-4-yl]acetate 73. a-{5-oxo-3-phenyl-6-[3-phenyl-1-(pivaloyloxy-methoxycarbonyl)propylamino]perhydro-1,4-thiazepin-4 -yl}acetic acid 74. t-butyl «-[6-(1-ethoxycarbonyl-3 -phenylpropyl-amino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetate 75. t-butyl a-[6-(1-ethoxycarbonyl- 3 -phenylpropyl-amino)-5 -oxo-2 -phenylperhydro-1,4-thiazepin-4-yl]acetate 76. t-butyl 2 -[6-(1-ethoxycarbonyl- 3 -phenylpropyl-amino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]-propionate 133. a - [ 6 - (1 -carboxy- 3 -phenylpropylamino)- 2 -(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 134. a-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 135. a-[6-(1-butoxycarbonyl-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 136. a-[6-(1-isobutoxycarbonyl-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 137. a - [6- (1-benzyloxycarbonyl-3-phenylpropylamino) -2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 138. a- [6-(1-carboxy-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 139. a - [6 - (1-ethoxycarbonyl-3-phenylpropylamino)-2- (2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 140. a - [6-(1-butoxycarbonyl-3-phenylpropylamino)-2- (2-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 141. a-[6-(1-isobutoxycarbonyl-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 142. a-[6-(1-benzyloxycarbony1-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 143. a-[6-(l-carboxynonylamino)-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 144. a-[6-(1-ethoxycarbonylnonylamino)-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 145. a-[6-(1-carboxy-3-methylbutylamino)-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 146. a-[6-(1-ethoxycarbonyl-3-methylbutylamino)-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 147. a-[6-(1-carboxy-3-cyclohexylpropylamino)- 2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 148. a-[6-(3-cyclohexyl-l-ethoxycarbonylpropylamino)-2-(1-naphthyl)- 5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 149. a -{6 -[1-carboxy- 3 -(2 -indanyl)propylamino]- 2 -(1-naphthyl)- 5-oxoperhydro-1,4 -thiazepin-4-yl}acetic acid 150. a-{6-[l-ethoxycarbonyl-3-(2-indanyl)propyl-amino]-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl}-acetic acid 151. 2-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-2- (1-naphthyl)- 5 -oxoperhydro-1,4-thiazepin-4-yl]propionic acid 152. a-[6-(1-ethoxycarbonylnonylamino)-2- (2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 153. a-[6-(l-ethoxycarbonyl-3-methylbutylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 154. a-[6-(3-cyclohexyl-l-ethoxycarbonylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 155. a-[6-(l-ethoxycarbonyl-2-phenylethylamino)-2- (2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 38 156. a-(6-[l-ethoxycarbonyl-3-(2-indanyl)propyl-amino]-2 -{2 -naphthyl)- 5 -oxoperhydro-1,4-thiazepin-4-y1}-acetic acid 157. pivaloyloxymethyl a-[6-(1-ethoxycarbonyl- 3 -phenylpropylamino)- 2 -(1-naphthyl}- 5 -oxoperhydro-1,4- .0 thiazepin-4-yl]acetate 158. pivaloyloxymethyl a-[6-(1-ethoxycarbonyl- 3 -phenylpropylamino}- 2 -(2 -naphthyl)- 5-oxoperhydro-1,4-thiazepin-4-yl]acetate 159. 1-(ethoxycarbonyloxy)ethyl at-[6-(l-ethoxy- carbony1- 3 -phenylpropylamino)-2 -(1-naphthyl)- 5-oxo- perhydro-1,4-thiazepin-4-yl]acetate 160. 1-(ethoxycarbonyloxy)ethyl a-[6-(1-ethoxy- carbonyl-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro- 1,4-thiazepin-4-yl]acetate 161. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl a-[6- (1-ethoxycarbonyl- 3 -phenylpropylamino)-2 -(l-naphthyl)-5 -oxoperhydro-1,4-thiazepin-4-yl]acetate 162. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl a-(6-(l-ethoxycarbonyl-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetate 39 163. t-butyl a-[6-(l-ethoxycarbonyl-3-phenylpropylamino )- 2 -(1-naphthyl)- 5 -oxoperhydro-1,4-thiazepin-4-yl]acetate 164. t-butyl a-[6-(l-ethoxycarbonyl-3-phenylpropylamino) -2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetate 165. a-{2-(1-naphthyl)-5-oxo-6-[3- phenyl-1-(pivaloyloxymethoxycarbonyl)propylamino]-perhydro-1,4-thiazepin-4-yl}acetic acid 166. a- {2-(2-naphthyl)-5-oxo-6-[3-phenyl- 1-(pivaloyloxymethoxycarbonyl)propylamino]perhydro-1,4 -thiazepin-4-yl}acetic acid 167. a-{6-[1-(1-ethoxycarbonyloxyethoxy-carbonyl) -3-phenylpropylamino] - 2- (1-naphthyl) -5-oxoperhydro -1,4-thiazepin-4-yl}acetic acid 168. «-{6-[1-(1-ethoxycarbonyloxyethoxy-carbonyl)-3-phenylpropylamino]-2-(2-naphthyl)-5-oxoperhydro-l, 4-thiazepin-4-yl}acetic acid 169. 3-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-2- (1-naphthyl)- 5 -oxoperhydro-1,4 -thiazepin-4 -yl]propionic acid 40 170. 3-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-2- (2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]propionic acid 171. a-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-3-methyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 172- a-[6-(1-carboxy-3-phenylpropylamino)-3-methyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 173. a-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-3-isopropyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 174. a-[6-(1-carboxy-3-phenylpropylamino)-3-isopropyl-5->oxoperhydro-1,4-thiazepin-4-yl] acetic acid 175. a-[3-sec-butyl- 6 -(1-ethoxycarbonyl- 3 -phenyl- propylamino)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 176. a-[3-sec-butyl-6-(1-carboxy-3-phenylpropyl- amino)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 177. a-[6-(1-ethoxycarbonyl-3-phenylpropylamino)- 2-methyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 178. a-[6-(1-butoxycarbonyl-3-phenylpropylamino)- 2-methyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 41 179. a-[6-(1-carboxy-3-phenylpropylamino)-2-methyl -5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 180. a-[6-(1-ethoxycarbonyl-3-phenylpropylamino)- 2 - isopropyl-5-oxoperhydro-1,4 -thiazepin-4-yl]acetic acid 181. a -[6 -(1-butoxycarbony1- 3 -phenylpropylamino)- 2-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 182. a-[6-(1-carboxy-3-phenylpropylamino)-2- isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 183. a-[6-(l-ethoxycarbonyl-3-phenylpropylamino)- 2-isobutyl-5-oxoperhydro-l,4-thiazepm-4-yl]acetic acid 184. a -[6-(1-butoxycarbony1- 3 -phenylpropylamino)- ^ 2-isobutyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 185. a-[6-(1-carboxy-3-phenylpropylamino)-2-isobutyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 186. a-[6-(1-butoxycarbonyl-3-phenylpropylamino)-5-oxo-3-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 187. a-[6-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-2 -phenylperhydro-1,4-thiazepin-4-y1]acetic acid 42 188. a-[6-(l-bucoxycarbonyl- 3-phenylpropylamino)- -oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 189. a-[6-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetic acid 192. a-[6-(1-butoxycarbonyl-3-phenylpropylamino)-3-methyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 193. a-[6-(1-butoxycarbonyl-3-phenylpropylamino)-3-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid 194. «-[6-(1-butoxycarbonyl-3-phenylpropylamino)-3-sec-butyl- 5 -oxoperhydro-1,4-thiazepin-4-yl]acetic acid 195. a -[6-(1-butoxycaronyl-3-phenylpropylamino)- 3-isobutyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid 202. t-butyl a-[6-(1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepin-4- yl]acetate. 203. t-butyl a-[6-(1-benzyloxycarbonyl-3-phenylpropylamino) -5 -oxo-2-phenylperhydro-1,4 -thiazepin-4-yl]acetate. 206. t-butyl a-[6-(l-ethoxycarbonyl-3-phenylpropylamino) -3-isopropyl-5-oxoperhydro-l,4-thiazepin-4-yl]acetate. 207. t-butyl a-[6-(l-ethoxycarbonyl-3-phenylpropylamino )- 3 -methyl- 5 -oxoperhydro-1,4-thiazepin- 4 -yl]acetate. 208. t-butyl a -[3 -benzyl- 6 -(1-ethoxycarbonyl- 3 -phenylpropylamino)-5-oxoperhydro-l,4 -thiazepin-4-yl]acetate.

Of the compounds listed above, preferred compounds from-the point of view of their biological activity, are Compounds Nos. 11, 12, 27, 28, 29, 30, 133, 134, 138, 139, 173, 174, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 188, 193, 194 and 195. Compounds Nos. 74, 75, 76, 163, 164, 202, 203 and 206 - 208 inclusive are of particular value in the synthesis of other, biologically more active, compounds.

The compounds of the present invention can contain many asymmetric carbon atoms and can thus exist in the form of many stereoisomers and the present invention envisages both the individual isolated isomers as well as mixtures thereof. The following carbon atoms are asymmetric in all of the compounds of the invention: the carbon atom to which the group represented by R1-A- is attached; the carbon atom at the 6-position of the thiazepine ring; and either or both of the carbon atoms at the 2 and 3 positions of the thiazepine ring. In 44 addition, depending upon the nature of the substituent groups on the compounds of the invention, other carbon atoms may also be asymmetric. The compounds of the invention may be prepared as mixtures of isomers and then separated by conventional techniques or they may be prepared by stereo-specific synthesis techniques, all of which are well-known to those skilled in the art.

The compounds of the present invention can be prepared by the condensation of a compound of formula (II) : (?>n (iii (in which R2, R4, R7, B and q are as defined above) with a compound of formula (III): COOR 6 R1-A-CH-X (III) (in which R1, R6 and A are as defined above and X 45 represents a halogen atom or a sulphonyloxy group) or by reductive condensation of the aforementioned compound of formula (II) with a compound of formula (IV): COOR6 1 I R -A-C-0 (IV) (in which R1, R6 and A are as defined above).

In the compound of formula (III), where X represents 15 a halogen atom, this is preferably a chlorine, bromine or iodine atom; where X represents a sulphonyloxy group, this is preferably a substituted or unsubstituted C1-Cg alkanesulphonyloxy group, such as a methane-sulphonyloxy, ethanesulphonyloxy or trifluoromethane-sulphonyloxy group, or a substituted or unsubstituted aromatic sulphonyloxy group, such as a benzenesulphonyloxy or £-toluenesulphonyloxy group; in the case of the substituted groups, substituents are selected from the group consisting of sxibstituents (a) defined above.

Condensation of the compound of formula (II) with the compound of formula (III) is preferably effected in the presence of a solvent and of a base. The nature of the solvent is not critical, provided that it has no adverse effect upon the reaction; suitable solvents include: aliphatic and aromatic hydrocarbons, such as hexane or benzene; halogenated aliphatic or aromatic, preferably aliphatic, hydrocarbons, such as methylene chloride or 1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane; esters, such as ethyl acetate; ketones, such as acetone; amides, such as dimethylformamide, dimethylacetamide or hexamethyl-phosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. There is likewise no criticality as to the nature of the base to be employed, provided that it does not adversely affect the reaction. Suitable bases include, for example: 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; or organic bases, such as triethylamine, pyridine, picoline or tetraethyl-ammonium hydroxide. If desired, the reaction may be carried out as a two-phase reaction employing water as the solvent for one phase and a water-immiscible solvent (such as methylene chloride or chloroform) for' the other phase; in this case, a phase-transfer catalyst (such as tetrabutylammonium bromide or benzyltriethylammonium iodide) should be employed and the base may be a relatively strong base, such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide). 47 The reaction will take place over a wide range of temperatures and the precise temperature chosen is not p. critical to the present invention; we generally find it convenient to carry out the reaction at a temperature within the range from 0 to 120°C. The time required for the reaction will vary depending upon many factors, but 10 primarily upon the natures of the solvent, base and reagents, and upon the reaction temperature, but a period of from 1 hour to 3 days will normally suffice.

After completion of the reaction, the desired compound may be obtained from the reaction mixture by conventional means. For example, one suitable recovery technique comprises: adding an organic solvent, such as ethyl acetate, to the reaction mixture; separating the organic layer and washing it with water; drying the organic layer; and distilling off the solvent to give 25 the desired product. If necessary, this product can be further purified by various conventional techniques, such as recrystallization and/or the chromatography techniques, particularly column chromatography.

Reaction of the compound of formula (II) with the compound of formula (IV) takes place under reductive condensation conditions. The reductive conditions may be provided by a variety of means, for example: catalytic reduction using a metal, such as platinum, palladium, Raney nickel or rhodium, optionally on a 48 carrier, in the presence of hydrogen; reduction with a metal hydride, such as lithium aluminium hydride, lithium borohydride, lithium cyanoborohydride, sodium cyanoboro- hydride, sodium borohydride or potassium borohydride; reduction with an active metal, such as sodium or magnesium, together with an alcohol, such as methanol or ethanol; or reduction with a metal, such as iron or zinc, and an acid, such as hydrochloric acid or acetic.acid. 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 (although it may participate in) the reaction. Suitable solvents include water and a variety of organic solvents, for example: alcohols, such as methanol or ethanol; ethers,, such as tetrahydrofuran, diethyl ether or dioxane; halogenated hydrocarbons, such as methylene chloride or chloroform; esters, such as ethyl acetate; aromatic hydrocarbons, such as benzene or toluene; amides, such as dimethylformamide or dimethylacetamide; and organic acids, such as acetic acid. It will be noted that certain of the compounds mentioned herein as potential solvents may also serve as part of the reduction system described above and, in that case, the same compound may serve both as a reagent and as a solvent, if desired.

The reaction will take place over a wide range of temperatures, for example from -20°C to +100°C, although 49 the precise temperature chosen will depend upon several factors, of which the most important is the nature of the reductive system employed. The reaction can be carried out under atmospheric pressure, although, in some cases, it may be desirable to carry it out under an elevated or reduced pressure.

Of the compounds of formula (I), the monoester monocarboxylic acids in which R6 represents an ester 7 residue and R represents a hydrogen atom and the 6 7 dicarboxylic acids in which both R and R represent hydrogen atoms, as well as the salts of these acids, are medically the most important compounds. The monoester monocarboxylic acid can be prepared by selective 7 deprotection of the ester residue represented by R in 6 7 a diester compound in which both R and R represent ester residues; alternatively, it may be prepared by the reductive condensation of an amino acid of formula (II) 7 in which R represents a hydrogen atom with a ketoester of formula (IV) in which R® represents an ester residue.

A dicarboxylic acid of formula (I) in which both R6 and R7 represent hydrogen atoms can also be prepared by hydrolyzing a diester or monoester of 6 7 formula (I) (in which R and R represent ester residues or R6 represents an ester residue and R7 represents a hydrogen atom) with an acid or base; it may 50 also be prepared by reductive removal of the ester group or groups of the diester or monoester. The reaction conditions employed are the same as those described for deprotection of the carboxy-protecting group represented 12 by R in the compound of formula (VII) described hereafter.

If desired, compounds of formula (I) in which n is 0 may be converted to the corresponding compounds in which n is 1 or 2 by oxidation, as described in more detail hereafter.

