AU6669100A - Dithiolan derivatives, their preparation and their therapeutic effect - Google Patents

Description

1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

r r r r Name of Applicant: Actual Inventors: Address for Service: Invention Title: Sankyo Company Limited Fujita TAKASHI AND Yokoyama TOMIHISA DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Dithiolan derivatives, their preparation and their therapeutic effect The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\PDB\235046S.DIVDOC 24/10/00 la This application is a divisional application derived from Australian Patent Application No.

59702/98, the entire contents of which are incorporated herein by reference.

Background to the Invention The present invention relates to a series of new dithiolan derivatives having an excellent ability to enhance the activity of glutathione reductase. The invention also provides a process for preparing these compounds and methods and compositions using them.

Glutathione is found throughout the tissues of the living body, is a major reducing agent in cells, and plays a very important role in the oxidation-reduction 10 metabolic processes. In particular, reduced glutathione (GSH), thanks to the presence of a thiol group, plays a key role in various cellular defence and repair mechanisms.

Glutathione peroxidase catalyses the reactions involved in these mechanisms, and is an 2* important enzyme in the antioxidant system, wherein peroxides hydrogen peroxide, lipid peroxides and so on) are reduced by GSH. On the other hand, glutathione reductase is an enzyme which reduces oxidized glutathione (oxidized-type Sglutathione: GSSG) in the presence of NADPH to regenerate GSH.

The antioxidant system comprising these materials and enzymes protects cells from the harmful effects of oxidising materials above described peroxides, free radicals and so on). Oxidative stress occurs when the balance between oxidising materials and the antioxidant mechanisms is shifted in favor of the former Appl.

Physiol. 1996 Nov., 81(5), 2199-2202]. It has been reported that oxidative stress is associated with various diseases, such as coronary heart disease, cataracts, pulmonary diseases idiopathic pulmonary fibrosis, adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis), chronic renal failure, disorders of the nervous system including the peripheral nervous system and the central nervous system Parkinson's disease, schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis and cerebral ischemia), gastric ulcers, diabetes, hepatocyte necrosis and apoptosis including ethanol-induced hepatopathy, viral diseases (including influenza, hepatitis B and HIV), and colorectal cancer Appl. Physiol. 1996 Nov., 81(5), 2199-2202; Free Radical Biology y:\wpdocs\dgtmss\98 1 2\usa\981 2sp .doc -2- Medicine, Vol. 21 No. 6, 845-853 (1996); Free Radical Biology Medicine, Vol. No. 7, 925-931 (1996); Gastroenterology, 112, 855-863 (1997); Free Radical Biology Medicine, Vol. 34, 161-165 (1996); Lancet, 338, 215-216 (1991); Diabetologia, 39, 357-363 (1996); Eur. J. Cancer., 1996 Jan, 32A(1), 30-38; Am. J. Med., 1991 Sep 91(3c), 95s-105s; Alcohol. Clin. Exp. Res., 1996 Dec. 20(9 Suppl), 340A-346A; Free Radical Biology Medicine, Vol. 21 No. 5, 641-649 (1996); Pharmacol. Toxicol., 1997 Apr, 80(4), 159-166; Cell. Mol. Biol. (Noisy-le-grand) 1996 Feb, 42(1), 17-26; Prostaglandins. Leukot. Essent. Fatty Acids, 1996 Aug, 55(1-2), 33-43; FASEB J., 1995 Sep, 9(12), 1173-1182].

10 In addition to the above, oxidative stress is thought to be a factor in Down's syndrome, nephritis, pancreatitis, dermatitis, fatigue, rheumatism, various malformations Duchenne muscular dystrophy, Becker dystrophy, Dubin-Johnson- Spring syndrome, favism and so on), Fanconi's anemia, canceration and metastases, septicemia, enhanced permeability of the blood vessels, leukocyte adherence, 15 retinopathy of prematurity, siderosis, toxic effects of medicines carcinostatics including platinum chelate, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane) and radiogenic damages [Yoshihiko Oyanagi, Superoxide dismutase and agents controlling active oxygen species].

In W094/12527, it is disclosed that compounds which enhance the synthesis of 20 endogenous GSH are suitable for human therapy, in particular for the treatment of various diseases induced by glutathione deficiency, such as the pathological states related to oxidative tissue damage, in particular when resulting from an excess of free radicals. Some examples of such diseases are: intracellular oxidative state disequilibrium following alcohol abuse, exposure to xenobiotic agents, damage caused by radiation, hepatic diseases, intoxication from drugs and chemical agents, poisoning by heavy metals, physiological brain ageing Parkinson's disease), brain degeneration due to decreased glutathione levels caused by altered antioxidant defence mechanisms, such as acute and chronic neurodegenerative diseases acute pathologies such as: acute ischemic states, in particular cerebral ictus, hypoglycemia, and epileptic attacks; chronic pathologies such as: amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea), diseases related to altered functionality of y:\wpdocs\dgtms\98 I 2\usa\981 2sp I.doc the immune system, in particular resulting from tumour immunotherapy, and infertility, in particular male infertility. It is also disclosed that the compounds are suitable for organ reperfusion following ischemic events mainly imputable to free radicals.

Furthermore, in Japanese patent publication Kokai Showa 64-26516, it is disclosed that a compound which increases glutathione levels is useful for the treatment and prevention of various diseases including cataracts, hepatic disorders, nephritic disorders.

At this time, lipoic acid (thioctic acid), which has dithiolan ring in its molecule, S: 10 is known to influence the biosynthesis and regeneration of reduced glutathione [I.

Maitra et al., Free Radical Biology Medicine, Vol. 18 No. 4, 823-829 (1995)]. In this literature, it is reported that the total glutathione (oxidized and reduced glutathione) level is decreased by administering buthionine sulfoximine (BSO), which is an inhibitor of glutathione synthetase, to newborn rats, that the decrease is prevented 15 by administering lipoic acid together with BSO, and that cataract formation is suppressed. In addition, the literature describes a test on the effects on glutathione reductase achieved by administering only BSO or by administering both BSO and lipoic acid. Considering these results, it is understood that the activity of glutathione reductase does not change when BSO is simply administered by itself, and that the 20 activity of glutathione reductase also does not increase when lipoic acid is administered in addition to BSO.

It can, therefore, be deduced from this literature that the total glutathione level will be increased and that disorders can be treated when lipoic acid is administered to a patient who is suffering from a disease caused by a deficiency of glutathione synthesis, but lipoic acid is not thought to provide sufficient effect against diseases which occur in spite of enough glutathione synthesis since it is understood not to increase glutathione reductase activity.

On the contrary, if the activity of glutathione reductase can be increased, then whether glutathione synthesis is or is not adequate, diseases which occur in spite of y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -4enough glutathione synthesis and which are caused by oxidative stress can be prevented or treated since the supply of reduced glutathione is increased.

Furthermore, in general, in the case of ophthalmologic diseases, such as cataracts, topical application to the eyes is preferred to oral administration. However, since lipoic acid is a powerful stimulant, it is impossible to administer it to the eyes.

We have now discovered a series of dithiolan derivatives, which have the ability to cause a significant increase in the activity of glutathione reductase and which also remove peroxides. Moreover, the compounds of the present invention are less stimulating to the eyes than lipoic acid and similar known compounds are thus S. 10 especially suitable for topical application.

For the avoidance of doubt, the compounds of the present invention are named following the IUPAC Rules, using, as appropriate, lipoic acid (also known as thioctic acid) as the parent compound. This compound has the formula:

COOH

it is an object of the present invention to providea series of new dithiolan derivatives.

It is a further and more specific object of the present invention to provide such compounds which increase the activity of glutathione reductase.

BriefSummary of Invention The compounds of the present invention are those compounds of formula r .(CH2)k-A-B-R1

S-S

II (I) y:\wpdocs\dgtfss\98 I 2\usa\981 2sp I.doc wherein: one of m and n represents 0, and the other represents 0, 1 or 2; k represents 0 or an integer of from 1 to 12;

R

1 represents: a hydrogen atom, a group selected from substituents a, defined below, or an alkyl group having from 1 to 12 carbon atoms which is unsubstituted or is substituted by from 1 to 3 substituents selected from the group consisting of substituents a and the substituents y or such a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and/or a sulfur atom; A represents a single bond, an oxygen atom, a carbonyl group or a group of formula

-N(R

2

-N(R

2

-N(R

2 )SO2-, -CON(R 2

)N(R

3

)CO-,

-CON(R

2

-CON(R

2

-CON(R

2

)SO

2

-O-CO-,

-ON(R

2

-ON(R

2 )SO2-, -O-CON(R 2

)N(R

3

)CO-,

-O-CON(R

2

-O-CON(R

2 )S0 2

-CO-CO-,

-CO-CON(R

2

)N(R

3

-CO-CON(R

2

-CO-CON(R

2 )SO2-,

-N(R

2

-N(R

2 )COCO-, -N(R 2

)N(R

3

-N(R

2

)N(R

3 )S02-,

-N(R

2

)CON(R

3

)N(R

4

-N(R

2

)CON(R

3

-N(R

2

)CON(R

3

)SO

2 or -N(R 2

)CON(R

3

)SO

2

N(R

4

)CO-

wherein R 2

R

3 and R 4 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group, an aralkyl group of which the aryl moiety is substituted with from 1 to 3 groups selected from the group consisting of substituents P, an acyl group or a group selected from the group consisting of substituents a; B represents a single bond, or a group of formula -N(R 5 or y:\wpdocs\dgt~mss\9812\usa\981 2sp I.doc wherein R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group, an aralkyl group of which the aryl moiety is substituted with from 1 to 3 groups selected from the group consisting of substituents P, an acyl group or a group selected from the group consisting of substituents a, or R 5 together with RI and the nitrogen atom to which they are bonded, may form a heterocyclic ring having from 5 to 7 ring atoms; or, where A represents a group of formula -N(R 2

-N(R

2

)CS-,

-CON(R

2

)N(R

3

-CON(R

2

-CON(R

2

-ON(R

2

)CO-,

10 -O-CON(R 2

)N(R

3

-O-CON(R

2

-CO-CON(R

2

)N(R

3

)CO-,

-CO-CON(R

2

-N(R

2

)N(R

3

-N(R

2

)CON(R

3

)N(R

4 )CO- or

-N(R

2

)CON(R

3 )CO- [wherein R 2

R

3 and R 4 are as defined above] and B represents a single bond, R 1 may represent a group of formula -OR 7 (wherein R 7 represents a lower alkyl group, a lower alkenyl group, an aralkyl group, an aralkyl group of which the aryl moiety is substituted with 1 to 3 groups selected from the group consisting of substituents p or a group selected from the group consisting of substituents c); or, where A represents a group of formula -CON(R 2 )SO2-, -ON(R2)SO 2

-O-CON(R

2

)SO

2 -CO-CO-, -CO-CON(R 2 )SO2-, -N(R 2 )COCO-, -N(R 2

)N(R

3

)SO

2 or -N(R 2

)CON(R

3 )S0 2 [wherein R 2 and R 3 are as defined above] and B represents a single bond, or, where A does not represent an oxygen atom, a group of formula -CO-O- or -N(R 6 and B represents -N(R 5 [wherein R 5 is as defined above], R 1 may represent a hydroxy group or a group of formula -OR 7 (wherein R 7 is as defined above); Substituents c are selected from the group consisting of aryl groups, heterocyclic groups, aryl groups substituted with from 1 to 3 of substituents p, and heterocyclic groups substituted with from 1 to 3 of substituents P; Substituents P are selected from the group consisting of lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups, lower alkylthio groups, hydroxy y:\wpdocs\dgtmss\98 12\usa\981 2sp I.doc -7groups, carboxy groups, carbamoyl groups of which the nitrogen atom may be substituted, lower alkoxycarbonyl groups, halogen atoms, nitro groups, amine residues, sulfo groups, sulfamoyl groups, cyano groups, hydroxy-substituted lower alkyl groups; Substituents y are selected from the group consisting of lower alkoxy groups, lower alkylthio groups, hydroxy groups, nitrooxy groups, carboxy groups, lower alkoxycarbonyl groups, halogen atoms, sulfo groups, sulfamoyl groups, amine residues, carbamoyl groups of which the nitrogen atom may be substituted; PROVIDED THAT: where A represents an oxygen atom, B represents a single bond or a group of 10 formula -N(R 5 [wherein R 5 is as defined above], where A represents a group of formula -CO-O- or -N(R 2 [wherein R 2 is as defined above], B represents a single bond, and where k represents 4, the group of formula -A-B-R 1 does not represent a carboxyl group and pharmaceutically acceptable salts thereof.

The present invention also provides a method of enhancing the activity of glutathione reductase in a mammal, which may be human, by administering to said mammal an effective amount of a compounds of formula or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for the treatment or prevention of cataract in a mammal, which may be human, by administering to said mammal an effective amount of a compounds of formula or a pharmaceutically acceptable salt thereof.

Detailed Description of Invention In the compounds of the present invention, one of m and n represents 0, and the other represents 0, 1 or 2. Preferably, either both of m and n represent 0, or one ofm y:\wpdocs\dgtmffss\98 1 2\usa\98I2spI .doc -8and n represents 0 and the other represents 1. More preferably, both ofm and n represent 0.

We prefer those compounds of formula wherein k represents 0 or an integer of from 1 to 6, more preferably an integer of from 2 to 6, and most preferably an integer of from 4 to 6.

Where R 1 or substituent a represents an aryl group, this is a carbocyclic aromatic hydrocarbon group having from 6 to 14 ring carbon atoms in one or more aromatic carbocyclic rings or is such a group which is fused to a cycloalkyl group having from 3 to 10 ring carbon atoms. Examples of carbocyclic aromatic 10 hydrocarbon groups having from 6 to 14 ring carbon atoms in one or more aromatic carbocyclic rings include the phenyl, naphthyl or 2- naphthyl), phenanthrenyl and anthracenyl groups. An example of a group in which an aromatic carbocyclic ring is fused to a cycloalkyl group is the 2-indanyl group.

Where R 1 or substituent cc represents a heterocyclic group, this has from 5 to 7 15 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of sulfur, oxygen and nitrogen hetero-atoms. The group may be saturated or it may be unsaturated and preferably aromatic.

Where the heterocyclic groups referred to herein have 3 hetero-atoms, we prefer that all three, two or one of these atoms are nitrogen atoms, and, correspondingly, none, one or two are sulfur and/or oxygen atoms.

Examples of such saturated heterocyclic groups include, for example, the pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dithiolanyl, thiadiazolidinyl, oxadiazolidinyl, dithiazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl dioxanyl and homopiperazinyl groups. Of these groups, we particularly prefer those 5- to 7-membered saturated heterocyclic groups which have one or two nitrogen atoms or have one nitrogen atom and one sulfur atom or one oxygen atom, such as the pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidyl, morpholinyl, thiomorpholinyl and piperazinyl groups.

y:\wpdocs\dgt_mss\9812\usa\9812sp I.doc -9- If desired, the above-described saturated heterocyclic groups may be substituted by one or two atoms selected from the group consisting of sulfur atoms and oxygen atoms to form an oxo group and/or a thioxo group. Examples of such groups include the piperidonyl, pyrrolidonyl, thiazolidonyl, dioxothiazolidinyl, thioxodithiazolidinyl, dioxoimidazolidinyl and dioxooxazolidinyl groups.

Also, if desired, the above-described saturated heterocyclic group may be fused with another cyclic group, preferably having 3, 4, 5 or 6 ring atoms, and which may be carbocyclic or heterocyclic, most preferably a benzene ring. Examples of such fused ring groups include the benzodioxanyl, indolinyl, isoindolinyl, benzooxazinyl, benzothiazolidinyl, benzothiazinyl, chromanyl, 6-acetoxy-2,5,7,8-tetramethylchroman- 2-yl, and isoindol-1,3-dion-2-yl groups.

Examples of such aromatic heterocyclic groups include the furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Of these, those 5- to 7-membered aromatic heterocyclic groups which have at least one nitrogen atom and may have an oxygen atom or a sulfur atom are preferred. Examples of such groups include the pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and 20 pyrazinyl groups. The pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups are most preferred.

Also, if desired, the above-described aromatic heterocyclic group may be fused with another cyclic group, preferably having 3, 4, 5 or 6 ring atoms, and which may be carbocyclic or heterocyclic, most preferably a benzene ring. Examples of such fused ring groups include the indolyl, benzofuryl, benzothienyl, benzooxazolyl, benzoimidazolyl, quinolyl, isoquinolyl, quinoxalyl groups.

Also, the above-described aromatic heterocyclic groups may be substituted by one or two atoms selected from the group consisting of sulfur atoms and oxygen atoms to form an oxo group and/or a thioxo group, and examples of such groups include the pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl and thioxodithiazolyl groups.

y:\wpdocs\dgtmss\9812\usa\9812sp I .doc If desired, any of the above aryl and heterocyclic groups may be substituted by one of more, preferably from 1 to 3, substituent selected from the group consisting of substituents 3, defined above and exemplified below.

Where R 1 represents an alkyl group having from 1 to 12 carbon atoms, this may be a straight or branched chain group which may be unsubstituted or may be substituted by from 1 to 3 substituents selected from the group consisting of substituents y, defined above and exemplified below. Examples of such unsubstituted alkyl groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tbutyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2- ***trimethylpropyl, 1,2.2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 3,3dimethylpentyl, octyl, 2-methylhepty, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, 2- 15 nonyl, 3-nonyl, 4-nonyl, 5-nonyl, 2-methyloctyl, 3-methyloctyl, 4-methyloctyl, methyloctyl, 6-methyloctyl, 7-methyloctyl, 8-methyloctyl, 6,6-dimethylheptyl, decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl, 2-methylnonyl, 3-methylnonyl, 4-methylnonyl, 6,6-dimethyloctyl, undecyl, 2-undecyl, 3-undecyl, 4-undecyl, 5-undecyl, 6-undecyl, 2-methyldecyl, 3-methyldecyl, 4-methyldecyl, 5-methyldecyl, 6-methyldecyl, 20 7-methyldecyl, 8-methyldecyl, 9-methyldecyl, 7-ethylnonyl, dodecyl, 2-dodecyl, 3-dodecyl, 4-dodecyl, 5-dodecyl, 6-dodecyl, 2-methylundecyl, 3-methylundecyl, 4-methylundecyl, 5-methylundecyl, 6-methylundecyl, 7-methylundecyl, 8-methylundecyl, 9-methylundecyl and 10-methylundecyl groups. Of these, straight or branched alkyl groups having from 1 to 6 carbon atoms are preferred, straight or branched alkyl groups having from 1 to 4 carbon atoms are more preferred, and the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups are most preferred.

Alternatively, R 1 may represent such an alkyl group in which the carbon chain is interrupted by one or more oxygen atoms and/or sulfur atoms. Examples of such groups include any of the above alkyl groups which are substituted by a single alkoxy or alkylthio group, which itself may be further substituted by an alkoxy or alkylthio group, the alkoxy and alkylthio groups being as exemplified below in relation to y:\wpdocs\dgtmss\98 1 2\usa\981 2sp I .doc -11substituents P and y. Specific examples of such groups include alkoxyalkyl groups having from 2 to 10 carbon atoms, alkylthioalkyl groups having from 2 to 10 carbon atoms, benzyloxyalkyl groups of which the alkyl part has from 1 to 5 carbon atoms and benzylthioalkyl groups of which the alkyl part has from 1 to 5 carbon atoms (the benzyl part of the benzyloxyalkyl and benzylthioalkyl groups may be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of substituents 3) groups. Of these, the methoxymethyl, methoxyethyl, ethoxymethyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, benzyloxymethyl, benzyloxyethyl, benzylthiomethyl and 4-methoxybenzylthiomethyl groups are preferred.

Where R 2

R

3

R

4

R

5 or R 6 represents an alkyl group having from 1 to 12 carbon atoms, this may be a straight or branched chain group, as defined and exemplified above in relation to R 1 Where R 2

R

3

R

4

R

5 or R 6 represents an aralkyl group, this is a lower alkyl group (preferably having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, still more preferably from 1 to 3 carbon atoms and most preferably 1 or 2 carbon atoms) which is substituted by from 1 to 3 aryl groups as defined and exemplified above in relation to R 1 Specific examples of such aralkyl groups include the benzyl, 1-phenylethyl, 2-phenylethyl, a-naphthylmethyl, P-naphthylmethyl, diphenylmethyl, triphenylmethyl, ac-naphthyldiphenylmethyl and 9-anthrylmethyl groups. Of these, the benzyl, 1-phenylethyl and 2-phenylethyl groups are preferred.

Any of the above groups may be unsubstituted or it may be substituted by from 1 to 3 substituents selected from the group consisting of substituents y defined and exemplified below.

Where R 2

R

3

R

4

R

5 or R 6 represents an acyl group, this may be an aliphatic, aromatic or heterocyclic acyl group, for example: an alkylcarbonyl group having from 1 to 30, preferably from 1 to 21 and more preferably from 1 to 8 carbon atoms, such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl, y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc 12 decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1 -methylpentadecylcarbonyl, 1 4-methylpentadecylcarbonyl, 13,1 3-dimethyltetradecylcarbonyl, heptadecylcarbonyl, hexadecylcarbonyl, octadecylcarbonyl, I -methyiheptadecylcarbonyl, nonadecylcarbonyl, eicosylcarbonyl and heneicosylcarbonyl groups; of these, the groups having from 1 to 5 carbon atoms are most preferred; a halogenated alkylcarbonyl group having from 2 to 6 carbon atoms, preferably 2 or 3 carbon atoms, such as the chioroacetyl, dichioroacetyl, *~.trichioroacetyl and trifluoroacetyl groups; lower alkoxyalkylcarbonyl group in which the alkyl and alkoxy parts each preferably has from 1 to 4 carbon atoms, such as the methoxyacetyl group; an unsaturated alkylcarbonyl group having from 3 to 6 carbon atoms, such as the acryloyl, propioloyl, methacryloyl, crotonoyl, allylcarbonyl, isocrotonoyl and (E)-2-methyl-2-butenoyl groups; an arylcarbonyl group, such as the benzoyl, ax-naphthoyl and P-naphthoyl groups; a halogenated arylcarbonyl group, such as the 2-bromobenzoyl and 4-chiorobenzoyl groups; a lower alkyl- substituted arylcarbonyl group, such as the 2,4,6-trimethylbenzoyl and 4-toluoyl groups; a hydroxy-substituted arylcarbonyl group, such as the 3,5-dimethyl-4hydroxybenzoyl and 3 ,5-di-t-butyl-4-hydroxybenzoyl groups; a lower alkoxy-substituted arylcarbonyl group, such as the 4-anisoyl group; a nitro-substituted arylcarbonyl group such as the 4-nitrobenzoyl and 2-nitrobenzoyl groups; y:\wpdocs\dgtmss\981I2\usa\981I2sp I .doc 13a lower alkoxycarbonyl-substituted arylcarbonyl group, such as the 2-(methoxycarbonyl)benzoyl group; an aryl-substituted arylcarbonyl group, such as the 4-phenylbenzoyl group; a lower alkoxycarbonyl group preferably having from 2 to 7 carbon atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups; a lower alkoxycarbonyl group, preferably having from 2 to 7 carbon atoms, which is substituted with a halogen atom or a tri-lower alkylsilyl group, such as the 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; an aralkylcarbonyl group, of which the aryl ring may be unsubstituted or may be substituted with 1 or 2 lower alkoxy or nitro groups, such as the benzylcarbonyl, 4-methoxybenzylcarbonyl, 3,4-dimethoxybenzylcarbonyl, 2-nitrobenzylcarbonyl and 4-nitrobenzylcarbonyl groups; a lower alkanesulfonyl group, preferably having from 1 to 6 carbon atoms, such as the methanesulfonyl, ethanesulfonyl and propanesulfonyl groups; a halogenated lower alkanesulfonyl group, preferably having from 1 to 6 carbon atoms, such as the chloromethanesulfonyl, trifluoromethanesulfonyl and pentafluoroethanesulfonyl groups; and an arylsulfonyl group, in which the aryl part is as defined and exemplified above in relation to R 1 such as the benzenesulfonyl and p-toluenesulfonyl group.

Of the above groups, we prefer the aliphatic acyl groups, the aromatic acyl groups, the alkoxycarbonyl groups and the lower alkanesulfonyl groups, more preferably the aikylcarbonyl groups and the lower alkoxycarbonyl groups.

y:\wpdocs\dgtmss\98 1 2\usa\981 2sp I.doc 14- Where R 5 together with R 1 and the nitrogen atom to which they are attached forms a heterocyclic group, this has from 5 to 7, more preferably 5 or 6, ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, at least one being a nitrogen atom. Preferably there are one or two nitrogen atoms and no or one oxygen atoms or sulfur atoms. Examples of such groups include the pyrrolidino, 3-thiazolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, imidazolidinyl and imidazolyl groups. Such groups may be substituted or unsubstituted, preferably with one or two oxygen atoms and/or with 1 to 3 substituents selected from the group consisting ofsubstituents P, as defined 10 above, and may be fused with another cyclic group, preferably having 3, 4, 5 or 6 ring atoms, and which may be carbocyclic or heterocyclic, most preferably a benzene ring.

Examples of such groups are the N-methylpiperazino, N-t-butoxycarbonylpiperazino, 1-indolinyl, 2-carboxy-l-indolinyl, 2-methoxycarbonyl-l-indolinyl, 3,4-dimethylindolin-2,5-dione-1-yl and isoindol-l,3-dion-2-yl groups.

15 Where R 7 or substituent p represents a lower alkyl group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 20 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3dimethylbutyl and 2-ethylbutyl groups. Of these, we prefer those alkyl groups having from 1 to 4 carbon atoms, particularly the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups, and most preferably the methyl group.

Where R 7 represents a lower alkenyl group, this may be a straight or branched chain group having from 2 to 6, preferably 3 or 4, carbon atoms, and examples include the vinyl, allyl, methallyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and 4-hexenyl groups, of which the vinyl, allyl, methallyl, 1-propenyl, isopropenyl and butenyl groups are preferred, the allyl and 2-butenyl groups being most preferred.

y:\wpdocs\dgt_mss\9812\usa\9812sp I.doc 15 Where R 7 represents an aralkyl group, this may be any of the aralkyl groups defined and exemplified above in relation to R 2 Where substituent P represents a halogenated lower alkyl group, this may be any of the above alkyl groups which is substituted by at least one halogen atom. Although there is no critical limitation on the number of halogen substituents, and the group may, if desired, be perhalogenated, in general, from 1 to 3 halogen atoms, selected from the group consisting of fluorine, chlorine, bromine and iodine atoms are preferred. Examples of such haloalkyl groups include the chloromethyl, dichloroniethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, 10 2-iodoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 3-fluoropropyl, 3-bromopropyl, 3-iodopropyl, 3,3,3-trichloropropyl, 3,3,3-trifluoropropyl, 4-chloro- ~butyl, 4-fluorobutyl, 4-bromobutyl and 4-iodobutyl groups.

Where substituent P or substituent y represents a lower alkoxy group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethyl- *butoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and 2-ethylbutoxy groups. Of these, we prefer those alkoxy groups having from 1 to 4 carbon atoms, particularly the methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups, and most preferably the methoxy group.

Where substituent 0 or substituent y represents a lower alkylthio group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, I-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio groups.

y:\wpdocs\dgimss\98 1 2\usa\981 2sp I.doc -16- Of these, we prefer those alkylthio groups having from 1 to 4 carbon atoms, particularly the methylthio, ethylthio, propylthio, isopropylthio, butylthio ahd isobutylthio groups, and most preferably the methylthio group.

Where substituent 3 or substituent y represents an amine residue, this is a group of formula -NRaRb, where R a and Rb are the same or different and each represents a hydrogen atom, a lower alkyl group (as defined and exemplified above in relation to

R

7 or substituent a cycloalkyl group having from 3 to 8, preferably 5 or 6, ring carbon atoms, an aryl group (as defined and exemplified above in relation to R 1 an aralkyl group (as defined and.exemplified above in relation to R 2 a heterocyclic 10 group (as defined and exemplified above in relation to R1), or R a and Rb together with the nitrogen atom to which they are attached represent a nitrogen-containing heterocyclic group (as defined and exemplified above in relation to R 5 and R 1 Examples of such groups include: the amino group; alkylamino and dialkylamino groups, such as the methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino and dibutylamino groups; cycloalkylamino and dicycloalkylamino groups, such as the cyclopentylamino, cyclohexylamino, dicyclopentylamino and dicyclohexylamino groups; saturated cyclic amino groups, that is heterocyclic groups having a nitrogen atom in the ring, such as the pyrrolidino, piperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino groups; aryl- and aralkylamino groups of which the nitrogen atom may be substituted with a lower alkyl group, such as the anilino, benzylamino, h-methylanilino and N-methylbenzylamino groups; and a heterocyclic-substituted amino group, in which the nitrogen atom may be substituted with a lower alkyl group, such as the pyridylamino, N-methylpyridylamino and N-ethylpyridylamino groups.

y:\wpdocs\dgt~mss\98 I 2\usa\981 Zsp .doc -17- Of these, we prefer the amino group, mono- and di-alkylamino groups, saturated cyclic amino groups (such as the pyrrolidino, piperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino groups) and aryl- and aralkylamino groups of which the nitrogen atom may be substituted with a lower alkyl group (such as the anilino, benzylamino, N-methylanilino and N-methylbenzylamino groups).

Where substituent 0 or substituent y represents a carbamoyl group of which the nitrogen atom may be substituted, this is a group of formula -CONRa'Rb', where Ra' and Rb' are the same or different and each represents any of the atoms or groups represented by Ra and Rb or a one of Ra and Rb represents a hydrogen atom and the other represents an acyl group (which may be any of the acyl groups defined and exemplified above in relation to R 2 or an aminosulfonyl group. Examples of such carbamoyl groups include: the carbamoyl group; alkylcarbamoyl and dialkylcarbamoyl groups, such as the methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, diisopropylcarbamoyl and dibutylcarbamoyl groups; cycloalkylcarbamoyl and dicycloalkylcarbamoyl groups, such as the i cyclopentylcarbamoyl, cyclohexylcarbamoyl, dicyclopentylcarbamoyl and dicyclohexylcarbamoyl groups; saturated cyclic aminocarbonyl groups, that is carbonyl groups attached to a heterocyclic group having a nitrogen atom in the ring, such as the pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl, morpholinocarbonyl and thiomorpholinocarbonyl groups; aryl- and aralkylcarbamoyl groups of which the nitrogen atom may be substituted with a lower alkyl group, such as the phenylcarbamoyl, benzylcarbamoyl, h-methylphenylcarbamoyl and h-methylbenzylcarbamoyl groups; y:\wpdocs\dgtmss\981 2\usa\981 Zsp I .doc 18a heterocyclic-substituted carbamoyl group, in which the nitrogen atom may be substituted with a lower alkyl group, such as the pyridylcarbamioyl, N-methylpyridylcarbamoyl and N-ethylpyridylcarbamoyl groups; and acylcarbamoyl groups, especially alkanesulfonylaminocarbonyl groups, such as the methanesulfonylaminocarbonyl group and the aminosulfonylaminocarbonyl group.

Of these, we prefer the carbamoyl group, mono- and di-alylcarbamoyl groups, saturated cyclic carbamoyl groups (such as the pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl, morpholinocarbonyl and 10 thiomorpholinocarbonyl groups), aryl- and aralkylcarbamoyl groups of which the nitrogen atom may be substituted with a lower alkyl group (such as the phenyl- **carbamoyl, benzylcarbamoyl, N-methylphenylcarbamoyl and N-methylbenzylcarbamoyl groups) or an alkanesulfonylaminocarbonyl group (such as the methanesulfonylaminocarbonyl group).

Where substituent P or substituent y represents a lower alkoxycarbonyl group, S this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms in the alkoxy part from 2 to 7 carbon atoms in the alkoxycarbonyl part), and examples include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,.neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1 -ethylpropoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl and 2-ethylbutoxycarbonyl groups. Of these, we prefer those alkoxycarbonyl groups having from 1 to 4 carbon atoms, particularly the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl groups, and most preferably the methoxycarbonyl group.

y:\wpdocs\dgt_mss\9812\usa\98I2sp I.doc -19- Where substituent P or substituent y represents a halogen atom, this may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

Where substituent P represents a hydroxy-substituted lower alkyl group, this may be any of the lower alkyl groups defined and exemplified above in relation to R2 which is substituted by one or more hydroxy groups. Examples of such groups include the hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.

Of the compounds of the present invention, those compounds of formula in which the group of formula -(CH 2 )k-ABR 1 is bonded to the 3-position of the dithiolan ring are preferred. Such compounds may be represented by the formula (CH2)k-A-B-R 1 S-s /I 0 )m 0 )n (in which A, B, R 1 k, m and n are as defined above).

Where the compounds of the present invention possess a basic group, such as an amino or imino group, the compounds can form salts with acids. On the other hand, where the compounds of the present invention possess an acidic group, such as a carboxy group or an imido group, they can form salts with bases. There is no particular restriction on the nature of such salts, provided that, where they are intended for pharmaceutical use, they are pharmaceutically acceptable, that is they are not less active (or unacceptably less active) than the compound of formula and are not more toxic (or unacceptably more toxic) than the compound of formula (I) Examples of such salts formed between a basic group in the compound of the present invention and an acid include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc or p-toluenesulfonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; and salts with amino acids, such as glycine, lysine, arginine, ornithine, glutamic acid or aspartic acid.

Examples of such salts formed between an acidic group in the compound of the present invention and a base include: salts with an alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; salts with another metal, such as magnesium, aluminum or iron; ammonium salts; organic base salts, such as a salt with t-octylamine, dibenzylamine, morpholine, glucosamine, a phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, methylamine, dimethylamine, diethylamine, triethylamine, diisopropylo. amine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, piperazine, tetramethylammonium, and tris(hydroxymethyl)aminomethane; and salts with an amino acid, such as glycine, lysine, arginine, ornithine, glutamic acid or aspartic acid.

Also, when a compound of the present invention is allowed to stand in the air, it may absorb water to form a hydrate. Such hydrates also form a part of the present invention.

20 Where a compound of the present invention contains an asymmetric carbon atom in its molecule, it can form optical isomers which are in the R- or S- configuration.

Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.

Of the compounds of the present invention, we prefer those compounds of formula and salts thereof in which: one ofm and n is 0, and the other is 0 or 1; y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -21 k is 0 or an integer of from 1 to 8;

R

1 represents a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms, a heterocyclic group, an alkyl group having from I to 12 carbon atoms which is unsubstituted or is substituted by from 1 to 3 substituents selected from the group consisting of substituents a and substituents y or such a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and/or a sulfur atom; A is a group of formula -CON(R2)S0 2 -N(R2)CO-, -N(R2)CS-,-CON(R2)CO-, -N(R2)COCO- or -N(R2)SO 2 [wherein, R 2 is a •10 hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group], in particular a group of formula -CON(R 2 )S0 2

-N(R

2

-CON(R

2

)CO-,

-N(R

2 )COCO-, or N(R2)S2 B represents a single bond, or a group of formula -N(R 5 or -N(R )N(R 6 [wherein R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group]; Of the above, we particularly prefer those compounds of formula in which m and n are as defined in above, k is as defined in above, R 1 is as defined in (C) above, A is as defined in above, and B is as defined in above.

More preferred compounds of the present invention are those compounds of formula and salts thereof in which: both ofm and n are 0; k is an integer of from 2 to 6;

R

1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group, an alkoxy group having from 1 to 5 carbon atoms or hydroxy group; y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -22- A represents a group of formula -CON(R 2 )SO2-, -N(R 2

)CO-,

-N(R2)CS-, -CON(R 2 -N(R2)COCO- or -N(R 2 )SO2- [wherei, R 2 represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms] in particular a group of formula -CON(R2)SO 2

-N(R

2

-CON(R

2

)CO-,

-N(R

2 )COCO-, or -N(R 2 )SO2-; B represents a single bond, or a group of formula -N(R or -N(R )N(R6)- [wherein R 5 and R 6 are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms]; Of the above, we particularly prefer those compounds of formula in which m 10 and n are as defined in above, k is as defined in above, R 1 is as defined in (H) above, A is as defined in above, and B is as defined in above.

*The most preferred compounds of the present invention are those compounds of formula and salts thereof in which: both of m and n are 0; k is 4 or

R

1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group or an alkoxy group having from 1 to 5 carbon atoms; A represents a group of formula -CONHSO 2

-CONCH

3

SO

2

-NHCO-,

-NHCS-, -CONHCO-, -NHCOCO-, -NHSOz- or in particular a group of formula -CONHSO 2

-CONCH

3

SO

2 -NHCS-, -CONHCO-, -NHCOCO-, or -NHSO 2 B represents a single bond, or a group of formula -NCH 3 or

-NHNCH

3 y:\wpdocs\dgtmss\9812\usa\9812sp .doc -23- Of the above, we particularly prefer those compounds of formula in which m and n are as defined in above, k is as defined in above, R 1 is as defined in (M) above, A is as defined in above, and B is as defined in above.

**O

o* **o y:\wpdocs\dgtmss\9812\usa\9812sp I.doc -24- Specific examples of individual compounds of the present invention are *hown in the following formulae and in which the substituent groups are as shown in the corresponding one of Tables 1 to 3. In the Tables, the following abbreviations are used: Ac acetyl; Bu butyl; iBu isobutyl; sBu. sec-butyl; tBu t-butyl; Bz benzyl; 1,3 -diox-lInd isoindol- 1,3-dione-2-yl; S3 ,4-diMe-2,5-diox- 1 -Imdd 3 ,4-dimethyl-imidazolidin- Et ethyl; Hx hexyl; Indn indolinyl; *Me methyl; Mor morpholino; Ph phenyl; *Pipra piperazino; Pipri piperidino; Pn pentyl; iPn isopentyl; Pr propyl; iPr isopropyl; Py pyridyl; Pyr pyrrolidinyl; Thiad 3-thiazolidinyl; Thmor thiomorpholino.

Also, in the Tables, the groups represented by Z-1 to Z-12 have the following formulae: y:\wpdocs\dgt_mss\981I2\98 12cpd I doc 25

COOCH

3 N

N

BOC

COOH

N

H

Z-3

N-S

/l s Z-6N

N

H

0" s

COOCH

3 a,,OCH 3

OH

Z-7 Z-9 Z-11I

COOR

H

Z- 10 COOH

H

N

s I.CH 3

N

CH

3 Z-12 Y:\-pdocs\dgtmss\981I2\981I2cpd I .doc 26

(CH

2 )k-A-B-Rl s-s Table 1 (I-1) 0**e 9 *9 9*9* Cpd. k A B R No. 1-1 4 CO NH H 1-2 4 CO NH Ph 1-3 4 CO NH 2-Me-Ph 1-4 4 CO. NiH 4-Me-Ph 1-5 T CO NH 2,4-diMe-Ph 1-6 4 Co NiH 3,4-diMe-Ph 1-7 4 CO NH 2-(CF 3 )Ph 1-8 4 CO NH 4-(CF 3 )Ph 1-9 4 CO NH 2-MeOPh 1-10 4 CO NH 4-MeOPh 1-11 4 CO NH 2-EtOPh 1-12 4 CO NHl 4-EtOPh 1-13 4 CO NH 2-HOPh 1-14 4 CO NHl 4-HOPh 1-15 4 Co NH 2-(HOOC)Ph 1-16 4 Co NHl 4-(HOOC)Ph 1-17 4 Co NH 2-(MeOOC)Ph 1-18 T CO NH 4-(MeOOC)Ph 1-19 4 CO NHl 2-(EtOOC)Ph 1-20 4 CO NH 4-(EtOOC)Ph 1-21 4 CO NH 2-(tBuOOC)Ph 1-22 4 CO NH 4-(tBuOOC)Ph 1-23 4 CO N 2-Cl-Ph Y:\wPdocs\dgtmffss\981I2\981I2cpd I .doc -27- Table 1 (cont) es *0 0

S@

0 0 0@eO *060 00.0 *000 Cpd. k A B R No.

1-24 T co NHl 4-Cl-Ph 1-25 4 CO NH 2-Br-Ph 1-26 T CO NH 4-Br-Ph 1-27 4 CO NH 2-I-Ph 1-28 4 CO NH 4-I-Ph 1-29 T CO NH 2-N0 2 -Ph 1-30 4 CO. NH 4-N0 2 -Ph 1-31 4 CO NH 2-NH 2 -Ph 1-32 4 CO NH 4-NI{ 2 -Ph 1-33 4 CO NH 2-(HO 3 S)Ph 1-34 4 CO NH 4-(HO 3 S)Ph 1-35 4 CO NH 2-(NFI 2

O

2 S)Ph 1-36 4 CO NH 4-(NH 2

O

2 S)Ph 1-37 4 CO NH 2-CN-Ph 1-38 4 CO NH 4-CN-Ph 1-39 4 CO NH 2-(HOCH 2 )Ph 1-40 4 CO NH 4-(HOCH 2 )Ph 1-41 4 CO NH Me 1-42 4 CO NH Et 1-43 4 CO NH Pr 1-44 4 CO NH iPr 1-45 4 CO NH Bu 1-46 4 CO NH HOOCCH 2 1-47 4 CO NH MeOOCCH 2 1-48 4 CO NH MeCH(COOH)- 1-49 4 CO NH HOOC-(CH 2 )2- 0000 0. 0* 00 y:\wpdocs\dgtmrrss\981I2\981I cpd I doc -28- TableI(cont.)

C.