The starting materials of formula (II) employed in the processes of the present invention may be prepared in a variety of ways. For example, those compounds of formula (II) in which q is 0, that is to say compounds of formula (Ila): COOR' (Ila) (in which R2-R4, B and R7 are as defined above) can be prepared, for example, by the process illustrated in the following reaction scheme: 51 R10 h v J1/ •SH toor12 + (V) .R r & V (VI) step A1 RlO \, s-y r2 .11/ (VIII coor12 }~lr<> N Rl3XR" R step A2 \| „l/ i R' cooh (Villi n NH2 r"> step A3 %/ R IV -J t-M // \ 0 H -rl (IX) step Al ,11 R10 \ N / (X) R*» c — n // 0 8 coor step A5 (Ila) COOR' 2 4 7 In the above formulae, R -R , R and B are as defined above. R10, R11, R13 and R14 are the same or different and each represents a hydrogen atom or an amino-protecting group (R10 and R11 preferably being different from R13 and R14) and R12 represents a hydrogen atom or a carboxy-protecting group.

The nature of the carboxy-protecting group 12 represented by R xs not critical to the present invention, as its purpose is merely to protect the carboxy group from participation in the reaction of step A1 and it is then immediately eliminated in step A2. Accordingly, any protecting group known in the art for use in this type of reaction may be employed, normally an ester residue. Examples include: methyl and substituted methyl groups, such as the methyl, allyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, phenacyl, £-bromophenacyl or phthalimidomethyl groups; other lower (e.g. C2-Cg, preferably C2-C4) alkyl groups, which may be substituted or unsubstituted, for example the ethyl, 2,2,2-trichloroethyl, 2-iodoethyl, 2-trimethyl-silylethyl, 2-(£-toluenesulphonyl)ethyl or t-butyl groups; benzyl groups which may be substituted or unsubstituted, for example the benzyl, benzhydryl (i.e. diphenylmethyl), E-methoxybenzyl or E-nitrobenzyl groups; or silyl groups, preferably trialkylsilyl groups in which each alkyl part has from l to 6, preferably 53 from 1 to 4, carbon atoms, for example the trimethylsilyl or t-butyldimethylsilyl groups. It should, however, be appreciated that these groups are given merely by way of exemplification and there is no limitation on the nature of the carboxy-protecting group, provided that it is capable of serving a jg protecting function.

Likewise, there is no criticality as to the nature of the amino-protecting group represented by R10, 15 R11, -R13 or R14, as these groups are present in certain of the steps of the reaction scheme merely in order to prevent participation of the amino group which they protect in the relevant reaction and they are removed either in step A2 or in step A5 and thus do not appear in the final product, the starting material of formula (Ila), of this reaction scheme. Accordingly, they have no influence on the nature of the final 25 1 product and may be chosen having regard solely to their protecting function. Examples of such protecting groups include: alkoxycarbonyl groups, in which the alkoxy part 30 preferably has from 1 to 6, more preferably from l to 4, carbon atoms and which may be substituted or unsubstituted [examples of substituents being any of those groups and atoms listed above as substituents (a) and (b) as well as lower (e.g. C1~C4) alkylidene groups], for example the 2,2,2-trichloroethoxycarbonyl, 2 -iodoethoxycarbonyl, trimethylsilylethoxycarbonyl, 54 t-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbony1, g-methoxybenzyloxycarbony1 or jo-nitrobenzyloxycarbonyl groups; alkanesulphonylalkoxycarbonyl groups in which each alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms or aromatic sulphonylalkoxycarbonyl groups in which the aryl part is Cg-C10 carbocyclic aryl and the alkyl part is C1'C6' Preferably Ci-C4' alkyl and where the aryl part may be unsubstituted or have one or more of the sxibstituents heretofore listed as substituents (a), for example the 2-methanesulphonyl-ethoxycarbonyl or 2-(£-toluenesulphonyl)ethoxycarbonyl groups; C1~C7 aliphatic acyl or (cg*c10 carbocyclic aryl) acyl groups, which may be unsubstituted or have one or more of the sxibstituents listed in group (a) above, for example the formyl, acetyl, benzoyl, chloroacetyl or trifluoroacetyl groups; cyclic diacyl groups, such as the phthaloyl or 2.3-diphenylmalonyl groups; substituted methyl groups, such as the methoxymethyl, benzyloxymethyl, benzyl, 3.4-dimethoxybenzyl or trityl groups; alkylidene or aralkylidene groups, such as the propylidene, -benzylidene or salicylidene groups; acylvinyl groups, such as the 2-acetyl-1-methylvinyl or 2-benzoyl- 1-methylvinyl groups; and silyl groups, particularly trialkylsilyl groups in which each alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, for example the trimethylsilyl or t-butyldimethylsilyl groups. It should, however, be appreciated that these groups are given by way of example only and that the nature of the group is not critical, provided that it serves its required protecting function.

The compound of formula (V) is a derivative of cysteine and its reaction in step A1 with the compound of formula (VI) is preferably effected in a suitable solvent and in the presence of a base. The nature of the solvent is not critical, provided that it has no adverse effect upon the reaction, and similarly the nature of the base is not critical. The reagents and reaction conditions, such as the solvent, base, reaction temperature, and reaction time, as well as the techniques for isolation and purification of the reaction product are similar to those described in detail in relation to the reaction of the compound of formula (II) with the compound of formula (III).

In step A2, the carboxy-protecting group represented 12 by R and the amino-protecting groups represented by 13 14 R and R are removed by conventional means well-known in chemical synthesis and, apart from one consideration, the reaction employed to remove these groups is not critical to the present process. It is, however, necessary that the removal reaction should have no effect on the amino-protecting groups represented by R10 and R11 in the cysteine part of the molecule of the compound of formula (VII). The precise removal 56 reaction or reactions chosen will, of course, depend upon the precise nature of the carboxy-protecting group 12 represented by R and the amino-protecting groups 13 14 represented by R and R , for example: 12 where R represents an alkyl group, such as a methyl or ethyl group, the compound may be deprotected by hydrolysis with an alkali, preferably an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide; 12 where R represents a protecting group such as a methoxymethyl, methoxyethoxymethyl, t-butyl, benzhydryl, E-methoxybenzyl, trimethylsilyl or t-butyldimethylsilyl group, the compound may be deprotected by reaction with an acid or a Lewis acid, such as hydrochloric acid, trifluoroacetic acid or aluminium chloride; where R13 14 and/or R represents a protecting group such as a t-butoxycarbonyl, B-methoxybenzyloxycarbonyl, trityl or t-butyldimethylsilylethoxycarbonyl group, this is similarly removed by reaction with an acid or a Lewis acid; 12 where R represents a group such as a benzyl or 13 14 E-nitrobenzyl group and/or R or R represents a group such as a benzyloxycarbonyl or £-nitrobenzyloxy-carbonyl group, the compound may be deprotected by catalytic reduction, employing hydrogen in the presence of a suitable catalyst, for example palladium, which may be supported, for example, on carbon; 12 where R represents a group such as a 2,2,2-tri- chloroethyl, 2-iodoethyl, phenacyl or e-bromophenacyl 13 14 group and/or R or R represents a group such as a 2,2,2-trichloroethoxycarbonyl or 2 -iodoethoxycarbonyl group, the compound may be deprotected by reduction employing a mixture of a metal powder (e.g. zinc powder) and an acid (e.g. acetic acid or hydrochloric acid); 12 where R represents a group such as an allyl group 13 14 and/or R or R represents a group such as an allyloxycarbony1 group, the compound may be deprotected by a catalytic reaction, employing, for example, tetrakis(triphenylphosphine)palladium (0); or 13 14 where R or R is a group such as a phthaloyl group, the compound may be deprotected by reaction with hydrazine or a hydrazine derivative, preferably an alkylhydrazine, such as hydrazine or methylhydrazine.

The reaction in this deprotection step A2 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. The optimum solvent will, of course, depend upon the precise reaction chosen and, as is obvious to those skilled in the art, in some 58 cases, the solvent may participate in the deprotection reaction. In general terms, suitable solvents may be chosen from the class consisting of: water; acids, preferably carboxylic and more preferably aliphatic carboxylic, acids such as acetic acid or formic acid; alcohols, such as methanol or ethanol; ethers, such as 10 tetrahydrofuran, dioxane or anisole; ketones, such as acetone; halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; and hydrocarbons, which may be aliphatic or aromatic, preferably aromatic, such as benzene or toluene. These reactions will take place over a wide range of temperatures, for example at a temperature within the range from -10°C to +100°C; in general, the time allowed for the reaction will vary depending upon the nature of the deprotection reaction and other reaction conditions, including the reaction 25 temperature; at one extreme, a relatively fast reaction will be complete within perhaps 30 minutes, whereas, at the other extreme, it may be advisable to allow a whole day and night for the reaction: however, these are matters well within the skill and knowledge of the laboratory technician.

It will, of course, be appreciated that removal of the amino-protecting groups and carboxy-protecting groups may be carried out in any order or (assuming a suitable removal reaction is chosen in relation to the 59 particular protecting groups) simultaneously; likewise, although it is not preferred, if the amino-protecting 13 14 groups R and R are different, these may be removed sequentially or simultaneously. In general, however, either the carboxy-protecting group represented 12 by R is first removed, and then the amino-protecting 13 14 groups R and/or R are removed or the amino-protecting groups represented by R13 and/or 14 R are first removed, and then the carboxy-protecting 12 12 group R is removed, or all protecting groups, R 13 14 and R and/or R , are removed together. For 12 13 example, if R represents a t-butyl group, R 14 represents a t-butoxycarbonyl group and R represents a hydrogen atom, the compound of formula (VIII) may be obtained in a single step by deprotection with an acid. 12 Similarly, if R represents a 2,2,2-tnchloroethyl group, R13 represents a 2,2,2-trichloroethoxycarbonyl 14 group and R represents a hydrogen atom, the compound of formula (VIII) may be obtained by deprotection in a single step with a combination of zinc powder and an acid.

If desired, the compound of formula (VIII) may be purified by various conventional means, for example by isoelectric precipitation, recrystallization or the various chromatography techniques, such as column chromatography; however, if desired, the crude product obtained from this reaction may be employed directly in the next step without any specific purification. 60 In step A3, the compound of formula (VIII) is cyclized to form a perhydrothiazepine derivative of formula (IX) by condensing the free amino group with the free carboxy group, to form an amide linkage, of a type which is well-known in the field of peptide chemistry. This reaction may generally be carried out by contacting the compound of formula (VIII) with a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, carbonyl-diimidazole, diphenylphosphoryl azide, diethyl cyanophosphate or phosphorus pentachloride. If a dehydrating agent of the carbodiimide kind is employed, the reaction can be accelerated by carrying out the reaction in the presence of l-hydroxybenzotriazole, N-hydroxysuccinimide or a similar compound. It may also be advantageous to carry out the reaction in the presence of a base, which may be an organic base, for 25 example pyridine, picoline, triethylamine or N-methylmorpholine, or an inorganic base, such as 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, hexamethylphosphoric triamide, or dimethylacetamide;; ethers, such as tetrahydrofuran or dioxane; halogenated hydrocarbons, preferably aliphatic hydrocarbons, such as methylene chloride or chloroform; esters, such as ethyl 61 acetate; or aromatic hydrocarbons, such as benzene or toluene. Sometimes, the product can be isolated as crystals from the reaction mixture; at other times, other recovery techniques (such as those described elsewhere in the specification) may be employed; if desired, the product can be purified by various conventional techniques, such as the chromatography techniques, especially column chromatography.

In step A4 of the reaction scheme, the compound of formula (X) can be prepared by N-alkylation of the compound of formula (IX), employing a compound of formula (XI): X-B-COOR7 (XI) 7 [in which B and R are as defined above and X represents a halogen atom or a sulphonyloxy group, examples of which are given in relation to the atom or group represented by X in the compound of formula (III), preferably a bromine atom]. This reaction is preferably effected in the presence of a solvent and of a base. The nature of the solvent employed is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example: hydrocarbons, which may be aliphatic or aromatic, for example hexane or benzene; halogenated hydrocarbons, which likewise may be aliphatic or aromatic, but which 62 are preferably aliphatic, such as methylene chloride or 1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane; esters, such as ethyl acetate; ketones, such as acetone; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulphoxides, such as dimethyl sulphoxide. The nature of the base is likewise not critical, and examples include: alkali metal hydrides, such as sodium hydride, lithium hydride or potassium hydride; alkyl-alkali metal compounds, 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; or organic amines, such as triethylamine, triethylenediamine, 1,5-diazabicyclo-[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-7-ene.

If desired, this reaction may be carried out as a two-phase reaction employing water and a water-immiscible solvent as the reaction media; suitable water-immiscible solvents include methylene chloride and chloroform. In the case of the two-phase reaction, a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltriethylammonium iodide, may be employed and the base may be a relatively strong base, such as an alkali metal hydroxide, e.g. sodium hydroxide or potassium hydroxide. The reaction will take place over a wide range of temperatures, for example from 63 -20°C Co +100°C. The time required for Che reaccion will vary widely, depending on many facCors, including che reaccion cemperacure as well as che nacures of che solvenc, base and reagencs, buc a period of from 3 0 minuces Co 24 hours will normally suffice.

Afcer completion of the reaction, the desired compound of formula (X) may be obtained from the reaction mixture by conventional means. For example, one 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 finally distilling off the solvent to give the desired compound. If necessary, this compound may be further purified by such conventional means as recrystallization or the various chromatography techniques, particularly column chromatography.

In step A5, the compound of formula (X) is converted to a compound of formula (Ila) by deprotection of the amino group at the 6-position of the thiazepine ring. The reactions involved are similar to those employed for removal of the amino-protecting groups represented by R13 and R14 from the compound of formula (VII) in step A2 and, depending upon the precise amino-protecting group or groups chosen, the same conditions and reagents as described in more detail in step A2 may be employed in step A5. After the reaction, the reaction product 64 may be separated from the reaction mixture, as described in relation to step A2 and may then, if necessary, be further purified by such conventional techniques as recrystallization and/or the various chromatography techniques, particularly column chromatography.

Compounds of formula (II) in which q is 1 or 2, that is to say compounds of formula (lib), may be prepared as illustrated in the following reaction scheme: 65 r „io \ n/ R' N .10 (0!m I »2 c — r // \ step 81 \ —il— I / H fl4 ,11 0 h c — n // \ 0 h (ix) (xi) step 8 2 step 83 coor' (x) coor' step 84 (xii) c —m 0 (lib) COOR' 66 2 4 7 In the above formulae, R , R , B and R are as defined above and m is 1 or 2.

In step B1 or B3 of this reaction sequence, the compound of formula (IX) or (X) (prepared as illustrated in steps A3 or A4 above) is oxidized to give, respectively, a compound of formula (XI) or (XII). 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: water; acids, preferably carboxylic acids and more preferably aliphatic carboxylic acids, such as acetic acid or formic acid; alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or dioxane; ketones, such as acetone; halogenated hydrocarbons, particularly halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; or hydrocarbons, particularly aromatic hydrocarbons, such as benzene or toluene. For the oxidation reaction, any oxidizing agent known for the oxidization of sulphides to sulphoxides (m=l) or sulphones (m-2) may be employed. Examples of suitable oxidizing agents include such organic oxidizing agents as peracetic acid or nj-chloroperbenzoic acid and such inorganic oxidizing agents as hydrogen peroxide, ozone or various periodates. The reaction will take place over a wide range of temperatures, for example from -80°C to +100°C, and the time required for the reaction 67 will vary, depending upon che nature of the reagents, the reaction conditions (notably reaction temperature) and the desired product. By controlling the nature and amount of oxidizing agent, the reaction temperature and the reaction time, it is possible to prepare selectively either a sulphoxide [a compound of formula (lib) in which m is 1] or a sulphone [a compound of formula (lib) in which m is 2].

After the reaction, excess oxidizing agent may be removed, if necessary, by treatment with dimethyl sulphide, an aqueous solution of sodium thiosulphate or an aqueous solution of sodium sulphite. The product of the oxidative reaction, the compound of formula (XI) or (XII), may then be obtained from the reaction mixture by extraction with a suitable organic solvent, washing, drying and then distillation of the organic solvent.

In step B2, the compound of formula (XI) is N-alkylated, precisely as in step A4, employing the same reagents and reaction conditions. The compound of formula (XII) which is the product of step B2 or step B3, is then deprotected, as described in more detail in step A5, employing the same reagents and reaction conditions. 68 Compounds of formula (lb): coor6 1 < 1 r — a'— ch—nh (lb) 1 7 (in which R -R , B and m are as defined above and A' represents a direct single bond, a methylene group, ah ethylene group.or an oxymethyl group, that is any one of the bond or groups represented by A except the thiomethyl group) can be prepared by oxidation of a corresponding compound of formula (Ic): r2 coor6 r'-a'-ch-nw—Li—r' I 8 coor7 del (in which R1-R7, B and A' are as defined above). The reaction conditions are precisely the same as described above in relation to steps B1 and B3, employing the same reagents. 69 The processes described above will normally produce mixtures of optical isomers of the compounds of the invention, even if the starting materials are isolated optical isomers, as the reactions involved will racemize the compounds. However, by adopting alternative stereo-10 specific reactions, it is possible to obtain specific isomers of the compounds of the invention. For example, in the reactions to produce the starting materials of formula (Ila), reaction of the compound of formula (V) with the compound of formula (VI) to produce the compound of formula (VII) tends to result in racemization of the carbon atom to which the cysteine ^ nitrogen atom is attached, depending on the groups represented by R10, R11 and R12 and the base used, 12 especially where R in the compound of formula (V) represents an ester residue. However, if, instead of 25 employing a compound of formula (VI) to react with the compound of formula (V) , a compound of formula (XX) : NO? (XXI H 70 2 (in which R is as defined above) is reacted with a compound of formula (V) in which R12 typically represents a hydrogen atom, under mild conditions, the resulting compound of formula (XXI): (in which R2, R1^, R11 and R12 are as defined above) retains an optically active, non-racemized, carbon atom at that point marked with an asterisk. This compound of formula (XXI) may then be reduced by conventional means (well-known for the reduction of nitro groups to amino groups) to give a compound of formula (VII) in which R4, R13 and R14 all represent hydrogen atoms and this may then subsequently be subjected to steps A2-A5 as already described.

In any case, where mixtures of optical isomers are produced at any stage during the preparation of the final product of formula (I) or the starting material of formula (II), the mixture of optical isomers may, if desired, be separated by conventional resolution 71 methods, for example the formation of salts with optically active bases, such as cinchonine, cinchonidine, quinine or quinidine, or with optically active organic acids, e.g. 1-camphorsulphonic acid or d-camphorsulphonic acid. Optical isomers can also be resolved by other known techniques, including various 10 kinds of chromatography, fractional crystallization etc.

As noted above, the compounds of the present invention have the ability to inhibit the activity of ACE, the enzyme which converts angiotensin I to angiotensin II and also inactivates bradykinin. The physiological activity of the compounds of the invention 2Q can be evaluated by determining the concentration of the test compound required to inhibit the activity of ACE by 50% in vitro (IC5Q), for example by the procedure of D.W. Cushman st sJL. [Biochemical Pharmachology, 2Q., 1637 25 (1971)]. Specifically, solutions of ACE extracted from rabbit lungs and, as substrate, hippurylhistidylleucine, to which had been added the test compound at various concentrations, were added to a borate buffer solution containing sodium chloride, and the pH was adjusted to a value of 8.3. The enzymatic reaction was allowed to proceed at 37°C for 30 minutes, after which time the reaction was terminated by adding IN aqueous hydrochloric acid. The hippuric acid formed by this reaction was extracted with ethyl acetate and the solvent was then distilled from the extract. The 72 residual hippuric acid was dissolved in water. The amount of hippuric acid in the resulting aqueous 5 solution was determined by the absorbency to ultraviolet radiation at 228 nm. The resulting values were then plotted to form a curve indicating the relationship between the amount of hippuric acid formed and the *0 concentration of the test compound. The IC5Q value can be obtained by reading on this curve the concentration of the test compound which reduces the amount of hippuric acid formed to one half of that formed when no test compound is present. The values obtained for various of the compounds of the invention by this procedure are shown in the following 20 Table. The compounds tested were as follows: A: <*-{6(R) -[1(£)-carboxy-3-phenylpropylamino]-5-oxo-3(£)-phenylperhydro-l,4:thiazepin-4-yl}acetic acid 25 (product of Example 6); B: a-{6(£)-[1(S)-carboxy-3-phenylpropylamino]-3(S)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetic acid (product of Example 29); C: a-[6-(1-carboxy-3-phenylpropylamino)-5- oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetic acid (product of Example 13); 73 H: a - [6- (1-carboxy-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid (product of Example 3 8); I: x-[6-(1-carboxy-3-phenylpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-yl]acetic acid (product of Example 41) ; J: a-{6(R)-[1(£)-carboxy-3-phenylpropylamino]-3 (£) -'methyl-5-oxoperhydro-l,4-thiazepin-4-yl}acetic acid (product of Example 32); K: a-{3(S)-benzyl-6(£)-[1(£)-carboxy-3-phenylpropylamino] - 5 -oxoperhydro-1,4-thiazepin-4-yl}acetic acid (product of Example 35).

Table Test Compound ICS0 (moles/litre) A 1.1 X -9 B 1.6 X ID'9 C 2.4 X -9 H 1.6 X -9 I 2.0 X "9 J 3.0 X -9 K 1.3 X o ■ U3 74 As can be clearly seen from the results in the above Table, the compounds of the invention inhibit ACE activity at very low concentrations and are thus useful as diagnostic, preventative and therapeutic agents for hypertensive patients; likewise, salts of these compounds would have similar activities.

For practical, therapeutic use, the compounds of the invention are preferably administered in combination with suitable pharmaceutically acceptable carriers, vehicles or diluents. The compounds can be administered orally or non-orally (e.g. parenterally by intravenous or intramuscular injection) and the form of the composition will, of course, be determined by the intended route of administration. For oral administration, the compounds of the invention may, for example, be administered as powders, granules, tablets, capsules, syrups or elixirs. For parenteral administration, the compounds will be administered in the form of a suitable injectible composition, in which the compound of the invention is dissolved or suspended in a pyrogen-free injectible medium. 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 1000 mg, more preferably from 75 to 100 mg, for oral administration, whilst the preferred dose at each administration for intravenous injection is from 0.5 to 100 mg, more preferably from 0.5 to 10 mg. One or more of these doses, preferably from 1 to 3 doses, may be administered daily.

The invention is further illustrated by the following Examples, which describe the preparation of various of the compounds of the invention, including separation and/or preparation of individual isomers thereof. In the nuclear magnetic resonance spectra reported in certain of these Examples, the abbreviation "Ph" signifies the phenyl group. The values for optical rotation were all measured with the sodium D-line, i.e. all values are C<*]D- EXAMPLE 1 t-Butyl a-r6(R)-(l-ethoxycarbonvl-3-phenylpropyl-amino)-5-oxo-3(R)-phenviperhydro-1. 4—thiazepin-4—vli-acetate (Compound No. 74) 1(a) 2-( R) - t-Butoxy carbonv latnino-2-phen vl ethanol .5 g of di-t-butyl pyrocarbonate were added, with ice-cooling, to a mixture of 6 g of 0-(-)-a-phenyIglycinol and 6 ml of triethylamine dissolved in 100 ml of methylene chloride, and the mixture was stirred for 15 hours at room temperature. The reaction solution was then concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of potassium hydrogen sulphate and an aqueous solution of sodium bicarbonate, and then dried over anhydrous magnesium sulphate. The solvent was distilled off, leaving the title compound as crystals. The compound was then washed with small amounts of diisopropyl ether and cyclohexane, to yield 9.9 g of the purified compound, melting at 136 - 138°C. 77 Nuclear Magnetic Resonance Spectrum [COCl^ t-sufficient (00^)^50 to dissolve the product] 8 ppm 1.36 (9H, singlet, t-butyl); 3.6-3.75 ( 3 H , multiplet, CH^-OH); 4-. 3-4.. 7 (1H, multiplet. Ph-CH-N); 6.34. (1H, broad doublet. J=7Hz. NH); 7.20 (5H, singlet, phenyl protons). 1(b) 1(R)-t-Butoxyearbony1amino-2-methanesulphonvloxy-15 l-phenylethane 11 ml of pyridine and then 6.6 ml of methanesulphony 1 chloride were added dropwise, at room temperature, to a solution containing 9.9 g of 2(R)-t-butoxycarbonylamino- 2-phenylethanol [prepared as described in step (a) above] dissolved in 120 ml of methylene chloride. This mixture was stirred for 15 hours at room temperature, after which the solvent was removed by distillation. The residue was dissolved in ethyl acetate and water and the ethyl acetate layer was 30 separated. This layer was washed with an aqueous solution of potassium hydrogen sulphate and an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulphate, after which the solvent was distilled off. The crystalline residue was collected by filtration and washed with a small amount of diisopropyl ether and cyclohexane to give 12.2 g of the title compound, melting at 108 - 109°C.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.4-2 (9H, singlet, t-butyl); 2.84 (3H, singlet, CH3S02); 4.36 (2H, doublet. J=5Hz, C-CHj-O); 4.7-5.4 (2H. multiplet. -NH-CH-Ph); 7.27 (5H, singlet, phenyl protons). 1(c) Benzhydryl ester of S-r2(R)-t-butoxycarbonylamino-2-phenvlethvll-N-phthalovl-L-cysteine 7.26 g of sodium bicarbonate mere added, under an atmosphere of nitrogen gas, to a mixture of 11.7 g of l-cysteine £-toluenesulphonate and 8.8 g of N-ethoxycarbonylphthalimide dissolved in 80 ml of dimethylformamide, and then the mixture was stirred for 3.5 hours at.90 - 100°C. The reaction mixture was then cooled and dissolved in a mixture of ethyl acetate and an aqueous solution of potassium hydrogen sulphate; the aqueous layer was acidified; and then the ethyl acetate layer was separated. The separated ethyl acetate layer was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulphate. 8.6 g of diphenyldiazomethane were then added. The resulting mixture was stirred for 1 hour under a stream of nitrogen and then the solvent was removed by distillation. The residue was dissolved in 140 ml of dimethylformamide, and then 12.2 g of 2(R)-t- 75 butoxycarbonylamino-2-methanesulphonyloxy- 1-phenylethane [prepared as described in step (b) aboue] and 12.2 g of sodium carbonate uiere added. The mixture was then stirred for 16 hours at 70°C under a stream of nitrogen. The reaction mixture was then dissolved in ethyl acetate and water; the ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off, and the residue was 15 subjected to silica gel column chromatography using a 1:4. by volume mixture of ethyl acetate and cyclohexane as the eluent; 9.9 g of the title compound were obtained as an amorphous substance.

Nuclear Magnetic Resonance Spectrum (CDC13) 8 ppm: 1.34 (9H, singlet, t-butyl); 2.88 (2H, broad doublet, J»6Hz. S-CH-); 25 2 3.28 (2H, broad doublet. J-8Hz, S-CH..); 4.6-5.5 (3H, multiplet. NH. N-CH-CO. Ph-CH-N); 6.91 (1H. singlet. CHPh2); 7.23 (10H. singlet. (CgH^CH); 7.28 (5H. singlet. CgHgCH-); 7.5-7.9 (4H. multiplet. phthaloyl protons). 1(d) S-T2(R)-Amino-2-ohenviethvll-N-phthalovl-L-cvsteine trifluoroacetate °0 A 50 ml of trifluoroacetic acid were added, with ice-cooling, to solution containing 9.9 g of the benzhydryl ester of S-[2(R)-t-butoxycarbonylamino-2-phenylethyl]-N-phthaloyl-L-cysteine [prepared as described in step (c) above] dissolved in 50 ml of anisole, and the mixture was allowed to react for 2 hours at room temperature. The reaction solution was concentrated by evaporation under reduced pressure, diisopropyl ether was added to the residue and the desired compound was obtained by filtration as a crude powder in a yield of 8.6 g. This crude compound was subjected to the next step of cyclization without purification. 1(e) 5-Oxo-3(R)-phenvl-6(R)-phthalimidoperhvdro-l.4-thiazepine At room temperature. 9.8 g of diphenylphosphoryl azide were added dropwise, followed by 6.1 ml of N-methylmorpholine. to a solution containing 8.6 g of S-[2(R)-amino-2-phenylethyl]-N-phthaloyl-L-cysteine trifluoroacetate [prepared as described in step (d) above] dissolved in 50 ml of dimethylformamide and 200 ml of methylene chloride, and the mixture was stirred for 16 hours. The solution was concentrated by evaporation of the methylene chloride, and the desired substance separated out as crystals during the addition a i of 100 ml of ethyl acetate and then an aqueous solution of sodium chloride to the reaction mixture which continued to be shaken and stirred. These crystals were then collected by filtration and washed with water and a small amount of ethyl acetate, to give 2.25 g of the title compound, melting at 280 - 282°C.

Nuclear Magnetic Resonance Spectrum [(C03)2S0] 5 ppm: V 2.95 (2H, broad doublet, J»7Hz, SCH2); 3.40 (2H, broad doublet. J-6Hz. SCH2>; 5.00 (1H, broad quartet, J-7Hz, HN-CHPh); 5.50 (1H, broad triplet. J«6Hz. N-CH-CO); 7.1-7.5 (5H, multiplet. phenyl protons); 7.7 (1H. broad doublet. J-7Hz. NH); 7.77 (4H. singlet, phthaloyl protons). 1(f) t-Butvl a-r5-0X0-3(R)-phenvl-6(R)-phthalimido-per hydro-1.4— thiazepin-4-v 11 acetate 270 mg of a 50% w/w suspension of sodium hydride in mineral oil were added to a solution containing 5 ml of hexamethylphosphoric triamide and 1.9 g of 5-oxo-3(R)-phenyl-6(R)-phthalimidoperhydro-l,4-thiazepine [prepared as described in step (e) above] dissolved in 20 ml of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature. 1.8 g of t-butyl 82 bromoacetate was then added to the mixture. The resulting mixture was stirred for 1 hour at room temperature, after which a further 0.2 g of a 55% w/w suspension of sodium hydride in oil and 1 g of t-butyl bromoacetate were added. The mixture was stirred for a 10 further l hour at room temperature. Ethyl acetate was then added to the mixture, and the mixture was washed with an aqueous solution of sodium chloride and then dried over anhyd-ous magnesium sulphate, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to give 1.65 g of the title compound as an amorphous substance.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 25 1.32 (9H, singlet, t-butyl); 2.8-4.0 (6H, multiplet, CHjSCHj. NCH2CO); 5.30 (1H, broad doublet, J»8Hz, N-CH-Ph); 5.72 (1H, doublet of doublets, J»4 & 7.5Hz, N-CH-CO); 7.30 (5H, singlet, phenyl protons); 7.45-7.85 (4H, multiplet. phthaloyl protons). 1(g) t-Butvl a-f6(R)-amino-5-oxo-3(R)-phenylperhvdro-1.4-thiazepin-4—vllacetate 83 0.7 ml of methyIhydrazine was added to a solution containing 1.65 g of t-butyl a-[5-oxo-3(R)-phenyl-6(R)-phthalimidoperhydro-l,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] dissolved in 20 ml of methylene chloride, and the mixture was allowed to stand at room temperature for 2 hours. The solvent and excess methyIhydrazine were then distilled off. and the residue was dissolved in 10 ml of methylene chloride and 1 ml of methanol. The resulting solution was allowed to stand overnight at room temperature, after which the solvent was removed by distillation. A small amount of methylene chloride was added to the residue, and the precipitate was filtered off. The filtrate was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of methanol and methylene chloride, to give 1.1 g of the title compound as an amorphous substance.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.38 (9H, singlet, t-butyl); 2.09 (2H, broad singlet, NH2); 2.7-3.4 (4H, multiplet. CHjSCHj); 3.64 (2H. AB quartet. A5»0.47 ppm. J»18Hz, NCH2CO); 4.47 (1H, doublet of doublets, J-5 & 7Hz.