Cpd. k A B R 1-50 T CO NH MeCH(COOMe)- 1-51 4 CO NH- 1-HOOC-iBu 1-52 4 CO NH 1-MeOOC-iBu 1-53 4 CO NH 1-HOOC-iPn 1-54 4 Co NH 1-MeOOC-iPn 1-55 4 Co NH 1-HOOC-2-Me-Bu 1-56 4 Co. NH 1-MeOOC-2-Me-Bu 1-57 4 Co NH CH 2

CH

2

SO

3

H

1-58 4 Co NH OH 1-59 4 CO NH MeO 1-60 4 CO NH EtO 1-61 4 Co NH Pro 1-62 4 Co NH iPro 1-63 4 Co NH BuO 1-64 4 CO NH iBuO 1-65 T Co NH sBuO 1-66 4 CO NH tBuO 1-67 4 CO NH HxO 1-68 4 CO NH PhO 1-69 4 CO NH BzO 1-70 4 CO NH Z-1 1-71 4 CO NH Z-2 1-72 4 CO NH Z-3 1-73 4 CO NH Z-4 1-74 4 CO NH 1-75 4 CO NH Z-6 1-76 4 CO NH Z-7 y:\wpdocs\dgt_mss\981I2\981I2cpd I doc 29 Table 1 (cont) Cpd. k A B R No.

1-77 4 CO NH Z-8 1-78 4 CO NHl Z-9 1-79 4 CO NHL 1-80 4 CO NiH Z-1lI 1-81 4 CO NHl Z-12 1-82 4 Co NiH 3-Py 1-83 4 Co. Nil 4-Py 1-84 4 CO N(Ac) H 1-85 4 CO N(Ac) Ph 1-86 4 CO N(Ac) 2-Me-Ph 1-87 4 CO N(Ac) 4-Me-Ph 1-88 4 CO N(Ac) 2,4-diMe-Ph 1-89 4 CO N(Ac) 3,4-diMe-Ph 1-90 4 CO N(Ac) 2-(CF 3 )Ph 1-91 4 CO N(Ac) 4-(CF 3 )Ph 1-92 4 CO N(Ac) 2-MeOPh 1-93 4 Co N(Ac) 4-MeOPh 1-94 T CO N(Ac) 2-EtOPh 1-95 4 CO N(Ac) 4-EtOPh 1-96 T CO N(Ac) 2-HOPh 1-97 4 CO N(Ac) 4-HOPh 1-98 4 CO N(Ac) 2-(HOOC)Ph 1-99 4 CO N(Ac) 4-(HOOC)Ph 1-100 4 CO N(Ac) 2-(MeOOC)Ph 1-101 4 CO N(Ac) 4-(MeOOC)Ph 1-102 4 CO N(Ac) 2-(EtOOC)Ph 1-103 4 CO N(Ac) 4-(EtOOC)Ph y:\wpdocs\dgtmss\981I2\981I2cpd I doc 30 Table I(cont Cpd. k A B R' No. 1-104 T CO N(Ac) 2(~OCP 1-105 4 CO N(Ac) 4-(tBuOOC)Ph 1-106 4 CO N(Ac) 2-Cl-Ph 1-107 4 CO N(Ac) 4-Cl-Ph 1-108 4 CO N(Ac) 2-Br-Ph 1-109 4 CO N(Ac) 4-Br-Ph 1-110 4 Co. N(Ac) 2-I-Ph 1-111 4 CO N(Ac) 4-I-Ph 1-112 4 CO N(Ac) 2-N0 2 -Ph 1-113 4 CO N(Ac) 4-NO 2 -Ph 1-114 4 CO N(Ac) 2-NH 2 -Ph 1-115 4 CO N(Ac) 4-N}1 2 -Ph 1-116 T CO N(Ac) 2-(HO 3 S)Ph 1-117 4 CO N(Ac) 4-(HO 3 S)Ph 1-118 4 CO N(Ac) 2-(NH 2

O

2 S)Ph 1-119 T CO N(Ac) 4-(NH 2

O

2 S)Ph 1-120 4 CO N(Ac) 2-CN-Ph 1-121 4 CO N(Ac) 4-CN-Ph 1-122 4 CO N(Ac) 2-(HOCH 2 )Ph 1-123 4 CO N(Ac) 4-(HOCH 2 )Ph 1-124 4 CO N(Ac) Me 1-125 4 CO N(Ac) Et 1-126 4 co N(Ac) Pr 1-127 4 CO N(Ac) iPr 1-128 4 CO N(Ac) Bu 1-129 T CO N(Ac) HOOCCH 2 y:\wpdocs\dgtinmss\9812\9812cpd1 .doc -31 TableI (cont) Cpd. T A B R No.

1-130 4 CO N(Ac) MeOOCCH 2 1-131 4 Co N(Ac) MeCH(COOH) 1-132 T CO N(Ac) HOOC-(CH 2 2 1-133 4 CO N(Ac) MeCH(COOMe) 1-134 4 CO N(Ac) 1-HOOC-iBu 1-135 4 CO N(Ac) 1-MeOOC-iBu 1-136 4 CO N(Ac) 1-HOOC-iPn 1-137 4 CO N(Ac) 1-MeOOC-iPn *1-138 4 CO N(Ac) 1-HOOC-2-Me-Bu :1-139 4 Co N(Ac) 1-MeOOC-2-Me-Bu 1-140 4 Co N(Ac) CH 2

CH

2

SO

3

H

1-141 4 Co N(Ac) OH 1-142 4 CO N(Ac) MeO 1-143 4 CO N(Ac) EtO 1-144 T CO N(Ac) Pro **1-145 T CO N(Ac) iPrO 1-146 4 CO N(Ac) BuO :1-147 4 CO N(Ac) iBuO 1-4 4ION(c:su 1-149 4 CO N(Ac) tBuO 1-150 4 CO N(Ac) HxO 1-151 4 CO N(Ac) PhO 1-152 4 CO N(Ac) BzO 1-153 T CO N(Ac) Z-1 1-154 4 CO N(Ac) Z-2 1-155 4 CO N(Ac) Z-3 1-156 4 CO N(Ac) Z-4 y:\wpdacs\dgt-mss\981I2\981I2cpd I doc 32 Table I(cont.) Cpd. k A BR No. 1-157 4 CO N(Ac) 1-158 4 CO N(Ac) Z-6 1-159 4 CO N(Ac) Z-7 1-160 T co N(Ac) Z-8 1-161 4 CO N(Ac) Z-9 1-162 4 CO N(Ac) 1-163 4 Co. N(Ac) Z-1 1 1-164 4 CO N(Ac) Z-12 1-165 4 CO N(Ac) 3-Py 1-166 4 CO N(Ac) 4-Py 1-167 4 coo H 1-168 4 coo Ph 1-169 4 COO 2-Me-Ph 1-170 4 coo 4-Me-Ph 1-171 4 coo 2,4-diMe-Ph 1-172 4 coo 3,4-diMe-Ph 1-173 4 coo 2-(CF 3 )Ph 1-174 4 coo 4-(CF 3 )Ph 1-175 4 coo 2-MeOPh 1-176 4 COO 4-MeOPh 1-177 4 coo 2-EtOPh 1-178 4 coo 4-EtOPh 1-179 4 COO 2-HOPh 1-180 T coo 4-HOPh 1-181 4 coo 2-(HOOC)Ph 1-182 4 coo 4-(HOOC)Ph 1-183 4 coo 2-(MeOOC)Ph y:\wpdocs\dgt_mss\9812\98I2cpdI .doc 33 Table I (cont.) Cpd. k A B R 1-184 T coo 4-(MeOOC)Ph 1-185 4 coo 2-(EtOOC)Ph 1-186 4 coo 4-(EtOOC)Ph 1-187 7 coo 2-(tBuOOC)Ph 1-188 4 coo 4-(tBuOOC)Ph 1-189 4 coo. 2-Cl-Ph 1-190 4 coo 4-Cl-Ph 1 -191 7 coo 2-Br-Ph 1-192 7 coo 4-Br-Ph :1-193 7 coo -2-I-Ph :.1-194 7 coo -4-I-Ph 1-195 7 coo 2-N0 2 -Ph 1-196 7 coo 4-N0 2 -Ph 1-197 7 coo 2-NH- 2 -Ph 1-198 7 coo 4-N11 2 -Ph 1-199 7 coo 2-(HO 3 S)Ph 1-200 7 coo 4-(HO 3 S)Ph *1-201 7 coo 2-(NH 2

O

2 S)Ph 1-202 7 coo 4-(NH 2

O

2 S)Ph 1-203 4 coo 2-CN-Ph 1-204 4 coo 4-CN-Ph 1-205 4 coo 2-(HOCH 2 )Ph 1-206 4 coo 4-(HOCH 2 )Ph 1-207 4 coo Me 1-208 4 coo Et 1-209 7 coo Pr y:\wpdocs\dgt_mss\981I2\981I2cpd I .doc 34 Tabl I(cnt.) Cpd. k A BR 1-210 4 coo p 1-211 4 coo -B 1-212 4 coo HOOCCH-- 1-2 13 4 coo HOOC-(CH 2 2 1-214 4 coo MeCH(COOMe) 1-215 4 coo 1-HOOC-iBu 1-216 4 coo- 1-HOOC-iPn 1-217 T coo -z-1 1-218 4 coo Z-2 1-219 T coo Z-3 1-220 4 coo Z-4 1-221 4 coo 1-222 4 coo Z-6 1-223 4 coo Z-7 1-224 4 coo Z-8 1-225 4 coo Z-9 1-226 4 coo Z- 1-227 4 coo 1 -1 1 1-228 4 coo Z-12 1-229 4 coo 3-Py 1-230 4 coo 4-Py 1-231 4 CONHCO -H 1-232 4 CONI-CO -Ph 1-233 4 CONECO 2-Me-Ph 1-234 4 CONHCO 4-Me-Ph 1-235 T CONi-CO 2,4-diMe-Ph 1-236 4 CONIICO -3,4-diMe-Ph y:\wpdocs\dgtmffss\981I2\981I2cpd L doc 35 Table 1 (cont.) Cpd. k A B R No.

1-237 4 CONHCO 2-(CF 3 )Ph 1-238 4 CONI-CO 4-(CF 3 )Ph 1-239 4 CONHCO 2-MeOPh 1-240 T CONIICO 4-MeOPh 1-241 4 CONI-CO -2-EtOPh 1-242 4 CONHCO -4-EtOPh 1-243 4 CONHCO -2-HOPh 1-244 4 CONHCO -4-HOPh 1-245 4 CONHCO 2-(HOOC)Ph 1-246 4 CONIICO 4-(HOOC)Ph 1-247 4 CONHCO 2-(MeOOC)Ph 1-248 4 CONHCO 4-(MeOOC)P~h 1-249 4 CONHCO 2-(EtOOC)Ph 1-250 4 CONHCO 4-(EtOOC)Ph 1-251 4 CONIICO 2-(tBuOOC)Ph 1-252 4 CONHCO 4-(tBuOOC)Ph 1-253 4 CONH-CO -2-Cl-Ph 1-254 4 CONHCO -4-Cl-Ph 1-255 4 CONHCO -2-Br-Ph 1-256 4 CONHCO -4-Br-Ph 1-257 4 CONHCO -2-1-Ph 1-258 4 CONHCO -4-I-Ph 1-259 4 CONHCO 2-N0 2 -Ph 1-260 4 CONH-CO 4-N0 2 -Ph 1-261 7 CONIICO 2-NH 2 -Ph 1-262 4 CONH-CO 4-NH 2 -Ph y:\wpdocs\dgt-mss\981I2\981 2cpd I doc -36- Table 1 (cont) Cpd. k A B R 1-263 4 CONHCO 2-(HO 3 S)Ph 1-264 4 CONHCO 4-(HO 3 S)Ph 1-265 4 CONHCO 2-(NH 2

O

2 S)Ph 1-266 4 CONIHCO 4-(NH 2

O

2 S)Ph 1-267 4 CONHCO -2-CN-Ph 1 -268 4 CONHCO -4-CN-Ph 1-269 4 CONHCO .2-(HOCH 2 )Ph 1-270 4 CONHCO 4-(HOCH 2 )Ph 1-271 4 CONIICO -Me 1-272 4 CONH-CO -Et 1-273 4 CONHCO -Pr 1-274 4 CONHCO -iPr 1-275 4 CONI-CO -Bu 1-276 4 CONH-CO HOOCCH 2 1-277 4 CONHCO MeOOCCH 2 1-278 4 CONI-CO MeCH(COOH) 1-279 4 CONIICO HOOC-(CH 2 2 1-280 4 CONHCO MeCH(COOMe) 1-281 T CONHCO 1-HOOC-iBu 1-282 4 CONHCO I1-MeOOC-iBu 1-283 4 CONHCO 1-HOOC-iPn 1-284 4 CONH-CO 1-MeOOC-iPn 1-285 4 CONIICO 1-HOOC-2-Me-Bu 1-286 4 CONHCO 1-MeOOC-2-Me-Bu 1-287 4 CONHCO

CH

2

CH

2 SO3H 1-288 T CONHCO z-1 y:\wpdocs\dgt_mss\9812\9812cpdt .doc 37 Table I (cont) 4 Cpd. k A B R No. 1-289 4 CONIICO -Z-2 1-290 4 CONIICO -Z-3 1-291 4 CONIHCO -Z-4 1-292 4 CONHiCO 1-293 4 CONHCO -Z-6 1-294 4 CONHCO -Z-7 1-295 4 CONHCO, Z-8 1-296 4 CONHCO -Z-9 1-297 4 CONIICO 1-298 4 CONHiCO -Z-1 1 1-299 4 CONHCO 12 1-300 4 CONHiCO -3-Py 1-301 4 CONI-CO -4-Py 1-302 4 CON(Ac)CO -H 1-303 4 CON(Ac)CO -Ph 1-304 4 CON(Ac)CO 2-Me-Ph 1-305 4 CON(Ac)CO 4-Me-Ph 1-306 4 CON(Ac)CO 2,4-diMe-Ph 1-307 4 CON(Ac)CO 3,4-diMe-Ph 1-308 T CON(Ac)CO 2-(CF 3 )Ph 1-309 T CON(Ac)CO 4-(CF 3 )Ph 1-310 4 CON(Ac)CO 2-MeOPh 1-311 4 CON(Ac)CO 4-MeOPh 1-3 12 T CON(Ac)CO -2-EtOPh 1-313 4 CON(Ac)CO -4-EtOPh 1-314 4 CON(Ac)CO -2-HOPh 1-315 4 CON(Ac)CO i4-HOPh y:\wpdocs\dgt_Tms\981I2\9BI2cpd L doc 38 Tabl I(cnt) Cpd. k A B R 1-3 16 4 CON(Ac)CO -2-(HOOC)Ph 1-317 4 CON(Ac)CO -4-(HOOC)Ph 1-318 T CON(Ac)CO -2-(MeOOC)Ph 1-3 19 4 CON(Ac)CO 4-(MeOOC)Ph 1-320 T CON(Ac)CO 2-(EtOOC)Ph 1-321 4 CON(Ac)CO 4-(EtOOC)Ph 1-322 4 CON(Ac)CO 2-(tBuOOC)Ph 1-323 4 CON(Ac)CO 4-(tBuOOC)Ph 1-324 4 CON(Ac)CO 2-Cl-Ph 1-325 T CON(Ac)CO 4-Cl-Ph 1-326 4 CON(Ac)CO 2-Br-Ph 1-327 T CON(Ac)CO 4-Br-Ph 1-328 4 CON(Ac)CO -2-I-Ph 1-329 4 CON(Ac)CO -4-I-Ph 1-330 T CON(Ac)CO 2-N0 2 -Ph 1-331 4 CON(Ac)CO 4-N0 2 -Ph 1-332 4 CON(Ac)CO 2-NH 2 -Ph 1-333 4 CON(Ac)CO 4-NH 2 -Ph 1-334 4 CON(Ac)CO 2-(HO 3 S)Ph 1-335 4 CON(Ac)CO 4-(HO 3 S)Ph 1-336 4 CON(Ac)CO 2-(NI{ 2 0 2 S)Ph 1-337 4 CON(Ac)CO 4-(NH 2

O

2 S)Ph 1-338 T CON(Ac)CO 2-CN-Ph 1-339 4 CON(Ac)CO 4-CN-Ph 1-340 T CON(Ac)CO 2-(HOCH 2 )Ph 1-341 4 CON(Ac)CO I 4-(HOCH 2 )Ph y:\wpdocs\dgt_mss\9812\9812cpdl .doc 39 Tabl I(cnt.) 0* Cpd. k A B R' 1-342 4 CON(Ac)CO -Me 1-343 4 CON(Ac)CO -Et 1-344 4 CON(Ac)CO -Pr 1-345 4 CON(Ac)CO -iPr 1-346 4 CON(Ac)CO -Bu 1-347 4 CON(Ac)CO HOOCCH 2 1-348 4 CON(AC)CO MeOOCCH 2 1-349 4 CON(Ac)CO MeCH(COOH) 1-350 4 CON(Ac)CO HOOC-(CH 2 2 1-351 4 CON(Ac)CO MeCH(COOMe) 1-352 4 CON(Ac)CO 1-HOOC-iBu 1-353 4 CON(Ac)CO 1-MeOOC-iBu 1-354 4 CON(Ac)CO 1-HOOC-iPn 1-355 4 CON(Ac)CO 1-MeOOC-iPn 1-356 4 CON(Ac)CO 1-HOOC-2-Me-Bu 1-357 4 CON(Ac)CO I-MeOOC-2-Me-Bu 1-358 4 CON(Ac)CO CH 2

CH

2

SO

3

H

1-359 4 CON(Ac)CO -Z-1 1-360 4 CON(Ac)CO -Z-2 1-36 1 4 CON(Ac)CO -Z-3 1-362 4 CON(Ac)CO -Z-4 1-363 4 CON(Ac)CO 1-364 4 CON(Ac)CO -Z-6 1-365 4 CON(Ac)CO -Z-7 1-366 4 CON(Ac)CO -Z-8 1-367 4 CON(Ac)CO -Z-9 y:\wPdocs\dgt_mfss\981I2\981I2cpd I doc Table I(cont.) s* S too* Cpd. k A BR 1-368 4 CON(Ac)CO 1-369 4 CON(Ac)CO -Z-1l1 1-370 4 CON(Ac)CO 12 1-371 4 CON(Ac)CO -3-Py 1-372 4 CON(Ac)CO -4-Py 1-373 4 CONHCO NHl H 1-374 4 CONI-CO NHl Ph 1-375 4 CONilCO NHl 2-Me-Ph 1-3 76 4 CONHCO Nil 4-Me-Ph 1-377 4 CONilCO Nil 2,4-diMe-Ph 1-378 4 CONilCO NHl 3,4-diMe-Ph 1-379 4 CONilCO Nil 2-(CF 3 )Ph 1-380 4 CONi-CO Nil 4-(CF 3 )Ph 1-381 4 CONilCO NHl 2-MeOPh 1-382 4 CONHCO Nil 4-MeOPh 1-383 4 CONilCO NHl 2-EtOPh 1-384 4 CONI-CO Nil 4-EtOPh 1-385 4 CONilCO Nil 2-HOPh 1-386 T CONilCO Nil 4-HOPh 1-387 4 CONilCO Nil 2-(HOOC)Ph 1-388 4 CONilCO Nil 4-(HOOC)Ph 1-389 T CONH-CO Nil 2-(MeOOC)Ph 1-390 4 CONilCO Nil 4-(MeOOC)Ph 1-391 4 CONHCO Nil 2-(EtOOC)Ph 1-392 4 CONilCO Nil 4-(EtOOC)Ph 1-393 4 CONHCO Nil 2-(tBuOOC)Ph 194 4 CONHCO Nil 4-(tBuOOC)Ph y:\wpdocs\dgt_ms\981I2\981I2cpd I doc -41- Table I (cont.) goes see* 0. so: Cpd. k A B R' No.

1-395 4 CONHCO NH 2-CI-Ph 1-396 4 CONHCO NH 4-CI-Ph 1-397 4 CONHCO NH 2-Br-Ph 1-398 4 CONHCO NH 4-Br-Ph 1-399 4 CONHCO NH 2-I-Ph 1-400 4 CONHCO NH 4-I-Ph 1-401 4 CONHCO NH 2-NO2-Ph 1-402 4 CONHCO NH 4-NO2-Ph 1-403 4 CONHCO NH 2-NH2-Ph 1-404 4 CONHCO NH 4-NH2-Ph 1-405 4 CONHCO NH 2-(HO3S)Ph 1-406 4 CONHCO NH 4-(HO3S)Ph 1-407 4 CONHCO NH 2-(NH202S)Ph 1-408 4 CONHCO NH 4-(NH202S)Ph 1-409 4 CONHCO NH 2-CN-Ph 1-410 4 CONHCO NH 4-CN-Ph 1-411 4 CONHCO NH 2-(HOCH2)Ph 1-412 4 CONHCO NH 4-(HOCH2)Ph 1-413 4 CONHCO NH Me 1-414 4 CONHCO NH Et 1-415 4 CONHCO NH Pr 1-416 4 CONHCO NH iPr 1-417 4 CONHCO NH Bu 1-418 4 CONHCO NH HOOCCH2- 1-419 4 CONHCO NH MeOOCCH2- 1-420 4 CONHCO NH MeCH(COOH) yAwpdocs\dgt_ ms\9812\9812cpd Ldoc -42 T~ale (c Cpd. k A B

R

No. 1-421 T CONI{CO NH HOOC-(CH 2 2 1-422 4 CONHCO NH MeCH(COOMe) 1-423 4 CONHCO NH 1-HOOC-iBu 1-424 4 CONHCO NH 1-MeOOC-iBu 1-425 4 CONHCO NH 1-HOOC-iPn 1-426 4 CONHCO NH 1-MeOOC-iPn 1-427 4 CONHCO NH 1-HOOC-2-Me-Bu 1-428 4 CONHCO NH 1-MeOOC-2-Me-Bu 1-429 4 CONHCO NH CH 2

CH

2

SO

3

H

1-430 4 CONHCO NH

HO

1-431 4 CONHCO NH MeO 1-432 4 CONHCO NH EtO 1-433 4 CONHCO NH Pro 1-434 4 CONHCO NH iPrO 1-435 T CONHCO NH BuO 1-436 4 CONHCO NH iBuO 1-437 4 CONHCO NH sBuO 1-438 4 CONHCO NH tBuO 1-439 4 CONHCO NH HxO 1-440 4 CONHCO NH PhO 1-441 4 CONHCO NH BzO 1-442 4 CONHCO NH Z-1 1-443 4 CONHCO NH Z-2 1-444 4 CONHCO NH Z-3 1-445 4 CONHCO NH Z-4 1-446 r 4 OHON 1 1-447 4 CONHCO Nial y:\wpdocs\dgt_mfss\9812\981 2cpdl .doc -44- Table I(conW) r Cpd. k A B R No. 1-473 T CONHS02 4-(MeOOC)Ph 1-474 4 CONIS02 2-(EtOOC)Ph 1-475 4 CON S02 4-(EtOOC)Ph 1-476 4 CON S02 2-(tBuOOC)Ph 1-477 4 CONHSO2 4-(tBuOOC)Ph 1-478 4 CONHS02 2-Cl-Ph 1-479 4 CONHS02 4-Cl-Ph 1-480 4 CONHS0 2 2-Br-Ph 1-481 4 CONHSO2 4-Br-Ph 1-482 4 CONHS02 2-I-Ph 1-483 4 CONHS02 4-I-Ph 1-484 4 CONHS02 2-N0 2 -Ph 1-485 4 CONHS02 4-N0 2 -Ph 1-486 4 CONHSO2 2-NH 2 -Ph 1-487 4 CONHS02 4-NH 2 -Ph 1-488 4 CONES02 2-(HO 3 S)Ph 1-489 4 CONHS02 4-(HO 3 S)Ph 1-490 4 CONHS02 2-(NH 2

O

2 S)Ph 1-491 4 CONHS02 4-(NH 2

O

2 S)Ph 1-492 4 CONHSO2 2-CN-Ph 1-493 4 CONHS02 4-CN-Ph 1-494 4 CONHSO 2 2-(HOCH 2 )Ph 1-495 4 CONHS02 4-(HOCH 2 )Ph 1-496 4 CONHS02 Me y:\wpdocs'dgtmss\98 12\981 2cpd I.doc Table I(cont.) Cpd. k A B R N o E t 1-497 4 CONHS0 2 Et 1-498 4 CONHS02 -Pr 1-499 4 CONHSO 2 iPr 1-500 4 CONHSO 2 Bu 1-501 4 CONHS0 2

HOOCCH

2 1-502 4 CONHS0 2 MeOOCCH 2 1-503 4 CONHSO 2 MeCH(COOH) 1-504 4 CONHS0 2

HOOC-(CH

2 2 1-505 4 CONHS0 2 MeCH(COOMe) 1-506 4 CONIS0 2 1-HOOC-iBu 1-507 4 CONHS0 2 1-MeOOC-iBu 1-508 4 CONHSO 2 1-HOOC-iPn 1-509 4 CONHS0 2 1-MeOOC-iPn 1-510 4 CONHS0 2 1-HOOC-2-Me-Bu 1-511 4 CONHS0 2 1-MeOOC-2-Me-Bu 1-512 4 CONHS0 2

CH

2

CH

2

SO

3

H

1-513 4 CONHS0 2

OH

1-514 4 CONES0 2 MeG 1-515 4 CONHS0 2 EtO 1-516 4 CONHSO 2 PrO 1-517 4 CONHS020 iPrO 1-518 4 CGNHSG 2 BuG 1-519 4 CONHS0 2 iBuG 1-520 4 CONHS0 2 sBuG y:\wpdocs\dgtmss\9812\981Zcpd .doc 46 Table I (cont.) Cpd. k A B R No. 1-521 4 CONHS0 2 tu 1-522 4 CONHIS0 2 -HxO 1-523 4 CONHS0 2 -PhO 1-524 4 CONHS0 2 -BzO 1-525 4 CONH-S0 2 1 1-526 4 CONHiS0 2 -Z-2 1-527 4 CONHS0 2 -Z-3 1-528 4 CONH-S0 2 -Z-4 1-529 4 CONHIS0 2 1-530 4 CONHIS0 2 -Z-6 1-531 4 CONHS0 2 -Z-7 1-532 4 CONHS0 2 -Z-8 1-533 4 CONHS0 2 -Z-9 1-534 4 CONH-S0 2 1-535 4 CONHS0 2 -Z-1 1 1-536 4 CONHS0 2 12 1-537 4 CONH-S0 2 -3-Py 1-538 4 CONH-S0 2 -4-Py 1-539 4 CONHS0 2 NH H 1-540 4 CONH-S0 2 NH Ph 1-541 4 CONHS0 2 NH 2-Me-Ph 1-542 4 CONHS0 2 NH 4-Me-Ph 1-543 4 CONHS0 2 NH 2,4-diMe-Ph 1-544 4 CONHS0 2 NH 3,4-diMe-Ph y:\wpdocs\dgtmffss\9812\981 2cpdl .doc 47 Cpd. k A B R 1-545 4 CONHS0 2 NH- 2-(CF 3 )Ph 1-546 4 CONHS0 2 NH 4-(CF 3 )Ph 1-547 4 CONHS0 2 NH- 2-MeOPh 1-548 4 CONH-S0 2 NiH 4-MeOPh 1-549 4 CONH-S0 2 NH- 2-EtOPh 1-550 4 CONH-S0 2 NH 4-EtOPh 1-551 4 CONHS0 2 NH 2-HOPh 1-552 4 CONHS0 2 NH 4-HOPh 1-553 4 CONH-S02 NH 2-(HOOC)Ph 1-554 4 CONHS0 2 NH 4-(HOOC)Ph 1-555 4 CONH-S0 2 NH 2-(MeOOC)Ph 1-556 4 CONH-S0 2 NH 4-(MeOOC)Ph 1-557 4 CONHS0 2 NH 2-(EtOOC)Ph 1-558 4 CONHS0 2 NH 4-(EtOOC)Ph 1-559 4 CONH-S0 2 NH 2-(tBuOOC)Ph 1-560 4 CONHS0 2 NH 4-(tBuOOC)Ph 1-561 4 CONHS0 2 NIH 2-Cl-Ph 1-562 4 CONHS0 2 NH 4-Cl-Ph 1-563 4 CONHS0 2 NH 2-Br-Ph 1-564 4 CONHS0 2 NH 4-Br-Ph 1-565 4 CONHS0 2 NH 2-I-Ph 1-566 4 CONHS0 2 NH 4-I-Ph 1-567 4 CONHS0 2 NH 2-N0 2 -Ph 1-568 4 CONHS0 2 NH 4-N0 2 -Ph y:\wpdocs\dgt_mss\981I2\981I2cpd I .doc 48 Cpd. k A B Rl No. 1-569 4 CONHS02 NH 2-NH 2 -Ph 1-570 4 CONHS02 NHl 4-NH 2 -Ph 1-57 7 ONIS02NH- 2-(HO 3 S)Ph 1-572 4 CONH1S02 NH 4-(HO 3 S)Ph 1-573 4 CONHS2 NH 2-(NH 2

O

2 S)Ph 1-574 4 CONH{S02 NH 4-(N11 2 0 2 S)Ph 1-575 4 CONHS2 NH 2-CN-Ph 1-576 4 CONHS2 NH 4-CN-Ph 1-577 4 CONHS2 NH 2-(HOCH 2 )Ph 1-578 4 CONHS2 NH 4-(HOCH 2 )Ph 1-579 7 CONHS0 2

N

1-580 4 CONHS02 NH

M

1-581 4 CONHS02 NH Pr 1-582 4 CONHS02 NH iPr 1-583 7 CONHS02 NH Bu 1-584 4 CONHS02 NH HOOCCH 2 1-585 4 CONHS02 NH MeOOCCH2- 1-586 4 CONHS02 NH MeCH(COOH) 1-587 7 CONHS0 2 NH HOOC-(CH 2 )2- 1-588 4 CONHS0 2 NH MeCH(COOMe) 1-589 4 CONHS0 2 NH 1-HOOC-iBu 1-590 4 CONHS02 NH I-MeOOC-iBu 1-591 4 CONHS02 NH 1-HOOC-iPn 1-592 4 CONHS02 NH 1-MeOOC-iPn y:\wpdocs\dgt_mss\9812\ 9 8 2CPdl .doc -49 TableI cot.

Cpd. k A B R 1-593 4 CONHIS0 2 NH 1-HOOC-2-Me-Bu 1-594 4 CONHIS02 NH 1-MeOOC-2-Me-Bu 1-595 4 CONHS02 NH CH 2

CH

2

SO

3

H

1-596 4 CONHS0 2 NH OH 1-597 4 CONH{S02 NH MeG 1-598 4 CONHS0 2 NH EtO 1-599 4 CONHS0 2 NH Pro 1-600 4 CONHS0 2 NH iPro 1-601 4 CONH-S0 2 NH BuG 1-602 4 CONHSG 2 NH iBuO 1-603 4 CONHS0 2 NH sBuO 1-604 4 CGNHSG2 NH tBuO 1-605 4 CONHS0 2 NiH HxO 1-606 4 CONHS0 2 NH PhG 1-607 4 CONHS0 2 NH BzO 1-608 4 CONHS0 2 Nil Z-1 1-609 4 CGNH-S0 2 NH Z-2 1-610 4 CONES0 2 NH Z-3 1-611 4 CONHSG 2 NH- Z-4 1-6 12 T CONHS0 2 NH 1-613 4 CONHS0 2 NH Z-6 1-614 4 CONHSG 2 NH Z-7 1-615 4 CONHIS02 NH Z-8 1-616 4 CONHS0 2 NH Z-9 y:\wpdocs\dgt-rnss\981I2\98 12cpd I .do Table (cnt) Cpd. k A B

R

No. 1-617 4 CONHS0 2 NH- 1-618 4 CONH-S0 2 NH Z-l11 1-619 4 CONHS0 2 NH Z-12 1-620 4 CONHS02 NH 3-Py 1-62 1 4 CONHS02 NH- 4-Py 1-622 4 NHCO

H

1-623 4 NHCO

-P

*1-624 4 NHCO 2-eP *1-625 4 NHCO 4-eP .1-626 4 NHCO 2,4-diMe-Ph 1-627 4 NHCO 3,4-diMe-Ph *1-628 4 NHCO 2-(CF 3 )Ph 1-629 4 Ni-CO 4-(CF 3 )Ph 1-630 4 NH-CO 2-MeOPh 1-631 4 NHCO 4-MeOPh 1-632 4 NHCO -2-EtOPh 1-633 4 NHCO -4-EtOPh 1-634 4 NHCO -2-HOPh 1-635 4 NHCO 4-HOPh 1-636 4 NHCO 2-(HOOC)Ph 1-637 4 NHCO 4-(HOOC)Ph 1-638 4 Ni-CO 2-(MeOOC)Ph 1-639 4 NHCO 4-(MeOOC)Ph 1-640 4 NHCO -2-(EtOOC)Ph 1-641 4 NHCO -4-(EtOOC)Ph 1-642 4 NHCO -2-(tBuOOC)Ph y:\wpdocs\dgt_miss\981I2\981I2cpd L doc -51 TableI (cnt.) Cpd. k A B

R

1-643 4 NI4CO 4-(tBuOOC)Ph 1-644 4 Ni-CO 2-Cl-Ph 1-645 4 NHCO 4-Cl-Ph 1-646 4 NHCO 2-Br-Ph 1-647 4 NHCO 4-Br-Ph 1-648 4 NHCO -2-I-Ph 1-649 4 NH-CO -4-I-Ph 1-650 4 NIICO 2-N0 2 -Ph .1-651 4 NH-CO 4-N0 2 -Ph *1-652 4 NHCO 2-NH- 2 -Ph 1-653 4 NHCO 4-NH 2 -Ph *1-654 4 NHCO 2-(I-AS)Ph 1-655 4 Ni-CO 4-(HO 3 S)Ph 1-656 4 NH-CO 2-(NE- 2 0 2 S)Ph *1-657 4 NH-CO 4-(NH 2

O

2 S)Ph 1-658 4 NIICO 2-NP 1-659 4 Ni-CO 4-NP 1-660 4 NH-CO 2-(HOCH 2 )Ph 1-661 4 NI-CO 4-(HOCH 2 )Ph 1-662 4 NH-CO -Me 1-663 4 NHCO Et 1-664 4 NHCO Pr 1-665 4 NHCO iPr 1-666 4 NHCO Bu 1-667 4 NHCO -HOOCCH2- 1-668 4 NHCO -MeOOCCFI2y.\wpdocs\dgt_rms\981I2\981I2cpd I .doc -52- Table I(conQ Cpd. k A B R No.

1-669 4 NHCO MeCH(COOH) 1-670 4 NiCO HOOC-(CH 2 2 1-671 7 NHCO MeCH(COOMe) 1-672 4 NHCO 1-HOOC-iBu 1-673 4 NICO 1-HOOC-iPn 1-674 4 NICO 1-HOOC-2-Me-Bu 1-675 4 NICO CH 2

CH

2

SO

3

H

1-676 4 NHCO MeO 1-677 7 NHCO EtO 1-678 7 NHCO PrO 1-679 4 NHCO -1 1-680 4 NHCO Z-2 1-681 4 NHCO Z-3 1-682 4 NiCO Z-4 1-683 4 NICO 1-684 4 NICO Z-6 1-685 4 N-CO Z-7 1-686 4 NICO Z-8 1-687 4 NHCO Z-9 1-688 7 NHCO 1-689 4 NHCO Z-l1 1-690 4 NHCO -Z-12 1-691 4 NHCO 3-Py 1-692 4 NHCO 4-Py 1-693 7 NHCO NH H 1-694 4 NHCO NH Ph 1-695 4 NHCO NH 2-Me-Ph y:\wpdocs\dgt_mss\9812\9812cpd .doc 53 TalI (ont.) 0 *00 00000* Cpd. k A B

R

No. 1-696 T NI-CO NH 4-Me-Ph 1-697 4 NHCO NH 2,4-diMe-Ph 1-698 4 NHCO NH 3,4-diMe-Ph 1-699 4 NIICO NH 2-(CF 3 )Ph 1-700 4 NI-lO NH 4-(CF 3 )Ph 1-701 4 NHCO NH 2-MeOPh 1-702 4 NHCO NH 4-MeOPh 1-703 4 NHCO NH 2-EtOPh 1-704 4 NHCO NH 4-EtOPh 1-705 4 NI-CO NH 2-HOPh 1-706 4 NHCO NHl 4-HOPh 1-707 4 NHCO Nil 2-(HOOC)Ph 1-708 4 NI-CO Nil 4-(HOOC)Ph 1-709 4 NHCO NHl 2-(MeOOC)Ph 1-7 10 4 NH-CO NHl 4-(MeOOC)Ph 1-711 4 NHCO Nil 2-(EtOOC)Ph 1-712 4 NHCO NH 4-(EtOOC)Ph 1-7 13 4 NILCO NH 2-(tBuOOC)Ph 1-714 4 NHCO NHl 4-(tBuOOC)Ph 1-715 4 NHCO NH 2-Cl-Ph 1-716 4 NHCO NEl 4-Cl-Ph 1-717 4 Ni-CO NE 2-Br-Ph 1-718 4 NHCO NHl 4-Br-Ph 1-719 4 NHCO NH 2-I-Ph 1-720 4 NHCO NH 4-I-Ph 1-721 4 NH-CO NE 2-N0 2 -Ph 1-7 22 4 NHCO NH 4-N0 2 -Ph y:\wpdocs\dgt_mss\9812\9812cpd1 .doc 54 Table I (nIJ Cpd. k A B R No. 1-723 4 NHCO NH 2-NH 2 -Ph 1-724 4 NHCO NH 4-NH 2 -Ph 1-725 4 NHCO NH 2-(HO 3 S)Ph 1-726 4 NHCO NH 4-(HO 3 S)Ph 1-727 4 NHCO NH 2-(NH 2

O

2 S)Ph 1-728 4 NHCO NH 4-(NH 2

O

2 S)Ph 1-729 4 NHCO NH 2-CN-Ph 1-730 4 NHCO NH 4-CN-Ph 1-731 4 NHCO NH 2-(HOCH 2 )Ph 1-732 4 NHCO NH 4-(HOCH 2 )Ph 1-733 4 NHCO NH Me 1-734 4 NHCO NH Et 1-735 4 NHCO NH Pr 1-736 4 NHCO NH iPr 1-737 4 NHCO NH Bu 1-738 4 NHCO NH HOOCCH 2 1-739 4 NHCO NH MeOOCCH 2 1-740 4 NHCO NH MeCH(COOH) 1-741 4 NHCO NH HOOC-(CH 2 2 1-742 4 NHCO NH MeCH(COOMe) 1-743 4 NHCO NH 1-HOOC-iBu 1-744 4 NHCO NH I-MeOOC-iBu 1-745 4 NHCO NIH 1-HOOC-iPn 1-746 4 NHCO NH 1-MeOOC-iPn 1-747 4 NHCO NH 1-HOOC-2-Me-Bu 1-748 4 NHCO NH 1-MeOOC-2-Me-Bu y:\wpdocs\.dgt_ms\9812\9812cpd1 .doc 55 TableI (cnL

S

S

.0S @0 @9 0

S.

0 S @0 0@ 0@ 9 9 0500

S

9S~S

C

0000 Cpd. k A B R No. 1-749 4 NHCO NH CH 2

CH

2

SO

3

H

1-750 4 j NHCO NH OH 1-751 4 NHCO NH MeG 1-752 4 NHCO NH EtO 1-753 4 NHCO NH Pro 1-754 4 NHCO NH iPrO 1-755 4 NHCO NH BuG 1-756 4 NHCO NH iBuG 1-757 4 NHCO NH sBuO 1-758 4 NHCO NH tBuO 1-759 4 NHCO NH HxO 1-760 4 NHCO NH PhO 1-761 4 NHCO NH BZO 1-762 4 NHCO NH Z-1 1-763 4 N-HCO NH Z-2 1-764 4 NHCO NH Z-3 1-765 4 NI-CO NH Z-4 1-766 4 NI-CO NH 1-767 4 NHCO NH Z-6 1-768 4 NHCO NH Z-7 1-769 4 NH-CO NH Z-8 1-770 4 NHCO NH Z-9 1-771 4 NHCO NH 1-772 4 NHCO NH Z-1 1 1-773 4 NHCO NH Z-12 1-774 4 NHCO NH 3-Py 1-775 4 NHCO NH 4-Py y:\wpdocs\dgt_mss\981I2\981I2cpd L doc 56 Table 1 (cont.) Cpd. k A B

R

No. 1-776 4 NI-CO NMe Ph 1-777 4 NHCO NMe 2-Me-Ph 1-778 4 NI{CO NMe 4-Me-Ph 1-779 4 NI{CO NMe 2,4-diMe-Ph 1-780 4 NIICO NMe 3,4-diMe-Ph 1-78 1 4 NIICO NMe 2-(CF 3 )Ph 1-782 4 NHCO NMe 4-(CF 3 )Ph 1-783 4 NHCO NMe 2-MeOPh 1-784 4 NI-CO NMe 4-MeOPh 1-785 4 NHCO NMe 2-EtOPh 1-786 4 NHCO NMe 4-EtOPh 1-787 4 Ni-CO NMe 2-HOPh 1-788 4 NHCO NWe 4-HOPh 1-789 4 NI-CO NMe 2-(HOOC)Ph 1-790 4 NHCO NMe 4-(HOOC)Ph 1-791 4 NH-CO NMe 2-(MeOOC)Ph 1-792 4 NHCO NMe 4-(MeOOC)Ph 1-793 4 NHCO NWe 2-(EtOOC)Ph 1-794 4 NI-CO NMe 4-(EtOOC)Ph 1-795 4 NH-CO NWe 2-(tBuOOC)Ph 1-796 4 NHCO NMe 4-(tBuOOC)Ph 1-797 4 NI-CO NMe 2-Cl-Ph 1-798 4 NHCO NMe 4-Cl-Ph 1-799 4 NI-CO NMe 2-Br-Ph 1-800 4 NHCO NMe 4-Br-Ph 1-801 4 NIICO NMe 2-I-Ph 1-802 4 NI-CO NMe 4-I-Ph y:\wpdocs\dgt~fmss\981 2\981I2cpd I .doc 57 Table I (cntj Cpd. k A B Rl No. 1-803 4 NIICO NMe 2-N0 2 -Ph 1-804 4 j NIICO NMe 4-N0 2 -Ph 1-805 4 NIICO NMe 2-NH 2 -Ph 1-806 4 NI-CO NMe 4-NI- 2 -Ph 1-807 4 NIICO NMe 2-(HO 3 S)Ph 1-808 4 NHCO NMe 4-(HO 3 S)Ph 1-809 4 NHCO NMe 2-(NH 2

O

2 S)Ph 1-810 4 NI{CO NMe 4-(NH 2 0 2 S)Ph 1-811 4 NI-CO NMe 2-CN-Ph 1-812 4 NHCO NMe 4-CN-Ph 1-813 4 NHCO NMe 2-(HOCH 2 )Ph 1-814 4 NHCO NMe 4-(HOCH 2 )Ph 1-815 4 NHCO NMe Me 1-816 4 NHCO NMe Et 1-817 4 Ni-CO NMe Pr 1-818 4 NHCO NMe iPr 1-819 4 Ni-CO NMe Bu 1-820 T NH-CO NMe HOOCCH 2 1-821 4 NH-CO NMe MeOOCCH 2 1-822 4 NH-CO NMe MeCH(COOH) 1-823 4 NH-CO NMe HOOC-(CH 2 )2- 1-824 4 Ni-CO NMe MeCH(COOMe) 1-825 4 NI-CO NMe 1-HOOC-iBu 1-826 4 NHCO NMe I-MeOOC-iBu 1-827 4 NHCO NMe 1-HOOC-iPn 1-828 4 NI-CO NMe I-MeOOC-iPn y:\wpdocs\dgt_mss\9812\9812cpdI .doc 58 Tabl I(cont.) No. 1-829 4 NHCO NMe L-HOOC-2-Me-Bu 1-830 4 NHCO NMe I-MeOOC-2-Me-Bu 1-831 4 NH-CO NMe CH 2

CH

2

SO

3

H

1-832 4 NHCO W~e OH 1-833 4 NHiCO NMe MeO 1-.834 4 NI-CO NMe EtO 1-835 4 NH-CO W~e Pro 1-836 4 Ni-CO NMe iPrO 1-837 4 NHCO NWe BuG 1-838 4 NHCO NMe iBuG 1-839 4 NI-CO NMe sBuO 1-840 4 NI-CO NMe tBuO 1-841 4 NECO NWe HxO 1-842 4 NHCO NMe PhO 1-843 4 NHCO NMe BzO 1-844 4 NHCO NMe Z-1 1-845 4 NI-CO NMe Z-2 1-846 4 NHCO NMe Z-3 1-847 4 Ni-CO NMe Z-4 1-848 4 NHCO NMe 1-849 4 Ni-CO NMe Z-6 1-850 4 NHCO NWe Z-7 1-851 4 NI-CO NMe Z-8 1-852 4 NHCO NMe Z-9 1-853 4 NHCO NMe 1-854 4 NHCO NMe Z-1 1 1-855 T NHCO NMe Z-12 y:\wpdocs\dgt_mfss\9812\9812cpd1 .doc 59 Table (cnt) Cpd. k A B R No. 1-856 4 NHCO NMe 3-Py 1-857 4 NilCO NMe 4-Py 1-858 4 NilCO NHNI- H 1-859 4 NilCO NIIMI Me 1-860 4 NHCO NilNi Et 1-861 4 NilCO NHNMe Me 1-862 4 NHCO NHNMe Et 1-863 4 NHCO NHNMe Pr 1-864 4 NHCONIHNHCO NHl H 1-865 4 N1-CONHNHCO Nil Ph 1-866 4 NHCONHNHCO NiH 2-Me-Ph 1-867 4 NI{CONI{NHCO NH 4-Me-Ph 1-868 4 NilCONH-NHCO NEl 2,4-diMe-Ph 1-869 4 NilCONHNilCO NHl 3,4-diMe-Ph 1-870 4 NilCONHNHCO NH 2-(CF 3 )Ph 1-871 4 NHCONHNI-CO NH 4-(CF 3 )Ph 1-872 4 NHCONHNilCO NH 2-MeOPh 1-873 4 NilCON1{NiCO NH 4-MeOPh 1-874 4 NilCONH-NHCO NH 2-EtOPh 1-875 4 NHCON-NHCO NIH 4-EtOPh 1-876 4 NHCON HNHCO NH 2-HOPh 1-877 4 NHCONHNHCO NH 4-HOPh 1-878 4 NHCONHNilCO NH 2-(HOOC)Ph 1-879 4 NHCONHNHCO NH 4-(HOOC)Ph 1-880 4 NHCONHNHCO NH 2-(MeOOC)Ph 1-881 4 NHCONHNilCO NH 4-(MeOOC)Ph 1 -882 4 NHCONHNilCO NH 2-(EtOOC)Ph y:\wpdocs\dgt_niss\981I2\981I2cpd I doc 60 Table (cnt.) Cpd. k A B R No. 1-883 4 NilCONHNilCO NiH 4-(EtOOC)Ph 1-884 4 NilCONHNilCO NHl 2-(tBuOOC)Ph 1-885 4 NHCONHNHCO NHl 4-(tBuOOC)Ph 1-886 4 NHCONHNHCO Nil 2-Cl-Ph 1-887 4 NilCONHNHCO Nil 4-Cl-Ph 1-888 4 NilCONHNilCO Nil 2-Br-Ph 1-889 4 NilCONIINiCO Nil 4-Br-Ph 1-890 4 NH-CONIHNilCO NiH 2-I-Ph 1-891 4 NHCONII-NHCO NHl 4-I-Ph 1-892 4 NilCONHNHCO Nil 2-N0 2 -Ph 1-893 4 NHCONI{NiCO Nil 4-N0 2 -Ph 1-894 4 NHCONilNHCO Nil 2-N11 2 -Ph 1-895 4 NHCONI{NHCO Nil 4-Nil 2 -Ph 1-896 4 NilCONilNiCO Nil 2-(HO 3 S)Ph 1-897 4 NilCONHNilCO NHl 4-(HO 3 S)Ph 1-898 4 NilCONI-NHCO NH 2-(Nil 2

O

2 S)Ph 1-899 4 NilCON{NH-CO Nil 4-(NH 2

O

2 S)Ph 1-900 4 NHCONHNilCO Nil 2-CN-Ph 1-901 4 NilCONHNilCO Nil 4-CN-Ph 1-902 4 NIICONHNilCO Nil 2-(HOCH 2 )Ph 1-903 4 NHCONH-NHCO Nil 4-(H-OCH 2 )Ph 1-904 -4 NilCONIINH-CO Nil Me 1-905 4 NHCONilNHCO NH E 1-906 4 NHCONHNI-CO NilP 1-907 4 NHCONIINiCO NH 1-908 4 NIICONHNHCO NH B y:\wpdocs\dgtinmss\9812\98I2cpd I .do -61 Table 1 (conit.

Cpd. k A B R No. 1-909 4 NHCONIINHCO NH HOOCCH 2 1-9 10 4 jNHCONHNHCO NH MeOOCCH 2 1-911 41 NHCONHNHCO NH MeCH(COOH) 1-912 4 NHCONHNHCO NH HOOC-(CH 2 2 1-913 4 NHCONHNHCO NH MeCH(COOMe) 1-914 4 NHCONHNHCO NH 1-HOOC-iBu 1-915 4 NHCONHNECO NH 1-MeOOC-iBu 1-916 4 NHCONH-NHCO NH 1-HOOC-iPn :1-917 4 NHCONH-NI4CO NH 1-MeOOC-iPn .1-918 4 NHCONHNHCO NH 1-HOOC-2-Me-Bu *1-919 4 NHCONHNHCO NH 1-MeOOC-2-Me-Bu 1-920 4 NHCONINTHCO NH CH 2

CH

2

SO

3

H

1-921 T NHCONHNHCO NH OH 1-922 4 NHCON1-NHCO NH MeO 1-923 4 NHCONHNHCO NH EtO 1-924 4 NHCONUNECO NH Pro 1-925 4 NHCONHN1-CO NH iPro S1-926 4 NHCON-N1-CO NH BuO 1-927 4 NHiCONHNHCO NH iBuO 1-928 T NHCONHNI-CO NH sBuO 1-929 4 NHCONHN-ICO NH tBuO 1-930 4 NHCONHNI-CO NH HxO 1-931 4 NHCONHNHCO NH PhO 1-932 4 NIICONILNHCO NH BzO 1-933 4 NHCONHNHCO NH Z-1 1-934 4 NHCONHNHCO NH Z-2 1-935 141 NHCONIHNHCO NH Z-3 y:\wpdocs\dgt-niss\981I2\9812 cpd I doc 62 TablI(cont.)

S.

Cpd. k A B

R

1-936 4 NilCONHN-HCO NHl Z-4 1-937 4 N}ICONlN-HCO NH 1-938 4 NilCONHNHCO NH Z-6 1-939 4 NilCONI{NHCO Nil Z-7 1-940 4 NHCONHNilCO Nil Z-8 1-941 4 NIICONI{NHCO Nil Z-9 1-942 4 NilCONIHilCO NH 1-943 4 NI-CONHNHCO Nil Z-1 1 1-944 4 NilCONHNHCO NH Z-12 1-945 4 NilCONHNHCO NHl 3-Py 1-946 4 NilCONHNHCO NH 4-Py 1-947 4 NH-CONHCO

-H

1-948 4 NH-CONHCO -Ph 1-949 4 NilCONi-ICO 2-Me-Ph 1-950 4 NH-CONH-CO -4-Me-Ph 1-95 1 4 NHCONHCO 2,4-diMe-Ph 1-952 4 N-HCONIICO 3,4-diMe-Ph 1-953 4 NHCONilCO 2-(CF 3 )Ph 1-954 4 NHCONilCO 4-(CF 3 )Ph 1-955 4 NHCONH-CO 2-MeOPh 1-956 4 NiCONHCO -4-MeOPh 1-957 4 NHCONilCO -2-EtOPh 1-958 4 NH-CONHCO -4-EtOPh 1-959 4 NE-CONHCO -2-HOPh 1-960 4 NliCONHCO -4-HOPh 1-961 4 NHCONHCO 2-(HOOC)Ph 1-962 4 NHCON'HCO 4-(HOOC)Ph y:\wpdocs\dgt_mfss\981I2\981I2cpd L doc 63 Tabl I(cnt.) Cpd. k A B

R

No. 1-963 4 NHCONHCO 2-(MeOOC)Ph 1-964 4 NHCONHCO 4-(MeOOC)Ph 1-965 4 N}{CONHCO 2-(EtOOC)Ph 1-966 4 NIICONHCO 4-(EtOOC)Ph 1-967 4 NHCONHCO 2-(tBuOOC)Ph 1-968 4 NHCONHCO 4-(tBuOOC)Ph 1-969 4 NH-CONHCO 2-Cl-Ph 1-970 4 NH-CONHiCO 4-Cl-Ph 1-971 4 NHCONH-CO 2-Br-Ph 1-972 4 NHCONHCO 4-Br-Ph 1-973 4 NHCONHCO -2-I-Ph 1-974 4 NHCONHCO -4-I-Ph 1-975 4 NHCONHCO 2-N0 2 -Ph 1-976 4 NH-CONH-CO 4-N0 2 -Ph 1-977 4 NIICONH-CO 2-NH 2 -Ph 1-978 4 Ni-CONI-CO 4-NH 2 -Ph 1-979 4 NHCONHCO 2-(HO 3 S)Ph 1-980 4 NHCONHCO 4-(HO 3 S)Ph 1-981 4 N}{CONHCO 2-(NH 2

O

2 S)Ph 1-982 4 NHCONHCO 4-(NH 2

O

2 S)Ph 1-983 4 NH-CONIICO -2-CN-Ph 1-984 4 NH-CONHCO 4-CN-Ph 1-985 4 NHCONH-CO -2-(HOCH 2 )Ph 1-986 4 NH-CONHCO -4-(HOCH 2 )Ph 1-987 4 NHCONHCO Me 1-988 4 NI-CONHCO Et y:\wpdocs\dgt-fmss\981I2\981I2cpd I Amo 64 TableI(cnt.) Cpd. k A B R No. 1-989 T NHCONIICO Pr 1-990 4 NIICONH-CO iPr 1-991 4 NH-CONHCO Bu 1-992 4 NI-CONI-CO HOOCCH 2 1-993 4 NHCONHCO MeOOCCH 2 1-994 4 NHCONIICO MeCH(COOH) 1-995 4 NHCONHCO HOOC-(CH 2 2 1-996 4 NHCONI{CO MeCH(COOMe) 1-997 4 NHCONI-CO 1-HOOC-iBu 1-998 4 NHCONHCO 1-MeOOC-iBu 1-999 4 NHCONH-CO 1-HOOC-iPn 1-1000 4 NHCONHCO 1-MeOOC-iPn 1-1001 4 NHCONHCO 1-HOOC-2-Me-Bu 1-1002 4 NH-CONH-CO I-MeOOC-2-Me-Bu 1-1003 4 NH-CONHCO CH 2

CH

2

SO

3

H

1-1004 4 N-HCONH-CO -MeO 1-1005 4 NHCON1-ICO -EtO 1-1006 4 NHCON1-CO -Pro 1-1007 4 NH1-CONHCO -iPrO 1-1008 4 NHCONH-CO -BuO 1-1009 4 NH-CONIICO iBuO 1-1010 4 NH-CONHCO -sBuO 1-1011 4 NHCONIICO -tBuO 1-1012 4 NHCONHCO -HxO 1-1013 4 NHCONHCO -PhO 1-1014 4 NH-CONIICO BzO y:\wpdocs\dgtmnss\981I2\981I2cpd I .doc 65 Table 1 (cont.) C C C C

C

C C

C

Cpd. k A B R No. 1-1015 T NHCONiiCO z- 1 1-1016 4 NHCONHCO Z-2 1-1017 4 NHCONHCO Z-3 1-1018 4 N HCONHCO -Z-4 1-1019 4 NHCONI{CO 1-1020 4 NHCONIICO -Z-6 1-1021 4 NH-CONHCO -Z-7 1-1022 4 NIICONH-CO -Z-8 1-1023 4 NH-CONHiCO -Z-9 1-1024 4 NHCONHCO 1-1025 4 NHCONI{CO -Z-1 1 1-1026 4 NH-CONH-CO 12 1-1027 T NHCONHCO -3-Py 1-1028 4 NHCONH-CO -4-Py 1-1029 4 NHCONH-S0 2

-H

1-1030 4 NH-CONH-S0 2 -Ph 1-1031 4 NHCONH1S02 -2-Me-Ph 1-1032 4 NH-CONHS0 2 4-Me-Ph 1-1033 4 NHCONHS0 2 2,4-diMe-Ph 1-1034 4 NHCONHS0 2 3,4-diMe-Ph 1-1035 4 NHCONH-S0 2 2-(CF 3 )Ph 1-1036 4 NHCONH1S0 2 4-(CF 3 )Ph 1-1037 4 NHICONHS0 2 2-MeOPh 1-1038 4 NHCONH-S0 2 4-MeOPh 1-1039 4 NHCONHS0 2 I2-EtOPh y:\wpdocs\dgtms\981I2\981I2cpd I .do -66- Table I (cont.) Cr

C

Cpd. k A B R No. 1-1040 T NHCONHSO2 4-EtOPh 1-1041 4 j INHCONHS0 2 2-HOPh 1-1042 4 NHCONHSO 2 4-HOPh 1-1043 4 NHCONHS0 2 2-(HOOC)Ph 1-1044 4 NHCONHS02 4-(HOOC)Ph 1-1045 4 NHCONHS02 2-(MeOOC)Ph 1-1046 4 NHCONHSO2 4-(MeOOC)Ph 1-1047 4 NHCONHS02 2-(EtOOC)Ph 1-1048 4 NHCON1-S0 2 4-(EtOOC)Ph 1-1049 4 NHCONHSO 2 2-(tBuOOC)Ph 1-1050 4 NHCONHS0 2 4-(tBuOOC)Ph 1-1051 4 NHCONHS0 2 2-Cl-Ph 1-1052 4 NHCONHS02 4-Cl-Ph 1-1053 4 NHCONHS0 2 2-Br-Ph 1-1054 4 NHCONHS0 2 4-Br-Ph 1-1055 4 NHCONHS02 2-I-Ph 1-1056 4 NICONES0 2 4-I-Ph 1-1057 4 NHCONHS02 2-N0 2 -Ph 1-1058 4 NECONHS02 4-N0 2 -Ph 1-1059 4 NHCONHS02 2-NH 2 -Ph 1-1060 4 NHCONHS0 2 4-NH 2 -Ph 1-1061 4 NHCONHS02 2-(HO 3 S)Ph 1-1062 4 NHCONHS02 4-(HO 3 S)Ph 1-1063 4 NHCONHS02 2-(NH 2

O

2 S)Ph y:\wpdocs\dgtmss\9812\9812cpd .doc -67- Table I (con Cpd. k A B R No. 1-1064 4 NHCONHS02 4-(NH 2 2 S)Ph 1-1065 4 NHCONHSO 2 2-CN-Ph 1-1066 4 NHCONHSO2 4-CN-Ph 1-1067 4 NHCONHSO2 2-(HOCH 2 )Ph 1-1068 4 NHCONHS02 4-(HOCH 2 )Ph 1-1069 4 NHCONHS02 Me 1-1070 4 NHCONHS02 Et 1-1071 4 NHCONHS0 2 Pr 1-1072 4 NHCONHS0 2 iPr 1-1073 4 NHCONHS02 Bu 1-1074 4 NHCONHSO2 HOOCCH 2 1-1075 4 NHCONHSO2 MeOOCCH 2 1-1076 4 NHCONHS0 2 MeCH(COOH) 1-1077 4 NHCONHSO 2

HOOC-(CH

2 2 1-1078 4 N-CONHSO2 MeCH(COOMe) 1-1079 4 NHCONHS02 1-HOOC-iBu 1-1080 4 NHCONHS0 2 1-MeOOC-iBu 1-1081 4 NHCONHS0 2 1-HOOC-iPn 1-1082 4 NHCONHS02 1-MeOOC-iPn 1-1083 4 NHCONHS02 1-HOOC-2-Me-Bu 1-1084 4 NHCONHSO2 1-MeOOC-2-Me-Bu 1-1085 4 NHCONHS0 2

CH

2

CH

2 SO3H 1-1086 4 NHCONHS02

OH

1-1087 4 NHCONHS02 MeO y:\wpdocs\dgtmss\98 I 2\981 2cpd 1.doc -68- Table I (cnt.) Cpd. k A B R No. 1-1088 4 NHCONHS02 EtO 1-1089 4 NHCONHS02 PrO 1-1090 4 NHCONHS02 iPrO 1-1091 4 NHCONHS02 BuO 1-1092 4 NHCONHS02 iBuG 1-1093 4 NHCONHS02 sBuO 1-1094 4 N-CONHSO 2 tBuO 1-1095 4 NHCONHSO2 HxO 1-1096 4 NHCONHS0 2 PhO 1-1097 4 NHCONHS02 BzO 1-1098 4 NHCONHS02 Z-1 1-1099 4 NHCONHS02 Z-2 1-1100 4 NHCONHSO 2 -3 1-1101 4 NHCONHSO2 Z-4 1-1102 4 NHCONHS0 2 1-1103 4 NHCONHS02 Z-6 1-1104 4 NHCONHS02 Z-7 1-1105 4 NECONHS02 Z-8 1-1106 4 NECONHS02 Z-9 1-1107 4 NHCONI-S02 1-1108 4 NHCONHS02 Z-11 1-1109 4 NHCONHS0 2 Z-12 1-1110 4 NICONHSO2 3-Py 1-1111 4 NHCONES02 4-Py y:\wpdocs\dgtjnss\98 12\98I2cpd .doc 69 Table I(cont) Cpd. k A B

R

No. 1-1112 T NHCONHS02 NH

H

1-1113 4 NHlCONHS0 2 NHl Me 1-1114 4 NH{CONH{S02 NH Et 1-1115 4 NHICONHIS0 2 NHl Pr 1-1116 4 NHCONHS02 NiH iPr 1-1117 4 NHCONHS0 2 Nil Bu 1-1118 4 NHCONHIS0 2 NMe Me 1-11 4.HOH02NE *1-1119 4 NHCONHS0 2 NMe Pr 1-12 4 NHOH0 :1-1122 4 NHCONH-S0 2 NMe Pr 1-1121 4 N-CNS2NHe

H~

1-1122 4 NiCNS 2 N14 Bu *1-1123 4 -NH Ht 1-1124 4 -NH Mer 1-1125 4 -NH Bu 1-1126 4 NH Prr 1-1127 4 NH iip r *1-112 4 NH Bur 1-1129 4 CO NPyr 1-1130 4 CO NPipi 1-1131 4 CO NPipra 1-1137 4 CO NHMor y:\wpdocs\dgt_mss\981I2\981I2cpd I .doc Table I(onW

S

S0 go 0@ 0 0* @0 0 g 00 0 OS*0 0 0000 Cpd. k A B R No.

1-1138 T Co NliThmor 1-1139 4 NICO Pyr 1-1140 4 NICO Pipri 1-1141 4 NHCO Pipra 1-1142 4 NICO Mor 1-1143 4 NHCO Thmor 1-1144 4 NHCO NHPyr 1-1145 4 NICO NlPipri 1-1146 4 NHCO NiPipra 1-1147 4 NHCO NHMor 1-1148 4 NHCO NHThmor 1-1149 4 CONHCO Pyr 1-1150 4 CONiCO Pipri 1-1151 4 CONHCO Pipra 1-1152 4 CONHCO Mor 1-1153 4 CONHCO Thmor 1-1154 4 CONHCO NHPyr 1-1155 4 CONHCO NHPipri 1-1156 4 CONHCO NHPipra 1-1157 4 CONHCO NHMor 1-1158 4 CONHCO NHThmor 1-1159 4 CONHS0 2 Pyr 1-1160 4 CONHS0 2 Pipri 1-1161 4 CONHS0 2 Pipra 1-1162 4 CONHSO 2 Mor 1-1163 4 CONHS0 2 Thmor 0

*OSS

@800 00 S 0S y:\wpdocs\dgt_ms\98 12\9812cpd I .doc -71 Table I (coWt.

Cpd. k A B R No.

1-1164 4 CONHSO 2 NHPyr 1-1165 4 CONHS02 NHPipri 1-1166 4 CONHSO 2 NHPipra 1-1167 4 CONHSO 2 NHMor 1-1168 4 CONHSO2 NHThmor 1-1169 4 NHS0 2 NH Z-4 1-1170 4 NHSO2 Me 1-1171 4 NHS02 Et 1-1172 4 N-SO 2 Pr 1-1173 4 NHSO 2

CH

2 C0 1-1174 4 NHS02 Ph 1-1175 4 NHS02 4-Me-Ph 1-1176 4 CO NMe Ph 1-1177 4 CO NMe 2-Me-Ph 1-1178 4 CO NMe 4-Me-Ph 1-1179 4 CO NMe 2,4-diMe-Ph 1-1180 4 CO NMe 3,4-diMe-Ph 1-1181 4 CO NMe 2-(CF 3 )Ph 1-1182 4 CO NMe 4-(CF 3 )Ph 1-1183 4 CO NMe 2-MeOPh 1-1184 4 CO NMe 4-MeOPh 1-1185 4 CO NMe 2-EtOPh 1-1186 4 CO NMe 4-EtOPh 1-1187 4 CO NMe 2-HOPh 1-1188 4 CO NMe 4-HOPh 1-1189 4 CO NMe 2-(HOOC)Ph y\wpdocs\dgtmss\98 12\98 1 Zcpd I .doc 72 Table 1 (cont.) S S Cpd. k A B R No. 1-1190 4 CO NMe 4-(HOOC)Ph 1-1191 4 CO NMe 2-(MeOOC)Ph 1-1192 4 CO NMe 4-(MeOOC)Ph 1-1193 4 CO NMe 2-(EtOOC)Ph 1-1194 4 CO NMe 4-(EtOOC)Ph 1-1195 4 CO NMe 2-(tBuOOC)Ph 1-1196 4 CO NMe 4-(tBuOOC)Ph 1-1 197 4 CO NMe 2-Cl-Ph 1-1198 4 CO NMe 4-Cl-Ph 1-1199 4 CO NMe 2-Br-Ph 1-1200 4 CO NMe 4-Br-Ph 1-1201 4 CO NMe 2-I-Ph 1-1202 4 CO NMe 4-1-Ph 1-1203 T CO NMe 2-N0 2 -Ph 1-1204 4 CO NMe 4-N0 2 -Ph 1-1205 4 CO NMe 2-NH 2 -Ph 1-1206 4 CO NMe 4-N7H 2 -Ph 1-1207 4 jCO NMe 2-(HO 3 S)Ph 1-1208 4 CO NMe 4-(HO 3 S)Ph 1-1209 4 CO NMe 2-(NE 2

O

2 S)Ph 1-1210 4 CO NMe 4-(NH- 2 0 2 S)Ph 1-1211 4 CO NMe 2-CN-Ph 1-1212 4 CO NMe 4-CN-Ph 1-1213 4 CO NMe 2-(HOCH 2 )Ph 1-1214 4 CO NMe 4-(HOCH 2 )Ph 1-1215 4 CO NMe Me y:\wpdocs\dgtmffss\981I2\981I2cpd I doc 73 Cpd. k A B R No. 1-1216 4 CO NMe Et 1-1217 4 CO NMe Pr 1-1218 4 CO NMe iPr 1-1219 4 CO NMe Bu 1-1220 4 CO NMe HOOCCH 2 1-1221 4 CO NMe MeOOCCH 2 1-1222 4 CO We MeCH(COOH) 1-1223 4 CO NMe HOOC-(CH 2 2 1-1224 4 CO We MeCH(COOMe) 1-1225 4 CO We 1-HOOC-iBu 1-1226 4 co We 1-MeOOC-iBu 1-1227 4 CO We 1-HOOC-iPn 1-1228 4 CO We 1-MeOOC-iPn 1-1229 4 CO We 1-HOOC-2-Me-Bu 1-1230 4 CO We 1-MeOOC-2-Me-Bu 1-1231 4 CO We CH 2

CH

2

SO

3

H

1-1232 4 CO We OH 1-1233 4 CO We MeO 1-1234 4 CO We EtO 1-1235 4 CO We Pro 1-1236 4 CO We iPrO 1-1237 4 CO We BuO 1-1238 4 CO We iBuO 1-1239 4 CO We sBuO 1-1240 4 CO We tBuO 1-1241 4 CO We HxO 1-1242 4 CO We PhO y:\wpdocs\dgt_mfss\981I2\981I2cpd I .do 74 Table I (co Cpd. k A B R No. 1-1243 T Co NMe BzO 1-1244 4 Co NMe Z-1 1-1245 4 Co NMe Z-2 1-1246 4 Co NMe Z-3 1-1247 4 Co NMe Z-4 1-1248 4 Co NMe 1-1249 4 Co NMe Z-6 1-1250 4 CO NMe Z-7 1-1251 4 CO NMe Z-8 0.1-1252 4 CO0 NMe Z-9 1-1253 4 CO NMe 1-1254 4 CO NMe Z-11I 1-1255 4 CO NMe Z-12 1-1256 4 CO NMe 3-Py 1-1257 4 CO NMe 4-Py 1-1258 4 CO Thiad 1-1259 4 CO NI-Thiad 1-1260 4 M-ICO Thiad 1-1261 4 NHCO NHThiad 1-1262 4 CONE-CO Thiad 1-1263 4 CONIICO NHThiad 1-1264 4 CONIHS0 2 Thiad 1-1265 4 CONE-S0 2 NHThiad 1-1266 4 NECS NHl H 1-1267 4 NH-CS NH Me 1-1268 4 Ni-CS NH- Et 1-1269 4 NH-CS NH Ph y:\wpdocs\dgtmrrss\981I2\981I2cpd I doc 75 TabI (cont.) Cpd. k A B Rl No. 1-1270 T NHCS NH HOOCCH 2 1-1271 4 NHCS NH MeOOCCH 2 1-1272 4 NHCS NH MeCH(COOH) 1-1273 4 NHCS NH HOOC-(CH 2 2 1-1274 4 NHCS NH MeCH(COOMe) 1-1275 4 CO NH HOOC-(CH 2 3 1-1276 4 NHCO NH HOOC-(CH 2 3 1-1277 4 NHCO -HOOC-(CH 2 3 1-1278 4 NI{CS NH HOOC-(CH 2 3 1-1279 4 CO NH MeSO 2 NHCOCH(Me) 1-1280 4 NHCO NH MeSO 2 NHCOCH(Me) 1-1281 4 NHCO -MeSO 2 NHCOCH(Me) 1-1282 4 Ni-ICS NH MeS0 2 NHCOCH(Me) 1-1283 4 NH HOOCCH 2 1-1284 4 NH MeOOCCH2- 1-1285 4 -NIH MeCH(COOH) 1-1286 4 -NH HOOC-(CH 2 2 1-1287 4 -NH MeCH(COOMe) 1-1288 4 -NH HOOC-(CH 2 3 1-1289 4 NIICOCO

OH

1-1290 4 NHCOCO -MeO 1-1291 4 NHCOCO -EtO 1-1292 4 NHCOCO Pro 1-1293 4 NHCOCO -iPrO 1-1294 4~ NHCOCO -BuO y:\wpdocs\dgtmffss\981 2\981I2cpd I .do 76 Table I(cnt.) Cpd. k A B R 1-1295 T NH-COCO iBuG 1-1296 4 NHCOCO sBuO 1-1297 4 NI-COCO -tBuO 1-1298 4 NIICOCO -HxO 1-1299 4 NIICOCO -PhO 1-1300 4 NHCOCO -BzO 1-1301 5 Co NH H 1-1302 5 Co NH Ph 1-1303 5 Co NH 2-Me-Ph 1-1304 5 Co NH 4-Me-Ph 1-1305 5 CO NH 2,4-diMe-Ph 1-1306 5 Co NHl 3,4-diMe-Ph 1-1307 5 CO NH 2-(CF 3 )Ph 1-1308 5 Co NH 4-(CF 3 )Ph 1-1309 5 CO NH 2-MeOPh 1-1310 5 CO NH 4-MeOPh 1-1311 5 CO NIH 2-EtOPh 1-1312 5 CO NH 4-EtOPh 1-1313 5 CO NH 2-HOPh 1-1314 5 CO NH 4-HOPh 1-1315 5 CO NH 2-(HOOC)Ph 1-1316 5 CO NH 4-(HOOC)Ph 1-1317 5 CO NH 2-(MeOOC)Ph 1-1318 5 CO NH 4-(MeOOC)Ph 1-1319 5 CO NH 2-(EtOOC)Ph 1-1320 5 CO NH 4-(EtOOC)Ph 1-1321 5 CO NH 2-(tBuOOC)Ph y:\wpdocs\dgt_mns\9812\9SI2cpdI .doc 77 Table 1 (cont.) Cpd. k A B

R

No. 1-1322 5 CO NH 4-(tBuOOC)Ph 1-1323 5 CO NH 2-Cl-Ph 1-1324 7 CO NH 4-Cl-Ph 1-1325 7 CO NH 2-Br-Ph 1-1326 5 CO NH 4-Br-Ph 1-1327 5 CO NH 2-I-Ph 1-1328 5 CO NH 4-I-Ph 1-1329 5 CO NH 2-N0 2 -Ph 1-1330 5 CO NH 4-NO 2 -Ph 1-1331 5 CO NH 2-NH- 2 -Ph 1-1332 5 CO NH 4-NH 2 -Ph 1-1333 7 CO NH 2-(HO 3 S)Ph 1-1334 7 CO NH 4-(HO 3 S)Ph 1-1335 5 CO NH 2-(NH 2

O

2 S)Ph 1-1336 5 CO NH 4-(NE- 2 0 2 S)Ph 1-1337 5 CO N

-NP

1-1338 7 CO N

-NP

1-1339 5 CO NH 2-(HOCH 2 )Ph 1-1340 5 CO NH 4-(HOCH 2 )Ph 1-1341 5 CO NH Me 1-1342 7 CO NH Et 1-1343 5 CO NiH Pr 1-1344 5 CO NH iPr 1-1345 5 CO NH Bu 1-1346 5 CO NH HOOCCH2- 1-1347 5 CO NH MeOOCCH2y:\wpdocs\dgt_ms\981I2\981I2CPd I .do 78 Tal I(cntJ Cpd. k A B R No. 1-1348 5 Co NH MeCH(COOH) 1-1349 5 Co NH HOOC-(CH 2 2 1-1350 5 Co NH- MeCH(COOMe) 1-1351 5 CO NH 1-HOOC-iBu 1-1352 5 CO NH 1-MeOOC-iBu 1-1353 5 CO NH 1-HOOC-iPn 1-1354 5 CO NH 1-MeO OC-iPn 1-1355 5 CO NH 1-HOOC-2-Me-Bu 1-1356 5 CO NH 1-MeOOC-2-Me-Bu 1-1357 5 CO NH CH 2

CH

2

SO

3

H

1-1358 5 CO NH OH *1-1359 5 CO NH MeO **>1-1360 5 CO NH EtO 1-1361 5 CO NH Pro 1-1362 5 CO NH iPrO 1-1363 5 CO NH BuO 1-1364 5 CO NH iBuO *1-1365 5 CO NiI sBuO 1-1366 5 CO NIH tBuO 1-1367 5 CO NH HxO 1-1368 5 CO NH PhO 1-1369 5 CO NH BzO 1-1370 5 CO NH Z-1 1-13 71 5 CO NH Z-2 1-1372 5 CO NH Z-3- 1-1373 5 CO NH Z-4 1-1374 5 CO NH y:\wpdocs\dgt_mss\981I2\981I2cpd I doc 79 Table I (cont.) Cpd. k A B R No. 1-1375 5 CO NH Z-6 1-1376 5 Co NH Z-7 1-1377 5 Co NH Z-8 1-1378 5 CO NH Z-9 1-1379 5 CO NH 1-1380 5 Co Nil Z-l11 1-1381 5 Co NH Z-12 1-1382 7 Co NH 3-Py 1-1383 5 CO NH 4-Py 1-1384 5 CO N(Ac) H .1-1385 7 CO N(Ac) Ph 1-1386 7 CO N(Ac) 2-Me-Ph *1-1387 7 CO N(Ac) 4-Me-Ph 1-1388 5 CO N(Ac) 2,4-diMe-Ph se.1-1389 5 CO N(Ac) 3,4-diMe-Ph **1-1390 5 CO N(Ac) 2-(CF 3 )Ph 1-1391 5 CO N(Ac) 4-(CF 3 )Ph 1-39 5 (c -e~ 1-1392 5 CO0 N(Ac) 2-MeOPh 1-1393 7 CO0 N(Ac) 4-MeOPh 1-1394 5 CO0 N(Ac) 2-EtOPh 1-1395 7 CO0 N(Ac) 4-EtOPh 1-1397 5 CO0 N(Ac) 2-HOPh 1-1397 5 CO0 N(Ac) -HOPh 1-1398 5 CO0 N(Ac) 2-(HOOC)Ph 1-1399 7 cO0 N(Ac) 4-(HeOOC)Ph 1-1400 5 CO0 N(Ac) 2-(MeOOC)Ph y:\wpdocs\dgt_mfss\981I2\981I2cpd I .doc 80 Table I (co Cpd. k A B

R

1-1402 5 CO N(Ac) 2-(EtOOC)Ph 1-1403 5 CO N(Ac) 4-(EtOOC)Ph 1-1404 5 CO N(Ac) 2-(tBuOOC)Ph 1-1405 5 CO N(Ac) 4-(tBuOOC)Ph 1-1406 5 CO N(Ac) 2-Cl-Ph 1-1407 5 CO N(Ac) 4-Cl-Ph 1-1408 5 CO N(Ac) 2-Br-Ph 1-1409 5 CO N(Ac) 4-Br-Ph 1-1410 5 CO N(Ac) 2-I-Ph 1-1411 5 CO N(Ac) 4-I-Ph 1-1412 5 CO N(Ac) 2-N0 2 -Ph 1-1413 5 CO N(Ac) 4-N0 2 -Ph 1-1414 5 CO N(Ac) 2-NH 2 -Ph 1-1415 5 CO N(Ac) 4-NH 2 -Ph 1-1416 5 CO N(Ac) 2-(HO 3 S)Ph 1-1417 5 CO N(Ac) 4-(HO 3 S)Ph 1-1418 5 CO N(Ac) 2-(NH 2

O

2 S)Ph 1-1419 5 CO N(Ac) 4-(NH- 2 0 2 S)Ph 1-1420 5 CO N(Ac) 2-CN-Ph 1-1421 5 CO N(Ac) 4-CN-Ph 1-1422 5 CO N(Ac) 2-(HOCH 2 )Ph 1-1423 5 CO N(Ac) 4-(HOCH 2 )Ph 1-1424 5 CO N(Ac) Me 1-1425 7 CO N(Ac) Et 1-1426 5 CO N(Ac) Pr 1-1427 5 CO N(Ac) iPr y:\wpdocs\dgtrnfss\981I2\981I2cpd I Ado -81i Table 1 (cont.) Cpd. k A B

R

No. 1-1428 5 Co N(Ac) Bu 1-1429 -5 CO N(Ac) HOOCCH 2 1-1430 5 CO N(Ac) MeOOCCH 2 1-1431 5 CO N(Ac) MeCH(COOH) 1-1432 5 CO N(Ac) HOOC-(CH-)) 2 1-1 433 5 Co N(Ac) MeCH(COOMe) 1-1434 5 CO N(Ac) 1-HOOC-iBu 1-1435 5 CO N(Ac) I-MeOOC-iBu 1-1436 5 Co N(Ac) 1-HOOC-iPn 1-1437 5 co N(Ac) 1-MeOOC-iPn 1-1438 5 CO N(Ac) 1-HOOC-2-Me-Bu 1-1439 5 CO N(Ac) 1-MeOOC-2-Me-Bu 1-1440 5 CO N(Ac) CH 2

CH

2

SO

3

H

1-1441 5 CO N(Ac) 0OH 1-1442 5 CO N(Ac) MeO 1-1443 7 CO N(Ac) EtO 1-1444 7 CO N(Ac) Pro 1-1445 5 CO N(Ac) iPrO 1-1446 5 CO N(Ac) BuO 1-1447 5 CO N(Ac) iBuO 1-1448 7 CO N(Ac) sBuO 1-1449 5 CO N(Ac) tBuO 1-1450 5 CO N(Ac) HxO 1-1451 5 CO N(Ac) PhO 1-1452 7 CO N(Ac) BzO 1-1453 5 CO N(Ac) Z-1 1-1454 5 CO N(Ac) Z-2 y:\wpdocs\.dgt_mfss\981 2\981I2cpd I .doc 82 Table (cnt.) 4* Cpd. k A B R' No. 1-1455 5 CO N(Ac) Z-3 1-1456 5 CO N(Ac) Z-4 1-1457 5 CO N(Ac) 1-1458 5 CO N(Ac) Z-6 1-1459 5 CO N(Ac) Z-7 1-1460 5 CO N(Ac) Z-8 1-1461 5 CO N(Ac) Z-9 1-1462 5 CO N(Ac) 1-1463 5 CO N(Ac) Z-1 1 1-1464 5 CO N(Ac) Z-12 1-1465 5 CO N(Ac) 3-Py 1-1466 5 CO N(Ac) 4-Py 1-1467 5 coo

H

1-1468 5 coo Ph 1-1469 5 COO 2-Me-Ph 1-1470 5 COO 4-Me-Ph 1-1471 5 coo 2,4-diMe-Ph 1-1472 7 coo 3,4-diMe-Ph 1-1473 5 COO 2-(CF 3 )Ph 1-1474 5 coo 4-(CF 3 )Ph 1-1475 5 coo 2-MeOPh 1-1476 5 coo 4-MeOPh 1-1477 5 coo 2-EtOPh 1-1478 5 coo 4-EtOPh 1-1479 5 coo 2-HOPh 1-1480 5 coo 4-HOPh 1-1481 5 COO -2-(HOOC)Ph y:\wpdocs\dgt_mss\981I2\981I2cpd I doc 83 Table 1 (conW.

Cpd. k A B R No. 1-1482 5 coo 4-(HOOC)Ph 1-1483 5 coo 2-(MeOOC)Ph 1-1484 5 coo 4-(MeOOC)Ph 1-1485 5 coo 2-(EtOOC)Ph 1-1486 5 coo 4-(EtOOC)Ph 1-1487 5 coo 2-(tBuOOC)Ph 1-1488 5 coo 4-(tBuOOC)Ph 1-1489 5 coo -2-Cl-Ph 1-1490 5 coo -4-Cl-Ph 1-1491 5 COO- 2-Br-Ph 1-1492 5 coo -4-Br-Ph 1-1493 5 coo -2-I-Ph 1-1494 5 coo -4-I-Ph 1-1495 5 coo 2-N0 2 -Ph 1-1496 5 coo 4-N0 2 -Ph 1-1497 5 coo 2-N14 2 -Ph 1-1498 5 coo 4-NH 2 -Ph 1-1499 5 coo 2-(HO 3 S)Ph 1-1500 5 coo 4-(HO 3 S)Ph 1-1501 5 coo 2-(NH 2 0 2 S)Ph 1-1502 5 coo 4-(N11 2 0 2 S)Ph 1-1503 5 coo -2-CN-Ph 1-1504 5 coo -4-CN-Ph 1-1505 5 coo 2-(HOCH 2 )Ph 1-1506 5 coo 4-(HOCH 2 )Ph 1-1507 5 coo -Me y:\wpdocs\dgt_mfss\981I2\981I2cpd I doc 84 TableI (cmt 000* .00* *.0 a9 0 Cpd. k A B Rl 1-1508 5 coo Et 1-1509 7 coo Pr 1-1510 5 coo iPr 1-1511 7 coo Bu 1-1512 7 coo HOOCCH 2 1-1513 5 coo HOOC-(CH 2 2 1-1514 5 coo MeCH(COOMe) 1-1515 7 coo 1-HOOC-iBu 1-1516 7 COO 1-HOOC-iPn 1-1517 7 coo 1 1-1518 5 coo -Z-2 1-1519 5 coo -Z-3 1-1520 -5 COO Z-4 1-1521 5YO co 1-1522 5 COO Z-6 1-1523 5 COO Z-7 1-1524 5 coo -Z-8 1-1525 7 coo -Z-9 1-1526 7 coo 1-1527 5 coo -Z-11I 1-1528 5 coo -Z-12 1-1529 7 coo -3-Py 1-1530 7 coo -4-Py 1-1531 5 CONHCO

H

1-1532 5 CONHCO Ph 1-1533 5 CONHCO 2-Me-Ph 1-1534 5 CONHCO 4-Me-Ph y:\wpdocs\dgt-mss\981I2\98 12cpd I Amo 85 Table I(cnt.) *.Oee@

C

e.g.