H2N-CH-CO); .36 (1H. doublet of doublets. J-2 &10Hz, N-CH.-Ph) ; 7.40 (5H, singlet, phenyl protons). 84 1(h) t-Butyl a-[6(R)-(l-ethoxycarbonvl-3-phenvl-propy1amino)-5-oxo-3(R)-phenylperhydro-1, 4— thiazepjn-4-v11 acetate 2.4 g of sodium carbonate were added to a mixture of 1.1 g of t-butyl a-[6(R)-amino-5-oxo-3(R)-phenyl-perhydro-1.4-thiazepin-4-yl]acetate [prepared as described in step (g) aboue] and 1.4 g of ethyl 2-bromo-4-phenethylbutyrate dissolved in 15 ml of dimethylformamide, and this mixture was stirred for 15 hours at 65°C. The reaction mixture was then dissolved in ethyl acetate and an aqueous sodium chloride solution. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulphate, after which the solvent was removed by distillation. The residue was subjected to silica gel column chromatography, using a 1:9 by volume mixture of ethyl acetate and methylene chloride as eluent. t-Butyl ot-[6( R.)-[l (R)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-I» 4-thiazepin-4-yl]acetate was obtained from the first fraction as an oily substance in a yield of 0.53 g.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.25 (3H, triplet. J-7HZ. C02CH2CH3); 1.37 (9H, singlet, t-butyl); 1.75-2.2 (2H. multiplet. PhCH2-CH2-S); 85 2.5-4.4 ( 11H , multiplet, PhCH2-, CO-CH-NH-CH-CH2-S-CH2-, N-CH2CO); 4.15 (2H, quartet, J=7Hz, CQ^CH^CHj); .22 (1H, broad doublet, J=»8.5Hz, N-CH-Ph); 7.23 (5H, singlet, phenyl protons); 7.31 (5H, singlet, phenyl protons).

From the next fraction was obtained 0.60 g of t-butyl a-[6(R)-[1(S)-ethoxycarbonyl-3-pheny1propylamino]-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate as an oily substance.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm 1.27 (3H, triplet. J-7Hz. COjCHjCHj); 1.36 (9H, singlet, t-butyl); 1.8-2.25 (2H, multiplet. PhCH2-CH.2-C) ; 2.5-4.3 (11H, multiplet. PhCHj.

CO-CH-NH-CH-CH2-S-CHj-, N-CHjCO); 4.15 (2H. quartet. J»7Hz. COjCHjCHj); 5.26 (1H. broad doublet. J»8.5Hz. N-CH-Ph); 7.18 (5H. singlet, phenyl protons); 7.29 (5H, singlet, phenyl protons). 86 EXAMPLE 2 t-Butyl a-[6(R)-(1-ethoxycarbonvl-3-phenvlpropyl-amino ) -5-OXO--3 (R)-phenylperhydro-1.4-thiazepin-4-y11 -acetate (Compound No.74) 2 g of molecular sieve 4A were added to 10 ml of an ethanolic solution of t-butyl a-[6(R)-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 1(g)] and 500 mg of ethyl 2-oxo-4-phenylbutyrate. The resulting ethanolic solution was stirred for 1 hour at room temperature, after which 6 ml of an ethanolic solution of 90 mg of sodium cyanoborohydride were added dropwise. The mixture was then stirred for 6 hours at room temperature, after which 5 ml of an ethanolic solution of 400 mg of ethyl 2-oxo-4-phenylbutyrate and 90 mg of sodium cyanoborohydride were added, and the mixture was stirred for a further 16 hours at room temperature. The reaction mixture was then filtered, and the filtrate was condensed by evaporation under reduced pressure. The condensate was diluted with ethyl acetate and washed with an aqueous solution of potassium hydrogen sulphate and then with an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulphate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography as described in Example 1(h), to giue 0.15 g of t-butyl a-{[6(R)-[1(R)-ethoxycarbonyl- 3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1.4-thiazepin-4-yljacetate and 0.15 g of t-butyl a-C6(R)-[1(R)-ethoxyearbonyl-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1. 4-thiazepin-4-y1)acetate, haying the same properties as the products of Example 1.

EXAMPLE 3 Nuclear Magnetic Resonance Spectrum (C0C13) Sppm : 1.25 (3H. triplet. J-7Hz. COj-CHjCHj); 1.8-2.35 (2H, multiplet. PhCHjCHj); 2.5-4.55 (10H. multiplet. PhCHj-, CO-CH-NH-CH-CH2-S-CH2. N-CH2CO-); 4.14 (2H, quartet. J»7Hz. C02CH2CH3); .17 (1H, broad doublet. J»8.5Hz. N-CH-Ph); 7.17 (5H, singlet, phenyl protons); 7.22 (5H. singlet, phenyl protons).

EXAMPLE 4. g-(6(RW HS)-Sthoxvcarbonvl-3-phenvlpropvlamino1-5-oxo-3(R)-ohenviperhydro-1.4-thiazepin-4-vl>acetic acid (Compound No. 27) 0.60 g of t-butyl a-C6(R)-[1(S)-ethoxy-carbony1-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1.4-thiazepin-4-yl)acetate was treated in the same 89 manner as described in Example 3, to gioe the title compound in the form of an amorphous solid, and in a yield of 0.21 g.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm: 1.28 (3H. triplet, J-7Hz, C02CH2CH3); 1.9-2.4 (2H, multiplet, PhCH2CH2); 2.5-3.8 (9H, multiplet, PhCH2.CH2-S-CH2.

NCH2CO, N-CH-CO); 4.65 (1H. broad triplet. J-4.5HZ. N-CHCO); 5.19 (1H, broad doublet. Ja8.5Hz. N-CH-Ph); 7.14 (5H. singlet, phenyl protons); 7.22 (5H, singlet, phenyl protons); 8.90 (2H, broad singlet. COjH. NH).

EXAMPLE 5 g-C6(R)-Tl(R)-Carboxv-3-phenvlpropylamino1-5-oxo-3(R)-phenvlperhvdro-1.4-thiazepin-4-vl)acetic acid (Compound No. 28) 170 mg of a-C6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1.4-thiazepin-4-yl)acetic acid (prepared as described in Example 4) were dissolved in 0.8 ml of a 1% w/u aqueous solution of sodium hydroxide, and the resulting solution was allowed to stand for 18 hours at room temperature. 90 0.8 ml of in hydrochloric acid was added dropwise to this reaction product, and the pH of the mixture was adjusted to a value of 2.0. The title compound was precipitated as a powder following the dropwise addition; this was separated and washed with a small amount of water and ethyl acetate, to yield 70 mg of the title compound.

Nuclear Magnetic Resonance Spectrum C(C03)2S0] & ppm : 1.7-2.1 (2H, multiplet. PhCH2CH.2); 2.4-3.4 (7H, multiplet. PhCHj. N-CH-CO.

CH2SCH2); 3.51 (2H. singlet. NCH2CO); 4.33 (1H. broad triplet. J»5Hz. N-CHCO); 5.30 (1H, broad doublet. J-9Hz. N-CH-Ph); 7.23 (5H, singlet, phenyl protons); 7.39 (5H, singlet, phenyl protons).

EXAMPLE 6 or.-C6(R)-ri fS)-Carboxv-3-Phenvlpropvlamino1-5-0X0-3(R) -phenvlperhvdro-1.4-thiazepin-4-vl)acetic acid (Compound No. 28) 165 mg of Nuclear Magnetic Resonance Spectrum C(CD3)2SO] S ppm: 1.65-2.2 (2H, multiplet. PhCH2CH2); 2.4-3.4. (7H. multiplet. PhCH2< N-CH-CO, CH2SCH2); 3.55 (2H. singlet. NCHjCO); 4.55 (1H. broad triplet, J=»5Hz, N-CHCO); 5.38 (1H. broad doublet, J-9Hz, N-CH-Ph); 7.25 (5H, singlet, phenyl protons); 7.41 (5H, singlet, phenyl protons).

EXAMPLE 7 t-Butvl a-r6-(l-ethoxvcarbonvl-3-phenvlpropvl-amino)-S-oxo-2-phenvlperhvdro-l.4-thiazepin-4-yll-acetate (Compound No. 75) 7(a) 2-t-Butoxvcarbonvlamino-l-phenvlethanol 28 g of t-butoxycarbonyl azide were added at room temperature to 200 ml of a methylene chloride solution containing 25.3g of DL-2-amino-l-phenylethanol and 45 ml of triethylamine. and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was then condensed by evaporation under reduced pressure, and water and diisopropyl ether were added to the condensate. The mixture was thoroughly stirred, yielding the title compound in the form of insoluble crystals melting at 123 - 124°C in8a yield of 20.6 g. These crystals were filtered off. The organic layer in the filtrate was separated and washed with an aqueous solution of potassium hydrogen sulphate and with an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulphate, and the solvent was distilled off. The crystals of the title compound in the residue were collected by filtration and washed with a mixture of diisopropyl ether and petroleum ether, yielding a further 18.7 g.

Nuclear Magnetic Resonance Spectrum [(C03)2S0] ppm: 1.40 (9H, singlet, t-butyl); 3.15 (2H, multiplet. C-CHj-N); 4.61 (IH, multiplet. Ph-CH-C); .12 (1H, doublet. J-4Hz. OH); 6.00 (1H, broad triplet. NH); 7.24 (5H, singlet, phenyl protons). 93 7(b) 2-t-Butox y carbony1amino-l-c hloro-1-phenyl ethane A mixture of 3.7 ml of pyridine and 2.2 ml of methanesulphonyl chloride was added dropwise to 35 ml of a solution of 3.5 g of 2-t-butoxycarbonylamino-l-phenyl-ethanol [prepared as described in step (a) above] in methylene chloride and the reaction mixture was allowed to stand ouernight at room temperature. The reaction mixture was then condensed by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then washed with an aqueous solution of potassium hydrogen sulphate and with 20 an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulphate. The solvent was then distilled off. The residue was subjected to silica gel column chromatography using a 15:85 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 0.75 g of the title compound as crystals melting at 57-59°C.

Nuclear Magnetic Resonance Spectrum (CDCl^) £ ppm: 1.44. (9H, singlet, t-butyl); 3.4-3.7 (2H, multiplet. -CHjN); 4.2-5.15 (2H, multiplet, NH, PhCHCl); 7.30 (5H, singlet, phenyl protons). 94 7(c) Benzhydryl ester of S-(2-t-butoxycarbonvlamino-phenvlethvl)-N-phthaloylcysteine l- The benzhydryl ester of N-phthaloyl-L-cysteine was prepared from 5.0 g of L-cysteine £-toluenesulphonate. 3.8 g of N-ethoxycarbonylphthalimide. 2.9 g of sodium bicarbonate and 3.3 g of diphenyldiazomethane, following the same procedure as described in Example 1(c). g of sodium bicarbonate were added to 60 ml of a solution of the resulting compound and 3.9 g of 2-t-butoxycarbonylamino-l-chloro-l-phenylethane [prepared as described in step (b) above] in dimethylformamide, and the mixture was stirred at 65°C for 40 hours. The reaction mixture was then diluted with ethyl acetate, washed with an aqueous solution of sodium chloride and then dried oyer anhydrous magnesium sulphate. The solvent was distilled off. and the residue was subjected to silica gel column chromatography using a 1:3 by volume mixture of ethyl acetate and cyclohexane as the eluent. giving the title compound in the form of an amorphous solid and in a yield of 4.0 g.

Nuclear Magnetic Resonance Spectrum (C0Cl3) S ppm: 1.36 (9H, singlet, t-butyl); 3.15-3.7 (4-H, multiplet. CHjS, C-CHj-N) ; 4.10 (1H, broad triplet. J=7Hz, S-CH-Ph); 4.6-5.2 (2H, multiplet. NM. N-CH-CO); 6.87 and 6.89 (together 1H, both singlets, CHPh2); 7.24 (10H, singlet, phenyl protons of benzhydryl); 7.29 (5H, singlet, C6H5-C-); 6.6-6.9 (4H, multiplet, phthaloyl protons). 7(d) S-(2-Amino-l-phenvlethvl)-N-phthalovlcvsteine A mixture of 40 ml of trifluoroacetic acid with 30 ml of an anisole solution containing 4.8 g of the benzhydryl ester of S-(2-t-butoxycarbonylamino-l-phenylethyl)-N-phthaloylcysteine [prepared as described in step (c) above] was allowed to stand for 4 hours at room temperature, and then the reaction product was condensed by- evaporation under reduced pressure. The residual oily substance was washed by decantation using diisopropyl ether. After the washing, 50 ml of water were added to the resulting solution. 5 g of sodium bicarbonate were then added, with stirring, and 2 4 g of the title compound precipitated. This product was separated and then subjected to the subsequent cyclization reaction in step (e) without further purification. 7(e) 2-Phenvl-6-phthalimidoperhvdro-l.q—thiazepin-5-one 830 mg of 1-hydroxybenzotriazole monohydrate and 1.13 g of N, N' -dicyclohexylcarbodiimide were added to 4-0 ml of a dimethylformamide solution containing 2.0 g of S-[2-amino-1-phenylethy1]-N-phthaloyIcysteine [prepared as described in step (d) above], and the mixture was stirred for 4 hours at room temperature. 300 ml of ethyl acetate were added to this reaction mixture. Insoluble matter was removed by filtration, and the filtrate was washed with water, and then dried over anhydrous magnesium sulphate. The solvent was distilled off, leaving the title compound in crystalline form. The crystals were collected by filtration and washed with a small amount of ethyl acetate and diisopropyl ether, yielding 2.0 g of the title compound, which softens at a temperature around 200°C and melts at 240 -247°C.

Nuclear Magnetic Resonance Spectrum [(CD^^SO] S ppm: 3.9 - 4.4 (5H, multiplet, Ph-CHS-, -CH2S-.