S

S. S

S.

C

0@S* S9 S S

S.

C

0*e*

C

6 *5@e

C

0 Cpd. k A B R No.

1-1535 5 CONI{CO 2,4-diMe-Ph 1-1536 5 CONHCO 3,4-diMe-Ph 1-1537 5 CONHCO 2-(CF 3 )Ph 1-1538 5 COYRCO 4-(CF 3 )Ph 1-1539 5 CONHCO 2-MeOPh 1-1-540 5 CONIICO 4-MeOPh 1-1541 5 CONHCO 2-EtOPh 1-1542 5 CONHCO 4-EtOPh 1-1543 5 CONH-CO 2-HOPh 1-1544 7 CONIICO 4-HOPh 1-1545 5 CONHCO 2-(HOOC)Ph 1-1546 5 CONHCO 4-(HOOC)Ph 1-1547 5 CONH-CO 2-(MeOOC)Ph 1-1548 5 CONHCO 4-(MeOOC)Ph 1-1549 5 CONH-CO 2-(EtOOC)Ph 1-1550 5 CONi-CO 4-(EtOOC)Ph 1-1551 7 CONHCO 2-(tBuOOC)Ph 1-1552 7 CONH-CO 4-(tBuOOC)Ph 1-1553 5 CONHCO -2-Cl-Ph 1-1554 5 CONE-CO -4-Cl-Ph 1-1555 5 CONI-CO -2-Br-Ph 1-1556 5 CONI-CO 4-Br-Ph 1-1557 5 CONHCO 2-I-Ph 1-1558 5 CONIICO 4-I-Ph 1-1559 5 CONIICO 2-N0 2 -Ph 1-1560 5 CONIICO 4-N0 2 -Ph y:\wpdocs\dgt_mss\981I2\981I2cpd I doc -86- Table I (coa Cpd. k A B

R

No. 1-1561 5 CONHCO 2-NH 2 -Ph 1-1562 5 CONI{CO 4-NH 2 -Ph 1-1563 5 CONHCO 2-(HO 3 S)Ph 1-1564 5 CONH-CO 4-(HO 3 S)Ph 1-1565 5 CONH-CO 2-(NI- 2 0 2 S)Ph 1-1566 5 CONIICO 4-(NH 2

O

2 S)Ph 1-1567 5 CONHCO 2-NP 1-1568 5 CONH-CO 4-NP 1-1569 5 CONHCO 2-(HOCH 2 )Ph :1-1570 5 CONH-CO -4-(HOCH 2 )Ph 1-1571 5 CONHCO Me *1-1572 5 CONHCO Et 1-1573 5 CONHCO Pr 1-1574 5 CONHCO iPr 1-1575 5 CONI-CO Bu 1-1576 7 CONHiCO -HOOCCH 2 *1-1577 5 CONHCO -MeOOCCH2- 1-1578 5 CONHCO -MeCH(COOH) 1-1579 5 CONHCO -HOOC-(CH 2 )2- 1-1580 71 CONHCO -MeCH(COOMe) 1-1581 5 CONHCO -HOOC-iBu 1-58 51OHC -MeOOC-iBu 1-1584 5 CONHCO -MeOOC-iPfl 1-1586 5 CONFICO -1-MeOOC-2-Me-Bu y:\wpdocs\dgtms\981I2\981I2cpd I doc 87 TableIcont.) Cpd. k A B R No. 1-1587 5 CONHCO

CH

2

CH

2

SO

3

H

1-1588 5 CONHCO 1 1-1589 7 CONHCO -Z-2 1-1590 7 CONHCO -Z-3 1-1591 7 CONIICO -Z-4 1 -1.592 5 CONHCO 1-1593 5 CONHCO -Z-6 1-1594 5 CONIICO -Z-7 1-1595 7 CONHCO -Z-8 1-1596 5 CONHCO -Z-9 1-1597 5 CONHCO 1-1598 5 CONI-CO -Z-1 1 1-1599 5 CONHCO 12 1-1600 5 CONHCO -3-Py 1-1601 5 CONI-CO -4-Py 1-1602 5 CON(Ac)CO -H 1-1603 5 CON(Ac)CO -Ph 1-1604 5 CON(Ac)CO -2-Me-Ph 1-1605 5 CON(Ac)CO -4-Me-Ph 1-1606 5 CON(Ac)CO 2,4-diMe-Ph 1-1607 5 CON(Ac)CO 3,4-diMe-Ph 1-1608 5 CON(Ac)CO 2-C3P 1-1609 5 CON(Ac)CO 4-(CF 3 )Ph 1-1610 5 CON(Ac)CO -2-MeOPh 1-16 11 5 CON(Ac)CO -4-MeOPh 1-16 12 5 CON(Ac)CO -2-EtOPh 1-1613 5 CON(Ac)CO -4-EtOPh y:\wpdocs\dgtms\981I2\981 Zcpd I Ado 88 TalI (cnt Cpd. k A B R No. 1-1614 5 CON(Ac)CO -2H~ 1-1615 5 CON(Ac)CO -4H~ 1-1616 5 CON(Ac)CO -2-(HOOC)Ph 1-1617 5 CON(Ac)CO 4-(HOOC)Ph 1-1618 5 CON(Ac)CO 2-(MeOOC)Ph 1-1619 5 CON(Ac)CO 4-(MeOOC)Ph 1-1620 5 CON(Ac)CO 2-(EtOOC)Ph 1-1621 5 CON(Ac)CO 4-(EtOOC)Ph 1-1622 5 CON(Ac)CO 2-(tBuOOC)Ph 1-1623 5 CON(Ac)CO 4-(tBuOOC)Ph 1-1624 5 CON(Ac)CO 2-Cl-Ph 1-1625 5 CON(Ac)CO 4-Cl-Ph 1-1626 5 CON(Ac)CO 2-Br-Ph 1-1627 5 CON(Ac)CO 4-Br-Ph 1-1628 5 CON(Ac)CO -2-I-Ph 1-1629 5 CON(Ac)CO -4-I-Ph 1-1630 5 CON(Ac)CO 2-N0 2 -Ph 1-1631 5 CON(Ac)CO 4-N0 2 -Ph 1-1632 5 CON(Ac)CO 2-NH 2 -Ph 1-1633 5 CON(Ac)CO 4-N}{ 2 -Ph 1-1634 5 CON(Ac)CO 2-(HO 3 S)Ph 1-1635 5 CON(Ac)CO 4-(HO 3 S)Ph 1-1636 5 CON(Ac)CO 2-(NH 2

O

2 S)Ph 1-1637 5 CON(Ac)CO 4-(NH 2

O

2 S)Ph 1-1638 5 CON(Ac)CO -2-CN-Ph 1-1639 5 CON(Ac)CO 4-CN-Ph y:\wpdocs\dgt_miss\981I2\98)I2cpd L doc 89 TableI(cont.) Cpd. k A B Rl No. 1-1640 5 CON(Ac)CO 2-(HOCH 2 )Ph 1-1641 5 CON(Ac)CO 4-(HOCH 2 )Ph 1-1642 5 CON(Ac)CO Me 1-1643 5 CON(Ac)CO Et 1-1644 5 CON(Ac)CO Pr 1-1645 5 CON(Ac)CO iPr 1-1646 5 CON(Ac)CO Bu 1-1647 5 CON(Ac)CO HOOCCH 2 1-1648 5 CON(Ac)CO MeOOCCH 2 1-1649 5 CON(Ac)CO MeCH(COOH) 1-1650 5 CON(Ac)CO HOOC-(CH 2 2 1-1651 5 CON(Ac)CO MeCH(COOMe) 1-1652 5 CON(Ac)CO 1-HOOC-iBu 1-1653 5 CON(Ac)CO I-MeOOC-iBu 1-1654 5 CON(Ac)CO 1-HOOC-iPn 1-1655 5 CON(Ac)CO 1-MeOOC-iPn 1-1656 5 CON(Ac)CO 1-HOOC-2-Me-Bu 1-1657 5 CON(Ac)CO 1-MeOOC-2-Me-Bu 1-1658 5 CON(Ac)CO

CH

2

CH

2

SO

3

H

1-1659 5 CON(Ac)CO -Z-1I 1-1660 5 CON(Ac)CO -Z-2 1-1661 7 CON(Ac)CO -Z-3 1-1662 5 CON(Ac)CO -Z-4 1-1663 5 CON(Ac)CO 1-1664 5 CON(Ac)CO -Z-6 1-1665 5 CON(Ac)CO -Z-7 y:\wpdocs\dgt_mss\981I2\981I2cpd L doc 90 Table -1cont.) Cpd. T A B R No. 1-1666 5 CON(Ac)CO -Z-8 1-1667 5 CON(Ac)CO -Z-9 1-1668 5 CON(Ac)CO -Z1 1-1669 5 CON(Ac)CO Z1I 1-1670 5 CON(Ac)CO Z-1 1-1671 5 CON(Ac)CO -3P 1-1672 5 CON(Ac)CO -4-Py 1-1673 5 CONHCO NH H *1-1674 5 CONHCO NH- Ph *1-1675 5 CONHCO NH 2-Me-Ph :1-1676 5 CONHCO NIH 4-Me-Ph 1-1677 5 CONHCO NH 2,4-diMe-Ph **1-1678 5 CONHCO NH 3,4-diMe-Ph 1-1679 5 CONHCO NH 2-(CF 3 )Ph *1-1680 5 CONHCO NH 4-(CF 3 )Ph 1 -1681 5 CONHCO NH 2-MeOPh 1-1682 5 CONHCO NH 4-MeOPh :11683 5 CONHCO NH 2-EtOPh 1-1684 7 CONHCO NH 4-EtOPh 1-1685 7 CONHCO NH 2H~ 1-1686 5 CONHCO NH 4-HOPh 1-1687 5 CONHCO NH 2-(HOOC)Ph 1-1688 5 CONHCO NH- 4-(HOOC)Ph 1-1689 7 CONHCO NH 2-(MeOOC)Ph 1-1690 5 CONHCO NH 4-(MeOOC)Ph 1-1691 5 CONH-CO NH 2-(EtOOC)Ph 1-1692 5 CONHCO NH 4-(EtOOC)Ph y:\wpdocs\dgt~mss\981I2\981I2cpd L doc 91- Table I(cnt.) 000.

0 0 Cpd. k A B Rl No. 1-1693 5 CONHCO NE 2-(tBuOOC)Ph 1-1694 5 CONHCO NH 4-(tBuOOC)Ph 1-1695 5 CONHCO NH 2-Cl-Ph 1-1696 5 CONHCO NH 4-Cl-Ph 1-1697 5 CONHCO NH 2-Br-Ph 1-1698 5 CONH-CO NH 4-Br-Ph 1-1699 5 CONHCO NH 2-I-Ph 1-1700 5 CONHCO NH 4-I-Ph 1-1701 5 CONHCO NH 2-N0 2 -Ph 1-1702 5 CONHCO NH 4-N0 2 -Ph 1-1703 5 CONHCO NH 2-NH 2 -Ph 1-1704 5 CONHCO NH 4-NH 2 -Ph 1-1705 5 CONHCO NH 2-(HO 3 S)Ph 1-1706 5 CONHCO NH 4-(HO 3 S)Ph 1-1707 5 CONHCO NH 2-(NH 2 0 2 S)Ph 1-1708 5 CONHCO NH 4-(NH 2 0 2 S)Ph 1-1709 5 CONHCO NH 2-CN-Ph 1-1710 5 CONHCO NH 4-CN-Ph 1-1711 5 CONHCO NIH 2-(HOCH 2 )Ph 1-1712 5 CONHCO NH 4-(HOCH 2 )Ph 1-1713 5 CONHCO NH Me 1-1714 5 CONHCO NH Et 1-1715 5 CONHCO NH Pr 1-1716 5 CONHCO NH iPr 1-1717 5 CONHCO NH Bu 1-1718 5 CONHCO NH HOOCCH 2 y:\wpdocs\dgt_miss\981I2\981 2cpd I doc 92 Table 1 (cont.) Cpd. k A B R No. 1-1719 5 CONHCO NHl MeOOCCH 2 1-1720 5 CONHCO NHl MeCH(COOH) 1-1721 5 CONilCO NHl HOOC-(CH 2 2 1-1722 5 CONilCO NHl MeCH(COOMe) 1-1723 5 CONHCO NHl 1-HOOC-iBu 1-1724 5 CONHCO NHl I-MeOOC-iBu 1-1725 5 CONHCO NH I1-HOOC-iPn 1-1726 5 CONilCO Nil 1-MeOOC-iPn 1-1727 5 CONHCO Nil 1-HOOC-2-Me-Bu 1-1728 5 CONH-CO NE 1-MeOOC-2-Me-Bu 1-1729 5 CONilCO Nil CH 2

CH

2

SO

3

H

1-1730 5 CONilCO Nil HO 1-1731 5 CONHCO Nil MeO 1-1732 5 CONHCO NH EtO 1-1733 5 CONH-CO NH Pro 1-1734 5 CONHCO NIH iPrO 1-1735 5 CONHCO Nil BuO 1-1736 5 CONIICO NH iBuO 1-1737 5 CONHCO NE sBuO 1-1738 5 CONH-CO NH tBuO 1-1739 5 CONHCO NH HxO 1-1740 5 CONHCO NH PhO 1-1741 5 CONHCO NH BzO 1-1742 5 CONHCO NH Z-1 1-1743 5 CONilCO NH Z-2 1-1744 5 CONilCO NH Z-3 1-1745 5 CONilCO NH Z-4 y:\wpdocs\dgt_mss\9812\9812cpd1 .doc 93 Table I (coW Cpd. k A B R No. 1-1746 5 CONTICO NH 1-1747 7 CONHCO NH Z-6 1-1748 5 CONHCO NH Z-7 1-1749 5 CONHCO NH Z-8 1-1750 5 CONHCO NH Z-9 1-1751 5 CONHCO NH 1-1752 5 CONHCO NH Z-l1I 1-1753 5 CONHCO NH Z-12 *1-1754 5 CONHCO NH 3-Py **.1-1755 5 CONHCO NH 4-Py 1-1756 5 CONHS0 2

-H

1-1757 5 CONHS0 2 -Ph *1-1758 5 CONHS0 2 -2-Me-Ph 1-1759 5 CONHS0 2 -4-Me-Ph 1-1760 5 CONHS0 2 2,4-diMe-Ph 1176 5 ONHO 2 3,4-diMe-Ph 1-1762 5

CONHS

2 2-(CF 3 )Ph *1-1763 5 CONIHS0 2 4-(CF 3 )Ph 1-1764 5 CONE-S0 2 -2-MeOPh 1-1765 5 CONHS0 2 -4-MeOPh 1-1766 5 CONHS0 2 -2-EtOPh 1-1767 5 CONHS0 2 -4-EtOPh 1-1768 5 CONHS0 2 -2-HOPh 1-1769 5 CONHS0 2 -4-HOPh 1-1770 5 CONHS0 2 -2-(HOOC)Ph y:\wpdocs\dgt_mfss\981I2\98 12cpd L doc -94- Table I(cont.) Cpd. k A B R No. 1-1771 5 CONHSO 2 4-(HOOC)Ph 1-1772 5 CONHSO 2 2-(MeOOC)Ph 1-1773 5 CONHS0 2 4-(MeOOC)Ph 1-1774 5 CONHSO 2 2-(EtOOC)Ph 1-1775 7 CONHS0 2 4-(EtOOC)Ph 1-1776 5 CONHS0 2 2-(tBuOOC)Ph 1-1777 7 CONHS0 2 4-(tBuOOC)Ph 1-1778 5 CONHS0 2 2-Cl-Ph 1-1779 5 CONHS02 4-Cl-Ph 1-1780 7 CONHS0 2 2-Br-Ph 1-1781 5 CONHSO2 4-Br-Ph 1-1782 5 CONHS0 2 2-I-Ph 1-1783 5 CONHS02 -4-I-Ph 1-1784 5 CONHSO 2 2-N0 2 -Ph 1-1785 5 CONHSO 2 4-N0 2 -Ph 1-1786 7 CONHS0 2 2-NH 2 -Ph 1-1787 5 CONHS0 2 4-NH 2 -Ph 1-1788 7 CONHS0 2 2-(HO 3 S)Ph 1-1789 5 CONHS0 2 4-(HO 3 S)Ph 1-1790 5 CONHS0 2 2-(NH 2

O

2 S)Ph 1-1791 5 CONHS0 2 4-(NH 2 0 2 S)Ph 1-1792 7 CONHS0 2 2-CN-Ph 1-1793 5 CONHSO 2 4-CN-Ph 1-1794 5 CONHS0 2 2-(HOCH 2 )Ph y:\wpdocs\dgt_mss\9812\9812cpd .doc 95 Table 1 (cont.

do..

0., do 00. 0 0:0.0 Cpd. k A B R No. 1-1795 5 CONHS0 2 -4(HC)P 1-1796 5 CONHS0 2 -Me 1-1797 5 CONHS0 2 -Et 1-1798 5 CONIHS0 2 -Pr 1-1799 5 CONHS0 2 -iPr 1-1800 5 CONHS02 -Bu 1-1801 5 CONHS0 2

HOOCCH

2 1-1802 5 CONH{S0 2 MeOOCCH 2 1-1803 5 CONHS0 2 MeCH(COOH) 1-1804 5 CONHS0 2

HOOC-(CH

2 2 1-1805 5 CONH-S0 2 MeCH(COOMe) 1-1806 5 CONH-S02 1-HOOC-iBu 1-1807 5 CONHS0 2 1-MeOOC-iBu 1-1808 5 CONH-S0 2 1-HOOC-iPn 1-1809 5 CONHS0 2 1-MeOOC-iPn 1-1810 5 CONH4S0 2 1-HOOC-2-Me-Bu 1-1811 5 CONH-S0 2 1-MeOOC-2-Me-Bu 1-1812 5 CONH-S0 2

CH

2

CH

2

SO

3

H

1-1813 5 CONH-S0 2

-OH

1-1814 5 CONHIS0 2 -MeO 1-1815 5 CONHS0 2 -EtO 1-1816 7 CONH-S0 2 -Pro 1-1817 5 CONHIS0 2 -iPrO 1- 1818 5 CONHS0 2 IBuO y:\wpdocs\dgtmffss\981I2\981I2cpd I doc 96 Table I (coot.

Cpd. k A B Rl No. 1-1819 5 CONH-S0 2 iu 1-1820 5 CONHS0 2 -sBuO 1-1821 5 CONHS02 -tBuO 1-1822 5 CONHIS0 2 -HxO 1-1823 5 CONHIS02 -PhO 1-1824 5 CONHS02 -BzO 1-1825 5 CONH-S0 2 -Z-1I 1-1826 5 CONH-S0 2 -Z-2 1-1827 5 CONH-S02 -Z-3 1-1828 5 CONHS0 2 -Z-4 1-1829 5 CONHS02 1-1830 5 CONH-S0 2 -Z-6 1-1831 5 CONH-S02 -Z-7 1-1832 5 CONH-S02 -Z-8 1-1833 5 CONHS02 -Z-9 1-1834 5 CONH1S0 2 1-1835 5 CONHS0 2 -Z-1 1 1-1836 5 CONH-S02 Z-12 1-1837 5 CONH-S02 3-Py 1-1838 5 CONHS02 4-Py 1-1839 5 CONHS02 NE

H

1-1840 5 CONH-S0 2 NH- Ph 1-1841 5 CONHS0 2 NH 2-Me-Ph 1-1842 5 CONH-S0 2 NH 4-Me-Ph y:\wpdocs\dgtmss\981I2\981I2cpd I .doc 97 TableI (coaQ Cpd. k A B R 1-1843 5 CONHS0 2 NH 2,4-diMe-Ph 1-1844 5 CONHS0 2 NH 3,4-diMe-Ph 1-1845 5 CONHS02 NH 2-(CF 3 )Ph 1-1846 7 CONHS02 NH 4-(CF 3 )Ph 1-1847 5 CONHS02 NH 2-MeOPh 1-1848 5 CONHS02 NH 4-MeOPh 1-1849 5 CONHS0 2 NH 2-EtOPh *1-1850 7 CONH-S0 2 NH 4-EtOPh *..1-1851 5 CONHS0 2 NH 2-HOPh :1-1852 5 CONH-S0 2 NH 4-HOPh 1-1853 5 CONHS0 2 NH 2-(HOOC)Ph 1-1854 5 CONH-S0 2 NH 4-(HOOC)Ph 1-1855 5 CONHS0 2 NH 2-(MeOOC)Ph ooeo1-1856 5 CONH-S0 2 NH 4-(MeOOC)Ph 0:6:1-1857 7 CONH1-1S0 NH 2-(EtOOC)Ph *:o1-1858 5 CONHS0 2 NH 4-(EtOOC)Ph *1-1859 5 CONHSO 2 NH 2-(tBuOOC)Ph 1-1860 5 CONHS0 2 NH 4-(tBuOOC)Ph 1-1861 5 CONHS0 2 NH 2-Cl-Ph 1-1862 5 CONHS02 NH 4-Cl-Ph 1-1863 5 CONHS0 2 NH 2-Br-Ph 1-1864 5 CONHS0 2 NH 4-Br-Ph 1-1865 7 CONHS02 NH 2-I-Ph 1-1866 5 CONHS0 2 NH 4-I-Ph y.\wpdocs\dgt_mfss\9812\9812cpdI .doc 98 TableiUcnt.

Cpd. k A B Rl No. 1-1867 5 CONHS0 2 NH 2-N0 2 -Ph 1-1868 -5 CONHS0 2 NH 4-N0 2 -Ph 1-1869 5 CONHS0 2 NH- 2-NI{ 2 -Ph 1-1870 5 CONHS0 2 NH- 4-NH 2 -Ph 1-1871 5 CONHS0 2 NH 2-(HO 3 S)Ph 1-1872 5 CONHS0 2 NH 4-(HO 3 S)Ph 1-1873 5 CONHS0 2 NH 2-(NH 2

O

2 S)Ph C..1-1874 5 CONH-S02, NH 4-(NH 2 O2-S)Ph :1-1875 5 CONH-S0 2 NH 2-CN-Ph :1-1876 5 CONH4S0 2 NH 4-CNPh 1-1877 5 CONH-S0 2 NH 2-(HOCH 2 )Ph 1-1878 5 CONHS0 2 NH 4-(HOCH 2 )Ph 1-1879 5 CONHS0 2 NH Me C..1-1880 5 CONH-S02, NIH Et 1-1881 5 CONHS02 NH Pr 1-1882 5 CONH-S0 2 NH iPr 1-1883 5 CONES0 2 NH Bu 1-1884 5 CONHSO', NH HOOCCH2- 1-1885 5 CONH-S0 2 N-H MeOOCCH2- 1-1886 5 CONHS0 2 NH MeCH(COOH) 1-1887 5 CONH-S0 2 NH HOOC-(CH2)2- 1-1888 5 CONHS0 2 NH MeCH(COOMe) 1-1889 5 CONHS0 2 NH 1-HOOC-iBu 1-1890 5 CONHS02 NH I-MeOOC-iBu y:\wpdocs\dgt_mss\981I2\981I2cpd L doc 99 Table I(cnt.) 0

S

*000 0* S.

S.

0 0 00 50 5 0000

S.

S

*559 *060 *000

*SS*

S

0SS*

S

Cpd. k A B R No. 1-1891 5 CONH{S0 2 NHl 1-HOOC-iPn 1-1892 5 CONHS0 2 NH 1-MeOOC-iPn 1-1893 5 CONH{S0 2 NHl I-HOOC-2-Me-Bu 1-1894 5 CONHS0 2 NHl 1-MeOOC-2-Me-Bu 1-1895 5 CONHIS0 2 NH CH 2

CH

2

SO

3

H

1-1896 5 CONHS0 2 NH OH 1-1897 5 CONHS0 2 NH MeG 1-1898 5 CONHJS0 2 NH EtO 1-1899 5 CONHS0 2 NH Pro 1-1900 5 CONHS0 2 NH iPro 1-1901 5 CONHS0 2 NH BuG 1-1902 5 CONHS0 2 NH iBuG 1-1903 5 CONHS0 2 NH sBuO 1-1904 5 CONHS0 2 NH tBuO 1-1905 5 CGNHSO, NH HxO 1-1906 5 CONHS0 2 NH PhO 1-1907 5 CONHS0 2 NH BzG 1-1908 5 CONHS0 2 NH Z-1 1-1909 5 CONHS0 2 NH Z-2 1-1910 5 CONHS0 2 NH Z-3 1-1911 5 CONHS0 2 NH Z-4 1-1912 5 CONHS0 2 NH 1-1913 5 CONHIS0 2 NH Z-6 1- 1914 5 CONHS0 2 NH Z-7 y:\wpdocs\dgt_jms\9812\9812cpd1 .doc 100 Table (cnt.) 000.

0 0 000.

Cpd. k A B R 1-1915 5 CONHS0 2 NiH Z-8 1-1916 5 CONHS0 2 NH Z-9 1-1917 5 CONHS0 2 NH 1-1918 5 CONHS0 2 NH- Z-1 1 1-1919 5 CONHS0 2 NH Z- 12 1-1920 5 CONHS0 2 NHl 3-Py 1-1921 5 CONHS0 2 NH 4-Py 1-1922 5 NIICO -H 1-1923 5 NH-CO -Ph 1-1924 5 NIICO 2-Me-Ph 1-1925 5 NI-CO 4-Me-Ph 1-1926 5 NI-CO 2,4-diMe-Ph 1-1927 5 Ni-CO 3,4-diMe-Ph 1-1928 5 Ni-CO 2-(CF 3 )Ph 1-1929 5 NH-CO 4-(CF 3 )Ph 1-1930 5 NHCO 2-MeOPh 1-1931 5 NHCO 4-MeOPh 1-1932 5 NH-CO -2-EtOPh 1-1933 5 NH-CO -4-EtOPh 1-1934 5 NI-CO -2-HOPh 1-1935 5 NHCO -4-HOPh 1-1936 5 NHCO 2-(HOOC)Ph 1-1937 5 NHCO 4-(HOOC)Ph 1-1938 5 NH-CO 2-(MeOOC)Ph 1-1939 5 NHCO 4-(MeOOC)Ph 1-1940 5 NHCO I 2-(EtOOC)Ph y:\wpdocs\dgt_mss\981I2\981I cpd L doc 101 Table 1 (cont.

Cpd. k A B R No. 1-1941 5 NH-CO 4-(EtOOC)Ph 1-1942 5 NHCO 2-(tBuOOC)Ph 1-1943 5 NHCO 4-(tBuOOC)Ph 1-1944 5 NHCO -2-Cl-Ph 1-1945 5 Ni-CO -4-Cl-Ph 1-1946 5 NI-CO -2-Br-Ph 1-1947 5 NHCO -4-Br-Ph 1-1948 5 NHCO -2-I-Ph 1-1949 5 NHCO -4-I-Ph 1-1950 5 Ni-CO 2-N0 2 -Ph 1-1951 5 NHCO 4-N0 2 -Ph 1-1952 5 NI-CO 2-NH 2 -Ph 1-1953 5 Ni-CO 4-N11 2 -Ph 1-1954 5 NHCO 2-(HO 3 S)Ph 1-1955 5 NHCO 4-(HO 3 S)Ph 1-1956 5 NHCO 2-(NH 2 O2'S)Ph 1-1957 5 NHCO 4-(NH 2

O

2 S)Ph 1-1958 5 NHCO -2-CN-Ph 1-1959 5 NHCO -4-CN-Ph 1-1960 5 NHCO 2-(HOCH 2 )Ph 1-1961 5 NI-CO 4-(HOCH 2 )Ph 1-1962 5 NI-CO -Me 1-1963 5 Ni-CO -Et 1-1964 5 NIICO -Pr 1-1965 5 NH-CO -iPr 1-1966 5 NHCO -Bu y:\wpdocs\dgt_mss\981I2\981I cpd I .doc 102 TableI (cnt.) Cpd. k A B

R

No. 1-1967 5 NHCO -HOOCCH 2 1-1968 5 N}{CO -MeOOCCH 2 1-1969 5 NHCO -MeCH(COOH) 1-1970 5 NHCO -HOOC-(CH 2 2 1-1971 5 NITCO -MeCH(COOMe) 1-1972 5 NHCO 1-HOOC-iBu 1-1973 5 NHCO -1 -HOOC-iPn :1-1974 5 Ni-CO 1-HOOC-2-Me-Bu 1-1975 5 NHCO

CH

2

CH

2

SO

3

H

*1-1976 5 NHCO MeO 1-1977 5 NHCO EtO *1-1978 5 NHCO -Pro 1-1979 57HO 1-1980 5 NHCO

Z-

1-1981 5 NI-CO

Z-

1-1982 5 N-HCO

Z-

1-1983 5 HO 1-1984 5 NI-CO -Z-6 1-1985 5 NE-CO -Z-7 1-1986 5 Ni-CO -Z-8 1-1987 7 NHCO -Z-9 1-1988 5 NH-CO Z- 1-1989 5 NI-CO 11 1-1990 7 NH-CO Z1 1-1991 5 NI-CO 3P 1-1992 5 Ni-CO 4P 1-1993 5 Ni-CO

N

y:\wpdocs\dgt-fmss\98 12\981I2cpd L doc 103 Table 1 (cont.)~ Cpd. k A B R No. 1-1994 5 NHCO NH Ph 1-1995 -5 NHCO NH 2-Me-Ph 1-1996 5 NHCO NH- 4-Me-Ph 1-1997 5 NHCO NH 2,4-diMe-Ph 1-1998 5 NHCO NH 3,4-diMe-Ph 1-1999 5 NHCO NH 2-(CF 3 )Ph 1-2000 7 NHCO NH 4-(CF 3 )Ph 1-2001 5 NIICO NH 2-MeOPh 1-2002 5 NHCO NH 4-MeOPh 1-2003 5 NI-CO NH 2-EtOPh 1-2004 5 NH-CO NH 4-EtOPh 1-2005 5 NHCO NH 2-HOPh 1-2006 5 NI-CO NH 4-HOPh 1-2007 7 NHCO NH 2-(HOOC)Ph 1-2008 7 NHCO NH 4-(HOOC)Ph 1-2009 7 NHCO NIH 2-(MeOOC)Ph 1-2010 5 NH-CO NIH 4-(MeOOC)Ph 1-2011 5 NHCO NH 2-(EtOOC)Ph 1-2012 5 NHCO NI-I 4-(EtOOC)Ph 1-2013 5 NHCO NH 2-(tBuOOC)Ph 1-2014 5 NH-CO NH 4-(tBuOOC)Ph 1-2015 5 NH-CO NIH 2-Cl-Ph 1-2016 5 NHCO NH 4-Cl-Ph 1-2017 5 NI-CO NH 2-Br-Ph 1-2018 5 NHCO NH 4-Br-Ph 1-2019 5 NHCO NH 2-I-Ph 1-2020 5 NHCO NH 4-I-Ph y:\wpdocs\dgt_mss\981I2\981 2cpd I .doc -104- Table I (cont.) Cpd. k A B

R'

No. 1-2021 5 NIICO NH 2-N02-Ph 1-2022 5 Ni-CO NH- 4-N0 2 -Ph 1-2023 5 NI-CO NHl 2-Nil 2 -Ph 1-2024 5 NIICO Nil 4-NH 2 -Ph 1-2025 5 NHCO NH 2-(HO 3 S)Ph 1-2026 5 NHCO NH 4-(HO 3 S)Ph 1-2027 5 Ni-CO NH 2-(NH 2

O

2 S)Ph 1-2028 5 NHCO NHl 4-(NH 2

O

2 S)Ph 1-2029 5 NI-CO NH 2-CN-Ph 1-2030 5 NHCO NH 4-CN-Ph 1-2031 5 Ni-CO NH 2-(HOCH 2 )Ph 1-2032 5 N-ICO NH 4-(HOCH 2 )Ph 1-2033 5 NHCO NH Me 1-2034 5 NH-CO Nil Et 1-2035 5 Ni-CO NI- Pr 1-2036 5 NH-CO NI- iPr 1-2037 7 NI-CO NH- Bu 1-2038 5 Nli-CO NH HOOCCH 2 1-2039 5 Ni-CO NE MeOOCCH2- 1-2040 7 Ni-CO NH MeCH(COOH) 1-2041 7 NH-CO NH HOOC-(CH 2 )2- 1-2042 5 NHCO NH MeCH(COOMe) 1-2043 5 NHCO NH 1-HOOC-iBu 1-2044 7 NIICO NH 1-MeOOC-iBu 1-2045 5 NHCO NH 1-HOOC-iPn 1-2046 5 NilCO NH 1-MeOOC-iPn y:\wpdocs\dgt_mrss\9812\9812cpd1 Idoc -105- Table I (cont.) Cpd. k A B R No.

1-2047 5 NiCO NHl 1-HOOC-2-Me-Bu 1-2048 5 NHCO NH 1-MeOOC-2-Me-Bu 1-2049 5 N-CO NH CH 2

CH

2

SO

3

H

1-2050 5 NICO NH

OH

1-2051 5 NHCO NH MeO 1-2052 5 NHCO NH EtO 1-2053 5 NHCO NH PrO 1-2054 5 NHCO NH iPrO 1-2055 5 NICO Ni BuG 1-2056 5 NHCO NH iBuO 1-2057 5 NICO Ni sBuO 1-2058 5 NHCO NH tBuO 1-2059 5 NICO Ni HxO 1-2060 5 NICO NH PhO 1-2061 5 NiCO NH BzO 1-2062 5 NHCO NH Z-1 1-2063 5 NHCO NH Z-2 1-2064 5 NICO NE Z-3 1-2065 5 N-CO NH Z-4 1-2066 5 NHCO NH 1-2067 7 NiCO NH Z-6 1-2068 5 NHCO NH Z-7 1-2069 5 N-CO NH Z-8 1-2070 5 NICO Ni Z-9 1-2071 7 NHCO NH 1-2072 5 NHCO NH Z-11 1-2073 5 NHCO NH Z-12 y:\wpdocs\dg_mss\9812\ 98 I2cpd .doc 106 Table 1 (conU.

.00.

Cpd. k A B R No. 1-2074 5 Ni-CO NH 3-Py 1-2075 5 NHCO NH 4-Py 1-2076 5 NECO NMe Ph 1-2077 5 Ni-CO NMe 2-Me-Ph 1-2078 5 NHCO NMe 4-Me-Ph 1-2079 5 NI-CO NMe 2,4-diMe-Ph 1-2080 5 NHCO NMe 3,4-diMe-Ph 1-2081 5 NHCO NMe 2-(CF 3 )Ph 1-2082 5 NHCO NMe 4-(CF 3 )Ph 1-2083 5 NIICO NMe 2-MeOPh 1-2084 5 NH-CO NMe 4-MeOPh 1-2085 5 NIICO NWe 2-EtOPh 1-2086 7 NH-CO NWe 4-EtOPh 1-2087 5 NH-CO NMe 2-HOPh 1-2088 5 NHCO NWe 4-HOPh 1-2089 5 NHCO NWe 2-(HOOC)Ph 1-2090 5 NI-CO W~e 4-(HOOC)Ph 1-2091 5 NJ-CO NWe 2-(MeOOC)Ph 1-2092 7 NHCO NWe 4-(MeOOC)Ph 1-2093 7 NHCO W~e 2-(EtOOC)Ph 1-2094 5 Ni-CO NWe 4-(EtOOC)Ph 1-2095 5 NHCO NMe 2-(tBuOOC)Ph 1-2096 5 Ni-CO NWe 4-(tBuOOC)Ph 1-2097 7 NHCO NMe 2-Cl-Ph 1-2098 5 NHCO NWe 4-Cl-Ph 1-2099 5 ,HCOC NWe 2-Br-Ph 1-2100 5 NHCO NWe 4-Br-Ph y:\wpdocs\dgt_tms\981I2\981I2cpd L doc 107- Table 1 (cont.) a.

a a a Cpd. k A B

R

1-2101 5 NHCO NMe 2-1-Ph 1-2102 7NHCO NMe 4-I-Ph 1-2 103 5 NIICO NMe 2-N0 2 -Ph 1-2104 5 NHCO NWe 4-N0 2 -Ph 1-2 105 5 NHCO NMe 2-NH 2 -Ph 1-2106 5 NH-CO NMe 4-NH 2 -Ph 1-2107 5 NHCO NMe 2-(HO 3 S)Ph 1-2108 5 NHCO NMe 4-(HO 3 S)Ph 1-2 109 5 NHCO NMe 2-(NH 2

O

2 S)Ph 1-2110 7 NHCO NMe 4-(NH 2 O2-S)Ph 1-2111 7 NH-CO NWe 2-CN-Ph 1-2112 7 NE-CO NMe 4-CN-Ph 1-2113 5 NE-CO NMe 2-(HOCH 2 )Ph 1-2114 5 Ni-CO We 4-(HOCH 2 )Ph 1-2115 7 NHCO We Me 1-2116 7 Ni-CO NMe Et 1-2117 5 NE-CO NWe Pr 1-2118 5 NHCO We iPr 1-21 19 5 NE-CO NMe Bu 1-2120 7 Ni-CO We HOOCCH2- 1-2121 5 NHCO We MeOOCCH2- 1-2122 5 Ni-CO We MeCH(COOH) 1-2123 7 NHCO We HOOC-(CH2)2- 1-2124 5 Ni-CO NMe MeCH(COOMe) 1-2125 5 NI-CO We l-HOOC-iBu 1-I-2126 5 Ni-CO NMe 1-MeOOC-iBu y:\wpdocs\dgtmnss\981I2\981I2cpd I doc 108 Table 1 (cont.)

*SSS

S.

S

S

S

Cpd. k A

BR

No. 1-2127 5 NI-CO NMe 1-HOOC-iPn 1-2128 7 NIICO NMe 1-MeOOC-iPn 1-2129 7 NHCO NMe 1-HOOC-2-Me-Bu 1-2130 5 NHCO NMe 1-MeOOC-2-Me-Bu 1-2131 7 NHCO NMe CH 2

CH

2

SO

3

H

1-2132 5 NICO NMe

OH

1-2133 5 NHCO NMe MeO 1-2134 5 NHCO NMe EtO 1-2135 5 NH-CO NMe Pro 1-2136 5 Ni-CO NMe iPrO 1-2137 7 NHCO NMe BuG 1-2138 7 NHCO NMe iBuO 1-2139 7 NH-CO NMe sBuO 1-2140 5 Ni-CO NMe tBuO 1-2141 5 NHCO NMe HxO 1-2142 5 NI-CO NMe PhO 1-2143 7 NHCO W~e BzO 1-2144 7 NHCO NMe Z-1 1-2145 5 NHCO NWe Z-2 1-2146 5 NH-CO W~e Z-3 1-2147 7 NHCO NMe Z-4 1-2148 7 NHCO NMe 1-2149 5 NHCO NMe Z-6 125 5 HONMe Z-7 125 5 HONMe Z-8 N-12 HC e Z-9 125 5 E NMe y:\wpdocs\dgt_mfss\981I2\981I2cpd I .doc 109- Table-1 (cont.) Cpd. k A B

R

1-2154 5 NI-CO NMe Z-1 1 1-2155 5 NHCO NMe Z-12 1-2156 5 NHCO NMe 3-Py 1-2157 5 Ni-CO NMe 4-Py 1-2158 5 NilCO NHNH

H

1-2159 5 NHCO NIINH Me 1-2160 5 NHCO NHNH Et 1-2161 5 NI-CO NHN1Me Me 1-2162 5 NI-CO NHNMe Et 1-2163 5 NHCO N-HNMe Pr 1-2 164 5 NI-CONHNHCO NHl

H

1-2165 5 NHCONHNHCO NHl Ph 1-2166 5 NHCONH-NHCO NHl 2-Me-Ph 1-2167 5 NHCONHN1-CO Nil 4-Me-Ph 1-2168 5 NHCONH-NilCO Nil 2,4-diMe-Ph 1-2169 5 NHCONilNHCO Nil 3,4-diMe-Ph 1-2170 5 NHCONHN-HCO NH- 2-(CF 3 )Ph 1-2171 5 NHCONI-NiCO NH 4-(CF 3 )Ph 1-2172 5 NHCONHNH-CO NH- 2-MeOPh 1-2173 5Y NHCONi-Ni-CO NH- 4-MeOPh 1-2174 5 NilCONH-NH-CO Nil 2-EtOPh 1-2175 5 NH-CONHNICO Nil 4-EtOPh 1-2176 5 NilCONI-NilCO Nil 2-HOPh 1-2177 5 NHCONHNI-CO Nil 4-HOPh 1-2178 5 NilCONI{NHCO NH 2-(HOOC)Ph 1-2179 5 NHCONilNH-CO Nil 4-(HOOC)Ph 1-2 180 7 NHCONilNHCO NHl 2-(MeOOC)Ph y:\wpdocs\dgtmss\981I2\981I2cpd L doc 110- Table 1 (cont.) Cpd. k A B R 1-2181 5 N .HCONHNHCO NH 4-(MeOOC)Ph 1-2182 5 NIICON}{NHCO NH 2-(EtOOC)Ph 1-2183 5 NHCONHNHCO NH 4-(EtOOC)Ph 1-2184 5 NHCONHNECO NIH 2-(tBuOOC)Ph 1-2185 5 N}ICONHNHCO NH 4-(tBuOOC)Ph 1-2 186 5 N1-CONIJNTCO NH 2-Cl-Ph 1-2187 5 Ni-CONI-NHCO NH 4-Cl-Ph *1-2188 5 N1-CON1-NHCO NH 2-Br-Ph :1-2189 5 NHCONRI\HCO NH 4-Br-Ph 1-2190 5 NHCONH-NHCO NH 2-I-Ph 1-2191 5 NHCONHNHCO NH 4IP 1-2192 5 NHCONH-NHCO NH 2-N0 2 -Ph 1-2193 5 N14CON-1NE-CO NEl 4-N0 2 -Ph 1-2194 5 NI-CON1-NHCO NE- 2-Nil 2 -Ph 1-2195 5 NHCON1-NHCO NHl 4-NH 2 -Ph 1-2196 5 NHCON1-NHCO NEl 2-(HO 3 S)Ph *1-2197 5 NH-CONHNHCO N-H 4-(HO 3 S)Ph 1-2198 5 N1-CONH-N1-CO N-H 2-(NiI 2

O

2 S)Ph 1-2 199 7 NI-CON1-NHCO NH- 4-(NH 2

O

2 S)Ph 1-2200 5 NHCONHNHCO NHl 2-CN-Ph 1-2201 5 NHCONHN1-CO NHl 4-CN-Ph 1-2202 5 NHCONilNiCO NHl 2-(HOCH 2 )Ph 1-2203 7 Ni-CONi-IilCO Nil 4-(HOCH 2 )Ph 1-2204 5 NHCON1{NHCO NH Me 1-2205 5 NilCONHNHCO NH Et 1-2206 5 NI-CONHNHCO NH- Pr y:\wpdocs\dgt_mfss\981I2\981I2cpd I .doc -111l- TableI (cont.) *see .00.

*0.

Cpd. k A B R No. 1-2207 5 NHCONHNI-CO NH iPr 1-2208 5 NIHCONHINHCO NH Bu 1-2209 5 NHCONHNHCO NH HOOCCH 2 1-2210 7 NHCONHNHCO N-H MeOOCCH 2 1-22 11 7 NHCONHNHCO NH MeCH(COOH) 1-2212 5 NE-CONHNHCO NH HOOC-(CH 2 2 1-2213 5 NHCONHNHCO NiH MeCH(COOMe) 1-2214 5 NHCONIINHCO NH 1-HOOC-iBu 1-2215 5 NECONHNHCO NH 1-MeOOC-iBu 1-2216 5 NHCONTHNHCO NH I1-HOOC-iPn 1-2217 5 NECONH-NHCO NIH 1-MeOOC-iPn 1-2218 5 NHCONHN1-CO N-H 1-HOOC-2-Me-Bu 1-2219 5 N1-CONHMICO Nil 1-MeOOC-2-Me-Bu 1-2220 5 NHCONHNHCO NE- CH 2

CH

2

SO

3

H

1-2221 7 NIHCONHNH-CO NiH OH 1-2222 7 NHCONHNECO Nil MeO 1-2223 7 NHCONHNIICO Nil EtO 1-2224 5 NI-CONHTNHCO Nil PrO 1-2225 5 NHCON{N-CO Nil iPrO 1-2226 5 N1-CONHNHCO NH BuO 1-2227 5 NHCONHNHCO NHl iBuG 1-2228 7 N1-CONHNHCO NHl sBuO 1-2229 5 NilCON1-NHCO Nil tBuO 1-2230 5 NI-CONHNHCO Nil HxO 1-2231 7 NHCONHNHCO NIH PhO 1-2232 7 NHCONI7NHCO Nil BzO 1-2233 5 NHCONHNHCO NHl Z-1 y:\wpdocs\dgt-ms\981I2\981I2cpd I Ado 112- Table I (cont.) 0* Cpd. k A BR 1-2234 5 NIICONHNHCO NiH Z-2 1-2235 5 NHCONIINHCO NH Z-3 1-2236 5 NI{CONH-NHCO NEl Z-4 1-2237 7 NilCONlN-HCO Ni 1-2238 5 NHCONHNHCO NHl Z-6 1-2239 5 NHCONilNiCO Nil Z-7 1-2240 5 NH-CONI{NBCO Nil Z-8 1-2241 5 NHCONHNHCO NHl Z-9 1-2242 5 N1-CONilNHCO NEl 1-2243 5 NHCONlNI-HCO NE Z-1 1 1-2244 5 NilCONHNi-CO NHl Z-12 1-2245 5 NH-CONilNHCO NH 3-Py 1-2246 5 NH-CONI{NHCO NH 4-Py 1-2247 5 NIHCONH-CO -H 1-2248 5 NH-CONI-CO -Ph 1-2249 7 NHCONHCO 2-Me-Ph 1-2250 5 Ni-COM-ICO 4-Me-Ph 1-2251 5 NHCONI-CO 2,4-diMe-Ph 1-2252 5 NHCONHCO 3,4-diMe-Ph 1-2253 7 N HCONI-ICO -2-(CF 3 )Ph 1-2254 7 NB-CONHCO -4-(CF 3 )Ph 1-2255 5 NHCONH-CO -2-MeOPh 1-2256 5 NilCONH-CO 4-MeOPh 1-2257 5 NHCONH-CO 2-EtOPh 1-2258 5 NiCONilCO 4-EtOPh 1-2259 5 NHCONilCO 2-HOPh 1-2260 T5 NilCONilCO 4-HOPh y:\wpdocs\.dgt_mfss\981I2\98 I2cpd I doc 113 Table 1 (cont.) .t.

Cpd. k A B R No. 1-2261 5 NH-CONHCO 2-(HOOC)Ph 1-2262 5 NH-CONI-CO 4-(HOOC)Ph 1-2263 5 NHCONHCO 2-(MeOOC)Ph 1-2264 5 NHCONH-CO 4-(MeOOC)Ph 1-2265 5 NH-CONHCO 2-(EtOOC)Ph 1-2266 5 NHCONHCO 4-(EtOOC)Ph 1-2267 5 NH-CONHCO 2-(tBuOOC)Ph 1-2268 5 NHCONHCO 4-(tBuOOC)Ph 1-2269 5 NH-CONHCO -2-Cl-Ph 1-2270 5 N HCONHCO -4-Cl-Ph 1-2271 5 NH-CONH-CO -2-Br-Ph 1-2272 5 NH-CONi-CO -4-Br-Ph 1-2273 5 NHCONH-CO -2-I-Ph 1-2274 5 N HCON HCO -4-I-Ph 1-2275 5 NHCONHCO 2-N0 2 -Ph 1-2276 5 NH-CONHCO 4-N0 2 -Ph 1-2277 5 NH-CONH-CO -2-NH 2 -Ph 1-2278 7 NHCONHCO 4-NH 2 -Ph 1-2279 5 NH-CONI-ICO 2-(HO 3 S)Ph 1-2280 5 NH-CONHCO -4-(HO 3 S)Ph 1-2281 5 Ni-CONH-CO 2-(NH 2

O

2 S)Ph 1-2282 7 NHCONH-CO 4-(NIH 2

O

2 S)Ph 1-2283 5 NH-CONI-CO -2-CN-Ph 1-2284 5 NHCONHiCO -4-CN-Ph 1-2285 5 NHCONHCO 2-(HOCH 2 )Ph 1-2286 15 NHCONHCO I I 4-(HOCH 2 )Ph y:\wpdocs\dgt_mss\98 12\981I2cpd I .doc -114- Table (cnt.)

S

9 *9 S S

S.

S S St*

S

*9SS Cpd. k A B R No. 1-2287 5 NHCONHCO Me 1-2288 7 NHCONHCO Et 1-2289 7 NHCONHCO Pr 1-2290 5 NH-CONHCO iPr 1-2291 5 NH-CONHCO Bu 1-2292 5 NI-CONHCO HOOCCH 2 1-2293 5 NHCONHCO MeOOCCH2- 1-2294 5 NH-CONH-CO MeCH(COOH) 1-2295 5 NH-CON}{CO HOOC-(CH 2 2 1-2296 5 NHCONH-CO MeCH(COOMe) 1-2297 5 NHCONHCO I1-HOOC-iBu 1-2298 5 NHCONHCO I -MeOOC-iBu 1-2299 7 NHCONH-CO I -HOOC-iPn 1-2300 7 NHCONH-CO I-MeOOC-iPn 1-2301 5 NHCONHCO 1-HOOC-2-Me-Bu 1-2302 5 N1ICONHCO 1-MeOOC-2-Me-Bu 1-2303 5 NHCONTCO CH 2

CH

2

SO

3

H

1-2304 5 NHTCONHCO -MeG 1-2305 5 NHCONI-CO -EtO 1-2306 5 NHCONH-CO -Pro 1-2307 7 N}ICONHCO -iprO 1-2308 5 NH-CONI4CO -BuG 1-2309 5 NHCGNEHCG iBuO 1-2310 5 NHCONHCO -sBuG 1-2311 5 NHCONHCO -tBuG 1-2312 5 NH-COM-ICO HxO y:\wpdocs\dgt_mss\981I2\981I2cpd I doc 115 Table I (cont.)

C

SC..

0* SC C

CC

S S .me.

C.

S

S

C

0 Cpd. k A B

R

No.

1-2313 5 NHCONHCO PhO 1-2314 5 NHCONICO BzO 1-2315 5 NHCONHCO Z-1 1-2316 5 NHCONHCO Z-2 1-2317 5 N-CONHCO Z-3 1-2318 5 NHCONHCO Z-4 1-2319 5 NHCONHCO 1-2320 5 NICONiCO Z-6 1-2321 5 NI-CONHCO Z-7 1-2322 5 NHCON-CO Z-8 1-2323 5 NHCONHCO Z-9 1-2324 5 N-CONHCO 1-2325 5 NHCONHCO Z-11 1-2326 5 NHCON-CO Z-12 1-2327 7 N-CONHCO 3-Py 1-2328 5 NECONHCO 4-Py 1-2329 5 NHCONHS020

H

1-2330 5 NHCONHS0 2 Ph 1-2331 5 NHCONHSO 2 2-Me-Ph 1-2332 5 N1CONHS02 4-Me-Ph 1-2333 5 N-CONHSO 2 2,4-diMe-Ph 1-2334 5 NHCONES0 2 3,4-diMe-Ph 1-2335 7 NHCONHS02 2-(CF3)Ph 1-2336 5 NHCONHSO2 4-(CF 3 )Ph 1-2337 5 NHCONHSO 2 2-MeOPh 1-2338 5 NHCONHS02 4-MeOPh 1-2339 5 NHCONHS0 2 2-EtOPh y:\wpdocs\dgt_mss\98 I2\9812cpd I.doc -116- Table I (ont.) Cpd. k A B R No. 1-2340 5 NHCONHS02 4-EtOPh 1-2341 5 NHCONHS0 2 2-HOPh 1-2342 5 NHCONHS02 4-HOPh 1-2343 5 NHCONHS0 2 2-(HOOC)Ph 1-2344 5 NHCONHS0 2 4-(HOOC)Ph 1-2345 5 NHCONHSO2 2-(MeOOC)Ph 1-2346 5 NHCONHS 2 4-(MeOOC)Ph 1-2347 5 NHCONHS0 2 2-(EtOOC)Ph 1-2348 5 NHCONHS02 4-(EtOOC)Ph 1-2349 5 NHCONHSO 2 2-(tBuOOC)Ph 1-2350 5 NHCONHS0 2 4-(tBuOOC)Ph 1-2351 5 N-CONHSO 2 2-Cl-Ph 1-2352 5 NHCON-S0 2 4-Cl-Ph 1-2353 5 NHCONHSO 2 2-Br-Ph 1-2354 5 NICON-S0 2 4-Br-Ph 1-2355 5 NHCONS0 2 2-I-Ph 1-2356 5 NHCON-HSS0 2 4-I-Ph 1-2357 5 NJ-CON-HSO2 2-N0 2 -Ph 1-2358 5 N-CON1-S0 2 4-N0 2 -Ph 1-2359 5 N-CONHS0 2 2-NH 2 -Ph 1-2360 5 NHCONHSO 2 -4-NH 2 -Ph 1-2361 5 NHCONHS0 2 2-(HO 3 S)Ph 1-2362 5 NHCONHS0 2 4-(HO 3 S)Ph 1-2363 5 NHCONHS0 2 2-(NH 2

O

2 S)Ph y:\wpdocs\dgt_ss\98 12\9812cpd I .doc -117- Table L(cont.) Cpd. k A B R No. 1-2364 5 NHCONHS0 2 4-(NH 2 2 S)Ph 1-2365 7 NHCONHSO 2 2-CN-Ph 1-2366 5 NHCONHS0 2 4-CN-Ph 1-2367 5 NHCONHSO 2 2-(HOCH 2 )Ph 1-2368 5 NHCONHS0 2 4-(HOCH 2 )Ph 1-2369 5 NHCONHSO 2 Me 1-2370 5 NHCONHS0 2 Et 1-2371 5 NHCONHSO2 Pr 1-2372 5 NHCONHSO 2 iPr 1-2373 5 NHCONHSO 2 Bu 1-2374 7 NHCONHS0 2

HOOCCH

2 1-2375 7 NHCONHS02 MeOOCCH 2 1-2376 5 NHCONHS02 MeCH(COOH) 1-2377 5 NHCONHS0 2

HOOC-(CH

2 2 1-2378 5 NHCONHS0 2 MeCH(COOMe) 1-2379 5 NHCONHS0 2 1-HOOC-iBu 1-2380 5 NHCONHS0 2 1-MeOOC-iBu 1-2381 5 NHCONHSO 2 1-HOOC-iPn 1-2382 7 NHCONHSO 2 1-MeOOC-iPn 1-2383 5 NHCONHSO 2 1-HOOC-2-Me-Bu 1-2384 5 NHCONHS0 2 1-MeOOC-2-Me-Bu 1-2385 5 NHCONHSO 2

CH

2

CH

2 SO3H 1-2386 5 NHCONHS0 2

OH

1-2387 5 NHCONES0 2 MeO y:\wpdocs\dgt_mss\98 I2\98 I Zcpd I .doc 118- Cpd. T A B R No. 1-2388 5 NHCONHS0 2 t 1-2389 5 NHCONHS0 2 -Pro 1-2390 5 NH-CONHS0 2 PrO 1-239 1 5 NH-CONH-S0 2 -BuG 1-2392 5 NHCONHS02 -iBuG 1-2393 5 NHCONHS02 -sBuO 1-2394 5 NHCONHS0 2 -tBuO .1-2395 5 NHCONHS0 2 -HxO 1-2396 5 NHCONH1S02 -PhO *1-2397 5 NH{CONHIS0 2 -BzO 1-2398 5 NH-CONH-S02 -Z-1 1-2399 5 NHCONH-S0 2 -Z-2 1-2400 5 NHCONHS02 -Z-3 1-2401 5 NH-CON1-S0 2 -Z-4 *1-2402 5 NHCONHS0 2 1-2403 5 NHCONH-S0 2 -Z-6 1-2404 5 NHCONHS0 2 -Z-7 1-2405 5 NB-CONHSO 2 -Z-8 1-2406 5 N}ICONESO 2 Z-9 1-2407 5 NHCONH-SO-, 1-2408 5 NHCONHS0 2 -Z-1 1 1-2409 5 NHCONH-S0 2 -Z-12 1-2410 5 NHCONHSO 2 -3-Py 1-2411 5 NECONH-S0 2 4-Py y.\wpdocs\dgt_ms\9812\9812cpdI .doc -119- Cpd. k A B

R

No. 1-2412 5 NHCONHS0 2 NiE

H

1-2413 5 NHCONHS02 NH Me 1-2414 5 NHCONH-S02 NH Et 1-2415 5 NHCONHIS02 NH Pr 1-2416 5 NHCONHS02 NiE iPr 1-2417 5 NHlCONH-S02 NEl Bu 1-2418 5 NHCONilS0 2 NMe Me 1-2419 5 NHCONilS0 2 NMe Et 1-2420 5 NH-CONHS02 NMe Pr 1-2421 5 NHlCONilS02 NMe iPr 1-2422 5 NHCONHlS0 2 NMe Bu 1-2423 5 NH-

H

1-2424 5 NH Me 1-2425 5 NH- Et 1-2426 5 NH- Pr 1-2427 5 NH iPr 1-2428 5 NH Bu 1-2429 5 CO Pyr 1-2430 5 CO Pipri 1-2431 5 CO Pipra 1-2432 5 CO Mor 1-2433 5 CO Thmor 1-2434 5 CO NHPyr 1-2435 5 CO NilPipri 1-2436 5 CO NilPipra 1-2437 5 CO NilMor y:\wpdocs\.dgtmss\981I2\981I2cpd I doc -120- Table I (coWt Cpd. k A BR No.

1-2438 5 CO NHThmor 1-2439 5 NIICO Pyr 1-2440 5 NHCO Pipri 1-244 1 5 NI{CO Pipra 1-2442 5 NHCO Mor 1-2443 5 NHCO Thmor 1-2444 5 Ni-CO NHPyr 1-2445 5 NH-CO NHPipri 1-2446 5 NHCO NHPipra 1-2447 5 NH-CO NHMor 1-2448 5 NHCO NHThmor 1-2449 5 CONHCO Pyr 1-2450 5 CONI-CO Pipri 1-2451 5 CONHCO Pipra 1-2452 5 CONHCO Mor 1-2453 5 CONH-CO Thmor 1-2454 5 CONHCO NHPyr 1-2455 7 CONI-CO NilPipri 1-2456 5 CONH-CO NHPipra 1-2457 5 CONH-CO NH-Mor 1-2458 5 CONH-CO N}{Thmor 1-2459 5 CONHS0 2 Pyr 1-2460 5 CONH-S0 2 Pipri 1-2461 5 CONH-S0 2 Pipra 1-2462 5 CONH-S0 2 Mor 1-2463 5 CONHS0 2 Thmor y:\wpdocs\dgtmss\981I2\981I2cpd I doc 121 Table I (cont.

a.

a Cpd. k A BR No.

1-2464 5 CONH-S0 2 NI-Pyr 1-2465 5 CONHIS0 2 NHpi 1-2466 5 CONH-S0 2 NHPipra 1-2467 5 CONHS0 2 NH-Mor 1-2468 5 CONH{S0 2 NHThmor 1-2469 5 NHS0 2 NH Z-4 1-2470 5 NHS0 2 -Me 1-2471 5 NHS0 2 -Et 1-2472 5 NHS0 2 -Pr 1-2473 5 NHS0 2

-CH

2 C1 1-2474 5 NHS0 2 -Ph 1-2475 5 NH-SO-) 4-Me-Ph 1-2476 5 CO NMe Ph 1-2477 5 CO NMe 2-Me-Ph 1-2478 5 CO NMe 4-Me-Ph 1-2479 5 CO NMe 2,4-diMe-Ph 1-2480 5 CO NMe 3,4-diMe-Ph 1-2481 5 CO NMe 2-(CF 3 )Ph 1-2482 5 CO NMe 4-(CF 3 )Ph 1-2483 5 CO NMe 2-MeOPh 1-2484 7 CO NMe 4-MeOPh 1-2485 5 CO NMe 2-EtOPh 1-2486 5 CO NMe 4-EtOPh 1-2487 5 CO We 2-HOPh 1-2488 7 CO NMe 4-HOPh 1-2489 5CO NMe 2-(HOOC)Ph y:\wpdocs\dgt-mss\9812\9812cpdI .doc 122 Table I (conti Cpd. k A B R No. 1-2490 5 CO NMe 4-(HOOC)Ph 1-2491 5 CO NMe 2-(MeOOC)Ph 1-2492 5 CO NMe 4-(MeOOC)Ph 1-2493 5 CO NMe 2-(EtOOC)Ph 1-2494 5 CO NMe 4-(EtOOC)Ph 1-2495 5 CO NMe 2-(tBuOOC)Ph 1- 2496 5 CO NMe 4-(tBuOOC)Ph 1-2497 5 CO NMe 2-Cl-Ph 1-2498 5 CO NMe 4-Cl-Ph 1-2499 5 CO NMe 2-Br-Ph 1-2500 5 CO NMe 4-Br-Ph 1-2501 5 CO NMe 2-I-Ph 1-2502 5 CO W~e 4-I-Ph 1-2503 5 CO NMe 2-N0 2 -Ph 1-2504 5 CO NMe 4-N0 2 -Ph 1-2505 5 CO NMe 2-NH 2 -Ph 1-2506 5 CO NMe 4-NH- 2 -Ph 1-2507 5 CO NMe 2-(HO 3 S)Ph 1-2508 5 CO W~e 4-(HO 3 S)Ph 1-2509 5 CO NMe 2-(NH 2

O

2 S)Ph 1-2510 5 CO NMe 4-(NH 2 0 2 S)Ph 1-2511 5 CO NMe 2-CN-Ph 1-2512 5 CO NMe 4-CN-Ph 1-2513 5 CO NMe 2-(HOCH 2 )Ph 1-25 14 5 CO NMe 4-(HOCH 2 )Ph 1-2515 5 CO NMe Me y:\wpdocs\dgtmss\981I2\981I2cpd L doc 123 S S Cpd. k A B

R

No. 1-2516 5 Co W~e Et 1-2517 5 Co NMe Pr 1-2518 5 Co NMe iPr 1-2519 5 CO NMe Bu 1-2520 5 CO We HOOCCH 2 1-2521 5 Co We HOOC-(CH 2 2 1-2522 5 Co We MeCH(COOH) 1-2523 7 Co NWe HOOC-(CH 2 )3- 1-2524 5 Co We MeCH(COOMe) 1-2525 5 CO We 1-HOOC-iBu 1-2526 5 CO We 1-MeOOC-iBu 1-2527 5 CO Wme 1-HOOC-iPn 1-2528 5 CO We 1-MeOOC-iPn 1-2529 5 CO We 1-HOOC-2-Me-Bu 1-2530 5 CO We 1-MeOOC-2-Me-Bu 1-2531 7 CO We CI- 2

CH

2

SO

3

H

1-2532 5 CO We

OH

1-2533 5 CO We MeO 1-2534 5 CO W~e EtO 1-2535 5 CO NMe Pro 1-2536 7 CO NWe iPro 1-2537 5 CO NMe BuO 1-2538 5 c "eiBuO 1-2539 57o sBuO 1-2540 5 cWetBuO 1-2541 5 c e-HxO 1-254 5 c N~ePhO

S

S SS

S.

y:\wpdocs\dgt_rms\981I2\981I2cpd L doc -124- TablI(cont.) so..0 e 69 0 G o doseS *Or* *000 000.

Cpd. k A B R 1-2543 5 Co NMe BzO 1-2544 5 CO NMe Z-1 1-2545 7 CO NMe Z-2 1-2546 5 CO NMe Z-3 1-2547 7 CO NMe Z-4 1-2548 5 CO NMe 1-2549 5 CO NMe Z-6 1-2550 5 CO NMe Z-7 1-2551 5 CO NMe Z-8 1-2552 5CO NMe Z-9 1-2553 5 CO NMe 1-2554 5 CO NMe Z-1 1 1-2555 5 co NMe Z-12 1-2556 5 CO NMe 3-Py 1-2557 5 CO NMe 4-Py 1-2558 5 CO Thiad 1-2559 7 co NH-Thiad 1-2560 5 NE-CO Thiad 1-2561 5 NE-CO NHThiad 1-2562 5 CONHCO Thiad 1-2563 5 CONHCO NHThiad 1-2564 7 CONH-S0 2 Thiad 1-2565 5 CONH-S0 2 NHThiad 1-2566 5 NBTCS NH H 1-2567 5 NliCS NH Me 1-2568 7 NHCS NH Et 11-2569 5 N}ICS NH Ph y:\wpdocs\dgt_rnss\981I2\981I2cpd I .doc 125 Table 1 (cont.

Cpd. k A B

R'

1-2570 5 NilCS N-H HOOCCH 2 1-2571 5 NHCS Nil MeOOCCH 2 1-2572 5 NilCS Nil MeCH(COOH) 1-2573 5 NHCS N-H HOOC-(CH 2 2 1-2574 7 NH-CS Nil MeCH(COOMe) 1-2575 5 CO Nil HOOC-(CH 2 3 1-2576 5 NilCO Nil HOOC-(CH 2 3 1-2577 5 NHCO -HOOC-(CH 2 3 1-2578 5 NHCS NE HOOC-(CH 2 3 1-2579 5 CO NH MeSO 2 NHlCOCH(Me) 1-2580 5 NHCO NH MeSO 2 NHCOCH(Me) 1-2581 5 NHCO -MeSO 2 NHCOCH(Me) 1-2582 7 NECS NH MeSO 2 NHCOCH(Me) 1-2583 57 NH HOOCCH 2 1-2584 5 -NH MeOOCCH 2 1-2585 5 -NiH MeCH(COOH) 1-25 86 5 Nil HOOC-(CH 2 2 1-2587 7 MAN MeCH(COOMe) 1-2588 5 MAN HOOC-(CH 2 )3- 1-2589 5 MACOCO

OH

1-2590 5 MACOCO MeO 1-2591 5 MACOCO EtO 1-2592 5 MACOCO Pro 1-2593 5 MACOCO iPrO 1-2594 5 NHCOCO BuG y:\wpdocs\dgtmrrss\981I2\981 2cpd I .doc 126 Table 1 (contA Cpd. k A B R 1-2595 5 NHCOCO BuO 1-2596 5 NHCOCO -sBuO 1-2597 5 NIICOCO -tBuO 1-2598 5 NI-COCO -HxO 1-2599 5 NIICOCO -PhO 1-2600 5 NI-COCO -BzO 1-2601 0 1 ,3-diox-IInd 1-2602 1 1 ,3-diox-Ilnd 1-2603 2 -1 ,3-diox-IInd 1-2604 3 1 ,3-diox-Ilnd 1-2605 4 -1 ,3-diox-IInd 1-2606 5 -1 ,3-diox-Ilnd 1-2607 6 -1 ,3-diox-Ilnd 1-2608 7 -1 ,3-diox-IInd 1-2609 8 -1 ,3-diox-Ilnd 1-26 10 9 -1 ,3-diox-Ilnd 1-2611 10 ,-oxIn 1-2612 11 ,-oxln 1-2613 12 ,-oxln 1-2614 4 NH-CONH-S0 2 NHICO N 1-2615 4 NHCONHSO 2 ICO NH P 1-2616 2 0

H

1-2617 4 0

H

1-2618 5 0

H

1-2619 5 0 -P 1-2620 5 0 -2P 1-2621 5 0 -3-Py y:\wpdocs\dgt_rms\981I2\981I2cpd I .doc 127- Table I atJ 000.

00..

Cpd. k A B R No. 1-2622 5 0 -4-Py 1-2623 5 0 1 1-2624 5 0 -Z-2 1-2625 5 0 -Z-3 1-2626 5 0 -Z-4 1-2627 5 0 1-2628 5 0 -Z-6 1-2629 5 0 -Z-7 1-2630 5 0 -Z-8 1-2631 5 0 -Z-9 1-2632 5 0 1-2633 5 0 -Z-1 1 1-2634 5 0 12 1-2635 4 NECO -3-Py 1-2636 5 NHCO -3-Py 1-2637 4 Co NHl HOCH 2

CH(CH

3

)CH

2 1-2638 5 Co NHl HOCH 2

CH(CH

3

)CH

2 1-2639 4 NI-CO NH HOCH 2

CH(CH

3

)CH

2 1-2640 5 NB-CO NH HOCH 2

CH(CH

3

)CH

2 1-2641 4 Co NH MeSO 2

NHCOCH

2 1-2642 5 Co NH MeSO 2

NHCOCH

2 1-2643 4 NHCO NH MeSO 2

NHCOCH

2 1-2644 5 NHCO NH MeSO 2

NHCOCH

2 1-2645 4 CO NH H 2

NSO

2

NHCOCH

2 1-2646 5 CO NH H 2

NSO

2

NHCOCH

2 1-2647 4 NHCO NH H 2

NSO

2 NHiCOCH 2 y:\wpdocs\dgttms\981I2\981I2cpd I .doc 128 Table I (cont.) Cpd. k A B R No. 1-2648 5 NHCO NHl H,NSO 2

N}ICOCH,

1-2649 4 Co NH 1-(MeSO 2 NHCO)-Et 1-2650 5 CO NEl 1-(MeSO 2 NHCO)-Et 1-2651 4 NIICO NHl 1 -(MeSO 2 NHCO)-Et 1-2652 5 NilCO NHl 1 -(MeSO 2 NHCO)-Et 1-2653 4 Co NEl I-(HNSO 2 NHCO)-Et 1-2654 5 Co NH 1 -(H 2

NSO

2 NHCO)-Et 1-2655 4 NH-CO Nil I-(H 2

NSO

2 NHCO)-Et 1-2656 5 Ni-CO Nil I-(H 2

NSO

2 NHCO)-Et 1-2657 4 Co NH HOOC-(CH 2 4 1-2658 5 CO NH HOOC-(CH 2 4 1-2659 4 NHCO Nil HOOC-(CH 2 4 1-2660 5 NH-CO Nil HOOC-(CH 2 4 1-2661 4 CO Nil HO-(CH 2 2 1-2662 5 CO NH HO-(CH 2 2 1-2663 4 NHCO NH HO-(CH 2 2 1-2664 5 NHCO Nil HO-(CH 2 2 1-2665 4 Co NH- HO-CH 2

-CH(CH

3 1-2666 5 CO NHl HO-CH 2

-CH(CH

3 1-2667 4 NHCO NH HO-CH 2

-CH(CH

3 1-2668 5 NiCO NH HO-CH 2

-CH(CH

3 1-2669 4 CO NMe HOOC-(CH 2 3 1-2670 4 NHCO NMe HOOC-(CH 2 3 1-2671 5 NHCO NMe HOOC-(CH 2 3 1-2672 4 CONMeSO 2 Me y:\wpdocs\dgt_mss\ 9 81I2\981I2cpd I .do 129 Table 1 (cont) Cpd. k A

BR

No.

1-2673 5 CONMeSO 2

M

1-2674 4 CO IId 1-2675 5 CO 1 -Indn 1-2676 4 Ni-CO I1-Indn 1-2677 5 NHCO 1-Indn 1-2678 4 CO 2-(HOOC)-l-Indn 1-2679 5 CO 2-(HOOC)-1-Indn 1-2680 4 Ni-CO 2-(HOOC)-1I-lndn 1-2681 5 NHCO 2-(HOOC)-1-Indn 1-2682 4 1 -Imdd 1-2683 5 -Imdd 1-2684 4 CONHS0 2

F

S.

5*55

S

y:\wpdocs'dgt_mss\981I2\981I2cpd I .doc 130-

(CH

2 )k-~A-B-Rl s-s 0 Table 2 (1-2) Cpd. k A B

R

No.

2-1 4 co NE

H

2-2 4 CO NiH Ph 2-3 4 CO NH 2-Me-Ph 2-4 4 Co NH 4-Me-Ph 2-5 4 CO NH 2,4-diMe-Ph 2-6 4 Co NHl 3,4-diMe-Ph 2-7 4 CO NiE 2-(CF 3 )-Ph 2-8 4 CO NH 4-(CF 3 )-Ph 2-9 4 CO NH 2-MeOPh 2-10 4 CO NH 4-MeOPh 2-11 4 CO NEl 2-EtOPh 2 -12 4 CO Nil 4-EtOPh 2-13 4 CO NiH 2-HOPh 2-14 4 CO NH- 4-HOPh 2-15 4 CO NHl 2-(HOOC)-Ph 2-16 4 CO NHl 4-(HOOC)-Ph 2-17 4 CO NHl 2-(MeOOC)-Ph 2-18 4 CO NH 4-(MeOOC)-Ph 2-19 4 CO NH 2-(EtOOC)-Ph 2-20 4 CO Nil 4-(EtOOC)-Ph 2-21 4 CO Nil 2-(tBuOOC)-Ph 2-22 4 CO Nil 4-(tBuOOC)-Ph 2-23 4 CO NH- 2-Cl-Ph 2-24 4 CO Nil 4-Cl-Ph y:\wpdocs\dgtmss\981 2\981I2cpd2.doc 131 Table 2 (cont.) Cpd. k A B R No. 2-25 4 CO Nil 2-Br-Ph 2-26 4 CO NHL 4-Br-Ph 2-27 4 Co NIL 2-I-Ph 2-28 4 Co NIL 4-I-Ph 2-29 4 CO NIL 2-N0 2 -Ph 2730 4 CO NIL 4-NO 2 -Ph 2-31 4 CO NE- 2-NIL 2 -Ph 2-32 4 CO NH 4-NIL 2 -Ph 2-33 4 Co NIL 2-(HO 3 S)-Ph 2-34 4 CO NH 4-(HO 3 S)-Ph 2-35 4 CO NH 2-(NIL 2

O

2 S)-Ph 2-36 4 CO NHL 4-(NI- 2 0 2 S)-Ph 2-37 4 Co NIL 2-CN-Ph 2-38 4 Co NIL 4-CN-Ph 2-39 4 CO NI- 2-(HOCH 2 )-Ph 2-40 T CO NIL 4-(HOCH 2 )-Ph 2-41 4 CO NIL Me 2-42 4 CO NH Et 2-43 4 CO NH Pr 2-44 4 CO NIL iPr 2-45 4 CO NH Bu 2-46 4 CO NIL HOOCCH2- 2-47 4 CO NHL MeOOCCH2- 2-48 4 CO NIL MeCH(COOH)- 2-49 4 CO NIL HOOC-(CH2)2- 2-50 4 CO NIL MeCH(COOMe)- 2-51 4 CO NIL 1-HOOC-iBu y:\wpdocs\dgt-fmss\ 9 8 1I2\981I2cpd2.doc 132 Cpd. k A B R No. 2-52 4 CO NH 1-MeOOC-iBu 2-53 4 Co NH 1-HOOC-iPn 2-54 4 CO NH I-MeOOC-iPn 2-55 4 Co NH 1-HOOC-2-Me-Bu 2-56 4 CO NH 1-MeOOC-2-Me-Bu 2-57 4 CO NH CH 2

CH

2

SO

3

H

2-58 4 CO NH OH 2-59 4 co NH MeG 2-60 4 CO NH DtO 2-61 4 Co NH Pro 2-62 4 CO NH iPrO 2-63 4 CO NH BuG 2-64 4 CO NH iBuG 2-65 4 CO NH sBuG 2-66 4 CO NH tBuO 2-67 4 CO NH HxO 2-68 4 CO NH PhO 2-69 4 CO NH BnG 2-70 4 CO NH Z-1 2-71 4 CO NH Z-2 2-72 4 CO NH Z-3 2-73 4 CO NH Z-4 2-74 4 CO NH 2-75 4 CO NH Z-6 2-76 4 CO NH Z-7 2-77 4 CO NH Z-8 2-78 4 CO NH Z-9 2-79 4 CO NH y:\wpdocs\dgt_mfss\981 2\981 2cpd2.doc 133 Table 2 (cont.) Cpd. k A B R No. 2-80 T co N~H z-1 1 2-81 4 Co NH Z-12 2-82 4 CO NE- 3-Py 2-83 4 CO NH- 4-Py 2-84 4 Co N(Ac) H 2-85 4 Co N(Ac) Ph 2-86 4 Co N(Ac) 2-Me-Ph 2-87 4 CO N(Ac) 4-Me-Ph 2-88 4 CO N(Ac) 2,4-diMe-Ph 2-89 4 CO N(Ac) 3,4-diMe-Ph 2-90 4 co N(Ac) 2-(CF 3 )Ph 2-91 4 CO N(Ac) 4-(CF 3 )Ph 2-92 4 CO N(Ac) 2-MeOPh 2-93 4 CO N(Ac) 4-MeOPh 2-94 4 CO N(Ac) 2-EtOPh 2-95 4 CO N(Ac) 4-EtOPh 2-96 4 CO N(Ac) 2-HOPh 2-97 4 CO N(Ac) 4-HOPh 2-98 4 jCO N(Ac) 2-(HOOC)Ph 2-99 4 CO N(Ac) 4-(HOOC)Ph 2-100 4 CO N(Ac) 2-(MeOOC)Ph 2-101 4 CO N(Ac) 4-(MeOOC)Ph 2-102 4 CO N(Ac) 2-(EtOOC)Ph 2-103 4 CO N(Ac) 4-(EtOOC)Ph 2-104 4 CO N(Ac) 2-(tBuOOC)Ph 2-105 4 CO N(Ac) 4-(tBuOOC)Ph 2-106 4 CO N(Ac) 2-Cl-Ph 2-107 4 CO N(Ac) 4-Cl-Ph y:\wpdocs\dgtrnss\9S12\981 2cpd2.doc 134- Table (cnt) Cpd. k A B R No. 2-108 4 CO N(Ac) 2-Br-Ph 2-109 4 CO N(Ac) 4-Br-Ph 2-110 4 CO N(Ac) 2-I-Ph 2-111 4 CO N(Ac) 4-I-Ph 2-112 4 CO N(Ac) 2-N0 2 -Ph 2-113 4 CO N(Ac) 4-N0 2 -Ph 2-114 4 CO N(Ac) 2-NH 2 -Ph 2-115 4 CO N(Ac) 4-NH 2 -Ph 2-116 4 CO N(Ac) 2-(HO 3 S)Ph 2-117 4 CO N(Ac) 4-(HO 3 S)Ph 2-118 4 CO N(Ac) 2-(NH 2

O

2 S)Ph 2-119 4 CO N(Ac) 4-(NI- 2 0 2 S)Ph 2-120 4 CO N(Ac) 2-CN-Ph 2-121 4 CO N(Ac) 4-CN-Ph 2-122 4 CO N(Ac) 2-(HOCH 2 )Ph 2-123 4 CO N(Ac) 4-(HOCH 2 )Ph 2-124 4 CO N(Ac) Me 2-125 4 CO N(Ac) Et 2-126 4 CO N(Ac) Pr 2-127 4 CO N(Ac) iPr 2-128 4 CO N(Ac) Bu 2-129 4 CO N(Ac) HOOCCH 2 2-130 4 CO N(Ac) MeOOCCH 2 2-131 4 CO N(Ac) MeCH(COOH) 2-132 4 CO N(Ac) HOOC-(CH 2 2 2-133 4 CO N(Ac) MeCH(COOMe) 2-134 4 CO N(Ac) 1-HOOC-iBu y:\wpdocs\dgt_mss\981I2\981I2cpd2 .doc 135 9* Cpd. k A B

R

No. 2-135 4 Co N(Ac) 1-MeOOC-iBu 2-136 4 CO N(Ac) 1-HOOC-iPn 2-137 4 CO N(Ac) 1-MeOOC-iPn 2-138 4 CO N(Ac) 1-HOOC-2-Me-Bu 2-139 4 co N(Ac) I-MeOOC-2-Me-Bu 2-140 4 CO N(Ac) CH 2

CH

2 SO3H 2-141 4 CO N(Ac)

OH

2-142 4 Co N(Ac) MeO 2-143 4 CO N(Ac) EtO 2-144 4 CO N(Ac) Pro 2-145 4 CO N(Ac) iPrO 2-146 4 CO N(Ac) BuO 2-147 4 CO N(Ac) iBuG 2-148 4 CO N(Ac) sBuO 2-149 4 CO N(Ac) tBuO 2-150 4 CO N(Ac) HxO 2-151 4 CO N(Ac) PhO 2-152 4 CO N(Ac) BnO 2-153 4 CO N(Ac) Z-1 2-154 4 CO N(Ac) Z-2 2-155 4 CO N(Ac) Z-3 2-156 4 CO N(Ac) Z-4 2-157 4 CO N(Ac) 2-158 4 CO N(Ac) Z-6 2-159 4 CO N(Ac) Z-7 2-160 4 CO N(Ac) Z-8 2-161 4 CO N(Ac) Z-9 2-162 4 CO N(Ac) y:\wpdocs\dgt_mfss\981I2\981I2cpd2.doc 136- Table (co 0* Cpd. k A B R No. 2-163 T CO N(Ac) Z-1 1 2-164 4 CO N(Ac) Z-12 2-165 4 CO N(Ac) 3-Py 2-166 4 Co N(Ac) 4-Py 2-167 4 coo H 2-168 4 coo Ph 2-169 4 coo 2-Me-Ph 2-170 4 coo 4-Me-Ph 2-171 4 coo 2,4-diMe-Ph 2-172 4 coo 3,4-diMe-Ph 2-173 4 COO 2-(CF 3 )Ph 2-174 4 coo 4-(CF 3 )Ph 2-175 4 COO 2-MeOPh 2-176 4 coo 4-MeOPh 2-177 4 coo 2-EtOPh 2-178 4 COO -4-EtOPh 2-179 4 coo 2-HOPh 2-180 4 COO -4-HOPh 2-181 4 coo 2-(HOOC)Ph 2-182 4 coo 4-(HOOC)Ph 2-183 4 COO 2-(MeOOC)Ph 2-184 4 coo 4-(MeOOC)Ph 2-185 4 coo 2-(EtOOC)Ph 2-186 4 coo 4-(EtOOC)Ph 2-187 4 coo 2-(tBuOOC)Ph 2-188 4 coo 4-(tBuOOC)Ph 2-189 4 coo 2-Cl-Ph 2-190 4 COO 4-Cl-Ph y:\wpdacs\dgt_rnss\981I2\981I2cpd2.doc 137 Table 2 (co Cpd. k A B R 2-191 4 coo -2-Br-Ph 2-192 4 coo -4-Br-Ph 2-193 4 coo -2-I-Ph 2-194 4 coo -4-I-Ph 2-195 4 coo 2-N0 2 -Ph 2.-196 4 coo 4-N0 2 -Ph 2-197 4 coo 2-NH- 2 -Ph 2-198 4 coo 4-NH 2 -Ph 2-199 4 coo 2-(HO 3 S)Ph 2-200 4 coo 4-(HO 3 S)Ph 2-201 4 coo 2-(NH 2

O

2 S)Ph 2-202 4 coo 4-(NH 2 0 2 S)Ph 2-203 4 coo -2-CN-Ph 2-204 4 coo -4-cN-Ph 2-205 4 COO 2-(HOCH 2 )Ph 2-206 4 coo 4-(HOCH 2 )Ph 2-207 4 coo -Me 2-208 4 coo -Et 2-209 4 coo -Pr 2-210 4 coo -iPr 2-211 4 coo -Bu 2-2 12 4 coo HOOCCH 2 2-213 4 coo -HOOC-(CH 2 2 2-2 14 4 coo -MeCH(COOMe) 2-215 4 coo -HOOC-iBu 2-216 4 coo -1-HOOC-iPn 2-217 4 COO Zy:\wpdocs\dgtmrrss\98I 2\981 2cpd2.doc 138 Table 2 (cont.) Cpd. k A B R No. 2-2 18 4 coo Z-2 2-219 4 coo Z-3 2-220 4 coo Z-4 2-22 1 4 coo 2-222 4 coo Z-6 2-223 4 coo Z-7 2-224 4 coo Z-8 2-22 5 4 coo Z-9 2-226 4 coo Z- 2-227 4 coo Z-1 1 2-228 4 coo Z- 12 2-229 4 coo 3-Py 2-230 4 coo -4-Py 2-231 4 CONHCO

H

2-232 4 CONH-CO Ph 2-233 4 CONiiCO 2-Me-Ph 2-234 4 CONHCO 4-Me-Ph 2-23 5 4 CONHCO 2,4-diMe-Ph 2-236 4 CONHCO- 3,4-diMe-Ph 2-237 4 COM-ICO- 2-(CF 3 )Ph 2-238 4 CONHCO- 4-(CF 3 )Ph 2-239 4 CONHCO 2-MeOPh 2-240 4 CONHCO 4-MeOPh 2-241 4 CONHCO 2-EtOPh 2-242 4 CONHCO 4-EtOPh 2-243 4 CONHCO 2-HOPh 2-244 4 CONHCO 4-HOPh 2-245 4 CONiHCO- 2-(HOOC)Ph y:\wpdocs\dgt_mss\981I2\981I2cpd2.doc 139 Table 2(cont) 4.