-CH2N-); .38 (1H, doublet of doublets, J-3 & 9Hz, N-CHCO); 7.41 (5H, singlet, phenyl protons); 7.93 (4H, singlet, phthaloyl protons); 8.18 (1H, broad triplet. J«6Hz, NH). 7(f) t-Butvl The isomer first eluted in a yield of 1.3 g, was called "diastereomer A", and was in the form of a crystalline powder, softening at around 100°C and melting at 118°C.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm : 1.4-7 (9H, singlet, t-butyl); 2.8-4.8 (7H, multiplet, N-CH-CH2-S-, N-CH2~C0, S-CHPh-CHj); 98 .68 (1H, doublet of doublets. J = 2 8, 10Hz, N-CH-CO) 7.40 (5H, singlet, phenyl protons); 7.65-8.0 (4H, multiplet, phthaloyl protons).

The next isomer eluted. in a yield of 0.4g, was called "diastereomer 8" and was an amorphous solid.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm ; 1.40 (9H, singlet, t-butyl); 2.45-4.5 (7H, multiplet. N-CH-CH2-S. N-CH2-CO, S-CHPh-CH2); .52 (1H, doublet of doublets. J-6 & 9 Hz, N-CH-CO) 7.2-7.5 (5H. multiplet. phenyl protons); 7.6-7.8 (4H. multiplet. phthalyl protons). 7(g) t-8utvl tt-T6-amino-5-oxo-2-phenvl-perhvdro-1.4-thiazepin-4-vl1acetate Fderiued from diastereomer A in step (f)1 1.2 g of diastereomer A of t-butyl a-[5.-oxo-2-phenyl-6-phthalimidoperhydro-l.4-thiazepin-4-yl]-acetate [prepared as described in step (f) aboue] were subjected to dephthaloylization with methylhydrazine in the same manner as described in Example 1(g). to give 0.66g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm : 1.46 (9H, singlet, t-butyl); 2.05 (2H, broad singlet. NH2); 2.4-4.5 (8H, multiplet. -N-CH-CH2SCH-CH2-. N-CH2C0); 7.29 (5H, singlet, phenyl protons). 7(h) t-Butvl a-r6-amino-5-oxo-2-phenvl-perhvdro-1.4-thiazepin-4-vl1acetate rderiued from diastereomer B in step (f)1 0.4 g of diastereomer B of t-butyl a-[5-oxo-2-phenyl-6-phthalimidoperhydro-l,4-thiazepin-4-yl]-acetate [prepared as described in step (f) aboue] was subjected to dephthaloylization with methylhydrazine the same manner as described in Example 1(g). to give 0.22g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm 1.41 (9H. singlet, t-butyl); 2.13 (2H, broad singlet, NH2); 2.7-3.1 (3H, multiplet. C-CHj-S-CH-Ph); 4.10-4.50 (5H, multiplet. N-CHjCO, N-CH-CO, N-CH2-C-Ph); 7.36 (5H, singlet, phenyl protons). 100 7(i) t-Butvl a-C6-ri-ethoxvcarbonyl-3-phenvl-propvlaminol-5-oxo-2-phenviperhydro-1.»-thiazepin-4-vl)acetate (Compound No. 75) 0.66g of the isomer of t-butyl a-[6-amino-5-oxo-2-phenylperhydro-l,4-thiazepin-4-yl]acetate produced as described in step (g) aboue was subjected to N-alkylation with 0.84 g of ethyl 2-bromo-4-phenyl-butyrate following the procedure described in Example 1(h). The resulting compound was subjected to silica gel column chromatography using a 1:20 by uolume mixture of ethyl acetate and methylene chloride as eluent. From the first fraction was obtained 0.28 g of t-butyl a-[6-(l-ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-l,4-thiazepin-4-yl]acetate as an oil.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.25 (3H. triplet. J-7Hz. C02CH2CH3); 1.47 (9H, singlet, t-butyl); 1.8-2.25 (2H, multiplet. Ph-CH2CH.2); 2.4-4.5 (14H, multiplet, Ph-CH2, co-ch-nh-ch-ch2-s-ch-ch2,nch2co.

C02CH2CH3); 7.25 (5H, singlet, phenyl protons); 7.33 (5H, singlet, phenyl protons). 1 0 1 From the second fraction to be eluted was obtained, as an oil, 0.26 g of the other isomer arising from the asymmetric carbon atom at the 6—position of the compound obtained aboue.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.25 (3H, triplet. j-7HZ, cojchjchj); 1.4-6 (9H. singlet, t-butyl); 1.8-2.25 (2H. multiplet. Ph-CHjCHj); 2. 5-4.. 5 (14-H. multiplet, Ph-CHj. co-ch-nh-ch-ch2-s-ch-ch2,nch2co. c02ch2ch3); 7.26 (5H. singlet, phenyl protons); 7.34 (5H, singlet, phenyl protons). 7(j) t-8utvl a-C6-rI-ethoxyearbony1-3-phenylpropylamino 1-5-oxo-2-phen viper hydro- 1 .4-thiazepin-4-vl)-acetate (Compound No. 75) 0.22 g of the isomer of t-butyl a-[6-amino-5-oxo-2-phenylperhydro-l,4-thiazepin-4-yl]acetate [prepared as described in step (h) aboue] was subjected to N-alkylation with 0.28 g of ethyl 2-bromo-4-phenyl-butyrate in the same manner as described in Example 1(h). The resulting product was subjected to silica gel column chromatography, using a 1:20 by uolume mixture of ethyl acetate and methylene chloride as the eluent. 102 From the Fraction first eluted was obtained 0.14 g 0F t-butyl ct—[6—(l-ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-l,4-thiazepin-4-yl]acetate as an oil.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.25 (3H, triplet. J»7Hz. CO CH CH ) ; 1.41 (9H, singlet, t-butyl); 1.8-2.25 (2H, multiplet. PhCH2CH.2); 2.6-4.5 (14H, multiplet. PhCH^ co-ch-nh-ch-ch2-s-ch-ch2. nch2co.

C02CH2CH3); 7.26 (5H, singlet, phenyl protons); 7.36 (5H, singlet, phenyl protons).

From the fraction eluted subsequently was obtained, as an oil, 0.08 g of the other isomer arising from the asymmetric carbon atom at the 6-position of the compound obtained aboue.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.25 (3H. triplet. J»7Hz. C02CH2CH3); 1.44 (9H, singlet, t-butyl); 1.8-2.25 (2H, multiplet. PhCH2CH.2); 2.4-4.5 (14H, multiplet, PhCH2> co-ch-nh-ch-ch2-s-ch-ch2, nch2co.

C02CH2CH3); 103 7.26 (5H, singlet, phenyl protons) 7.34 (5H, singlet, phenyl protons) EXAMPLE 8 g-f 6-(1-Ethoxyearbony1-3-phenylpropylamino)-5-oxo-2-phenvlperhydro-1.4—thiazepin-4-vllacetic acid (Compound No. 29) 0.28 g of t-butyl g-[6-(1-ethoxycarbony1-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1.4-thiazepin-4-yl]acetate [prepared as described in Example 7(i) aboue (the first fraction)] was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3. giuing the title compound as an amorphous solid in a yield of 0.18 g.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm 1.25 (3h. triplet. J»7Hz. COjCHjCHj); 1.8-2.25 (2h. multiplet. phchjchj); 2.5-4.6 (13H. multiplet. PhCHj, co-ch-nh-ch-ch2-s-ch-ch2-, n-ch2co. co2ch2ch3); 7.25 (5H, singlet, phenyl protons); 7.34 (5H, singlet, phenyl protons). 104 EXAMPLE 9 g-f6-(1-Ethoxyearbony 1-3-phenylpropylamino)-5-oxo- 2-phenvlperhydro-l.4-thiazepin-4-vllacetic acid (Compound No. 29) 0.26 g of t-butyl a-[6-(1-ethoxycarbony1- 3-pheny1propylamino)-5-oxo-2-phenylperhydro-1,4-thiazepin- 4-yl]acetate [prepared as described in Example 7(i) aboue (the second fraction)] mas subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, giuing the title compound as an amorphous solid in a yield of 0.17 g.

Nuclear Magnetic Resonance Spectrum (COCl^) S ppm: 1.26 (3H. triplet. J«7Hz, COjCHjCHj); 1.8-2.25 (2H. multiplet. PhCHjCHj); 2.5-4.6 (13H. multiplet. PhCHj, co-ch-nh-ch-ch2-s-ch-ch2-.

N-CH2C0.C02CH2CH3); 7.25 (5H. singlet, phenyl protons); 7.36 (5H, singlet, phenyl protons). 105 EXAMPLE 10 g-f6-(1-Ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1.4—thia2epin-4—ylTacetic acid (Compound No. 29) 0.14 g of t-butyl a-[6-(1-ethoxycarbonyl- 3-phenylpropy1amino)-5-oxo-2-phenylperhydro-1,4-thiazepin- 4--y 1 ]acetate [prepared as described in Example 7(]) aboue (the first fraction)] was subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, giuing the title compound as an amorphous solid in a yield of 0.09 g.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm 1.25 (3H, triplet. J-7Hz. C02CH2CH3); 1.8-2.25 (2H. multiplet. PhCH2CH2>; 2.5-4,5 (13H, multiplet. PhCHj, co-ch-nh-ch-ch2-sch-ch2. n-ch2co. coch2ch3); 7.25 (5H. singlet, phenyl protons); 7.35 (5H. singlet, phenyl protons). 106 EXAMPLE 11 g-f6-(1-Ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1.4—thiazepin-4—yllacetic acid (Compound No. 29) 0.08 g of t-butyl a-[6-(1-ethoxycarbonyl- 3-pheny1propylamino)-5-oxo-2-phenylperhydro-1. 4—thiazepin- 4-yl]acetate [prepared as described in Example 7(j) aboue (the second fraction)] was subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, giuing the title compound as an amorphous solid in a yield of 0.05 g.

Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm: 1.26 (3H, triplet. J«7Hz. COjCHjCHj); 1.8-2.25 (2H, multiplet. PhCHjCHj); 2.5-5.1 (13H. multiplet. PhCHj. co-ch-nh-ch-ch2-s-ch-ch2- n-ch2co.co2ch2ch3); 7.25 (5H, singlet, phenyl protons); 7.34 (5H, singlet, phenyl protons). 1 07 EXAMPLE 12 g-f6-(1-Carboxy-3-phenylpropylamino)-5-oxo-2-phenvl-perhydro-1.4-thiazepin-4-yl1acetic acid (Compound No. 30^ 0.18 g of g-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-l.4-thiazepin-4-yl]acetic acid (prepared as described in Example 8 aboue) was hydrolysed with aqueous sodium hydroxide in the manner described in Example 5, giuing the title compound as a powder in a yield of 0.14 g.

Nuclear Magnetic Resonance Spectrum [(CD^^SO] ppm: 1.75-2.IS (2H. multiplet. PhCHjCHj); 2.55-4.6 (11H, multiplet, PhCHj.

-CH-NH-CH-CH2-S-CH-CH2, NCHjCO); 7.30 (5H, singlet, phenyl protons); 7.40 (5H, multiplet. phenyl protons).

EXAMPLE 13 g-r6-(l-Carboxv-3-phenylpropylamino)-5-oxo-2-phenvlperhvdro-1.4-thiazepin-4-vnacetic acid (Compound No. 30) 0.17 g of g-[6-(l-ethoxycarbonyl-3- 108 phenylpropylamino)-S-oxo-2-phenylperhydro-l,4-thiazepin-4-yl]acetic acid (prepared as described in Example 9 aboue) was hydrolysed with aqueous sodium hydroxide in the manner described in Example 5, giuing the title compound as a powder in a yield of 0.13 g.

Nuclear Magnetic Resonance Spectrum [(CD^^SO] ppm: 1.75-2.1 (2H, multiplet, PhCH2CH.2); 2.55-4.5 (11H, multiplet, PhCHj.

-CH-NH-CH-CH2-S-CH-CH2. NCHjCO); 7.27 (5H, singlet, phenyl protons): 7.38 (5H, singlet, phenyl protons).

EXAMPLE 14 EXAMPLE 15 g-r 6-(l-Carboxv-3-phenvlpropylamino)-5-oxo-2-phenvlperhydro-l. 4-thiazepin-4-vnacetic acid (Compound No. 30) 50 mg of a-[6-(l-ethoxycarbonyl-3-phenyl-propylamino)-S-oxo-2-phenylperhydro-1,4-thiazepin-4-y1]-acetic acid (prepared as described in Example 11 aboue) were hydrolysed with aqueous sodium hydroxide in the manner described in Example 5. giuing the title compound as a powder in a yield of 40 mg.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO] ppm: 1.7-2.1 (2H. multiplet. PhCHjCHj); 2.6-5.1 (9H. multiplet. PhCH2< 1 10 3.97 (2H, A8 quartet. AS=0.27 ppm, J=19Hz, NCH2C0); 7.26 (5H, singlet, phenyl protons); 7.4-0 (5H, singlet, phenyl protons).

EXAMPLE 19 t-8uty1 a-(6-f1-butoxycarbonvl-3-phenylpropylamino 1-5-oxo-2-phenvlperhydro-l. 4—thiazepin-4-yl)acetate (Compound No. 202) 0.34 g of t-butyl a-(6-amino-5-oxo-2-pheny1-perhydro-l,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g) aboue] was N-alkylated with 0,45 g of butyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The resulting product was subjected to silica gel column chromatography using a 1:40 by uolume mixture of ethyl acetate and methylene chloride as the eluent. As a result, the title compound was separated into isomers A and 8 (resulting from the asymmetric carbon atom to which the phenethyl group is attached).

Isomer A, first eluted: an oily substance, yield 0.13g. 111 Nuclear Magnetic Resonance Spectrum (CDC13) 6 ppm 0.7-1.1 (3H, multiplet, CH^ of n-butyl); 1.46 (9H, singlet, t-butyl); 1.1-2.3 [7H, multiplet. C02CH2(CH2)2CH3, PhCH2CH2. NH]; 2.3-4.4 [13H. multiplet. PhCH^H 2~CH~N. protons of the thiazepine ring, N-CH2~C0( C02CH2(CH2)2CH3]; 7.17 (10H, singlet, protons of the 2 phenyl groups).

Isomer B subsequently eluted: an oily substance, yield 0.12 g.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 0.7-1.1 (3H, multiplet, CHj of n-butyl); 1.46 (9H, singlet, t-butyl); 1.1-2.25 [7H, multiplet. C02CH2(CH2>2CH3.

PhCHjCHj, NH]; 2.3-4.4 [13H, multiplet. PhCH.2CH2CH-N. protons of the thiazepine ring, N-CH2CO.

C02CH2(CH2)2CH3]; 7.15 (10H, singlet, protons of the 2 phenyl groups). 1 1 2 EXAMPLE 20 a- (6-f 1-Butox yearbony1-3-phenylpropylamino 1-5-oxo-2-phenvl perhydro-1,4—thiazepin-4—ypacetic acid (Compound No. 188) 0.12 g of isomer B of t-butyl a-[6-(1-butoxycarbonyl- 3 -phenyl propylamino ) -5-oxo-2-pheny lper hydro- 1. 4— thiazepin-4—yl]acetate (prepared as described in Example 1.9 above) was subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, to give 78 mg of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm. 0.7-1.1 (3H, multiplet. CH^ of n-butyl); 1.1-1.8 [4H. multiplet. C02CH2 (CH2) 2CH3 ] ; 1.95-2.5 (2H, multiplet. PhCHjCHj); 2.5-4.7 [13H. multiplet. PhCH2CH2CH-N. protons of the thiazepine ring. N-CH2-C0.