.4 4 4 *44* 4*4 Cpd. k A B R No. 2-246 4 CONH-CO 4-(HOOC)Ph 2-247 4 CONHCO 2-(MeOOC)Ph 2-248 4 CONI-CO 4-(MeOOC)Ph 2-249 4 CONHCO 2-(EtOOC)Ph 2-250 4 CONHCO 4-(EtOOC)Ph 2-25 1 4 CONI-CO 2-(tBuOOC)Ph 2-252 4 CONHCO 4-(tBuOOC)Ph 2-253 4 CONH-CO -2-Cl-Ph 2-254 4 CONHCO -4-Cl-Ph 2-255 4 CONHCO 2-rP 2-256 4 CONIICO 4-rP 2-257 4 CONI-CO -21P 2-258 4 CONI-CO -41P 2-259 4 CONH-CO 2-N0 2 -Ph 2-260 4 CONI-CO 4-N0 2 -Ph 2-26 1 4 CONH-CO 2-NH 2 -Ph 2-262 4 CONE-CO 4-NH- 2 -Ph 2-263 4 CONH-CO 2-(HO 3 S)Ph 2-264 4 CONI-CO 4-(HO 3 S)Ph 2-265 4 CONH-CO 2-(NH- 2 0 2 S)Ph 2-266 4 CONHCO 4-(NH 2

O

2 S)Ph 2-267 4 CONH-CO -2-CN-Ph 2-268 4 CONH-CO -4-CN-Ph 2-269 4 CONHCO -2-(HOCH- 2 )Ph 2-270 4 CONHCO -4-(HOCH 2 )Ph 2-271 4 CONIICO Me 2-272 4 CONHCO Et y:\wpdocs\dgt_mrss\981I2\981 2cpd2.doc 444* 4. 4 44 4 44 140 Table2 con-LJ 9* 9 p p Cpd. k A B R 2-273 4 CONHCO -Pr 2-274 4 CONH-CO -iPr 2-275 4 CONHCO -Bu 2-276 4 CONI-CO ROOCCH 2 2-277 4 CONHCO MeOOCCH 2 2-278 4 CONH-CO MeCH(COOH) 2-279 4 CONHCO HOOC-(CH 2 2 2-280 4 CONIICO MeCH(COOMe) 2-281 4 CONHCO 1-HOOC-iBu 2-282 4 CONILCO I1-MeOOC-iBu 2-283 4 CONH-CO 1-HOOC-iPn 2-284 4 CONH-CO 1-MeOOC-iPn 2-285 4 CONHCO 1-HOOC-2-Me-Bu 2-286 4 CONH-CO I-MeOOC-2-Me-Bu 2-287 4 CONI-CO CH 2

CH

2

SO

3

H

2-288 4 CONH-CO -Z-1 2-289 4 CONH-CO -Z-2 2-290 4 CONB-CO -Z-3 2-291 4 CONECO -Z-4 2-292 4 CONH-CO 2-293 4 CONH-CO -Z-6 2-294 4 CONHCO -Z-7 2-295 4 CONHCO -Z-8 2-296 4 CONHCO -Z-9 2-297 4 CONECO 2-298 4 CONHCO -Z-1 I 2-299 4 CONH-CO Z-12 y:\wvpdocs\dgt-fmss\981I2\981I2cpd2.doc 141 Table 2 (cont.) Cpd. k A B R No. 2-300 4 CONI{CO 3-Py 2-30 1 4 CONHCO 4-Py 2-3 02 4 CON(Ac)CO

H

2-303 4 CON(Ac)CO Ph 2-304 4 CON(Ac)CO 2-Me-Ph 2-305 4 CON(Ac)CO 4-Me-Ph 2-306 4 CON(Ac)CO 2,4-diMe-Ph *00:2-307 4 CON(Ac)CO 3,4-diMe-Ph to: 2-308 4 CON(Ac)CO 2-(CF 3 )Ph *.*2-309 4 CON(Ac)CO 4-(CF 3 )Ph 0 0 2-31 .04.2-310 4 CON(Ac)CO 2-MeOPh o ::02-311 4 CON(Ac)CO 4-MeOPh .2-312 4 CON(Ac)CO 2-EtOPh 2-313 4 CON(Ac)CO 4-EtOPh 4:02-314 4 CON(Ac)CO -2-HOOPh *2-315 4 CON(Ac)CO 4-HOPh 2-316 4 CON(Ac)CO 2-(HeOOC)Ph 0O~2 31 4 2-317 4 CON(Ac)CO 4-(HtOOC)Ph 2-31 4 CON(Ac)CO 2-(MeOOC)Ph 2-319 T CON(Ac)CO 4-(MeuOOC)Ph 2-320 4 CON(Ac)CO 2-(tuOOC)Ph 2-322 4 CON(Ac)CO 2-uOCPh 2-323 4 CON(Ac)CO 4-uOCPh 2-324 4 CON(Ac)CO -2-Cl-Ph 2-325 4 CON(Ac)CO -4-Cl-Ph y:\wPdocs\dgt-rnss\981I2\981I2cpd2.doc 142- Table 2 (cOnt.

0 Cpd. k A B R No. 2-328 4 CON(Ac)CO -2-I-Ph 2-329 4 CON(Ac)CO -4-I-Ph 2-330 4 CON(Ac)CO 2-N0 2 -Ph 2-331 4 CON(Ac)CO 4-N0 2 -Ph 2-332 4 CON(Ac)CO 2-NH 2 -Ph 2-333 4 CON(Ac)CO 4-NH 2 -Ph 2-334 4 CON(Ac)CO 2-(HO 3 S)Ph 2-335 4 CON(Ac)CO 4-(HO 3 S)Ph 2-336 4 CON(Ac)CO 2-(NH 2

O

2 S)Ph 2-337 4 CON(Ac)CO 4-(NH 2

O

2 S)Ph 2-338 4 CON(Ac)CO 2-CN-Ph 2-339 4 CON(Ac)CO 4-CN-Ph 2-340 4 CON(Ac)CO 2-(HOCH 2 )Ph 2-341 4 CON(Ac)CO 4-(HOCH 2 )Ph 2-342 4 CON(Ac)CO -Me 2-343 4 CON(Ac)CO -Et 2-344 4 CGN(Ac)CO -Pr 2-345 4 CON(Ac)CO -iPr 2-346 4 CON(Ac)CO -Bu 2-347 4 CON(Ac)CO HOOCCH 2 2-348 4 CON(Ac)CO MeOOCCH2- 2-349 4 CON(Ac)CO MeCH(COOH) 2-350 4 CON(Ac)CO HOOC-(CH 2 2 2-351 4 CON(Ac)CO MeCH(COOMe) 2-352 4 CON(Ac)CO I -HOOC-iBu 2-353 4 CON(Ac)CO -MeOOC-iBu y:\wpdocs\dgtmnss\981 2\9812cpd2.doc 143 Cpd. k A B R No. 2-354 4 CON(Ac)CO 1-HOOC-iPn 2-355 4 CON(Ac)CO I -MeOOC-iPn 2-356 4 CON(Ac)CO 1-HOOC-2-Me-Bu 2-357 4 CON(Ac)CO I-MeOOC-2-Me-Bu 2-358 4 CON(Ac)CO

CH

2

CH

2

SO

3

H

2-359 4 CON(Ac)CO -Z-1I 2-360 4 CON(Ac)CO -Z-2 2-361 4 CON(Ac)CO -Z-3 2-362 4 CON(Ac)CO -Z-4 2-363 4 CON(Ac)CO 2-364 4 CON(Ac)CO -Z-6 2-365 4 CON(Ac)CO -Z-7 2-366 4 CON(Ac)CO -Z-8 2-367 4 CON(Ac)CO -Z-9 2-368 4 CON(Ac)CO 2-369 4 CON(Ac)CO 1 2-370 4 CON(Ac)CO 12 2-371 4 CON(Ac)CO -3-Py 2-372 4 CON(Ac)CO -4-Py 2-373 4 CONHCO NiE H 2-374 4 CONHCO NH Ph 2-3 75 4 CONHCO NH 2-Me-Ph 2-3 76 4 CONHCO NHl 4-Me-Ph 2-3 77 4 CONHCO NHl 2,4-diMe-Ph 2-378 4 CONI-CO Ni- 3,4-diMe-Ph 2-379 4 CONHCO NE 2-(CF 3 )Ph 2-380 4 CONHCO NH 4-(CF 3 )Ph 2-381 4 CONHCO NH- 2-MeOPh y:\wpdocs'dgt_ ms\981 2\9812cpd2.doc -144- Table 2 (cont.) Cpd. k A -B Rl No. 2-382 4 CONI{CO NH 4-MeOPh 2-3 83 4 CONHiCO NH 2-EtOPh 2-3 84 4 CONHCO NH 4-EtOPh 2-385 4 CONH-CO NHl 2-HOPh 2-386 4 CONHCO Nil 4-HOPh 2-387 4 CONI{CO NH 2?-(HOOC)Ph 2-388 4 CONHCO NH 4-(HOOC)Ph 2-3 89 4 CONHCO NH 2-(MeOOC)Ph 2-390 4 CONI-CO Nil 4-(MeOOC)Ph 2-39 1 4 CONHCO Nil 2-(EtOOC)Ph 2-3 92 4 CONHCO NEl 4-(EtOOC)Ph 2-393 4 CONHCO Nil 2-(tBuOOC)Ph 2-394 4 CONilCO Nil 4-(tBuOOC)Ph 2-395 4 CONHCO NHl 2-Cl-Ph 2-396 4 CONHCG NiH 4-Cl-Ph 2-397 4 CONHCO Nil 2-Br-Ph 2-398 4 CONHCO NHl 4-Br-Ph 2-399 4 CONE-CO Nil 2-I-Ph 2-400 4 CONHCO NH 4-I-Ph 2-401 4 CONi-CO NH 2-N0 2 -Ph 2-402 4 CONHCO NH 4-N0 2 -Ph 2-403 4 CONHCO Nil 2-NH 2 -Ph 2-404 4 CONHCO NH 4-NH 2 -Ph 2-405 4 CONilCO NH 2-(HO 3 S)Ph 2-406 4 CONHCO Nil 4-(HO 3 S)Ph 2-407 T CONHCO Nil 2-(NH 2

O

2 S)Ph 2-408 4 CONHCO Nil 4-(NH 2

O

2 S)Ph y:\wpdocs\d gt_rms\981 2\981 2cpd 2.doc 145 Table 2 (cont.) S.0.0 Cpd. k A B R No. 2-409 4 CONH-CO NH 2-CN-Ph 2-410 4 CONHCO NH 4-CN-Ph 2-411 4 CONHCO NHl 2-(HOCH 2 )Ph 2-412 4 CONECO NHl 4-(HOCH 2 )Ph 2-413 4 CONHCO NH Me 2?414 4 CONH-CO NH Et 2-415 4 CONIICO NH Pr 2-416 4 CONECO NH iPr 2-417 4 CONHCO NH Bu 2-418 4 CONHCO NH HOOCCH 2 2-419 4 CONHCO NH MeOOCCH 2 2-420 4 CONHCO NH MeCH(COOH) 2-42 1 T CONH-CO NH HOOC-(CH 2 2 2-422 4 CONECO NH MeCH(COOMe) 2-423 4 CONHCO NH l-HOOC-iBu 2-424 4 CONHCO NH 1-MeOOC-iBu 2-425 T CONHCO NH 1-HOOC-iPn 2-426 4 CONI-CO NH 1-MeOOC-iPn 2-427 4 CONECO NH 1-HOOC-2-Me-Bu 2-428 4 CONI-CO NH 1-MeOOC-2-Me-Bu 2-429 4 CONHCO NH CH 2

CH

2

SO

3

H

2-430 4 CON-HCO NH HO 2-431 4 CONHCO NH MeO 2-432 4 CONI-CO NH EtO 2-433 4 CONECO NH Pro 2-434 4 CONRHCO NH iPrO 2-43 5 4 CONHCO NH BuO 2-436 4 CONHCO NHM iBuO y:\wpdocs\dgt_Tms\981I2\981I cpd2.doc 146- Table 2 (conti Cpd. k A B R 2-437 4 CONHCO NiH sBuO 2-43 8 4 CONHCO NH tBuO 2-439 4 CONI-CO NH HxO 2-440 4 CONHCO NH PhO 2-44 1 4 CONHCO NH BnO 2-442 4 CONHCO NH Z-1 2-443 4 CONH-CO NH Z-2 2-444 4 CONI-CO NH Z-3 2-445 4 CONHCO NH Z-4 2-446 4 CONH-CO NH 2-447 4 CONHCO NH Z-6 2-448 4 CONI-CO NH Z-7 2)-449 4 CONE-CO NH Z-8 2-450 4 CONHCO NH Z-9 2-451 4 CONH-CO NH 2-452 4 CONI-CO NH Z-1 1 2-453 4 CONH-CO NEl Z-12 2-454 4 CONHCO NH 3-Py 2-455 4 CONHCO NE- 4-Py 2-456 4 CONHSO2) H 2-45 7 4 CONHS0 2 -Ph 2-458 4 CONES0 2 2-eP 2-459 4 CONHS0 2 -4-Me-Ph 2-460 4 CONE-S0 2 2,4-diMe-Ph 2-461 4 CONHS0 2 -3,4-diMe-Ph 2-462 4 CONHS0 2 2-(CF 3 )Ph 2-463 4 CONHS0 2 -4-(CF 3 )Ph y:\wpdocs\dgtmffss\981I2\981I2cpd2.doc 147 Table 2 (cont.) Cpd. k A B

R

2-464 T CONHiS0 2 2-MeOPh 2-465 4 CONH-S0 2 -4-MeOPh 2-466 4 CONHS0 2 2-EtOPh 2-467 4 CONH{S0 2 4-EtOPh 2-468 4 CONHIS0 2 2-H-OPh 2:469 4 CONHIS0 2 4-HOPh 2-470 4 CONHIS0 2 2-(HOOC)Ph 2-471 4 CONHS0 2 4-(HOOC)Ph 2-472 4 CONH1S0 2 2-(MeOOC)Ph 2-473 4 CONHS0 2 4-(MeOOC)Ph 2-474 4 CONH-S02 2-(EtOOC)Ph 2-475 4 CONH-S02 4-(EtOOC)Ph 2-476 4 CONH-S02 2-(tBuOOC)Ph 2-477 4 CONH-S02 4-(tBuOOC)Ph 2-478 4 CONHS0 2 -2-Cl-Ph 2-479 4 CONH-S0 2 -4-Cl-Ph 2-480 4 CONH-S0 2 -2-Br-Ph 2-481 4 CONH-S02 4-Br-Ph 2-482 4 CONHS0 2 -2-I-Ph 2-483 4 CONHS0 2 -4-I-Ph 2-484 4 CONH-S0 2 2-N0 2 -Ph 2-48 5 4 CONH-S0 2 -4-N0 2 -Ph 2-486 4 CONHS0 2 -2-NH 2 -Ph 2-487 4 CONH-S0 2 -4-NI- 2 -Ph 2-488 4 CONHS0 2 I 2-(HO 3 S)Ph y:\wpdocs\dgt_mss\981I2\98 12cpd2.doc 148 Table 2(cont.) Cpd. k A B

R'

2-489 4 CONHS0 2 4-(HO 3 S)Ph 2-490 4 CONHS0 2 2-(NH 2

O

2 S)Ph 2-491 4 CONH{S02 4-(NH 2 O2-S)Ph 2-492 4 CONH-S0 2 2-CN-Ph 2-493 4 CONHS02 4-CN-Ph 2-494 4 CONH-S02 2-(HOCH 2 )Ph 2-495 4 CONHS02 4-(HOCH 2 )Ph 2-496 4 CONHso2) Me 2-497 4 CONH-S02 -Et 2-498 4 CONHS0 2 -Pr 2-499 4 CONHS0 2 -iPr 2-500 4 CONHS02 -Bu 2-501 4 CONH-S02

HOOCCH

2 2-502 4 CONHS0 2 MeOOCCH 2 2-503 4 CONHSO9) MeCH(COOH) 2-504 4 CONH1S0 2

HOOC-(CH

2 2 2-505 4 CONHS0 2 MeCH(COOMe) 2-506 4 CONH-S02 I-HOOC-iBu 2-507 4 CONHS0 2 1-MeOOC-iBu 2-508 4 CONIIS02 -1-HOOC-iPn 2-509 4 CONH-S02 I-MeOOC-iPn 2-510 4 CONE-S02 l-H-OOC-2-Me-Bu 2-511 4 CONE-S0 2 1-MeOOC-2-Me-Bu 12 4 CONHS0 2

CH

2

CH

2

SO

3

H

2-513 4 CONES0 2

-OH

y:\wpdocs\dgt~mss\981I2\981I2cpd2.doc 149 Table (cnt.) 9 99.999 Cpd. k A B R No.

2-514 4 CONHS0 2 Me 15 4 CONHS0 2

-D

2-516 4 CONHS0 2 -Pro 2-517 4 CONH-S02 PrO 18 4 CONH~S02 -BuO 2-519 4 CONH-S02 BuO 2-520 4 CONHS0 2 sBuO 2-521 4 CONH-S0 2 tBuO 2-522 4 CON1-S09) HxO 2-523 4 CONHS0 2 -PhO 2-524 4 CONH-S0 2 -BnO 2-525 4 CONHS02 -Z-1 2-526 4 CONHS02 -Z-2 2-527 4 CONHS02 -Z-3 2-528 4 CONH-S02) Z-4 2-529 4 CONH-S0 2 2-530 4 CONH-S0 2 -Z-6 2-531 4 CONB-S0 2 -Z-7 2-532 4 CON'HSO 2 -Z-8 2-533 4 CONH-S0 2 -Z-9 2-534 4 CONH-S0 2 2-535 4 CONE-S0 2 11 2-536 4 CONE-S0 2 12 2-537 4 CONHS0 2 -3-Py 2-538 4 CONESO2 14-Py y:\wpdocs\.dgt_mss\981 2\981 2cpd2.dAm 150- Table 2 (cont.

S

S.

OS

S 0 *500

S.

S

*5 5 5@S@ .00.

a 00 Cpd. k A B R 2-539 4 CONHS0 2 NiE H 2-540 4 CONHS0 2 NH Ph 2-54 1 4 CONHIS0 2 NH 2-Me-Ph 2-542 4 CONHS0 2 NE 4-Me-Ph 2-543 4 CONHS0 2 NEl 2,4-diMe-Ph 2-544 4 CONHS0 2 NHl 3,4-diMe-Ph 255 4 CONHS02 NE 2-(CF 3 )Ph 2-546 4 CONHS02 NH 4-(CF 3 )Ph 2-547 4 CONH-S02 N-H 2-MeOPh 2-548 4 CONHS0 2 NH 4-MeOPh 2-549 4 j CONHIS02 NH 2-EtOPh 2-550 4 CONH-S0 2 NH 4-EtOPh 2-551 4 CONHS0 2 NH 2-HOPh 2-552 4 CONHIS02 NH 4-HOPh 2-553 4 CONHSO9) NH 2-(HOOC)Ph 2-554 4 CONHS0 2 NH 4-(HOOC)Ph 2-555 4 CONHS0 2 NiH 2-(MeOOC)Ph 2-556 4 CONHS0 2 NH- 4-(MeOOC)Ph 2-557 4 CONH-S0 2 NH 2-(EtOOC)Ph 2-558 4 CONHS0 2 NH 4-(EtOOC)Ph 2-559 4 CONHS0 2 NH 2-(tBuOOC)Ph 2-560 4 CONHS0 2 NH 4-(tBuOOC)Ph 2-56 1 4 CONHS0 2 NH 2-Cl-Ph 2-562 4 CONHS0 2 NH 4-Cl-Ph 63 4 CONHS02 NH 2-Br-Ph y:\wpdocs\dgt_mss\981I2\981I2cpd2.doc 151 Table 2 (cont.) Cpd. k A B

R

No.

64 4 CONHS0 2 N -rP 2-565 4 CONHS0 2

NHI-I-P

2-566 4 CONH-S0 2 NH 4-I-Ph 2-567 4 CONHS0 2 NIH 2-N0 2 -Ph 2-568 4 CONHS02 NH 4-N0 2 -Ph 2-569 4 CONHS0 2 NH 2-NH 2 -Ph 70 T CONHS0 2 NE 4-NH 2 -Ph 2-571 4 CONHS02 N-H 2-(HO 3 S)Ph 2-572 4 CONHS0 2 NH 4-(HO 3 S)Ph 2-573 4 CONHS0 2 NH 2-(NH 2

O

2 S)Ph 2-574 4 CONH-S0 2 NH 4-(NH 2

O

2 S)Ph 2-575 4 CONHS0 2 NH- 2-CN-Ph 2-576 4 CONHS0 2 NH 4-CN-Ph 2-577 4 CONHS0 2 NH 2-(HOCH 2 )Ph 2-578 4 CONHS0 2 NH 4-(HOCH 2 )Ph 2-579 4 CONH-S0 2 NH Me 2-580 4 CONHS0 2 NH Et 2-581 4 CONHS0 2 NH Pr 2-582 4 CONHS0 2 NH iPr 2-583 4 CONHS0 2 NHl Bu 84 4 CONHS0 2 NH HOOCCH 2 85 4 CONHS0 2 NH MeOOCCH2- 2-586 4 CONHS0 2 NH MeCH(COOH) 87 4 CON'HSO 2 Nil HOOC-(CH 2 2 2-588 4 CONHS0 2 NH MeCH(COOMe) y:\wpdocs\dgt_mss\981I2\981I2cpd2.doc 152 Table 2 (cont.) Cpd. k A B

R

2-589 4 CONHLS0 2 NiE 1-HOOC-iBu 2-590 4 CONH{S02 NiH I-MeOOC-iBu 2-591 4 CONHS02 NH 1-HOOC-iPn 2-592 4 CONHS0 2 Nil 1-MeOOC-iPn 2-593 4 CONHS0 2 NHl 1-HOOC-2-Me-Bu 2-594 4 CONHlS02 NHl 1-MeOOC-2-Me-Bu 2-595 4 CONHLS0 2 Nil CH 2

CH

2

SO

3

H

2-596 4 CONHS0 2 Nil OH 2-597 4 CONHS02 NHl MeO 2-598 4 CONHlS0 2 Nil EtO 2-599 4 CONHS0 2 NH Pro 2-600 4 CONHS0 2 Nil iPrO 2-601 4 CONHLS0 2 Nil BuO 2-602 4 CONHS02 NHl iBuO 2-603 4 CONH-S0 2 NH- sBuO 2-604 4 CONHlS0 2 NH tBuO 2-605 4 CONHS02 Nil HxO 2-606 4 CONHS0 2 Nil PhO 2-607 4 CONHlS02 NH BnO 2-608 4 CONHlS0 2 NH Z-1 2-609 4 CONHS0 2 NH Z-2 2-6 10 4 CONHS0 2 NH Z-3 2-611 4 CONHS0 2 NH Z-4 2-612 4 CONHMSO 2 NHm 2-613 4 CONHS0 2 NH Z-6 y:\wpdocs\dgt_rms\981I2\981I2cpd2.doc 153 Table 2 (cont.) Cpd. k A B

R

No. 2-614 4 CONHlS0 2

N

2-615 4 CONHS02 NH Z-8 2-616 4 CONHS0 2 NH Z-9 2-617 4 CONHS0 2 NHl 2-618 4 CONHS0 2 NHl Z-11 2-619 4 CONH-S02 NHl Z-12 2-620 4 CONH-S0 2 NH 3-Py :2-621 4 CONHS0 2 NH 4-Py *2-622 4 NHCO

H

*2-623 4 NH-CO -Ph 2-624 4 NHCO 2-Me-Ph 2-625 4 NHCO 4-Me-Ph 2-626 4 NH-CO 2,4-diMe-Ph 2-627 4 NHCO 3,4-diMe-Ph 2-628 4 NHCO 2-(CF 3 )Ph 2-629 4 NHCO 4-(CF 3 )Ph 2-630 4 NHCO 2-MeOPh 2-63 1 4 NI-CO 4-MeOPh 2-632 4 NH-CO -2-EtOPh 2-633 4 NH-CO -4-EtOPh 2-634 4 NHCO -2-HOPh 2-63 5 4 NHCO -4-HOPh 2-636 4 NHCO 2-(HOOC)Ph 2-63 7 4 NHCO 4-(HOOC)Ph 2-638 4 NHCO 2-(MeOOC)Ph 2-639 T NIHCO 4-(MeOOC)Ph 2-640 4 NHCO 2-(EtOOC)Ph y:\wlpdocs\dgt-ris\9812\981 2cpd2.doc 154- Table2 (cont)

S

Cpd. k A B R No. 2-641 4 NHCO 4-(EtOOC)Ph 2-642 4 NIICO 2-(tBuOOC)Ph 2-643 4 NHCO 4-(tBuOOC)Ph 2-644 4 NHCO 2-Cl-Ph 2-645 4 NH-CO 4-Cl-Ph 2-646 4 NHCO 2-Br-Ph 2-647 4 NHCO 4-Br-Ph 2-648 4 Ni-CO -2-I-Ph 2-649 4 NH-CO -4-I-Ph 2-650 4 NHCO 2-N0 2 -Ph 2-651 4 NHCO 4-N0 2 -Ph 2-652 4 Ni-CO 2-N~H-Ph 2-653 4 NI-CO 4-N-H 2 -Ph 2-654 4 Ni-CO 2-(HO 3 S)Ph 2-655 4 Ni-CO 4-(HO 3 S)Ph 2-656 4 NH-CO 2-(NH- 2 0 2 S)Ph 2-657 4 Ni-CO 4-(NH 2

O

2 S)Ph 2-658 4 NHCO 2-CN-Ph 2-659 4 NH-CO 4-CN-Ph 2-660 4 NE-CO 2-(HOCH 2 )Ph 2-66 1 4 NI-CO 4-(HOCH 2 )Ph 2-662 4 Ni-CO -Me 2-663 4 NHCO -Et 2-664 4 NIICO -Pr 2-665 4 NH-CO J, Pr 2-666 4 NHCO -Bu 2-667 4 NI-CO HOOCCH 2 y:\wpdocs\d gt_ms\981 2\981 2cpd 2.doc 155 Table2 cot.

Cpd. k A B R No.

2-668 4 NI-CO MeOOCCH 2 2-669 4 NHCO MeCH(COOH) 2-670 4 NHCO HOOC-(CH2)2- 2-67 1 4 NHCO -MeCH(COOMe) 2-672 4 NHCO 1-HOOC-iBu 2-673 4 NH-CO 1-HOOC-iPn 2-674 4 NH-CO 1-HOOC-2-Me-Bu 2-675 4 NHCO

CH

2

CH

2 SO3H 2-676 4 NHCO -MeO 2-677 4 NHCO -EtO 2-678 4 NH-CO -Pro 2-679 4 NHCO Z-1 2-680 4 NI-CO -Z-2 2-68 1 4 NHCO -Z-3 2-682 4 NE-CO -Z-4 2-683 4 NE-CO 2-684 4 NHCO -Z-6 2-685 4 NH-CO -Z-7 2-686 4 NHCO -Z-8 2-687 4 NE-CO Z-9 2-688 4 NHCO Z- 2-689 4 NHCO Z-1 I 2-690 4 NHiCO Z- 12 2-691 4 NHCO 3-Py 2-692 4 NHCO 4-Py 2-693 4 NHCO NE- H 2-694 4 NHCO NH Ph 2-695 4 NHCO NH 2-Me-Ph y:\wpdocs\dgtmss\981I2\981I2cpd2 .doc 156- Table 2 (cont.) Cpd. k A B

R

No.

2-696 4 NIICO NE 4-Me-Ph 2-697 4 NI-CO NHl 2,4-diMe-Ph 2-698 4 NBCO NH 3,4-diMe-Ph 2-699 4 NHCO NHl 2-(CF 3 )Ph 2-700 4 NHCO NH 4-(CF 3 )Ph 2>701 4 NI-CO NH 2-MeOPh 2-702 4 NHCO NIH 4-MeOPh 2-703 4 NI-CO NH 2-EtOPh 2-704 4 NHCO NH 4-EtOPh 2-705 4 NIICO NHl 2-HOPh 2-706 4 NH-CO NH 4-HOPh 2-707 4 NH-CO NH 2-(HOOC)Ph 2-708 4 NH-CO NH 4-(HOOC)Ph 2-709 4 NHCO NH 2-(MeOOC)Ph 2-710 4 Ni-CO NE- 4-(MeOOC)Ph 2-711 4 NHCO NH 2-(EtOOC)Ph 2-712 4 NHCO Nil 4-(EtOOC)Ph 2-713 4 NHCO NH- 2-(tBuOOC)Ph 2-714 4 Ni-CO NH- 4-(tBuOOC)Ph 2-715 4 NI-CO NHl 2-Cl-Ph 2-7 16 4 NHCO NH- 4-Cl-Ph 2-7 17 4 NI-CO NH 2-Br-Ph 2-718 4 NHCO Nil 4-Br-Ph 2-7 19 4 Ni-CO NEl 2-I-Ph 2-720 4 NHCO NH- 4-I-Ph 2-721 4 NiICO NH 2-N0 2 -Ph 2-722 4 NH-CO NHl 4-N0 2 -Ph 2-723 4 NHCO NH 2-NH 2 -Ph Y:\wPdocs\dgt_mss\981I2\981I2cpd2.doc 157- Table2 (ont) Cpd. k A B R No. 2-724 4 NHCO NH- 4-NH2-Ph 2-725 4 NHCO NH 2-(HO 3 S)Ph 2-726 4 NHCO NH 4-(HO 3 S)Ph 2-727 4 NHCO Nil 2-(NH 2

O

2 S)Ph 2- 728 4 NHCO NH 4-(NH 2

O

2 S)Ph 2-729 4 NHCO NH 2-CN-Ph 2-730 4 NHCO NH 4-CN-Ph 2-731 4 NHCO Nil 2-(HOCH 2 )Ph 2-732 4 NHCO NH 4-(HOCH 2 )Ph 2-733 4 NH-CO NH Me 2-734 4 NIICO NH Et 2-735 4 NI-CO NH Pr 2-736 4 NI-CO NH iPr 2-737 4 NH-CO NH Bu 2-738 4 NH-CO Nil HOOCCH 2 2-739 4 NI-CO NH MeOOCCH 2 2-740 4 Ni-CO NH MeCH(COOH) 2-741 4 NH-CO NH HOOC-(CH 2 2 2-742 4 Ni-CO NH MeCH(COOMe) 2-743 4 NHCO NiH l-HOOC-iBu 2-744 4 NHCO NH 1-MeOOC-iBu 2-745 4 NHCO NH 1-HOOC-iPn 2-746 4 NHCO NH 1-MeOOC-iPn 2-747 4 NHCO NH 1-HOOC-2-Me-Bu 2-748 T NH-CO NH -MeOOC-2-Me-Bu 2-749 4 NHCO NH CH 2

CH

2 SO3H 2-750 4 NHCO NH OH y:\wpdocs\dgt_ms\981I2\981 2cpd2 Ado 158- Table 2ADnIJ a Cpd. k A B

R

No.

2-751 4 NHCO NH MeG 2-752 4 NHCO NH EtO 2-753 4 NHCO NH PrO 2-754 4 NHCO NH iPrO 2-755 4 NHCO NH BuG 2-756 4 NICO NH iBuG 2-757 4 NHCG NH sBuO 2-758 4 NHCO Ni tBuG 2-759 4 NHCG NH HxG 2-760 4 NHCG Ni PhO 2-761 4 NHCO Ni BnG 2-762 4 NHCO NH Z-1 2-763 4 NHiCO NH Z-2 2-764 4 NHCO NE Z-3 2-765 4 NHCO NE Z-4 2-766 4 NHCG Ni 2-767 4 NICO NE Z-6 2-768 4 NHCO Ni Z-7 2-769 4 N-CO NH Z-8 2-770 4 N-CO NH Z-9 2-771 4 NHCG Ni 2-772 4 NliCO Ni Z-1 2-773 4 NICO Ni Z-12 2-774 4 NHCO NH 3-Py 2-775 4 NICO NH 4-Py 2-776 4 NHCO NMe Ph 2-777 4 NHCO -NMe 2-Me-Ph 2-778 4 NHCO NMe 4-Me-Ph y:\wpdocs\dgtmss\98 12\9812cpd2.doc 159- *9*Se9 *9@9 .9 99 E~ 0* 9 9

S

*9 9 9 4**S

S

9 Cpd. k A B Rl No. 2-779 4 NHCO NMe 2,4-diMe-Ph 2-780 4 NHCO NMe 3,4-diMe-Ph 2-781 4 NHCO NMe 2-(CF 3 )Ph 2-782 4 NHCO NMe 4-(CF 3 )Ph 2-783 4 NHCO NMe 2-MeOPh 2z784 4 NHCO We 4-MeOPh 2-785 4 NHCO NMe 2-EtOPh 2-786 4 NHCO We 4-EtOPh 2-787 4 NHCO NM e 2-HOPh 2-788 4 NH-CO We 4-HOPh 2-789 4 NHCO We 2-(HOOC)Ph 2-790 4 NHCO We 4-(HOOC)Ph 2-79 1 4 NIICO We 2-(MeOOC)Ph 2-792 4 NHCO We 4-(MeOOC)Ph 2-793 4 Ni-CO We 2-(EtOOC)Ph 2-794 4 NH-CO We 4-(EtOOC)Ph 2-795 4 NHCO We 2-(tBuOOC)Ph 2-796 4 NI-CO We 4-(tBuOOC)Ph 2-797 4 Ni-CO We 2-Cl-Ph 2-798 4 NHCO We 4-Cl-Ph 2-799 4 Ni-CO We 2-Br-Ph 2-800 4 NI-CO We 4-Br-Ph 2-801 4 NHCO WNe 2-I-Ph 2-802 4 Ni-CO NMe 41P 2-803 4 NHCO We 2N2P 2-804 4 NI-CO We 4-N0 2 -Ph 2-805 4 NHCO We 2N2P .99.

S

@9

OS

y:\wpdocs\dgt_ ms\9812\9 8 1 2cpd2.doc 160- Table2 (coW Cpd. k A B

R

No. 2-806 4 NIICO NMe 4-NH 2 -Ph 2-807 4 NHCO NMe 2-(HO 3 S)Ph 2-808 4 NIICO NMe 4-(HO 3 S)Ph 2-809 4 NHCO NWe 2-(NH 2

O

2 S)Ph 2-810 4 NHCO NMe 4-(N~HO2S)Ph 2 -811 4 NHCO NMe 2-CN-Ph 2-8 12 4 NIICO We 4-CN-Ph 2-8 13 4 NI-CO We 2-(HOCH 2 )Ph 2)-8 14 4 NH-CO We 4-(HOCH 2 )Ph 2-815 4 NHCO We Me 2-816 4 NHCO We Et 2-817 4 NH-CO NMe Pr 2-818 4 Ni-CO W~e iPr 2-8 19 4 NH-CO NMe Bu 2-820 4 Ni-CO We HOOCCH2- 2-821 4 NIICO We MeOOCCH 2 2-822 4 Ni-CO NMe MeCH(COOH) 2-823 4 NH-CO We HOOC-(CH2)2- 2-824 4 NH-CO We MeCH(COOMe) 2-825 4 NI-CO We l-HOOC-iBu 2-826 4 Ni-CO We I-MeOOC-iBu 2-827 4 Ni-CO NMe 1-HOOC-iPn 2-828 4 NHCO NMe 1-MeOOC-iPn 2-829 4 NHCO We l-I-OOC-2-Me-Bu 2-830 4 NHCO We 1-MeOOC-2-Me-Bu 2-83 1 4 NHCO WF e CH 2

CH

2 SO3Hy:\wpdocs\dgtmffss\981I2\981I2cpd2 .doc 161 Table 2 (cont.) Cpd. k A B Rl No. 2-832 4 NHCO W~e

OH

2-833 4 NI-CO NMe MeO 2-834 4 NHCO W~e EtO 2-835 4 NHCO NMe Pro 2-836 4 NI-CO NMe iPrO 2-837 4 NHCO NMe BuO 2-83 8 4 Ni-CO W~e iBuO 2-839 4 NHCO NMe sBuO 2-840 4 NH-CO NMe tBuO 2-841 4 NH-CO NMe HxO 2-842 T NH-CO W~e PhO 2-843 4 NILCO NMe BnO 2-844 4 NHCO We Z-1 2-845 4 NHCO W~e Z-2 2-846 4 NHCO We Z-3 2-847 4 NHCO WeZ4 2-848 4 NHCO W~e 2-849 4 NHCO We Z-6 2-850 4 NHCO We Z-7 2-851 4 NHCO We Z-8 2-852 4 NHCO We Z-9 2-853 4 NHCO We 2-854 4 NHCO We Z-1 1 2-855 4 NHCO We Z-12 2-856 4 NHCO We 3-Py 2-857 4 NHCO We 4-Py 2-858 4 NHCO NHNH-

H

y:\wpdocs\dgt_mss\981I2\98 12cpd2 .doc 162 Table 2 (conQ.

Cpd. k A B R 2-859 T NHCO NHM-I Me 2-860 4 NHCO NHNH Et 2-86 1 4 NHCO NHNMe Me 2-862 4 NHCO NHNMe Et 2-863 4 NI-CO NHNMe Pr 2-864 4 NHCONHNHCO NHl H 2-865 4 NITCONIINHCO NHl Ph 2-866 4 NHCONHNHCO NH 2-Me-Ph 2-867 4 N1-CONHNHCO NiH 4-Me-Ph 2-868 4 NilCONHNI-CO NHl 2,4-diMe-Ph 2-869 4 NHCONHNHCO Nil 3,4-diMe-Ph 2-870 4 NHCON1{NHCO NEl 2-(CF 3 )Ph 2-87 1 4 NilCONHNHCO Nil 4-(CF 3 )Ph 2-872 4 NHCONHNilCO NHl 2-MeOPh 2-873 4 NHCONHNilCO NHl 4-MeOPh 2-874 4 NilCONHNACO Nil 2-EtOPh 2-875 4 NIHCONHNH-CO NIH 4-EtOPh 2-876 T NB-CONHNH-CO Nil 2-HOPh 2-877 4 NH-CONHNH-CO NH 4-HOPh 2-878 4 NilCONHNHCO NH 2-(HOOC)Ph 2-879 4 NHCONHNHCO NH 4-(HOOC)Ph 2-880 T NHCONHNHCO NH 2-(MeOOC)Ph 2-881 4 NHCONHNH-CO NH 4-(MeOOC)Ph 2-882 4 NHCON-1N1-CO NH 2-(EtOOC)Ph 2-883 4 NIHCONI{NHCO NH 4-(EtOOC)Ph 2-884 4 NHCONHNilCO. Nl2-(tBuOOC)Ph 2-885 4 NI4CONIINHCO NH 4-(tBuOOC)Ph y:\wpdocs\dgtmss\981I2\9812 cpd2.doc 163 Table 2(coWI Cpd. k A B R No. 2-886 T NHCONHNHCO NH 2-Cl-Ph 2-887 4 NilCONHNHCO NH 4-Cl-Ph 2-888 4 NilCONHNHCO NiH 2-Br-Ph 2-889 4 NHCONIINHCO Nil 4-Br-Ph 2-890 4 NilCONiINHCO NH 2-I-Ph 2-7891 4 NHCONIINHCO NH 4-IPh 2-892 4 NHCONilNHCO Nil 2-N0 2 -Ph 2-893 4 NilCONilNHCO NH 4-N0 2 -Ph 2-894 4 NHCONHNI-CO NH 2-NH- 2 -Ph 2-895 4 NHCONHNilCO NH 4-NH 2 -Ph 2-896 4 NHCONHNHCO NH 2-(HO 3 S)Ph 2-897 4 NHCONilNiCO NH 4-(HO 3 S)Ph 2-898 4 NHCON1-NHCO NH 2-(NH 2

O

2 S)Ph 2-899 4 NHCON1{NiCO NH 4-(NR 2

O

2 S)Ph 2-900 4 NHCONilN1-CO NH 2-CN-Ph 2-901 4 N}ICONHNHCO NH 4-CN-Ph 2-902 4 NHCON1-NHiCO NH 2-(HOCH 2 )Ph 2-903 4 NHCONHi-CO NH 4-(HOCH 2 )Ph 2-904 T NH-CONilNiCO NH Me 2-905 4 NilCONHNHCO NH Et 2-906 4 NilCONI{NHCO Nil Pr 2-907 4 NH-CONilNHCO NH iPr 2-908 4 NHCONHNilCO NHL Bu 2-909 4 NHCONHNHCO NH HOOCCH2- 2-9 10 4 NHCONIINIC0- NH MeOOCCH2- 2-911 141 NHCONHNHCO NH MeCH(COOH) y:\wpdocs\dgtmffss\981I2\9S I cpd2.doc -164- Table 2 (cnt.) a a Cpd. k A B

R

No.