C02CH2(CH2)2CH3]; 7.18 (10H, singlet, protons of the 2 phenyl groups). 1 1 3 EXAMPLE 21 t-Butvl a-T6-(l-benzvloxvcarbonvl-3-phenvlpropyl-amino)-5-oxo-2-phenvlperhvdro-l,4-thiazepin-4-v11 acetate (Compound No. 203> 0.34 g of t-butyl a-(6-amino-5-oxo-2-phenyl-perhydro-1.4-thiazepin-4-yl)acetate [prepared as described in Example 7(g)] uias N-alkylated with 0.50 g of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:40 by uolume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).

Isomer A was eluted first as an oil in a yield of 0.15g.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.46 (9H, singlet t-butyl); 1.8-2.2 (2H, multiplet, PhCHjCH^); 2.4-4.5 ( 12H, multiplet. PhCHjCH^CH-NH, protons of the thiazepine ring, N-CH2~CO); .09 (2H, AB quartet. AS-0.20 ppm, J-13HZ, CH2Ph); 1 1 4 7.1-7.4. (15H, multiplet, protons of the 3 phenyl groups).

Isomer 8 uias eluted next as an oil in a yield of 0.15 g.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.4-6 (9H. singlet, t-butyl); 1.8-2.25 (2H. multiplet, PhCHjCH^); 2.4.5-4.45 (12H, multiplet, PhCHjCHj-CH-NH, protons of the thiazepine ring, N-CH2-C0); .12 (2H, singlet, CHjPh); 7.16, 7.27, 7.33 (together 15H, each singlet. protons of the 3 phenyl groups).

EXAMPLE 22 a.- T 6 - (1 -Benzvlox year bony 1-3-phenv lpropylami no)-5-ox o-2-phenvlperhvdro-1.4-thiazepin-4-vl1acetic acid (Compound No. 189) 0.10 g of isomer B of t-butyl a-[6-(1-benzyloxy-carbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-l, 4-thiazepin-4-yl]acetate (prepared as described in Example 21) was treated with trifluoroacetic acid to remove its t-butyl group by the process described in Example 3. 70 mg of the title compound were obtained as amorphous 1 15 solid.

Nuclear Magnetic Resonance Spectrum C(CD3)2SO] ppm: 1.95-2.3 (2H, multiplet, PhCH2CH2); 2.4.-5.0 ( 11H, multiplet, PhCH2CH2-CH-N, protons of the thiazepine ring); .28 (2H, AS quartet. AS-2.0ppm. J-13HZ, CH2Ph); 7.1-7.35 (5H, multiplet, CH,Ph); 7.4-. 7.47 (together 10H, each singlet, protons of the 2 phenyl groups).

EXAMPLE 27 t-Butvl a-T6(R)-(1-ethoxvcarbonvl-3-phenvlpropyl-amjno)-3(R)-isopropyl-5-oxoperhvdro-l.4-thiazepin-4-yll-acetate (Compound No. 206) The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-3-methyl-1-butanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl a-C6(R)-[1(R)-ethoxycarbony1-3-phenyIpropylamino]- 3(R)-isopropyl-5-oxoperhydro-1.4-thiazepin-4-yl)acetate (isomer A) and t-butyl a-(6(R)-[i(S)-ethoxycarbonyl-3-phenyIpropylamino]-3(R)-isopropyl-5-oxoperhydro-1.a- 1 1 6 (isomer 8), were obtained a Isomer ft thiazepin-4-yl)acetate ails .

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 0.98 [6H. doublet of doublets, J=3 4 6.5Hz, CH(CH3)2]; 1.22 (3H, triplet, J=7Hz. C02CH2CH.3) ; 1.47 (9H, singlet, t-butyl); 1.6-2.2 (2H , multiplet. PhCH2CH.2) ; 2.4-4.4 [1SH. multiplet. PhCHjC^CHCO-NH. protons of the thiazepine ring, CH(CH3)2, N-CH2-CO. C02CH2CH3]; 7.19 (5H, singlet, phenyl protons).

Isomer 8 Nuclear Magnetic Resonance Spectrum (COCl3) 5 ppm 1.00 [6H, doublet. J=6.5Hz. CH(CH3)2]; 1.23 (3H, triplet. J-7Hz. C02CH2CH3); 1.47 (9H, singlet, t-butyl); 1.7-2.2 (2H. multiplet. PhCH2CH.2); 2.4-4.2 multiplet. PhCHjCHjCHCO-NH. protons of the thiazepine ring. CH(CH3)2. N-CH2-CO]; 4.12 (2H. quartet, J-7.5HZ. C02CH2CH3); 1.19 (5H, singlet, phenyl protons). 1 17 EXAMPLE 28 a-C 6(R)-f1(S)-Ethoxycarbonvl-3-phenvIpropylamino1 -3(R)-isopropyl-5-oxoperhydro-l.4—thiazepin-4— yl)acetic acid (Compound No. 173) 0.32 g of t-butyl a-(6(R)-[1(S)-ethoxycarbonyl-* 3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-l.4-thiazepin-4—yl}acetate (isomer B) synthesized as described in Example 27 mas subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3, to giue 260 mg of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (COCl^) 8 ppm: 0.98 [6H. broad doublet. J-4Hz. CH(CH3>2]; 1.24 (3H, triplet. J«7Hz. COjCHjCHj); 1.7-2.3 (2H. multiplet. PhCHjCHj); 2.4-4.8 U2H. multiplet. PhCHjCHjCHCO-NH. protons of the thiazepine ring, CH(CH3)2, N-CH2-CO]; 4.15 (2H, quartet. J«7Hz. COjCHjCHj); 7.12 (5H. singlet, phenyl protons). 1 18 EXAMPLE 29 g-(6(R)-r1(S)-Carboxy-3-phenylpropylamino1-3(R)-isopropvl-5-oxoperhydro-i,4-thiazepin-4-v1)acetic acid (Compound No. 174) 160 mg of a-(6(R)-[ 1 (S)-ethoxycarbonyl-3-phenyIpropylamino]-3(R)-isopropyl-5-oxoperhydro-l.4-thiazepin-4-yl)acetic acid (prepared as described in Example 28 aboue) were hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 5, giuing 113 mg of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD3)2S0] & ppm: 0.97 [6H. doublet. J=6Hz. CH(CH.3)2]; 1.7-2.2 (2H. multiplet. PhCHjCHj); 2.3-4.4 ClOH. multiplet. PhCHjCHjCHCO-NH. protons of the thiazepine ring, CH(CH3)2]; 3.83 (2H. singlet. N-CHj-CO); 7.25 (5H. singlet, phenyl protons). 1 1 9 EXAMPLE 30 t-Butvl a-f6(R)-( 1-ethoxycarbonvl-3-phenylpropyl-amino)-3(R)-methy 1-5-oxoperhydro -1. 4.-thiazepin-4-v 11 -acetate (Compound No. 207) The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-1-propanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl a-C6(R)-[1(R)-ethoxycarbony1-3-phenyIpropylamino]-3(R)-methy1-5-oxoperhydro-I,4-thiazepin-4-yl)acetate (isomer A) and t-butyl a-(6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methy1-5-oxoperhydro-1.4-thiazepin-4-yl}acetate (isomer B) were obtained as oils .

Isomer ft Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.22 (3H, triplet. J»7Hz, COjCHjCHj); 1.29 (3H. doublet. J»6Hz, 3-CH^); 1.46 (9H. singlet, t-butyl); 1.7-2.2 (2H. multiplet. PhCHjCHj); 2.3-4.2 (10H, multiplet. PhCHjCHjCHCO-NH. protons of the thiazepine ring); 1 20 3.97 (2H, singlet, N-CH2-CO); 4.11 (2 H, quartet, J=7Hz, CC>2CH2CH3); 7.19 (5H, singlet, phenyl protons).

Isomer B Nuclear Magnetic Resonance Spectrum (COClj) & ppm: 1.26 (3H, triplet. J=7Hz, CO^HjCHj); 1.32 (3H, doublet. J=6Hz. 3-CH3); 1.7-2.3 (2H, multiplet. PhCH2CH2); 2.35-4.35 (10H. multiplet, PhCH2CH2CHCO-NH, protons of the thiazepine ring); 3.98 (2H, AB quartet, A5«0.33 ppm, Jal7Hz, N-CH2-C0); 4.13 (2H. quartet. J=7Hz. C02CH.2CH3); 7.18 (5H. singlet, phenyl protons).

EXAMPLE 31 tt-t6(R)-fICS)-Ethoxvcarbonvl-3-phenvlpropylamino 1-3(R)-methvl-5-oxoperhvdro-l.4-thiazepin-4-vl)acetic acid (Compound No. 171) 0.41 g of t-butyl a-(6(R)-CKS)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methyl-5-oxoperhydro-l,4-thiazepin-4-yl)acetate (isomer B) synthesized as described in Example 30 was subjected to de-t-butylation 1 2 1 uiith trif luoroacetic acid in the same manner as described in Example 3, to give 334 mg of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.26 (3H, triplet. J=7Hz. CO^h^CH^); 1.32 (3 H, doublet. J=6Hz, 3-CH3); 1.8-5.0 (15H, multiplet. PhCH2CH2CHC0-NH, protons of the thiazepine ring, N-CH -CO.CO CH CH ); 7.12 (5H, singlet, phenyl protons).

EXAMPLE 32 tt-C6(R)-f 1(S)-Carboxv-3-phenylpropylamino1-3(R)-methy1-5-oxoperhydro-l.4-thiazepin-4-yDacetic acid (Compound No. 172) 175 mg of a-(6(R)-[1(S)-ethoxycarbony1-3-phenyIpropylamino]-3(R)-methy1-5-oxoperhydro-l.4-thiazepin-4-yl)acetic acid (prepared as described in Example 31 aboue) mere hydrolyzed uiith aqueous sodium hydroxide in the same manner as described in Example 5. to giue 93 mg of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(C03)230] ppm: 1 22 1.28 (3 H, doublet, J=6.SHz, 3-CH3); 1.7-2.1 (2H, multiplet, PhCH^CH^; 2.3-4.35 (9H, multiplet, PhCH2CH2CHCO-NH, protons of the thiazepine ring); 3.98 (2H, AB quartet, &5=0.28 ppm, Jal7Hz, N-CH2-CO); 7.26 (5H, singlet, phenyl protons).

EXAMPLE 33 t-Butvl cr-r3(S)-benzyl-6(R)-( 1-ethoxycarbonv 1-3-phenylpropylamino)-5-oxoperhvdro-l. 4—thiazepin-4-vll-acetate (Compound No. 208) The procedure described in steps (a) to (h) of Example 1 was repeated, except that L-2-amino-3-phenyl-1-propanol was used as the starting material. Tujo isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl a-(3(S)-benzyl-6(R)-[l(R)-ethoxycarbonyl-3-phenyl-propylamino]-5-oxoperhydro-l.4-thiazepin-4-yl)acetate (isomer A) and t-butyl a-(3(S)-benzyl-6(R)-[l(S)- ethoxycarbonyl-3-phenylpropylamino]-5-oxoperhydro-l, 4- thiazepin-4—y1)acetate (isomer B) were obtained as Isomer ft 123 Nuclear Magnetic Resonance Spectrum (CDCl3) 5 ppm: 1.24 (3H, triplet. J»7Hz. COjCHjCHj); 1.43 (9H. singlet, t-butyl); 1.7-2.2 (2H, multiplet. PhCH2CH2); 2.3-4.4 (14H, multiplet. PhCH2CH2CHCO-NH. protons of the thiazepine ring, 3-CH2Ph. N-CH2-CO); 4.14 (2H, quartet. J=7Hz. C02CH2CH3); 7.19 (10H, singlet, protons of two phenyl groups).

Isomer B Nuclear Magnetic Resonance Spectrum (COCl3) 8 ppm 1.27 (3H, triplet. J«7Hz. C02CH2CH3); 1.47 (9H. singlet, t-butyl); 1.8-2.2 (2H, multiplet, PhCH2CH.2) ; 2.4-4.4 (14H, multiplet. PhCH2CH2CHCO-NH. protons of the thiazepine ring. 3-CH2Ph, N-CH2-CO); 4.16 (2H, quartet. J-7HZ, C02CH.2CH3) ; 7.20 (10H, singlet, protons of two phenyl groups). 12 4 EXAMPLE 34 a-C3(5)-Benzvl-6(R)-ri(S)-ethoxycarbonvl-3-phenvl-propylamino1-5-oxoperhydro-l,4—thiazepin-4-yl)acetic acid (Compound No. 17) 630 mg of t-butyl a-C3(S)-benzyl-6(R)-[1(S)-ethoxycarbony1-3-phenylpropylamino]-5-oxoperhydro-l,4-thiazepin-4-yl)acetate (isomer B) synthesized as described in Example 33 was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3, to giue 438 mg of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.23 (3H, triplet. J-7Hz. COjCHjCHj); 1.7-2.3 (2H, multiplet. PhCH2CH2); 2.4-4..6 (13H. multiplet. PhCt^CHjCHCO-NH, protons of the thiazepine ring, 3-CH2Ph, N-CH2-CO); 4.14 (2H, quartet. J-7Hz, C02CH.2CH3); 7.18 (10H. singlet, protons of two phenyl groups). 125 EXAMPLE 35 a-(3(S)-8enzvl-6(R)-ri(5)-carboxv-3-phenylpropvl- amino 1-5-oxoperhydro-1,4-thiazepin-4-yl)acetic acid (Compound No. 18) 326 mg of a-(3(S)-benzy1-6(R)-[1(S)-ethoxy-carbony1-3-phenylpropylamino]-5-oxoperhydro-1,4-thiazepin-4- yljacetic acid were hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 5, to giue 225 mg of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD^^SO] 20 5 ppm: 1.6-2.2 (2H, multiplet. PhCH2CH.2); 2.4-4.5 ( 13H , multiplet. PhCHjC^CHCO-NH . protons of the thiazepine ring. 3-CH2Ph, 25 N-CH2-CO); 7.22 (10H, singlet, protons of two phenyl groups).

EXAMPLE 36 t-Butvl g-T6-(l-ethoxvcarbonvl-3-phenvlpropylamino)-2-(i-naphthvl)-5-oxoperhvdro-l,4-thiazepin-4-y11 acetate (Compound No. 163) 1 26 36(a) 2- t-Butoxyearbony lamino-i-( 1-naohthypefchanni Crude 2-amino-l-(1-naphthyl)ethanol (obtained by the reduction of 4-4 g of 1-naphthaldehyde cyanohydrin with lithium aluminium hydride) was stirred with 12.8 g of triethylamine and 20 g of di-t-butyl pyrocarbonate in 200 ml of methanol for 1 hour at room temperature.

The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulphate, and the solvent was distilled off. The crystalline residue was collected by filtration using diisopropyl ether to give 14.. 2 g of the title compound melting at 109 - 110°C Nuclear Magnetic Resonance Spectrum (COCl^) 5 ppm: 1.44. (9H, singlet, t-butyl); 3.OS - 3.9 (3H, multiplet. -CH2< OH); .08 (1H. broad. NH); .60 (ltt, doublet of triplets, J=4 & 8Hz. -CH-OH); 7.25 -8.25 (7H, multiplet. naphthyl protons). 36(b) 2-t-Butoxvcarbonvlamino-l-chloro-(1-naphthyl)ethane To a solution of 13 g of 2-t-butoxycarbonylamino-1- 1 27 (1-naphthyl)ethanol [prepared as described in step (a) aboue] in 200 ml of anhydrous methylene chloride was 5 added at 0 - 5°C a solution of 9.4 g of phosphorus pentachloride in 190 ml of anhydrous methylene chloride. The reaction mixture was then stirred for 5 minutes, after which 195 ml of 4N aqueous sodium hydroxide was added all at once to the reaction mixture and the mixture was stirred for 30 minutes whilst ice-cooling. The methylene chloride layer was separated, washed with , a large amount of water and dried over anhydrous magnesium sulphate; the solvent was then evaporated off. The residue was subjected to silica gel column chromatography eluted with a 1:7 by uolume mixture of 20 ethyl acetate and cyclohexane, to give 9.0 g of the title compound as a syrup.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 25 1.43 (9H, singlet, t-butyl); 3.3-4.2 (2H, multiplet. CH2); .00 (1H. broad triplet. NH); .83 (1H. doublet of doublets. J-5.5 & 8Hz.

-CH-naphthyl); 7.2-8.3 (7H, multiplet. naphthyl protons). 36(c) Benzhvdrvl ester of S-r2-t-butoxvcarbonvlamino-l-(l-naphthvl)ethvl1-N-phthalovievsteine 1 28 To a solution of 10 g of l-cysteine £-toluene-sulphonate and 7.5 g of N-ethoxycarbonylphthalimide in 68 ml of dimethylformamide were added 6.2 g of sodium bicarbonate under a nitrogen atmosphere. The reaction mixture was then stirred at 90-100°C for 3.5 hours, after which it was cooled. The reaction mixture was then poured into a mixture of ethyl acetate and an aqueous solution of potassium hydrogen sulphate, to acidify it. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate.

To the resulting solution were added 7.4. g of diphenyldiazomethane. and the reaction mixture was stirred for 1 hour under a nitrogen atmosphere. The solvent was then evaporated off and the residue was dissolved in 60 ml of dimethylformamide. To this solution were added 9.6 g of 2-t-butoxycarbonylamino-l-chloro-l-(1-naphthyl)ethane [prepared as described in step (b) above], and the reaction mixture was stirred at 70°C for 16 hours under a stream of nitrogen. The reaction mixture was then dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate, and the solvent was evaporated off. The residue was subjected to silica gel column chromatography using a 129 1.4 by uolume mixture of ethyl acetate and cyclohexane as eluent, to giue the title compound as an amorphous solid in a yield of 10.4g.

Nuclear Magnetic Resonance Spectrum (CDC13) 8 ppm: 1.35 (9H, singlet, t-butyl); 3.15 - 3.8 (4H, multiplet, CH2-S,C-CH2-N); 4.5-5.1 (3H, multiplet. NH. N-CH-CO. S-CH-naphthy1); 6.61 and 6.70 (together 1H, two kinds of singlet, CHPh2); 6.75-8.3 [2 1H, multiplet, CH(C,Hc)_. naphthyl protons, phthaloyl protons], 36(d) S-r2-ftmino-l-(1-naphthyl)ethyl1-N-phthalovl-cvsteine To a solution of 10.4 g of the benzyhydryl ester of S-[2-t-butoxycarbonylamino-I-(I-naphthyl)ethyl]-N-phthaloylcysteine [prepared as described in step (c) aboue] in 40 ml of anisole were added 50 ml of trifluoroacetic acid, and the reaction mixture was stirred for 2 hours at room temperature. The solvent was evaporated off. and 40 ml of ethyl acetate. 30 ml of water and 2.0 g of sodium bicarbonate were added to the residue, with stirring. The pH of the reaction mixture was adjusted to a value of 5.8 with 3N hydrochloric acid. Whilst ice-cooling, the reaction mixture was 1 30 stirred and the precipitate of the title compound ^as collected by filtration and washed with a 1:1 by uolume mixture of acetone and diethyl ether, to yield 5 6 g of the title compound melting at 195-199°C 36(e) 2-( l-Naphthyl)-5-oxo-6-phthalimidoperhydro-i . 4.-thiazepine To a solution of 55 g of S-[2~amino-l-(1-naphthyl)-ethyl]-N-phthaloylcysteine [prepared as described in step (d) aboue] in 110 ml of dimethylformamide were added 5.1 g of diphenylphosphoryl azide and 2.6 ml of N-methylmorpholine, and the mixture was stirred for 15 hours at room temperature. Water (about 200 ml) and ethyl acetate (about 500ml) were added to the reaction inixutre, with stirring. The precipitate of the title compound was collected by filtration and washed witn water and ethyl acetate, to yield 3.5 g of the title compound melting aboue 300°C Nuclear Magnetic Resonance Spectrum [(C03) SO] S ppm: 2.7-4.6 (4H, multiplet. CH2-S. N-CH^C), 4.94 (1H, broad doublet. J=8Hz, S-CH-naphthyl). 5.47 (1H, doublet of doublets, J=3 4 8Hz. N-CH-CO); 7.4-8.5 (11H, naphthyl protons, phthaloyl protons). 131 36(f) t-Butvl a-r2-(l-naphthyl)-S-oxo-6-phthalimidoperhydro-l,4-thiazepin-4—yllacetate To a suspension of 3.4 g of 2-( 1-naphthyl)-S-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) aboue] in a mixture of 34 ml of dimethyIformamide and 10 ml of hexamethylphosphoric triamide were added dropwise 2.25 ml of t-butyl bromoacetate and then, bit by bit, 609 mg of a 55% w/w suspension of sodium hydride in oil at 0 - S°C, under a nitrogen stream. After this addition, the reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate and water were then added to the reaction mixture. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulphate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to give 2.6 g of the title compound as crystals, melting at 21l-2l3°C Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm 1.47 (9H, singlet, t-butyl); 3.0-4.9 (6H, multiplet, -CH^-S, N-CH^-CO, -CH2-N); .30 (1H, doublet. J»9Hz, N-CH-CO); .78 (1H. broad doublet. J»10Hz. S-CH-naphthyl); 1 32 7.3-8.35 (11H, naphthyl protons, phthaloyl protons). 36(g) t-Butvl a-r6-amino-2-f1-naphthvl)-5-oxoperhvdro-1. 4-thiazepjn-4-y11 acetate To a solution of 2.5 g of t-butyl 2-(1-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepin-4-y1]acetate [prepared as described in step (f) above] in a mixture of 20 ml of methylene chloride and 2 ml of methanol was added 0.77 ml of methylhydrazine, and the reaction mixture was allowed to stand for 2 days at room temperature. The reaction mixture was then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride were added to the residue and the mixture was stirred. The resulting precipitate was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography using a 1:20 by uolume mixture of methanol and ethyl acetate as eluent, to giue 1.92 g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm. 1.4-7 (9H. singlet, t-butyl); 2.11 (2H. broad singlet, NH2); 2.45-4.8 (7H, multiplet. N-CHj-CO. HjN-CH-CH^S.

N-CH2-C); 133 .15 (1H, doublet, J=9.5Hz, S-CH-naphthyl); 7.2—8.3 (7H, multiplet, naphthyl protons). 36(h) t-8uty1 a-r6-(l-ethoxvcarbonvl-3-phenvlpropyl-amino)-2-(1-naphthvl)- 5-oxoperhydro-l. 4.-thiazepin-4-yll-acetate (Compound No. 163) To a solution of a mixture of 803 g of t-butyl g-[6-amino-2-(l-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-y.l]acetate [prepared as described in step (g) aboue] and 1.13 g of ethyl 2-bromo-4-phenylbutyrate in 10 ml of dimethylformamide uas added 0.66 g of sodium carbonate. The reaction mixture was stirred at 80®C for 15 hours and then dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer uas separated, washed uith water and dried over anhydrous magnesium sulphate, and the solvent uas then evaporated off. The residue was subjected to silica gel column chromatography using a 1:30 by volume mixture of ethyl acetate and methylene chloride as eluent. which separated the product into two isomers. A and 8. (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).

Isomer A was eluted first : an oily substance in a yield of 0.4-9 g 13^ Nuclear Magnetic Resonance Spectrum (CDC13)S ppm: 1.24. (3 H, triplet, J=7.5 Hz, C02CH2CH3); 1.4-6 (9H, singlet, t-butyl); 1.7-2.2 (2H, multiplet, PhCH2CH.2) ; 2. 4.-4.. 7 (13H, multiplet, PhCH2CH2CH-NH, co-ch-ch2s-ch-ch2 . n-ch2-co, c02ch2ch3); .13 (1H, broad doublet, J=9Hz, S-CH-naphthyl); 7.14 (5H, singlet, phenyl protons); 7.2-8.2 (7H, multiplet, naphthyl protons).

Isomer B.was eluted next; an oily substance in a yield of 0.46 g.

Nuclear Magnetic Resonance Spectrum (CDCl3)5 ppm: 1.28 (3H, triplet. J-7. 5 Hz, COjCHjCHj); 1.48 (9H, singlet, t-butyl); 1.8-2.3 (2H. multiplet. PhCH2CH2); 2.5-4.8 (13H. multiplet. PhCHjCHjCH-NH, co-ch-ch2s-ch-ch2. n-ch2-co. co2ch2ch3); .18 (1H, doublet. J=9.5Hz. S-CH-naphthyl); 7.21 (5H, singlet, phenyl protons); 7.35-8.3 (7H, multiplet, naphthyl protons). 135 EXAMPLE 37 a-l"6-( l-Ethoxycarbonvl-3-phenvlpropvlamino)-2-( 1 -naphthvl)-5-oxoperhydro-1.4-thiazepin-4-yllacetic acid (Compound No. 134) 455 mg of isomer B of t-butyl a-[6-(l-ethoxycarbony1-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-l,4-thiazepin-4-y1]acetate [prepared as described in Example 36(h)] were dissolved in a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid. The reaction mixture was then stirred for 4 hours at room temperature, after which it was concentrated by evaporation under reduced pressure. Diisopropyl ether was added to the residue, whilst stirring, and the resulting crystalline powder was collected by filtration, a yield of 447 mg.

This powder was dissolved in a mixture of 2 ml of ethyl acetate and 2 ml of water. 0.2 g of sodium bicarbonate was added to the resulting solution. The reaction mixture was adjusted to a pH value of 2.5 by adding 3N hydrochloric acid. The precipitate of the title compound was collected by filtration to yield 216 mg. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. These resulting ethyl acetate solutions were combined and 136 dried over anhydrous magnesium sulphate, and the solvent was then evaporated off to giue the title compound as crystals. These crystals (a further 70 mg) were collected by filtration using diisopropyl ether The crystalline compound melted at 201-203°C.

Nuclear Magnetic Resonance Spectrum [(CD3)2S0] ppm: 1.28 (3H, triplet, J=7.5 Hz, C02CH2CH.3) ; 2.0-2.4 (2H, multiplet. PhCH2CH2); 2.5-5.4 C13H. multiplet. PhCH2CH2CH-N, protons of the thiazepine ring, N-CH2-C0, C02CH2CH3); 7.32 (5H, singlet, phenyl protons); 7.2-8.3 (7H, multiplet. naphthyl protons).

EXAMPLE 38 Nuclear Magnetic Resonance Spectrum [(C03)2s0] ppm: 1.7-2.1 (2H. multiplet, PhCH2CH2); 2.5-5.35 (11H. multiplet. PhCHjCHjCH-N, protons of the thiazepine ring, N-CH2-C0); 7.28 (5H. singlet, phenyl protons); 7.1-8.3 (7H, naphthyl protons).

EXAMPLE 39 t-Butvl a-T6-(l-ethoxvcarbonvl-3-phenvl- propvlamino)-2-(2-naphthvl)-5-oxoperhydro-l.»-thiazepin-4-vllacetate (Compound No. 164.) 39(a) 2-t-Butoxvcarbonylamino-l-(2-naphthyl)ethanol Crude 2-amino-l-(2-naphthyl)ethanol (obtained by the reduction of 26 g of 2-naphthaldehyde cyanohydrin with lithium aluminium hydride) was t-butoxycarbonylated in 1 38 the same manner as described in Example 36(a). to giue 16 g of the title compound as a crystalline solid melting at 99-100.5°C.

Nuclear Magnetic Resonance Spectrum (CDCl3)5ppm: 1.43 (9H, singlet, t-butyl); 3.1-3.75 (3 H, multiplet, -CH2-,0H); 4.95 (1H, broad. NH); 4.96 (1H, doublet of doublets, J»4 & 8Hz, -CH-OH); 7.4-8.0 (7H, multiplet, naphthyl protons). 39(b) 2-t-Butoxycarbonylamino-l-chloro-l-(2-naphthyl)-ethane 16 g of 2-t-butoxycarbonylamino-l-(2-naphthyl)ethanol [prepared as described in step (a) aboue] were chlorinated with phosphorus pentachloride the same manner as in Example 36(b) to giue 9.1 g of t crystalline title compound, melting at 97-98°C Nuclear Magnetic Resonance Spectrum (C0Cl3)Sppm: 1.43 (9H, singlet, t-butyl); 3.4-4.0 (2H. multiplet. CH2); 4.93 (1H. broad. NH); .18 (1H, doublet of doublets, J»6 8, 7Hz.

-CH-naphthyl); 7.45-8.0 (7H, multiplet. naphthyl protons). '.3 9 39(c) Benzhydryl ester of S-r2-t-butoxycarbonylamino-l- (2-naphthyl)ethy11-N-ohthalovleysteine To a solution of the benzhydryl ester of N-phthaloylcysteine [which was prepared by treating 10 g of L-cysteine g,-toluenesulphonate, 7.5 g of N-ethoxy-carbonylphthalimide, 6 . 2g of sodium bicarbonate and 7.4 g of diphenyldiazomethane in the same manner as in Example 36(c)] and 9.6 g of 2-t-butoxycarbonyl-amino-l-chloro-l-(2-naphthyl)ethane [prepared as described in step (b) aboue] in 80 ml of dimethylformamide were added 7.3 g of sodium carbonate. The reaction mixture was stirred at 80°C for 18 hours under a stream of nitrogen. Treatment of the reaction solution was conducted in the same manner as described in Example 36(c), to giue 12.3g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (C0Cl3)5ppm: 1.37 (9H. singlet, t-butyl); 3.2 - 3.7 (4H. multiplet. CH2S. C-CH2-N); 4.22 (1H. triplet. J»4.SHz. S-CH-naphthyl); 4.67 (1H, broad. NH); .05 (1H. multiplet. N-CH-CO); 6.79 and 7.82 (together 1H. two kinds of singlet.

CHPh2); 7.0-8.0 [21H, multiplet. CH(CgH5)2< naphthyl protons, phthaloyl protons]. 1 40 39(d) S-r2-flmino-l-(2-naphthyl)ethyl1-N-phthalovl -cysteine 12.3g of the benzhydryl ester of S-[2-t-butoxy- carbonylamino-l-(2-naphthyl)ethyl]-N-phthaloyIcysteine [prepared as described in step (c) above] were treated with trifluoroacetic acid to remove its t-butyl group in the same manner as described in Example 36(d). The title compound (6.6 g) was obtained as powder, melting at 196-200°C. 39(e) 2-(2-Naphthyl)-5-oxo-6-phthalimidoperhydro-1,0—thiazepine 6.5g of S-[2-amino-l-(2-naphthyl)ethyl]-N-phthaloylcysteine [prepared as described in step (d) aboue] were subjected to condensation and cyclization with diphenylphosphoryl azide in the same manner as described in Example 36(e), to giue 4.25g of the title compound, softening from 270°C and melting at 283 -285°c.