2-912 4 M-ICONHNHCO NH HOOC-(CH2) 2 2-913 T NHCONHN}ICO NH- MeCH(COOMe) 2-9 14 4 NHCONHNHCO NH 1-HOOC-iBu 2-915 4 NHCONHNHCO NH 1-MeOOC-iBu 2-9 16 4 NI-CONHNHCO NH 1-HOOC-iPn 2-917 4 NI-CONHNHCO NH 1-MeOOC-iPn 2-918 4 N1-CONHNHCO NH 1-HOOC-2-Me-Bu 2-919 4 NHCONHMICO NH 1-MeOOC-2-Me-Bu 2-920 4 N1-CONIINHCO NH CH 2

CH

2 SO3H 2-921 4 NHCONI{NHCO NH

OH

2-922 4 NHCONI-NIICO NH MeO 2-923 4 N1-CONHNE-CO NH EtO 2-924 4 NHCONHNHCO NH Pro 2-925 4 Nl-ICON1IN-CO NH iPrO 2-926 4 NHCONHN1ICO NH BuO 2-927 4 N HCONI-NHiCO NH iBuO 2-928 4 N1-CONHNE-CO NH sBuO 2-929 4 NH-CONi-Ni-CO NiH tBuO 2-930 4 NHCON1-NHCO NH HxO 2-931 4 NHCONH-NI-CO NH PhO 2-93 2 4 NHCON1*NHCO NH BnO 2-933 4 NHCONHM-ICO NH Z-1 2-934 4 NHCONHNI-CO NH Z-2 2-93 5 4 NHCONHNH-CO NHl Z-3 2-936 4 NHCONI-NHCO NHl Z-4 2-93 7 4 NBCONIINHCO. NEl 2-938 4 NI-CONHNHCO Nil Z-6 y:\wpdocs\dgtmffss\981I2\981I2cpd2.doc 165 Table 2 (cont) Cpd. k A B

R

No. 2-939 4 NH-CONHNIECO NHl Z-7 2-940 4 NHCONHNHCO NH Z-8 2-941 4 NilCONHNHCO NH Z-9 2-942 4 NH-CONI{NHCO NI- 2-943 4 NHCONHNHCO Nil Z-1 1 2-944 4 NHCONHNHCO NHl Z-12 2-945 4 NE-CONI4NHCO Nil 3-Py 2-946 4 NI{CONH-NHiCO NHl 4-Py 2-947 4 NHCONHCO

-H

2-948 4 NH-CONHCO -Ph 2-949 4 NHCONHCO 2-Me-Ph 2-950 4 NHCONHCO 4-Me-Ph 2-951 4 NilCONH-CO 2,4-diMe-Ph 2-952 4 NHCONH-CO 3,4-diMe-Ph 2-953 4 NHCONH-CO 2-(CF 3 )Ph 2-954 4 NilCONI-CO 4-(CF 3 )Ph 2-95 5 4 NilCONHCO 2-MeOPh 2-956 4 NHCONHCO 4-MeOPh 2-957 4 NHCONHCO -2-EtOPh 2-95 8 4 NHCONHCO 4-EtOPh 2-959 4 NI-ICONH-CO 2-HOPh 2-960 4 NH-CONH-CO 4-HOPh 2-96 1 4 NE-CONE-CO -2-(HOOC)Ph 2-962 4 NHCONHCO -4-(HOOC)Ph 2-963 4 NHCON'HCO -2-(MeOOC)Ph 2-964 4 NI-CONHCO -4-(MeOOC)Ph y:\wpdocs\dgt_miss\981I2\981I2cpd2 .doc 166 Table 2 (co Cpd. k A B R 2-965 T NIICONIICO 2-(EtOOC)Ph 2-966 4 NIICONHCO 4-(EtOOC)Ph 2-967 4 NHCONHCO 2-(tBuOOC)Ph 2-968 4 NH-CONHCO 4-(tBuOOC)Ph 2-969 4 NHCONHCO -2-Cl-Ph 2-970 4 NHCONIHCO -4-Cl-Ph 2-971 4 NH-CONIHCO -2-Br-Ph 2-972 4 NH-CONI-CO -4-Br-Ph 2-973 4 NH-CONHiCO -2-I-Ph 2-974 4 NHCONHCO -4-I-Ph 2-975 4 NH-CONIICO 2-N0 2 -Ph 2-976 4 NH-CONI-CO 4-N0 2 -Ph 2-977 4 NHCONH-CO 2-NH 2 -Ph 2-978 4 NE-CONHCO 4-NH 2 -Ph 2-979 4 NHCON1-CO 2-(HO 3 S)Ph 2-980 4 NH-CONHCO 4-(HO 3 S)Ph 2-981 4 NH-CONHCO 2-(NH 2

O

2 S)Ph 2-982 4 NHCONHCO 4-(NH 2

O

2 S)Ph 2-983 4 Ni-CONI-CO -2-CN-Ph 2-984 4 M-ICONHCO -4-CN-Ph 2-985 4 NHCONH-CO 2-(HOCH 2 )Ph 2-986 4 NHCONH-CO 4-(HOCH 2 )Ph 2-987 4 NI-CONHCO -Me 2-988 4 NH-CONHCO -Et 2-989 4 NHCONHCO Pr 2-990 4 NHCONHCO iPr 2-991 4 NH-CONHCO Bu y:\wpdocs\dgtniss\981I2\981I2cpd2.doc 167- Table 2 (cont.) a Cpd. k A B R No. 2-992 4 NIICONHCO HOOCCH 2 2-993 4 NIHCONI1CO MeOOCCH 2 2-994 4 TH{CONHCO MeCH(COOH) 2-995 4 NHCONH-CO HOOC-(CH 2 2 2-996 4 NI-CONIICO MeCH(COOMe) 2*997 4 NH-CONIICO 1-HOOC-iBu 2-998 4 NHCONI-CO 1-MeOOC-iBu 2-999 4 NHCONH-CO 1-HOOC-iPn 2-1000 4 NHCONH-CO 1-MeOOC-iPn 2-1001 4 NIICONIICO 1-HOOC-2-Me-Bu 2-1002 4 NI-CONH-CO 1-MeOOC-2-Me-Bu 2-1003 4 NH-CONHCO

CH

2

CH

2

SO

3

H

2-1004 4 NI-ICONHCO -MeG 2-1005 4 Ni-CONI-CO -EtO 2-1006 4 NI-CONI-CO -Pro 2-1007 4 NHCONHCO -iPrO 2-1008 4 NHCONH-CG BuG 2-1009 4 NHCONHCG iBuG 2-1010 4 NH-CONH-CO -sBuG 2-1011 4 NHCGNHCO -tBuG 2-1012 4 NHCONHCG HxG 2-1013 4 N1-CGNHCG PhO 2-1014 4 NE-CONHCO BnO 2-1015 4 NHCONHCO -Z-1 2-1016 4 NHCONHCG Z-2 2-1017 4 NH-CGNHCG Z-3 y:\wpdocs\dgt_mss\9812\98 1 2cpd2.dAm 168- Tabl 2 (cont.)

S.

E Cpd. k A B R No.

2-1018 4 NHCONHCO Z-4 2-1019 4 NHCONHCO 2-1020 4 NHCONHCO Z-6 2-1021 4 N-CONIHCO Z-7 2-1022 4 NHCONHCO Z-8 2-1023 4 NHCONHCO Z-9 2-1024 4 N-CONHCO 2-1025 4 NHCONHCO Z- 1 2-1026 4 NHCONHCO Z-12 2-1027 4 NHCONHCO 3-Py 2-1028 4 NICONHCO 4-Py 2-1029 4 NHCONES02

H

2-1030 4 NHCONHS02 Ph 2-1031 4 NHCONHS0 2 2-Me-Ph 2-1032 4 NHCONHS02 4-Me-Ph 2-1033 4 NHCONHS0 2 2,4-diMe-Ph 2-1034 4 NHCONHS0 2 3,4-diMe-Ph 2-1035 4 NHCONHSO 2 2-(CF 3 )Ph 2-1036 4 NICON-S02 4-(CF 3 )Ph 2-1037 4 NHCONHS02 2-MeOPh 2-1038 4 NHCONHSO2 4-MeOPh 2-1039 4 NHCONHS02 2-EtOPh 2-1040 4 NHCONHS02 4-EtOPh 2-1041 4 NHCONHS0 2 2-HOPh 2-1042 4 NHCONHS02 4-HOPh

S

S. S y:\wpdos\dgt mss\98 1 2\981 Zcpd2.doc -169- Table 2 (cont.) Cpd. k A B R No.

2-1043 4 NHCONHS0 2 2-(HOOC)Ph 2-1044 4 NHCONHS0 2 4-(HOOC)Ph 2-1045 4 NHCONHS02 2-(MeOOC)Ph 2-1046 4 NHCONHS02 4-(MeOOC)Ph 2-1047 4 NHCONHS02 2-(EtOOC)Ph 2-1048 4 NHCONHS02 4-(EtOOC)Ph 2-1049 4 NHCON-S02 2-(tBuOOC)Ph 2-1050 4 NHCONHS02 4-(tBuOOC)Ph 2-1051 4 NHCONHS0 2 2-Cl-Ph 2-1052 4 NHCON1HS02 4-Cl-Ph 2-1053 4 NHCONHSO 2 2-Br-Ph 2-1054 4 NHCONHS02 4-Br-Ph 2-1055 4 NHCONHS02 2-I-Ph 2-1056 4 NHCONHS02 4-I-Ph 2-1057 4 NHCONHS0 2 2-N0 2 -Ph 2-1058 4 NHCONHS02 4-NO2-Ph 2-1059 T NHCONHSO2 2-NH 2 -Ph 2-1060 4 NHCONHS02 4-NH 2 -Ph 2-1061 4 N-iCONHS02 2-(HO 3 S)Ph 2-1062 4 NHCON-S02 4-(HO 3 S)Ph 2-1063 4 NHCONHSO2 2-(NH20 2 S)Ph 2-1064 4 NHCONHS02 4-(NI 2 0 2 S)Ph 2-1065 4 NHCONHS02 2-CN-Ph 2-1066 4 NHCON}S02 4-CN-Ph y:\wpdocs\dgt_mss\981 2\981 2cpd2.doc -170- Table 2 (cont.) Cpd. k A B R No. 2-1067 4 NHCONHS0 2 2-(HOCH 2 )Ph 2-1068 4 NHCONHSO 2 4-(HOCH 2 )Ph 2-1069 4 NHCONHSO 2 Me 2-1070 4 NHCONHSO2 Et 2-1071 4 NHCONHSO 2 Pr 2-1072 4 NHCONHS02 iPr 2-1073 4 NHCONHS02 Bu 2-1074 4 NHCONHS02

HOOCCH

2 2-1075 4 NECONHS0 2 MeOOCCH 2 2-1076 4 NHCONHS0 2 MeCH(COOH) 2-1077 4 NHCONHS02 HOOC-(CH 2 2 2-1078 4 NHCONHS0 2 MeCH(COOMe) 2-1079 4 NHCONHS02 1-HOOC-iBu 2-1080 4 NECONHS0 2 1-MeOOC-iBu 2-1081 4 NHCONIS0 2 1-HOOC-iPn 2-1082 4 NHCON1S0 2 1-MeOOC-iPn 2-1083 4 NHCONHS02 1-HOOC-2-Me-Bu 2-1084 4 NHCONHS02 1-MeOOC-2-Me-Bu 2-1085 T NHCONHSO 2

CH

2

CI

2 S0 3

H

2-1086 4 NECONHS02

OH

2-1087 4 NHCONHS02 MeO 2-1088 4 NHCONHS02 EtO 2-1089 4 NHCONES02 Pro 2-1090 4 NHCONHSO2 iPrO y:\wpdocs\dgt-mss\ 98 12\981 2cpd2.doc 171 Table 2 (coWt' Cpd. k A B R No.

2-1091 4 NEiCONHS02 -BuO 2-1092 4 NHCON-HS02 -iBuO 2-1093 4 NH-CONHS02 -sBuO 2-1094 4 NHCONH{S02 -tBuO 2-1095 4 NHCONH-S02 -HxO 2-1096 4 NHCONH{S02 -PhO 2-1097 4 NHCONHS0 2 -BnO 2-1098 4 NHCONH-S0 2 1 2-1099 4 NH-CONHS02 -Z-2 2-1100 4 NHCONHIS0 2 -Z-3 2-1101 4 NH-CONHS02 -Z-4 2-1102 4 NECONHS02 2-1103 4 NH-CONHS0 2 -Z-6 2-1104 4 NH-CONHS0 2 -Z-7 2-1105 4 NE-CONE-S0 2 -Z-8 2-1106 4 NH-CONHS0 2 -Z-9 2-1107 4 NE-CONE-S0 2 2-1108 4 NHICONH-S0 2 -Z-1 1 2-1109 4 NHCONE-S0 2 12 2-1110 4 N1ICONE-S0 2 -3-Py 2-1111 4 NH-CONHSO 2 -4-Py 2-1112 4 NHCONH-S02 NH H 2-1113 4 NHCON'HSO 2 NH Me 2-1114 4 NHCONHS02 NH Et y:\wpdocs\dgt__ms\981 2\9812cpd2.-doc -172- Table 2 Iont Cpd. k A B R No.

2-1115 4 NHCONHSO 2 NH Pr 2-1116 4 NHCONHSO 2 NH iPr 2-1117 4 NHCONHS02 NH Bu 2-1118 4 NHCONHSO2 NMe Me 2-1119 4 NHCONHSO 2 NMe Et 2-1120 4 NHCONHS0 2 NMe Pr 2-1121 4 NHCONHSO 2 NMe iPr 2-1122 4 NHCONHSO 2 NMe Bu 2-1123 4 NH H 2-1124 4 NH Me 2-1125 4 NH Et 2-1126 4 NH Pr 2-1127 4 NH iPr 2-1128 4 NH Bu 2-1129 4 CO Pyr 2-1130 4 CO Pipri 2-1131 4 CO Pipra 2-1132 4 CO Mor 2-1133 4 CO Thmor 2-1134 4 CO NHPyr 2-1135 4 CO NHPipri 2-1136 4 CO NHPipra 2-1137 4 CO NHMor 2-1138 4 CO NHThmor 2-1139 4 NHCO Pyr 2-1140 4 NHCO Pipri y:\wpdocs\dgtmss\981 2\9812cpd2.doc 173 Table 2 (OAt.

S

.5

S

*5SS

S.

S

**SS

S

S

S

*5 S *5 Cpd. k A

BR

No. 2-1141 4NHCO Pipra 2-1142 4 NIICO Mor 2-1143 4 NIICO Thmor 2-1144 4 NECO NHPyr 2-1145 4 NHCO NIHPipri 2-1146 4 NHCO NHPipra 2-1147 4 NHCO NHMor 2-1148 4 Ni-CO NHThmor 2-1 149 4 CONI-CO Pyr 2-1150 4 CONHCO Pipri 2-1151 4 CONHCO Pipra 2-1152 4 CONHCO Mor 2-1153 4 CONH-CO Thmor 2-1154 4 CONHCO NHPYr 2-1155 4 CONHCO NHPipri 2-1156 4 CONHCO NHPipra 2-1157 4 CONH-CO NHMor 2-1 158 4 CONHCO NIIThmor 2-1159 4 CONIS-1S0 Pyr 2-1160 4 CONH-S0 2 Pipri 2-1 161 4 CONH1S0 2 Pipra 2-1162 4 CON-HS0 2 Mor 2-1163 4 CONH-S02 Thmor 2-1164 4 CONH-S0 2 NHlPyr 2-1165 4 CONHS02 NHPipri 2-1166 4 CONHS02 NHPipra y:\wpdocs\.dgt_mss\981I2\981I2cpd2.doc 174- Table 2 (co-nti S S

S

S

S

S

*5SS 5555

S

Cpd. k A B

R

No. 2-1 167 4 CONH-S0 2 NHMor 2-1168 4 CONHS0 2 NH-Thmor 2-1169 4 NH-SO 2 NH Z-4 2-1170 4 NH{S02 -Me 2-1171 4 NHS0 2 -Et 2- 1172 4 NHS02 -Pr 2-1173 4 NHSO 2 CH2..Cl 2-1174 4 NI-SO-, Ph 2-1175 4 NH-SO-, 4-Me-Ph 2-1176 4 CO NMe Ph 2-1177 4 CO NMe 2-Me-Ph 2-1178 4 CO NMe 4-Me-Ph 2-1179 4 CO NMe 2,4-diMe-Ph 2-1180 4 CO NMe 3,4-diMe-Ph 2-1181 4 CO NMe 2-(CF 3 )Ph 2-1182 4 CO NMe 4-(CF 3 )Ph 2-1183 4 CO NMe 2-MeOPh 2-1184 4 CO NMe 4-MeOPh 2-1185 4 CO NMe 2-EtOPh 2- 1186 4 CO NMe 4-EtOPh 2-1187 4 CO NMe 2-HOPh 2-1188 4 CO e H h 2-1189 4 CO NMe 2-(H-OOC)Ph 2-1190 4 CO NMe 4-(HOOC)Ph 2-1 191 4 CO NMe 2MeOOC)Ph 2-1192 4 CO WeC 4-(MeOOC)Ph y:\wpdocs\dgtmss\9S I2\981 2cpd2.doc 175 Table 2 (conO.

S. S

S.

*SSS

S *5 S

*SSS

S

S

Cpd. k A B R 2-1193 T CO NMe 2-(EtOOC)Ph 2-1194 4 CO NMe 4-(EtOOC)Ph 2-1195 4 Co NMe 2-(tBuOOC)Ph 2-1196 4 Co NMe 4-(tBuOOC)Ph 2 -119 7 4 CO NMe 2-Cl-Ph 2-1 198 4 CO NMe 4-Cl-Ph 2-1199 T CO NMe 2-Br-Ph 2-1200 4 CO W~e 4-Br-Ph 2 -12 01 4 CO NMe 2-I-Ph 2-1202 4 CO NMe 4-I-Ph 2 -12 03 4 CO W~e 2-N0 2 -Ph 2-1204 4 CO W~e 4-N0 2 -Ph 2- 1205 4 CO NMe 2-NH- 2 -Ph 2-1206 4 CO NMe 4-NH- 2 -Ph 2-1207 4 CO NMe 2-(HO 3 S)Ph 2-1208 4 CO NMe 4-(HO 3 S)Ph 2-1209 4 CO NMe 2-(NH 2

O

2 S)Ph 2-1210 4 CO NMe 4-(NH 2

O

2 S)Ph 2-1211 4 CO NMe 2-CN-Ph 2-1212 4 CO NMe 4-CN-Ph 2-1213 4 CO NMe 2-(HOCH 2 )Ph 2-1214 4 CO NMe 4-(HOCH 2 )Ph 2-1215 4 CO NMe Me 2-1216 4 CO NMe Et 2-1217 4 CO WNe' Pr 2-1218 4 CO NWe iPr y:\wpdacs'dgt_ffiss\981I2\981I2cpd2.doc 176 Table2(cnt.)

S

*5 S S

S

4555 5.5

S

S5**55

S

Cpd. k A B R 2-1219 4 CO NWe Bu 2-1220 4 CO NWe HOOCCH 2 2-122 1 4 CO NMe MeOOCCH- 2-1222 4 CO NMe MeCH(COOR) 2-1223 4 CO NMe HOOC-(CH 2 2 2-1i224 4 CO NMe MeCH(COOMe) 2-1225 4 CO NWe I -HOOC-iBu 2-1226 4 Co NMe 1-MeOOC-iBu 2-1227 4 Co We 1-HOOC-iPn 2-1228 4 Co We 1-MeOOC-iPn 2-1229 4 CO We 1-HOOC-2-Me-Bu 2-1230 4 Co We 1-MeOOC-2-Me-Bu 2-1231 4 CO We CH 2

CH

2

SO

3

H

2-1232 4 Co We

OH

2-1233 4 CO We MeO 2-1234 4 CO We EtO 2-1235 4 CO We Pro 2-1236 4 CO We iPrO 2-1237 4 CO We BuO 2-1238 4 CO We iBuO 2-1239 4 CO We sBuO 2-1240 4 CO We tBuO 2-1241 4 CO We HxO 2-1242 4 CO NMe PhO 2-1243 4 CO We BnO 2-1244 4 CO We Z-1 2-1245 4 CO We Z-2 y:\wpdocs\dgtmffss\981I2\98 12cpd2.-doc 177- Table 2 (cot.)

C

C. C r 9*

C

C

C

C

C. C

S

CC

Cpd. k A B R No.

2-1246 4 CO NMe Z-3 2-1247 4 CO NMe Z-4 2-1248 4 CO NMe 2-1249 4 CO NMe Z-6 2-1250 4 CO NMe Z-7 2-1251 4 CO NMe Z-8 2-1252 4 CO NMe Z-9 2-1253 4 CO NMe 2-1254 4 CO NMe Z-1 2-1255 4 CO NMe Z-12 2-1256 4 CO NMe 3-Py 2-1257 4 CO NMe 4-Py 2-1258 4 CO Thiad 2-1259 4 CO NHThiad 2-1260 4 NICO Thiad 2-1261 4 NHCO NHThiad 2-1262 4 CONHCO Thiad 2-1263 4 CONHCO NHThiad 2-1264 4 CONHS0 2 Thiad 2-1265 4 CONHSO 2 NHThiad 2-1266 4 NiCS NH

H

2-1267 4 NICS NH Me 2-1268 4 NHCS NH Et 2-1269 4 NHCS NH Ph 2-1270 4 NHCS NH HOOCCH2- 2-1271 4 NHCS NH MeOOCCH2- 2-1272 4 NHCS NH MeCH(COOH) y:\wpdocs\dgtjnss\98 12\981 2cpd2.doc 178- Table 2 (cont.) 0 0@S0 0* S. 0S 56 0 0ss@ @6 6 6 6

S

6 0

*OO

Cpd. k A B R No.

2-1273 T NHCS NH HOOC-(CH 2 2 2-1274 4 NICS NH MeCH(COOMe) 2-1275 4 CO NH HOOC-(CH 2 3 2-1276 4 NICO Ni HOOC-(CH 2 3 2-1277 4 NHCO HOOC-(CH 2 3 2-1278 4 NHCS NH HOOC-(CH 2 3 2-1279 4 CO Ni MeSO 2 NHCOCH(Me) 2-1280 4 NHCO Ni MeS0 2 NHCOCH(Me) 2-1281 4 NHCO MeSO 2 NHCOCH(Me) 2-1282 4 NHCS NH MeSO 2 NHCOCH(Me) 2-1283 4 NH HOOCCH 2 2-1284 4 Ni MeOOCCH2- 2-1285 4 NH MeCH(COOH) 2-1286 4 NH HOOC-(CH 2 )2- 2-1287 4 NH MeCH(COOMe) 2-1288 4 NH HOOC-(CH2)3- 2-1289 4 NHCOCO

OH

2-1290 4 NICOCO MeG 2-1291 4 NliCOCO EtO 2-1292 4 NHCOCO PrO 2-1293 4 NICOCO iPrO 2-1294 4 N-COCO BuG 2-1295 4 N-COCO iBuG 2-1296 4 NHCOCO sBuO 2-1297 4NHCGCO tBuO 2-1298 4 NHCOCO HxO y:\wpdocs\dgt_mss\9812\ 98 1 2cpd2.doc 179- Table 2 (cont.) Cpd. k A B Rl No. 2-1299 4 NHCOCO PhO 2-1300 4 NHCOCO BnO 2-1301 5 Co NiH

H

2-1302 5 Co NH Ph 2-1303 5 Co NH 2-Me-Ph 2-1304 5 CO NH 4-Me-Ph 2-1305 5 Co NH 2,4-diMe-Ph 2-1306 5 Co NH 3,4-diMe-Ph 2-1307 5 CO NH 2-(CF 3 )Ph 2-1308 5 CO NH 4-(CF 3 )Ph 2-1309 5 Co NH 2-MeOPh 2-1310 5 CO NH 4-MeOPh 2-1311 5 Co NH 2-EtOPh 2-1312 5 Co NH 4-EtOPh 2-1313 5 CO NH 2-HOPh 2-1314 5 Co NH 4-HOPh 2-1315 5 Co NH 2-(HOOC)Ph 2-1316 5 CO NH 4-(HOOC)Ph 2-1317 5 CO NH 2-(MeOOC)Ph 2-1318 5 CO NH 4-(MeOOC)Ph 2-1319 5 CO NH 2-(EtOOC)Ph 2-1320 5 CO NH 4-(EtOOC)Ph 2-1321 5 CO NH 2-(tBuOOC)Ph 2-1322 5 CO NH 4-(tBuOOC)Ph 2 -1323 5 CO NH 2-Cl-Ph 2-1324 5 CO NH 4-Cl-Ph 2-1325 5 Co NH 2-Br-Ph y:\wpdocs\dgtmss\981I2\981I2cpd2 .doc 180- Table 2(coD~ Cpd. k A B Rl No.

2-1326 5 CO NH 4-Br-Ph 2-1327 5 jCO NH 2-I-Ph 2-1328 5 CO NH 4-I-Ph 2-1329 5 Co NH 2-N0 2 -Ph 2-1330 5 CO NH 4-N0 2 -Ph 241331 5 CO NH 2-NH 2 -Ph 2-1332 5 Co NH 4-NH 2 -h 2-1333 5 CO NH 2-(HO 3 S)Ph 2-1334 5 CO NH 4-(HO 3 S)Ph 2-33 5* 2-1336 5 CO NH 2-(NH 2

O

2 S)Ph 2-1336 5 CO NH 4-N 2 2 Ph *2-1337 5 CO NH 2-CN-Ph 2-1339 5 CO NH 2-(HOCH 2 )Ph 2-1340 5 CO0 NH 4-(HOCH 2 )Ph 2-1341 5 CO0 NH Me :2-1342 5 CO0 NH Et 2-1343 5 CO NH Pr 2-1344 5 CO NH- iPr 2-1345 5 CO NH Bu 2-1346 5 CO NH- H-OOCCH2- 2-1347 5 CO NH- MeOOCCH2- 2-1348 5 CO NHl MeCH(COOH) 2-1349 5 CO NH- HOOC-(CH2)2- 2-1350 5 CO NH MeCH(COOMe) 2-1351 5 CONH1OCiu y.\wpdacs\dgt_mss\981I2\981 2cpd2.doc a 181 TableZAQftJ Cpd. k A B

R

2-1352 5 Co NH 1-MeOOC-iBu 2-1353 5 Co NH{ 1-HOOC-iPn 2-1354 5 CO NH 1-MeOOC-iPn 2-1355 5 Co NH 1-HOOC-2-Me-Bu 2-1356 5 CO NH 1-MeOOC-2-Me-Bu 2-1357 5 CO NH

CH

2

CH

2 SO3H 2-1358 5 CO NH

OH

2-1359 5 Co NH MeO 2-1360 5 CO NH EtO 2-1361 5 co NH Pro 2-1362 5 Co NH iPrO 2-1363 5 CO NH BuO 2-1364 5 CO NH iBuO 2-1365 5 CO NH sBuO 2-1366 5 CO NH tBuO 2-1367 5 CO NH HxO 2-1368 5 CO NH PhO 2-1369 5 CO NH BnO 2-1370 5 CO NH Z-1 2-32 5CO NIL Z-3 2-37 5CO NE Z-8 2-38 5CO NH Z-9 y:\wpdocs\dgt_Tnss\981I2\981I2cpd2 .doc 182 Table 2 (cont.) Cpd. k A B R No. 2-1379 5 CO NH 2-1380 5 CO NH Z-1 1 2-1381 5 CO NH Z-12 2-1382 5 CO NH 3-Py 2-1383 5 Co NH 4-Py 2-1384 5 CO N(Ac)

H

2-1385 5 CO N(Ac) Ph 2-1386 5 CO N(Ac) 2-Me-Ph 2-1387 5 CO N(Ac) 4-Me-Ph 2-1388 5 CO N(Ac) 2,4-diMe-Ph 2-1389 5 CO N(Ac) 3,4-diMe-Ph 2-1390 5 CO N(Ac) 2-(CF 3 )Ph 2-1391 5 CO N(Ac) 4-(CF 3 )Ph 2-1392 5 CO N(Ac) 2-MeOPh 2-1393 5 CO N(Ac) 4-MeOPh 2-1394 5 CO N(Ac) 2-EtOPh 2-1395 7 CO N(Ac) 4-EtOPh 2-1396 5 CO N(Ac) 2-HOPh 2-1397 5 CO N(Ac) 4-HOPh 2-1398 5 CO N(Ac) 2-(HOOC)Ph 2-1399 7 CO N(Ac) 4-(HOOC)Ph 2-1400 5 CO N(Ac) 2-(MeOOC)Ph 2-1401 5 CO N(Ac) 4-(MeOOC)Ph 2-1402 5 CO N(Ac) 2-(EtOOC)Ph 2-1403 7 CO N(Ac) 4-(EtOOC)Ph 2-1404 5 CO N(Ac) 2-(tBuOOC)Ph 2-1405 5 CO N(Ac) 4-(tBuOOC)Ph y:\wpdocs\dgt_ms\9812\98I 2cpd2.dac 183 Tabe (ImJ Cpd. k A B

R

2-1406 5 CO N(Ac) 2-Cl-Ph 2-1407 5 CO N(Ac) 4-Cl-Ph 2-1408 5 CO N(Ac) 2-Br-Ph 2-1409 5 CO N(Ac) 4-Br-Ph 2-1410 5 CO N(Ac) 2-I-Ph 2-1411 5 CO N(Ac) 4-I-Ph 2-1412 5 CO N(Ac) 2-N0 2 -Ph 2-1413 5 CO N(Ac) 4-N0 2 -Ph 2-1414 5 CO N(Ac) 2-NH 2 -Ph 2-1415 5 CO N(Ac) 4-NH 2 -Ph 2-1416 5 CO N(Ac) 2-(HO 3 S)Ph 2-1417 5 CO N(Ac) 4-(HO 3 S)Ph 2-1418 5 CO N(Ac) 2-(NH 2

O

2 S)Ph 2-1419 5 CO N(Ac) 4-(NH 2

O

2 S)Ph 2-1420 5 CO N(Ac) 2-CN-Ph 2-1421 5 CO N(Ac) 4-CN-Ph 2-1422 5 CO N(Ac) 2-(HOCH 2 )Ph 2-1423 5 CO N(Ac) 4-(HOCH 2 )Ph 2-1424 5 CO N(Ac) Me 2-1425 5 CO N(Ac) Et 2-1426 5 CO N(Ac) Pr 2-1427 5 CO N(Ac) iPr 2-1428 5 CO N(Ac) Bu 2-1429 5 CO N(Ac) HOCCH2- 2-1430 5 CO N(Ac) MeOOCCEI2- 2-1431 5 1c MeCH(COOH) y:\wpdocs'dgtms\981I2\981I2cpd2.doc 184 Cpd. k A B Rl 2-1432 5 CO N(Ac) HOOC-(CH 2 2 2-1433 5 CO N(Ac) MeCH(COOMe) 2-1434 5 co N(Ac) 1-HOOC-iBu 2-1435 5 Co N(Ac) 1-MeOOC-iBu 2-1436 5 Co N(Ac) 1-HOOC-iPn 2-1437 5 CO N(Ac) 1-MeOOC-iPn 2-1438 5 Co N(Ac) 1-HOOC-2-Me-Bu 2-1439 5 Co N(Ac) 1-MeOOC-2-Me-Bu 2-1440 5 Co N(Ac) CH 2

CH

2

SO

3

H

2-1441 5 Co N(Ac)

OH

2-1442 5 Co N(Ac) MeO 2-1443 5 CO N(Ac) EtO 2-1444 5 Co N(Ac) Pro 2-1445 5 CO N(Ac) zPrO 2-1446 5 Co N(Ac) BuO 2-1447 5 CO N(Ac) iBuO 2-1448 5 CO N(Ac) sBuO 2-1449 7 CO N(Ac) tBuO 2-1450 5 CO N(Ac) HxO 2-1451 5 CO N(Ac) PhO 2-1452 5 CO N(Ac) BnO 2-1453 5 CO N(Ac) Z-1 2-1454 5 CO N(Ac) Z-2 2-1455 5 CO N(Ac) Z-3 2-1456 5 CO N(Ac) Z-4 2-1457 7 CO N(Ac) 2-1458 5 CO N(Ac) Z-6 y:\wpdocs\dgt_mss\981I2\981I2cpd2 .doc 185 Table2 cot.

Cpd. k A B R No. 2-1459 5 CO N(Ac) Z-7 2-1460 5 CO N(Ac) Z-8 2-1461 7 CO N(Ac) Z-9 2-1462 5 CO N(Ac) 2-1463 5 CO N(Ac) Z-11I 2-1464 7 CO N(Ac) Z-12 2-1465 5 Co N(Ac) 3-Py 2-1466 7 CO N(Ac) 4-Py 2-1467 5 coo

H

2-1468 5 coo Ph 2-1469 5 coo 2-Me-Ph 2-1470 5 COO 4-Me-Ph 2-1471 5 coo 2,4-diMe-Ph 2-1472 5 COO 3,4-diMe-Ph 2-1473 5 coo 2-(CF 3 )Ph 2-1474 5 coo 4-(CF 3 )Ph 2-1475 5 coo 2-MeOPh 2-1476 5 COO 4-MeOPh 2-1477 5 coo 2-EtOPh 2-1478 5 coo 4-EtOPh 2-1479 5 coo 2-HOPh 2-1480 5 coo 4-HOPh 2-148 1 5 coo- 2-(HOOC)Ph 2-1482 5 coo 4-(HOOC)Ph 2-1483 5 coo 2-(MeOOC)Ph 2-1484 7 coo 4-(MeOOC)Ph 2-1485 5 coo 2-(EtOOC)Ph y:\wpdocs\dgtffmss\9S12\981 2cpd2.dac 186- Table 2 [cont.) Cpd. k A B

R

2-1486 5 coo 4-(EtOOC)Ph 2-1487 5 COO 2-(tBuOOC)Ph 2-1488 5 COO 4-(tBuOOC)Ph 2-1489 5 coo -2-Cl-Ph 2-1490 5 coo 4-Cl-Ph 2-J491 5 coo 2-Br-Ph 2-1492 5 COO 4-Br-Ph 2-1493 5 COO 2-I-Ph 2-1494 5 coo -4-I-Ph 2-1495 5 COO 2-N0 2 -Ph 2-1496 5 COO 4-N0 2 -Ph 2-1497 5 COO 2-NH- 2 -Ph 2-1498 5 COO 4-NIH 2 -Ph 2-1499 5 COO 2-(HO 3 S)Ph 2-1500 5 coo 4-(HO 3 S)Ph 2-1501 5 coo 2-(N11 2 0 2 S)Ph 2-1502 5 coo 4-(NH 2 0 2 S)Ph 2-1503 5 coo 2-CN-Ph 2-1504 5 coo -4-CN-Ph 2-1505 5 coo 2-(HOCH 2 )Ph 2-1506 5 coo 4-(HOCH- 2 )Ph 2-1507 5 coo Me 2-1508 5 coo Et 2-1509 7 coo Pr 2-1510 5 COO iPr 2-1511 5 COO Bu y:\wpdocs\dgt_mfss\981I2\981 2cpd2.doc 187 Tabl (cnt.) Cpd. k A B

R

No. 2-1512 5coo -HOOCCH 2 2-1513 5 coo- HOOC-(CH2)2- 2-1514 5 COO- MeCH(COOMe) 2-1515 5 coo 1-HOOC-iBu 2-1516 5 coo 1-HOOC-iPn 2-1517 5 coo Z1 2-1518 5 coo

Z-

2-1519 5 coo

Z-

2-1520 5 COO

Z-

2-1521 5 coo 2-1522 5 coo Z-6 2-1523 5 coo Z-7 2-1524 5 coo -Z-8 2-1525 5 coo -Z-9 2-1526 5 coo 2-1527 5 coo Z11 2-1528 5 coo 12 2-1529 5 coo -3-Py 2-1530 5 COO 4-Py 2-1531 5 COM-ICO

H

2-1532 5 CONHCO Ph 2-1533 5 CONHCO 2-Me-Ph 2-1534 5 CONBCO 4-Me-Ph 2-1535 5 CONH-CO- 2,4-diMe-Ph 2-1536 5 CONliCO- 3,4-diMe-Ph [2-1537 5 CONHCO 2-(CF 3 )Ph y:\wpdocs\dgt_ ms\9812\ 98 1 2cpd2.doc 188- Table 2 (conti e Cpd. k A B R No. 2-1538 5 CONHCO 4-(CF 3 )Ph 2-1539 5 CONHCO 2-MeOPh 2-1540 5 CONHCO 4-MeOPh 2-1541 5 CONTICO -2-EtOPh 2-1542 5 CONIICO -4-EtOPh 2-1543 5 CONlICO -2-HOPh 2-1544 5 CONHCO -4-HOPh 2-1545 5 CONHCO 2-(HOOC)Ph 2-1546 5 CONHCO 4-(HOOC)Ph 2-1547 5 CONHCO 2-(MeOOC)Ph 2-1548 5 CONHCO 4-(MeOOC)Ph 2-1549 5 CONHCO 2-(EtOOC)Ph 2-1550 5 CONH-CO 4-(EtOOC)Ph 2-1551 5 CONi-CO 2-(tBuOOC)Ph 2-1552 5 CONI-CO 4-(tBuOOC)Ph 2-1553 5 CONHCO -2-Cl-Ph 2-1554 5 CONHCO -4-Cl-Ph 2-1555 5 CONHCO -2-Br-Ph 2-1556 5 CONi-CO -4-Br-Ph 2-1557 5 CONIICO -2-I-Ph 2-1558 5 CONHCO -4-I-Ph 2-1559 5 CONHCO 2-N0 2 -Ph 2-1560 5 CONIICO 4-N0 2 -Ph 2-1561 5 CONH-CO 2-NH 2 -Ph 2-1562 5 CONHCO 4-NH 2 -Ph 2-1563 5 CONHCO 2-(HO 3 S)Ph y:\-pdocs\dgtmss\981 2\981I2cpd2.doc 189- Table (cnt.) Cpd. k A B

R

2-1564 5 CONHCO 4-(HO 3 S)Ph 2-1565 5 CONHCO 2-(NH 2

O

2 S)Ph 2-1566 5 CONHCO 4-(NH 2

O

2 S)Ph 2-1567 5 CONHCO 2-CN-Ph 2-1568 5 CONHCO 4-CN-Ph 2-1569 5 CONHCO 2-(HOCH 2 )Ph 2-1570 5 CONHCO 4-(HOCH 2 )Ph *:.2-1571 5 CONI-CO Me .0:2-1572 5 CONI-CO Et 2-57 5 COHO-P 2-1573 5 CONHCO iPr 2-1574 5 CONHCO Bur 2-1576 5 CONHCO

HOOCCH

2 *2-1577 5 CONI-CO MeOOCCH2- 2-1578 5 CONH-CO MeCH(COOH) 2-1579 5 CONHCO HOOC-(CH2)2- 2-1580 5 CONI-CO MeCH(COOMe) 2-1581 5 CONHCO 1-HOOC-iBu 2-1582 5 CONHCO 1-MeOOC-iBu 2-1583 5 CONHCO 1-HOOC-iPn 2-1584 5 CONHCO -MeOOC-iPn 2-1585 5 CONHCO -1-HOOC-2-Me-Bu 2-1586 5 CONH-CO -MeOOC-2-Me-Bu 2-1587 5 CONHCO -CH)CH-)SO3H 2-1588 5 CONHCO .Z-1 2-1589 5 CONHCO Z-2 y:\wpdocs'.dgt-rms\981I2\981I2cpd2.doc -190- Table2 1 -nWI Cpd. k A B R 2-1 590 5 CONI-CO Z-3 2-1591 5 CONHCO -Z-4 2-1592 5 CONHCO 2-1593 5 CONH-CO -Z-6 2-1594 5 CONIICO -Z-7 2-.1595 5 CONH-CO -Z-8 2-1596 5 CONHCO -Z-9 2-1597 5 CONITCO 2-1598 5 CONIICO -Z-1 1 2-1599 5 CONI-CO 12 2-1600 5 CONH-CO -3-Py 2-1601 5 CONi-CO -4-Py 2-1602 5 CON(Ac)CO -H 2-1603 5 CON(Ac)CO -Ph 2-1604 5 CON(Ac)CO -2-Me-Ph 2-1605 5 CON(Ac)CO -4-Me-Ph 2-1606 5 CON(Ac)CO 2,4-diMe-Ph 2-1607 5 CON(Ac)CO 3,4-diMe-Ph 2-1608 5 CON(Ac)CO 2-(CF 3 )Ph 2-1609 5 CON(Ac)CO 4-(CF 3 )Ph 2-1610 5 CON(Ac)CO -2-MeOPh 2-16 11 5 CON(Ac)CO -4-MeOPh 2-1612 5 CON(Ac)CO -2-EtOPh 2-1613 5 CON(Ac)CO -4-EtOPh 2-1614 5 CON(Ac)CO -2-HOPh 2-1615 5 CON(Ac)CO 4-HOPh 2-1616 5 CON(Ac)CO -2-(HOOC)Ph y:\wpdocs\dgt_ms\9812\9 81 2cpd2.doc -191 Cpd. k A B

R

2-1617 5 CON(Ac)CO 4-(HOOC)Ph 2-1618 5 CON(Ac)CO 2-(MeOOC)Ph 2-1619 5 CON(Ac)CO 4-(MeOOC)Ph 2-1620 5 CON(Ac)CO 2-(EtOOC)Ph 2-1621 5 CON(Ac)CO 4-(EtOOC)Ph 2-1622 5 CON(Ac)CO 2-(tBuOOC)Ph 2-1623 5 CON(Ac)CO 4-(tBuOOC)Ph 2-1624 5 CON(Ac)CO -2-Cl-Ph 2-1625 5 CON(Ac)CO -4-Cl-Ph 2-1626 5 CON(Ac)CO -2-Br-Ph 2-1627 5 CON(Ac)CO -4-Br-Ph 2-1628 5 CON(Ac)CO -2-I-Ph 2-1629 5 CON(Ac)CO -4-I-Ph 2-1630 5 CON(Ac)CO 2-N0 2 -Ph 2-1631 5 CON(Ac)CO 4-N0 2 -Ph 2-1632 5 CON(Ac)CO 2-N11 2 -Ph 2-1633 5 CON(Ac)CO 4-NH 2 -Ph 2-1634 5 CON(Ac)CO 2-(HO 3 S)Ph 2-1635 5 CON(Ac)CO 4-(HO 3 S)Ph 2-1636 5 CON(Ac)CO 2-(NI- 2 0 2 S)Ph 2-1637 5 CON(Ac)CO 4-(NI1 2 0 2 S)Ph 2-1638 5 CON(Ac)CO -2-CN-Ph 2-1639 5 CON(Ac)CO -4-CN-Ph 2-1640 5 CON(Ac)CO 2-(HOCH 2 )Ph 2-1641 5 CON(Ac)CO 4-(HOCH 2 )Ph 2-1642 5 CON(Ac)CO -Me 0* 0* y:\wpdocs\dgt_miss\981I2\981I2cpd2.doc 192 Tabl 2(cnt) Cpd. k A B R No. 2-1643 5 CON(Ac)CO -Et 2-1644 5 CON(Ac)CO -Pr 2-1645 5 CON(Ac)CO -iPr 2-1646 5 CON(Ac)CO -Bu 2-1647 5 CON(Ac)CO HOOCCH 2 2-1648 5 CON(Ac)CO MeOOCCH 2 2-1649 5 CON(Ac)CO MeCH(COOH) 2-1650 5 CON(Ac)CO HOOC-(CH 2 )2- 2-1651 5 CON(Ac)CO MeCH(COOMe) 2-1652 5 CON(Ac)CO 1-HOOC-iBu 2-1653 5 CON(Ac)CO 1-MeOOC-iBu 2-1654 5 CON(Ac)CO I1-HOOC-iPn 2-1655 5 CON(Ac)CO 1-MeOOC-iPn 2-1656 5 CON(Ac)CO 1-HOOC-2-Me-Bu 2-1657 5 CON(Ac)CO 1-MeOOC-2-Me-Bu 2-1658 5 CON(Ac)CO CH 2

CH

2

SO

3

H

2-1659 5 CON(Ac)CO -Z-1I 2-1660 5 CON(Ac)CO -Z-2 2-1661 5 CON(Ac)CO -Z-3 2-1662 5 CON(Ac)CO -Z-4 2-1663 5 CON(Ac)CO 2-1664 5 CON(Ac)CO -Z-6 2-1665 5 CON(Ac)CO -Z-7 2-1666 7 CON(Ac)CO Z-8 2-1667 5 CON(Ac)CO Z-9 2-1668 151 CON(Ac)CO y:\wpdocs\dgt-fmss\981I2\981I2cpd2.doc 193 Tabl2(conI

.OS

a S. *5 a a a a a a Cpd. k A B R No.