Nuclear Magnetic Resonance Spectrum [(CD3)2SO] S ppm: 3.1-4.6 (5H, multiplet. CHj-S, N-CH^-CH-S); 5.43 (IH, multiplet, N-CH-CO); 7.5-8.4 (11H, multiplet. naphthyl protons, phthaloyl protons).

Ml 39(f) t-Butvl a-f2-(2-naphthyl)-5-oxo-6-phthalimidoperhydro-1.4— thiazepin-4— yllacetate 4.. 15 g of 2-(2-naphthyl)-5-oxo-6-phthalimido-perhydro-1,4—thiazepine [prepared as described in step (e) aboue] uuere treated with t-butyl bromoacetate in same manner as described in Example 36(f). to giue 3.3Sg of the title compound as a crystalline solid, melting at 208-209.5°C.

Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.4-7 (9H, singlet, t-butyl); 2.9-4-.85 [7H. multiplet.

N-CH2-CH(naphthyl)-S-CH2.

N-CH2-C0]; .72 (1H. doublet of doublets. J=2 8. 10Hz.

N-CH-CO); 7.3-8.0 (11H. multiplet. naphthyl protons, phthaloyl protons). 39(g) t-Butvl tt-r6-amino-2-(2-naphthvl)-5-oxoperhydro-1.4—thiazepin-4-vllacetate 3.25g of t-butyl a-[2-(2-naphthyl)-5-oxo-6-phthalimidoperhydro-1.4-thiazepin-4-yl]acetate [prepared as described in step (f) aboue] were subjected to dephthaloylization with methylhydrazine in the same manner as the title 1 U2 described in Example 36(g), to giue compound as an amorphous poujder. 2.6 g of Nuclear Magnetic Resonance Spectrum (C0C13) 5 ppm: 1.46 (9H, singlet t-butyl); 2.26 (2H, singlet, NH ^); 2.45-4.75 (8H, multiplet, protons of the thiazepine ring, -N-CH2~CO); 7.2-7.9 (11H, multiplet, naphthyl protons, phthaloyl protons). 39(h) t-Butvl a-f6-(1-ethoxycarbonv1-3-phenylpropyl-amino )-2-(2-naphthyl)-5-oxoperhydro-l.4-thiaz9Pin-4-vll-acetate (Compound No. 164) 0.85g of t-butyl Nuclear Magnetic Resonance Spectrum (CDCl^) 5 ppm: 1.25 (3H, triplet. J»7.5Hz, C02CH2CH3); 1.47 (9H, singlet, t-butyl); 1.7-2.2 (2H, multiplet. PhCH2CH.2); 2.4-4.6 (12H, multiplet. PhCHjCHj-CH-NH. protons of the thiazepine ring, N-CH2-CO); 4.14 (2H, quartet. J-7.5HZ. COjCHjCHj); 7.20 (5H, singlet, phenyl protons); 7.1-7.9 (7H. multiplet, naphthyl protons).

Isomer 8 was eluted next : an oily substance in a yield of O.50g.

Nuclear Magnetic Resonance Spectrum (CDCl^) S ppm 1.27 (3H, triplet. J-7.SHZ, COjCHjCHj); 1.47 (9H. singlet, t-butyl); 1.8-2.25 (2H. multiplet, PhCH2CH.2); 2.5-4.6 (12H. PhCHjCHj-CH-NH; protons of the thiazepine ring, N-CHj-CO); 4.16 (2H, quartet. J«7.5Hz, COjCHjCHj); 7.20 (5H, singlet, phenyl protons); 7.1-7.9 (7H, multiplet. naphthyl protons). 144 EXAMPLE 40 g-f6-( 1-Ethoxyearbony 1-3-phenyIpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l.4-thiazepin-4-y11 acetic acid (Compound No. 139) 0.47g of isomer B of t-butyl a-[6-(1-ethoxy-carbony1-3-phenyIpropylamino)-2-(2-naphthyl)-5-oxo-perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 39(h)] was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 37, to giue 0.42 g of the title compound as a crystalline pouder softening from 115°C and melting at 175-180°C.

Nuclear Magnetic Resonance Spectrum [(C03)2S0] ppm: 1.30 (3H. triplet, J=7.5Hz, C02CH2CH3); 2.0-2.35 (2H, multiplet. PhCHjCHj); 2.55-5.2 (13H, multiplet. PhCHjCHj-CH-N. protons of the thiazepine ring, N-CH2~C0, C02CH2CH3); 7.33 (5H, singlet, phenyl protons); 7.2-8.1 (7H, multiplet. naphthyl protons). 145 EXAMPLE 41 g-f6-( 1-Carboxy-3-phenyIpropylamino)-2-(2-naphthyl)-5-oxoperhydro-l.4-thiazepin-4-vllacetic acid (Compound No. 138) JO 200mg of a-[6-(1-ethoxycarbonyl-3-pheny1- propylamino)-2-(2-naphthyl)-5-oxoperhydro-1,4— thiazepin-4— yljacetic acid (prepared as described in Example 40 aboue) were hydrolyzed with aqueous sodium hydroxide in 15 the same manner as described in Example 38, to giue 133 mg of the title compound as a powder.

Nuclear Magnetic Resonance Spectrum [(CD^jSO] 2° 6 ppm: 1.7-2.1 (2H, multiplet, PhCH2CH.2); 2.5-4.8 (11H, multiplet, PhCHjCHj-CH-N. protons of the thiazepine ring. N-CH-CO); 25 ^ 7.30 (5H, singlet, phenyl protons); 7.2-8.1 (7H, multiplet. naphthyl protons).

Attention is drawn to Irish Parent Application No. 893/85. 146

Claims (10)

CLAIMS 10 15

1. An acid of formula (I): COOH I R1—A—CH— NH wherein: COOH (I) 20 25 R represents a C1-C1Q alkyl group, a C3-Cg cycloalkyl group, a carbocyclic aryl group having from 6 to 14 ring carbon atoms, a partially hydrogenated carbocyclic aryl group having from 6 to 14 ring carbon atoms or a heterocyclic group having from 5 to 14 ring atoms, of which from 1 to 5 are nitrogen, sulphur or oxygen hetero-atoms, said groups represented by R1 being unsubstituted or having at least one substituent selected from the group consisting of: 30 35 (a) oxo groups, ^-Cg alkyl groups, Cg-C10 carbocyclic aryl groups, aralkyl groups wherein the alkyl part is C^-Cg alkyl and the aryl part is Cg-C1Q carbocyclic aryl, hydroxy groups, C1-Cg alkoxy groups, alkoxyalkoxy groups where each alkoxy part is C^-Cg, aralkyloxy groups, wherein the alkoxy part is C1~Cg alkoxy and the aryl part is Cg-C1Q carbocyclic aryl, aryloxy groups wherein the aryl part is Cg-C1Q carbocyclic aryl, halogen atoms, nitro groups, cyano 147 groups, carboxy groups, alkoxycarbonyl groups wherein the alkoxy part is C1-Cg alkoxy, amino groups, ^1-Cg alkylamino groups, dialkylamino groups wherein each alkyl part is alkyl, aliphatic or carbocyclic aromatic carboxylic acylamino groups, carbamoyl groups, alkylcarbamoyl groups where the alkyl part is <^1'C6 dialkylcarbamoyl groups where each alkyl part is C^-Cg alkyl, C^-Cg alkylthio groups, Cg-C1Q carbocyclic arylthio groups, C^-Cg alkylsulphonyl groups and Cg-C10 carbocyclic arylsulphonyl groups wherein the aryl part is unsubstituted or has from 1 to 3 C1-Cg alkyl substituents; 2 4 R and R are the same or different and each represents a hydrogen atom, a C1-C1Q alkyl group, a C3-Cg cycloalkyl group, an aralkyl group wherein the alkyl part is C^-Cg alkyl and the aryl part is Cg-C1Q carbocyclic aryl, or a Cg-C-4 carbocyclic aryl group, provided that R2 and R do not both represent hydrogen atoms, said groups represented by 2 4 R and R being unsubstituted or having at least one substituent selected from the group consisting of the substituents defined in (a) above, A represents a direct carbon-carbon bond, a methylene group, an ethylene group, an oxymethyl group or a thiomethyl group; B represents a C1-C4 alkylene or alkylidene group or a C.--C,. cycloalkylene or cycloalkylidene group j b n is 0, 1 or 2; and pharmaceutically acceptable salts thereof; and carboxy protected esters thereof selected from carboxy 148 protected esters of use as synthetic intermediates and carboxy protected esters of use as pharmaceuticals; 10 15 20 25

2. An acid or ester as claimed in Claim 1, represented by the formula (la): _-s- H COOR6 H1—A—CH—NH—1 —a1 <1*1 1 4 wherein R -R , A, B and u are as defined in Claim 1 30 6 7 and R and R , which are the same or different, each represents a hydrogen atom or a ^-C^g alkyl group, an aralkyl group in which the aryl part is a Cg-C10 carbocyclic aryl group which is unsubstituted or substituted as defined in (b) below and the alkyl part is C1-Cg alkyl, a cg*c14 carbocyclic aryl group, a partially hydrogenated Cg-C14 carbocyclic aryl group, a phthalidyl group or a trialkylsilyl group where each alkyl part is C,-C- alkyl, said groups 6 7 represented by R and R being unsubstituted or having at least one substituent selected from the group consisting of: 35 (b) halogen atoms, hydroxy groups, C1-Cg alkoxy groups, (^-Cg alkoxy) - (C1-C3 alkoxy) groups, aliphatic and carbocyclic aromatic carboxylic acyloxy groups, oxo groups, carboxy groups, alkoxycarbonyl groups where the alkoxy part is C.-Cc alkoxy, alkoxycarbonyloxy groups where x o the alkoxy part is C1-Cg alkoxy, aliphatic and carbocyclic aromatic carboxylic acylamino groups, 9 149 nitro groups, cyano groups, amino groups, C. -Cc X b alkylamino groups, dialkylamino groups where each alkyl part is C^-Cg alkyl, c6"c10 carbocyclic arylamino groups, C,-Cc alkylthio X b groups, Cg-C1Q carbocyclic arylthio groups, C1*Cg alkylsulphonyl groups, Cg-C10 carbocyclic arylsulphonyl groups and heterocyclic groups having from 5 to 14 ring atoms, of which from 1 to 5 are nitrogen, sulphur or oxygen hetero-atoms, said heterocyclic groups being unsubstituted or having at least one substituent selected from the group consisting of the sxibstituents defined in (a) of Claim 1; and pharmaceutically acceptable salts thereof.

3. An acid, ester or salt as claimed in Claim 2, in which: R1 represents a phenyl group or a C2-C7 alkyl group; R2 and R4 are the same or different and each represents a hydrogen atom, a C^-C^q alkyl group, a phenyl group, a naphthyl group or a C3-Cg cycloalkyl group; A represents an ethylene group; B represents a methylene group; and n is 0.

4. An acid, ester or salt as claimed in Claim 3 in which R^ represents a hydrogen atom, a alkyl group or an aralkyl group in which the aryl part is a Cg-C1Q carbocyclic aryl group and the alkyl part is a C1-Cg alkyl group. 150

5. An acid, ester or salt as claimed in Claim 2, in which: g R1 represents a phenyl group or a C2*C7 alkyl group; 2 R represents a C^-C^g alkyl group, a phenyl group, a naphthyl group or a C3-CQ cycloalkyl group; 10 4 R represents a hydrogen atom; R6 represents a hydrogen atom, a alkyl group or an aralkyl group of which the aryl part is a 15 C6"C10 carbocYclic aryl group and the alkyl part is a C^-Cg alkyl group; 7 R represents a hydrogen atom, a (c1"c4 alkoxy)carbonyloxy(C1-C4 alkyl) group, a (C2-C5 20 alkanoyl)oxy(C1-C4 alkyl) group, a (5-alkyl-2-oxo-l,3-dioxolen-4-yl)alkyl group in which each alkyl group has from 1 to 4 carbon atoms, a (5-phenyl-2-oxo-l,3-dioxolen-4-yl)alkyl group in which the alkyl part has from 1 to 4 carbon atoms, or a 25 phthalidyl group; A represents an ethylene group; B represents a methylene group; and 30 a is o.

6. An acid, ester or salt as claimed in Claim 2, in which: 35 R1 represents a phenyl group or a C2'C7 alkyl group; 151 2 R represents a phenyl group, a naphthyl group, a C1-C6 alkyl group or a C^-Cg cycloalkyl group; 4 R represents a hydrogen atom; 5 R represents a hydrogen atom, a C^-Cg alkyl group or an aralkyl group of which the aryl part is a C6-C10 carbocyclic aryl group and the alkyl part is a C1~C4 alkyl group; 10 7 R represents a hydrogen atom, an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a (2-oxo-l,3-dioxolen-4-yl)alkyl group where the alkyl group is and which has a C1~C4 alkyl or phenyl substituent at the 15 5-position, or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and 20 n is 0.

7. Compounds as claimed in Claim 2, in which: 25 r1 represents a phenyl group or a C2-C7 alkyl group; 2 R represents a naphthyl group; •an 4 R represents a hydrogen atom; R6 represents a hydrogen atom, a C^-Cg alkyl group or an aralkyl group of which the aryl part is a C--C,n carbocyclic aryl group and the alkyl part is 35 ° a C1-C4 alkyl group; R7 represents a hydrogen atom, an acyloxyalkyl group, 152 an alkoxycarbonyloxyalkyl group, a (2-oxo-1,3-dioxolen- 4-yl) alkyl group where the alkyl group is and which has a C^-C4 alkyl or phenyl substituent at the 5-position, or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0.

8. An acid, ester or salt claimed in Claim 2, in which R1 represents a phenyl group or a C2*C7 alkyl group; 2 R represents a hydrogen atom; 4 R represents a ^-Cg alkyl group, a phenyl group, a naphthyl group or a C3-CQ cycloalkyl group; R6 represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group or a phenylethyl group; 7 R represents a hydrogen atom, a (C2'C5 alkanoyl)oxy(C1-C3 alkyl) group, a (C1*C4 alkoxy)carbonyloxy(C1-C3 alkyl) group, a (5-allcyl-2-oxo-1,3-dioxolen-4-yl)alkyl group in which each alkyl part is C1-C3, a (5-phenyl-2-oxo-l,3- dioxolen-4-yl)alkyl group in which the alkyl part is C1-C3 or a phthalidyl group; A represents an ethylene group; B represents a methylene group; and n is 0. 153

9. A pharmaceutical composition for the treatment of angiotensin-induced hypertension, which composition comprises a hypotensive agent in admixture with a pharmaceutically acceptable carrier or diluent, wherein said hypotensive agent is at least one acid, ester or salt as claimed in any one of Claims 1 to 8. 10 15 20 25

10. A process for preparing a compound as claimed in any one of Claims 1 to 8, which process comprises: condensing a compound of formula (II): <;»n (III COOR? (in which R , R , B and q are as defined in Claim 1 7 and R represents a hydrogen atom or a carboxy-protecting group) with a compound of formula (III): ? OOR R -A-CH-X (III) 30 (in which R and A are as defined in Claim 1, X represents a halogen atom or a sulphonyloxy group and R6 represents a hydrogen atom or a carboxy-protecting group) or, under reductive conditions, with a compound of formula (IV): 35 COOR 1 ' R -A-C=0 (IV) (in which R1, R6 and A are as defined above) and 154 optionally thereafter subjecting the product to one or more of the reactions: oxidation, deprotection, esterification, group interchange or salification. 5 TOMKINS & CO. 10 -15 20 25 30 35