2-1669 5 CON(Ac)CO -Z-1 1 2-1670 5 CON(Ac)CO 12 2-1671 5 CON(Ac)CO -3-Py 2-1672 5 CON(Ac)CO -4-Py 2-1673 5 CONHCO NH H 2-1674 5 CONHCO NH Ph 2-1675 5 CONIICO NH 2-Me-Ph 2-1676 5 CONHCO NE 4-Me-Ph 2-1677 5 CONHCO NH- 2,4-diMe-Ph 2-1678 5 CONE-CO NH 3,4-diMe-Ph 2-1679 5 CONHCO NH 2-(CF 3 )Ph 2-1680 5 CONHCO NHl 4-(CF 3 )Ph 2-1681 5 CONHCO NH 2-MeOPh 2-1682 7 CONHCO NH 4-MeOPh 2-1683 5 CONECO NH 2-EtOPh 2-1684 5 CONH-CO NH 4-EtOPh 2-1685 5 CONHCO NH 2-HOPh 2-1686 5 CONECO NH 4-HOPh 2-1687 5 CONHCO NH 2-(HOOC)Ph 2-1688 7 CONIHCO NH 4-(HOOC)Ph 2-1689 5 CONECO NH 2-(MeOOC)Ph 2-1690 5 CONECO NH 4-(MeOOC)Ph 2-1691 5 CONECO NH 2-(EtOOC)Ph 2-1692 7 CONHCO NH 4-(EtOOC)Ph 2-1693 5 CONHCO NH 2-(tBuOOC)Ph 2-1694 5 CONHCO NH 4-(tBuOOC)Ph 2-1695 5 CONHCO NH 2-Cl-Ph y:\wpdocs\dgt_ ms\981I2\98 I2cpd2.doc 194 Cpd. k A B R 2-1696 5 CONHCO NiH 4-Cl-Ph 2-1697 5 CONHCO Nil 2-Br-Ph 2-1698 5 CONHCO NH 4-Br-Ph 2-1699 5 CONilCO NH 2-I-Ph 2-1700 5 CONHCO NHl 4-I-Ph 2-1701 5 CONH-CO Nil 2-N0 2 -Ph 2-1702 5 CONH-CO Nil 4-N0 2 -Ph 0:.:2-1703 5CONHCO NH 2-Nil 2 -Ph 2-170 5 2-1704 5 CONHCO NH -Nil 2 -Ph -70 OHON 4(OSP 2-1705 5 CONHCO NH 2-(HO 3 S)Ph 2-1706 5 CONHCO NH 4-(NHO 3 S)Ph 2-1707 5 CONHCO NH 2-N-OPh 2-1710 5 CONHCO NH 4-N-OPh **2-1709 5 CONI-CO NH 2-HC-Ph 71 2-1710 5 CONHCO NH 4MCeP 2-1711 5 CONHCO NH EtHOH 2

P

2-1712 5 CONH-CO NH- 4-HOCH 2

P

2-1713 5 CONI-ICO Nil MeOC 2-1715 5 CONH-CO NH PrHCOH 2-17;1 5 CONHCO NH HOOC-(CH 2 2 y:\wpdocs\dgt mfss\981I2\981 2cpd2.doc 195 Cpd. k A B

R

2-1722 5 CONHCO NH MeCH(COOMe) 2-1723 5 cONHCO NH 1-HOOC-iBu 2-1724 5 CONHCO NH 1-MeOOC-iBu 2-1725 5 CONHCO NE 1-HOOC-iPn 2-1726 5 CONHCO Nil 1-MeOOC-iPn 2-1727 5 CONHCO NH 1HOC-2-Me-Bu 2-1728 5 CONHCO NH I-MeOOC-2-Me-Bu 2-1729 5 CONHCO NH

CH

2

CH

2 SO3H 2-1730 5 CONHCO NH

HO

2-1731 5 CONH-CO NH MeO 2-1732 5 CONHCO NH EtO 2-1733 5 CONHCO NH PrO 2-1734 5 CONBCO NH iPrO 2-1735 5 CONHCO NH BuO 2-1736 5 CONHCO NH iBuO 2-1737 5 CONHCO NH sBuO 2-1738 5 CONI-CO NHu 2-1739 5 CONI-CO NH x 2-1740 5 CONHCO NH h 2-1741 5 CONHCO N n 2-1745 5 CONE-CO NH 1 2-1746 7 CONI-CO NH Z-2 2-1747 5 CONHCO NH Z-3 2-1745 5 CONH-CO NH Z-7 y:\wpdocs\dgt_mns\981I2\981I2cpd2.dAm 196 Ta (oL *C Cpd. k A B R 2-1749 5 CONHCO NH Z-8 2-1750 5 CONilCO NHl Z-9 2-1751 7 CONilCO NiH 2-1752 5 CONHCO NiH Z-11 2-1753 5 CONilCO NHl Z- 12 2-1754 5 CONHCO NHl 3-Py 2-1755 5 CONilCO NHl 4-Py 2-1756 5 CONHlS0 2

H

2-1757 5 CONilSO 2 Ph 2-1758 5 CONHS0 2 2-Me-Ph 2-1759 7 CONHSO-, 4-Me-Ph 2-1760 5 CONilSO', 2,4-diMe-Ph 2-1761 5 CONHS02, 3,4-diMe-Ph 2-1762 5 CONHSO 2 2-(CF 3 )Ph 2-1763 5 CONH-S02 4-(CF 3 )Ph 2-1764 7 CONIISO2) 2-MeOPh 2-1765 7 CONH-S02 4-MeOPh 2-1766 7 CONilSO2) 2-EtOPh 2-1767 5 CONHS02 4-EtOPh 2-1768 5 CONHSO 2 2-HOPh 2-1769 7 CONHS02 4-HOPh 2-1770 7 CONHS02 2-(HOOC)Ph 2-1771 7 CONHlS02 4-(HOOC)Ph 2-1772 5 CONHlS02 2-(MeOOC)Ph 2-1773 5 CONHlS0 2 -4-(MeOOC)Ph y:\wpdocs\d gtmss\981I2\981 2cpd2.-doc 197 Tabl 2(cnt.) Cpd. k A B Rl N o. -E O C P 2-1774 5 CONHS02-2(EOCP 2-1775 -5 CONHS02 4-(EtOOC)Ph 2-1776 5 CONH~S02 2-(tBuOOC)Ph 2-1777 5 CONH{S02 4-(tBuOOC)Ph 2-1778 5 CONI{S02 -2-Cl-Ph 2-1779 5 CONHS02 -4-Cl-Ph 2-1780 5 CONHS02 -2-Br-Ph 2-1781 5 CONHS0 2 -4-Br-Ph 2-1782 5 CONHS0 2 -2-I-Ph 2-1783 5 CONHIS02 -4-I-Ph 2-1784 5 CONH-S02 2-N0 2 -Ph 2-1785 5 CONHS02 4-N0 2 -Ph 2-1786 5 CONHS-1S0 2-NH 2 -Ph 2- 1787 5 CONHSO 2 4-NH- 2 -Ph 2- 1788 5 CONHSO 2 2-(HO 3 S)Ph 2-1789 5 CONHS0 2 4-(HO 3 S)Ph 2-1790 5 CONHSO? 2-(NH 2

O

2 S)Ph 2-1791 5 CONHS02 4-(NH 2

O

2 S)Ph 2-1792 5 CONHS-1S02 2-CN-Ph 2-1793 5 CONHSO2) 4-CN-Ph 2-1794 5 CONHS0 2 2-(HOCH 2 )Ph 2-1795 5 CONH-S0 2 4-(HOCH 2 )Ph 2-1796 5 CONHS0 2 -Me 2-17 97 5 CONHS0 2 IEt y:\wpdocs\dgt_mfss\ 98 1I2\981I2cpd2.doc 198 Cpd. k A B R No. 2-1798 5 CONI-1S0 2 Pr 2-1799 5 CONHS0 2 iPr 2-1800 5 CONHS0 2 Bu 2-1801 5 CONHIS0 2

HOOCCH

2 2-1802 5 CONHS0 2 MeOOCCH 2 2-1803 5 CONHS0 2 MeCH(COOH) ooo2-1804 5 CON7HS0 2

HOOC-(CH

2 2 *2-1805 5 CONH-S0 2 MeCH(COOMe) 2-86 ON-S0

I-OO*~

2-1807 5 CONH-S0 2 1-MeOOC-iBu *o 2-1808 5 CONH-S02 -HeOOC-i~n 2-1809 5 CONHS02 1-MeOOC-iPn 2-180 5 CONH-S02- 1-OOC-M-B 2-1811 7 CONHS02 1-MeOOC-2-Me-Bu *:2-1812 5 CONHS02

CH

2

CH

2

SO

3

H

2-1813 5 CONHSO?

OH

2-1814 5 CONHSO2) MeO 2-1815 5 CON-HSOy EtO 2-1816 7 CONH-SO', Pro 2-1817 5 CONHS-1S02 iPrO 2-1818 5 CONH-S0 2 -BuO 2-1819 5 CONH1S0 2 -iBuO 2-1820 5 CONHS0 2 -sBuO 2-182 1 5 CONH-S0 2 -tBuO y:\wpdocs\dgt-mss\ 98 1 2\98I2cpd2.doc 199 Table 2 (cont.) Cpd. k A B Rl 2-1822 5 CONHS0 2 HxO 2 1823 -5 CONHS0 2 PhO 2-1824 5 CONHS0 2 BnO 2-1825 5 CONHS0 2 Z-1 2-1826 .5 CONHS0 2 Z-2 2-1827 5 CONI-S0 2 -Z-3 2-1828 5 CONHSO2 -Z-4 2-1829 5 CONHIS02 2-1830 5 CONHS0 2 -Z-6 2-1831 5 CONH-S0 2 -Z-7 2-1832 5 CONHS0 2 -Z-8 2-1833 5 CONHSO 2 Z-9 2-1834 5 CONHSO 2 Z- 2-1835 5 CONILSO-, Z-1 I 2-1836 5 CONHS-{S2 Z-712 2-1837 5 CON1-S0 2 -3-Py 2-1838 5 CONH-S0 2 -4-Py 2-1839 5 CONH-S02 NH

H

2-1840 5 CONHS0 2 NH- Ph 2-1841 5 CONH-S02 NH- 2-Me-Ph 2-1842 5 CONHS0 2 NH 4-Me-Ph 2-1843 5 CONH-S0 2 NH- 2,4-diMe-Ph 2-1844 5 CONHS0 2 NH 3;4-diMe-Ph 2-1845 5 CONHS0 2 NHl 2-(CF 3 )Ph y:\wpdocs\dgt-mss\981I2\981I2cpd2 .doc 200 Table 2 (cnt.) Cpd. k A B

R

2-1846 5 CONHS02 NH 4-(CF 3 )Ph 2-187 7 COKSO2NH 2-MeOPh 2-1848 5

CONHS

2 NHl 4-MeOPh 2-1849 5 CONHS0 2 N -t~ 2-1849 5 CONHLS0 2 NH 4-EtOPh 2-1851 5 CONHS02 NH 2-EtOPh 2-1852 5 CONHS0 2 NH 4-HOPh 2-1852 5 CONHS0 2 NH 2-HOPh 2-1854 5 CONHIS02 NH 4-(HOOC)Ph 2-1854 5 CONHS0 2 NH 2-(MeOOC)Ph 2-1856 5 CONHS02 NH 4-(MeOOC)Ph 2-1856 5 CONHS02 NH 2-(MeOOC)Ph 2-1858 5 CONHS02 NH 4-(EtOOC)Ph 2-1859 5 CONHS02 NH 2-(tuOOC)Ph 2-1860 5 CONHS02 NH- 4-(tBuOOC)Ph 2-1 861 5 CONH-S0 2 NH- -uOCl-Ph 2-1862 5 CONHSO2) NH 4-Cl-Ph 2-1862 7 CONHS02 NH 2-Br-Ph 2-1864 5 CONHS02 NH 4-Br-Ph 2-1865 5 CONHS0 2 NH -I-Ph 2-1866 5 CONH-S0 2 NH 4-I-Ph 2-1867 7 CONHS02 NH 2-N0 2 -Ph 2-1868 7 CONHS02 NH 4-N0 2 -Ph 2-1869 5 CONHS0 2 NH 2-NH 2 -Ph y:\wpdocs\dgt_mss\981 2\981 2cpd2.doc -201- Cpd. k A B

R

2-1870 5 CONHS0 2 NH 4-NH 2 -Ph 2-1871 5 CONHS0 2 NH 2-(HO 3 S)Ph 2-1872 5 CONHS0 2 NH 4-(HO 3 S)Ph 2-1873 5 CONHS02 NH 2-(NH 2

O

2 S)Ph 2-1874 5 CONHS0 2 NH 4-(NH 2

O

2 S)Ph 2-1875 5 CONHS0 2 NH 2-CN-Ph 2-1876 5 CONHSO 2 NH 4-CN-Ph 2-1877 5 CONHSO 2 NH 2-(HOCH 2 )Ph 2-1878 5 CONH-S02) NH 4-(HOCH 2 )Ph 2-1879 5 CONHS02 NH Me 2-1880 5 CONHS0 2 NH Et 2-1881 5 CON1S-1S0 NH Pr 2-1882 5 CONHS02 NH iPr 2-1883 7 CONHS0 2 NH Bu 2-1884 5 CONIISO2) NH HOOCCH 2 2-1885 5 CONHS0 2 NH MeOOCCH2- 2-1886 5 CONHS0 2 NH MeCH(COOH) 2-1887 7 CONES-1S0 NH HOOC-(CH 2 )2- 2-1888 5 CONi-SO-, NH MeCH(COOMe) 2-1889 5 CONHS02 NH 1-HOOC-iBu 2- 1890 5 CONHSO-2 NH 1-MeOOC-iBu 2-1891 5 CONHS0 2 NH 1-HOOC-iPn 2-1892 7 CONH-S02 NH 1-MeOOC-iPn 2-1893 7 CONHS02 NH 1-HOOC-2-Me-Bu y:\wpdocs\dgt_mfss\981I2\981I2cpd2.doc 202 Tal2(cnt.) Cpd. k A BR No.

2-1894 5 CONHS0 2 NH- I-MeOOC-2-Me-Bu 2-1895 5 CONH-S02 Nil CH 2

CH

2

SO

3

H

2-1896 5 CONHS02 NH OH 2-1897 5 CONHIS0 2 NH MeO 2-1898 5 CONH1S0 2 NH EtO 2-1899 5 CONHS0 2 NH Pro 2-1900 5 CONHS0 2 NH iPro 2-1901 5 CONHS02 NH BuO 2-1902 5 CONHS0 2 NH iBuO 2-1903 5 CONHS02 NH sBuO 2-1904 5 CONHS0 2 NH tBuO 2-1905 5CON-HS0 2 NH HxO 2-1906 5 CONHS02 NH PhO 2-1907 5 CONB-S0 2 NH BnO 2-1908 5 CONHSO2) NH Z- 1 2-1909 5 CONHSO? NH Z-2 2-1910 5 CONHSO2) NH Z-3 2-1911 5 CONHSO? NH Z-4 2-1912 5 CONHS02 NH 2-1913 7 CONHS0 2 NH Z-6 2-1914 7 CONH-S0 2 NH Z-7 2-1915 5 CONHS0 2 NH Z-8 2-1916 5 CONHS0 2 NH Z-9 2-1917 5 CONHS0 2 NH y:\wpdocs\dgtmffss\981 2\981 2cpd2.doc 203 Cpd. k A

BR

No. 2-1918 5 CONHS02 NH Z-1 1 2-1919 5 CONHS02 NH- Z-12 2-1920 5 CONHS02 NH 3-Py 2-1921 5 CONHS0 2 NH 4-Py 2-1922 5 NHCO

H

2-1923 5 NIICO Ph 2-1924 5 NHCO 2-Me-Ph A DtL 2-1925 j5 NHCU 2-1926 5NHCO I 2-1927 NHCO L A 2-1928 5 2-1929 5~

NHCO

NHCO

2-1930 NHCO 2-1931 2-1932 2-1933

NIICO

Ni-ICO 2,4-diMe-Ph 3,4-diMe-Ph 2-(CF 3 )Ph 4-(CF 3 )Ph 2-MeOPh 4-MeOPh 2-EtOPh 4-EtOPh 2-HOPh 4-HOPh 2-(HOOC)Ph 4-(HOOC)Ph 2-(MeOOC)Ph 4-(MeOOC)Ph 2-(EtOOC)Ph 2-1934 1-5i 11-C 2-193 5 N-HCO i i I 2-1936 2-1937 2-193 8 2-1939 2-1940 2-1941 2-1942 2-1943

NH-CO

NHCO

NE-CO

NE-CO

NB-CO

5 1ONHCO 4-(EtOOC)Ph

I

NHCO

NHCO

I 2-(tBuOOC)Ph 4-(tBuOOC)Ph

I

y:\wpdocs\d gtmnss\981 2\981 2cpd2.-doc 204 Table 2 (cont.

2-19474

IC

2-1948 5

NEIC)

2-1949 5

NI-CO

2-1950 5

NHCO

2-1951 5

NI-CO

2-1952 5

NHCO

**2-953 5

NCO

2-1954 5

NI-CO

2-95 2-1955 5

NHCO

2-1956 5

NHCO

2-1957 y:\wpdocs\dgt-mss\981I2\98 12cpd2.doc 205 Table 2 (coit." 999*99 9 99 99 p 9.

99 9 9.

9 9 99 9 9 Cpd. k A B R No.

2-1969 5 NHCO MeCH(COOH) 2-1970 7 NHCO HOOC-(CH 2 2 2-1971 5 NHCO MeCH(COOMe) 2-1972 5 NHCO 1-HOOC-iBu 2-1973 5 NHCO 1-HOOC-iPn 2-1974 5 NHCO 1-HOOC-2-Me-Bu 2-1975 5 NHCO

CH

2

CH

2

SO

3

H

2-1976 5 NH-CO -MeO 2-1977 7 NHCO -EtO 2-1978 5 NH-CO -Pro 2-1979 5 NH-CO -Z-1I 2-1980 5 NHCO -Z-2 2-1981 5 NHCO -Z-3 2-1982 5 Ni-CO -Z-4 2-1983 7 NIICO 2-1984 7 tNmCO

Z-

2-1985 5 NHCO

Z-

2-1986 5 NHCO

Z-

2-1987 5 Ni-CO Z9 2-1988 5 NI-CO -Z1 2-1989 7 NH-CO -z-1 1 2-1990 7 NHCO -Z-12 2-1991 7 NI-CO -3-Py 2-1992 5 NHCO -4-Py 2-1993 5 NECO NH H 2-1994 5 NiICO NH Ph 2-1995 7 NHCO Nil 2-Me-Ph 9 9 y:\wpdocs\dgtms\981I2\981I2cpd2.doc 206 Table 2(cont.) Cpd. k A B

R

No. 2-1996 5 NilCO NHl 4-Me-Ph 2-1997 7 NHCO NHl 2,4-diMe-Ph 2-1998 5 NHCO NiH 3,4-diMe-Ph 2-1999 5 NHCO NH 2-(CF 3 )Ph 2-2000 5 NHCO NiH 4-(CF 3 )Ph 2-200 1 5 N7HCO Nil 2-MeOPh 2-2002 5 NHCO NH 4-MeOPh 2-2003 5 NIICO Nil 2-EtOPh 2-2004 7 NHTCO Nil 4-EtOPh 2-2005 7 NHCO NH 2-HOPh 2-2006 5 NHTCO NH 4-HOPh 2-2007 5 NHCO NH 2-(HOOC)Ph 2-2008 5 NHCO NH 4-(HOOC)Ph 2-2009 5 NHTCO NH 2-(MeOOC)Ph 2-2010 7 NH-CO NH 4-(MeOOC)Ph 2-2011 5 NH-CO NH 2-(EtOOC)Ph 2-2012 5 NH-CO NH 4-(EtOOC)Ph 2-2013 5 NHCO NH 2-(tBuOOC)Ph 2-2014 5 Ni-CO NH 4-(tBuOOC)Ph 2-2015 7 NH-CO NH 2-Cl-Ph 2-2016 7 Ni-CO NH 4-Cl-Ph 2-2017 5 NHCO NH 2-Br-Ph 2-2018 5 NI-CO NH 4-Br-Ph 2-2019 5 NH-CO NH- 2-I-Ph 2-2020 7 NE-CO NH 4-I-Ph 2-2021 7 NHCO NH 2-N0 2 -Ph 2-2022 7NHCO Nil 4-N0 2 -Ph y:\wpdocs\dgt-mss\ 98 I 2\9812cpd2.doc 207 Tal 2unt.

Cpd. k A B R No. 2-2023 5 NHCO NIH 2-NH 2 -Ph 2-2024 5 NI-CO NH 4-NH 2 -Ph 2-2025 5 NHCO NH 2-(HO 3 S)Ph 2-2026 5 NHCO NH 4-(HO 3 S)Ph 2-2027 5 NI-CO NH 2-(NI- 2 0 2 S)Ph 2-2028 5 NHCO NH 4-(NH 2

O

2 S)Ph 2-2029 5 NHCO NH 2-CN-Ph 2-2030 5 NHTCO NH 4-CN-Ph 2-2031 5 NH-CO NH 2-(HOCH 2 )Ph 2-2032 5 NI{CO NH 4-(HOCH 2 )Ph 2-2033 5 NH-CO NH M 2-2034 5 Ni-CO NH E 2-2035 5 N-HCO NH P 2-2036 5 NH-CO NH r 2-2037 5 NE-CO NH B 2-2038 5 NE-CONHOCH2 2-2039 5 N-CO NH MeOOCCH 2 2-2040 5 N-HCO NH MeCH(COOH) 2-2041 5 NHCO NH HOOC-(CH 2 )2- 2-2042 5 NE-CO NH MeCH(COOMe) 2-2043 5 NHCO NIH I-HOOC-iBu 2-2044 5 NHCO NH I-MeOOC-iBu 2-2045 5 NHCO NH 1-HOOC-iPn 2-2046 5 NHCO NH I-MeOOC-iPn 2-2047 5 NHCO NH 1-HOOC-2-Me-Bu 2-2048 5 NHCO NH 1-MeOOC-2-Me-Bu y:\wpdocs\dgt-nmss\98 I 2\981I2cpd2.dAm 208 Table 2 (conQ.

Cpd. k A B

R

No. 2-2049 5 NHCO NHl CH 2

CH

2 SO3H 2-2050 5 NHCO NH

OH

2-2051 5 j NIICO NHl MeO 2-2052 5 NI-CO NHl EtO 2-2053 5 NHCO NH Pro 2-2054 5 NI-CO NiH iPrO 2-2055 5 NHCO NHl BuO 2-2056 5 NHCO NHl iBuG 2-2057 5 Ni-CO Nil sBuO 2-205 8 5 NHCO NHl tBuO 2-205 9 5 NH-CO NH HxO 2-2060 5 NHCO NH PhO 2-206 1 5 NH-CO Nil BnO 2-2062 5 NI-CO Nil Z-1 2-2063 5 NHCO Nil Z-2 2-2064 5 NI-CO NHl Z-3 2-2065 5 NH-CO NH Z-4 2-2066 5 NHCO NHl 2-2067 5 NHCO NHl Z-6 2-2068 5 NHiCO NH Z-7 2-2069 5 NHCO NH Z-8 2-2070 5 NHCO Nil Z-9 2-2071 7 NHCO NH 2-2072 5 NI-CO NH Z-1 1 2-2073 5 NiICO NH Z-12 2-2074 5 NH-CO NH 3-Py 2-2075 5 NHCO NH 4-Py y:\wpdocs\.dgt_mfss\981I2\98 I 2cpd2.-doc 209 Tabe2 (cnt.) Cpd. k A B

R

No. 2-2076 5 NHCO NMe Ph 2-2077 7 Ni-CO NMe 2-Me-Ph 2-2078 5 NHCO NMe 4-Me-Ph 2-2079 '5 NIICO NMe 2,4-diMe-Ph 2-2080 5 NHCO NMe 3,4-diMe-Ph 2-2081 5 Ni-CO NMe 2-(CF 3 )Ph 2-2082 5 N-ICO NMe 4-(CF 3 )Ph 2-2083 7 NIICO NMe 2-MeOPh 2-2084 5 NI-CO NMe 4-MeOPh 2-2085 5 NH-CO NMe 2-EtOPh 2-2086 5 NHCO NWe 4-EtOPh 2-2087 5 Ni-CO NWe 2-HOPh 2-2088 5 NH-CO NWe 4-HOPh 2-2089 5 NH-CO NMe 2-(HOOC)Ph 2-2090 5 Ni-CO NWe 4-(HOOC)Ph 2-2091 5 Ni-CO W~e 2-(MeOOC)Ph 2-2092 5 Ni-CO NWe 4-(MeOOC)Ph 2-2093 5 NHCO NMe 2-(EtOOC)Ph 2-2094 5 NHCO NMe 4-(EtOOC)Ph 2-2095 5 NHCO NWe 2-(tBuOOC)Ph 2-2096 5 NHCO NMe 4-(tBuOOC)Ph 2-2097 5 Ni-CO NMe 2-Cl-Ph 2-2098 7 Ni-CO NMe 4-Cl-Ph 2-2099 5 Ni-CO NMe 2-Br-Ph 2-2 100 5 NHCO NMe 4-Br-Ph 2-2101 5 NHCO NMe 2-I-Ph 2-2102 5 NI-CO N -Me 4-I-Ph y:\wpdocs\dgtmtss\981 2\981 2cpd2.doc -210- Table2(cont.) Cpd. k A B R No.

2-2103 5 NIHCO NMe 2-N0 2 -Ph 2-2104 5 NECO NMe 4-N0 2 -Ph 2-2 105 5 NIICO NMe 2-NH 2 -Ph 2-2106 5 N7HCO NMe 4-NH2-Ph 2-2107 5 NHCO NMe 2-(HO 3 S)Ph 2-2108 5 NHCO NMe 4-(HO 3 S)Ph 2-2109 5 NHCO NMe 2-(NH 2

O

2 S)Ph 2-2110 5 NH-CO NMe 4-(NH 2

O

2 S)Ph 2-2111 5 NI-CO NMe 2-CN-Ph 2-2112 5 NHCO NMe 4-CN-Ph 2-2113 5 NHCO NMe 2-(HOCH 2 )Ph 2-2114 5 NECO NMe 4-(HOCH 2 )Ph 2-2115 5 NE-CO NMe Me 2-2116 7 NHCO We Et 2-2117 7 NI-CO NMe Pr 2-2118 5 NHCO NMe iPr 2-2119 5 NECO NMe Bu 2-2 120 5 NE-CO We HOOCCH 2 2-2121 5 NHCO We MeOOCCH 2 2-2122 5 NI-CO We MeCH(COOH) 2-2123 5 NI-CO We HOOC-(CH2)2- 2-2124 7 NHCO We MeCH(COOMe) 2-2 125 7 NH-CO We I-HOOC-iBu 2-2126 5 NHCO We 1-MeOOC-iBu 2-2127 5 NIHCO We 1-HOOC-iPn 2-21,28 5 NHCO We 1-MeOOC-iPn y:\wpdocs\dgt-mss\981I2\981I2cpd2.doc -211- Table 2 (cont.) Cpd. k A B

R

2-2129 5 NHCO NMe 1-HOOC-2-Me-Bu 2-2130 5 NIICO W~e 1-MeOOC-2-Me-Bu 2-2131 5 Ni-CO NMe CH 2

CH

2

SO

3

H

2-2 132 5 NHCO NMe

OH

2-2133 7 NHCO We MeO 2-2134 5 NHCO We EtO 2-2135 5 NHCO We Pro 2-2136 5 NHCO We iPro 2-2137 5 NI-CO WeBuO *2-2138 5 NH-CO W~e iBuG *2-2139 5Y NHCO N"Me sBuO *2-2140 7 NHCO We tBuO *2-2141 5 NHCO We HxO 2-2142 5 NHCO We PhO 2-14 5*BON 2-2143 5 NHCO We Bn1 2-21445 5 NHCO NMe Z-2 2-2145 5 NHC-O NMe Z-3 *2-2146 5 NHCO NMe Z-4 2-2148 7 NB-CO NMe Z-4 2-2149 7 NHCO NMe Z-6 2-2 149 5 NHCO W~e Z-7 2-2150 5 Ni-CO NMe Z-7 2-2152 5 NH-CO NMe Z-9 2-2153 7 NHCO We 2-2154 5 NH-CO NMe Z-1 1 2-2155 5 NI-CO We Z-12 y:\wpdocs\dgt-mss\981I2\981I2cpd2.doc 212 Table 2 (conW.

Cpd. k A B R No. 2-2156 5 NHCO NMe 3-Py 2-2 157 5 NHCO NMe 4-Py 2-2158 5 NHCO NHNI{ H 2-2159 5 NIICO NHNH Me 2-2 160 5 NI-CO NHNH Et 2-2161 5 NHCO NHNMe Me 2-2162 5 NHCO NHNMe Et 2-2163 5 NHCO NHNMe Pr 2-2164 5 NiICONHNHCO NH H 2-2165 5 NI-CONI{NHCO NHl Ph 2-2166 5 NI-CONHNHCO NH 2-Me-Ph 2-2167 5 NHCONHNHCO NH 4-Me-Ph 2-2 168 5 NI-CONH-NHCO NH 2,4-diMe-Ph 2-2169 5 NilCONHN1~HCO NH 3,4-diMe-Ph 2-2170 5 NHCONH-NH-CO NH 2-(CF 3 )Ph 2-2171 5 NHCONH-NI-CO NH 4-(CF 3 )Ph 2-2172 5 NHCON4NHTCO NH 2-MeOPh 2-2173 5 NHCONHNHCO NHl 4-MeOPh 2-2174 5 NI-CONHNHCO NH 2-EtOPh 2-2175 7 NHCONHNHiCO NiH 4-EtOPh 2-2176 5 NHCONH-NH-CO NH 2-HOPh 2-2 177 7 NHCONHNHCO NH 4-HOPh 2-2178 7 NHCONHNH-CO NH 2-(HOOC)Ph 2-2179 7 NHCONHINH-CO NH 4-(HOOC)Ph 2-2180 5 N-HCONHNHCO NH 2-(MeOOC)Ph 2-2181 5 NHCONHNHCO NH 4-(MeOOC)Ph 2-2182 5 NHCONHNI-CO NH 2-(EtOOC)Ph y:\wpdocs\dgtmss\981I2\981I2cpd2.doc -214- Table2 (cnL) *500 *5 5

S

*5 Cpd. k A B

R

2-2209 5 NHCONI{NHCO NH HOOCCH2- 2-2210 5 NHCONHNHCO NH MeOOCCH2- 2-2211 5 NHCONIIMICO NH MeCH(COOH) 2-22 12 7 NHCONI{MICO NH HOOC-(CH 2 2 2-2213 5 NHCONH7NHCO NH MeCH(COOMe) 2-2214 5 NHCONIINHCO NH 1-HOOC-iBu 2-2215 5 NHCONHM{CO NH 1-MeOOC-iBu 2-2216 5 NHCONHI-IHCO NH 1-HOOC-iPn 2-2217 5 NHCONHNHCO NH I-MeOOC-iPn 2-22 18 5 NHCONHNHCO NH 1-HOOC-2-Me-Bu 2-2219 7 NHCON1-IM-CO NH 1-MeOOC-2-Me-Bu 2-2220 7 NHCONHNECO NH CH 2 CH,)SOiH 2-2221 7 NHCONHN}ICO NH OH 2-2222 5 NHCON-N-HCO NH MeG 2-2223 5 NHiCON1-HCO NH EtO 2-2224 5 NHCONHNHCO NH Pro 2-2225 7 NHCOMH-[HCO NH iPro 2-2226 7 NHCON}{NHCO NH BuG 2-2227 7 NHCON}INHCG NH iBuG 2-2228 5 NHCGNHNECG NH sBuG 2-2229 5 NHCON1-N1-CG NH tBuG 2-2230 5 NHCONNMCG NH HxG 2-2231 5 NHCON1HNHCO NH PhO 2-2232 7 NHCON}INHCG NH BnG 2-2233 71 MICONHNI-CG NH Z-1 2-2234 5 N1-CONHNI-CO NH Z-2 2-223 5 5 NHCON1-NHCG NH Z-3 y:\wpdocs\dgt-mss\981I2\981I2cpd2.doc 215 Tabe2 (cnt.

Cpd. k A B R 2-2236 5 NHCONHNHCO NiH Z-4 2-2237 5 NHCONHNHCO Ni 2-223 8 5 NHCONHNHCO Nil Z-6 2-2239 5 NHCONIINHCO NHl Z-7 2-2240 5 NHCONHNHCO Nil Z-8 2-2241 5 NHCONHNI{CO NH- Z-9 2-2242 5 NI-CONHNHCO NHl 2-24 5 NHOHHON *2-2243 5 NHCONHNHCO NiH Z-12I 2-2244 5 NHCONH-NHCO NHL Z-12 2-2246 5 NHCONHNHCO NHl 3-Py 2-2246 5 NECONLMCO NH 4P *2-2247 5 NIICONI-CO Ph 2 -2248 5 NE-CONi-CO 2-Ph 2-2249 5 NHCONl-CO 2-Me-Ph 2-2250 5 NHCONi-ICO 24-dMe-Ph 2-22521 5 NE-CONI-CO 2,4-diMe-Ph :2-2252 5 NECONE-CO 3,-diFe-Ph 2-2253 5 NE-CONi-ICO 2-(CF 3 )Ph 2-2255 5 NE-CONI-CO 2-MeOPh 2-2256 7 NHCONE-CO -4-MeOPh 2-2257 5 Ni-CONI-CO -2-EtOPh 2-225 8 5 NHCONE-CO -4-EtOPh 2-2259 5 NE-CONE-CO -2-HOPh 2-2260 5 NILCONE-CO -4-HOPh 2-2261 5 NILCONE-CO 2-(HOOC)Ph 2-2262 5 NH-CONE-CO -4-(HOOC)Ph y:\wpdocs\dgtmss\981 2\981 Zcpd2.doc 216 Cpd. k A B

R

No.

2-2263 5 NHCONHCO -2-(MeOOC)Ph 2-2264 5 NIICONHiCO 4-(MeOOC)Ph 2-2265 5 NHCONHCO 2-(EtOOC)Ph 2-2266 5 NHCONH-CO 4-(EtOOC)Ph 2-2267 5 NHCONH-CO 2-(tBuOOC)Ph 2-2268 5 NHCONHCO 4-(tBuOOC)Ph 2-2269 5 NH-CONI0C 2-Cl-Ph 2-2270 5 NHCONI-ICO 4-Cl-Ph 2-227 1 5 N}ICONH-CO -2-Br-Ph 2-2272 5 NH-CONHCO -4-Br-Ph 2-2273 5 NHCON}ICO -2-I-Ph 2-2274 5 NH-CONHCO -4-I-Ph 2-2275 7 NHCONHCO 2-N0 2 -Ph 2-2276 5 N}ICONHCO -4-N0 2 -Ph 2-2 2 77 5 M-{CONHCO 2-NH- 2 -Ph 2-2278 7 NiCONH-CO -4-NH- 2 -Ph 2-2279 5 NH-CONH-CO 2-(HO 3 S)Ph 2-2280 5 N HCON~i-CO 4-(HO 3 S)Ph 2-2281 5 Ni-iCONli-CO 2-(NH 2

O

2 S)Ph 2-2282 5 NE-CONB-CO 4-(NH- 2 0 2 S)Ph 2-2283 7 NHCONHCO -2-CN-Ph 2-2284 5 NHCONIICO -4-CN-Ph 2-2285 5 NHCONIHCO 2-OCH 2 )Ph 2-2286 7 NH-CONHCO 4-(HOCH 2 )Ph 2-2287 5 NHCON}{CO -Me 2-2288 5 NHCON'HCO Et y:\wpdocs\d gt.mss\98 I 2\981I2cpd2.-doc -217- Cpd. k A B

R

2-2289 5 NHCONHCO -Pr 2-2290 5 NHCONI{CO -iPr 2-2291 5 NHCONHCO -Bu 2-2292 5 NHCONHCO

HOOCCH

2 2-2293 5 NIICONHCO MeOOCCH2- 2-2294 5 NHCONHCO MeCH(COOH) 2-2295 5 NHCONHCO HOOC-(CH2) 2 2-2296 5 NHCONHCO MeCH(COOMe) 2-2297 5 NHCONH-CO 1-HOOC-iBu 2-2298 5 NH-CONIHCO 1-MeOOC-iBu 2-2299 5 NHCONI{CO I1-HOOC-iPn 2-2300 5 NH-CONHCO I-MeOOC-iPn 2-2301 5 NH-CONI-CO 1-HOOC-2-Me-Bu 2-2302 5 NH-CONH-CO 1-MeOOC-2-Me-Bu 2-2303 5 NH-CONHCO

CH

2

CH

2 SO3H 2-2304 5 NE-CONI-CO -MeO 2-2305 5 Ni-CONI-CO -EtO 2-2306 5 NH-CONHCO -Pro 2-2307 5 NI{CONH-CO -iPrO 2-2308 5 NH-CONI-CO -BuO 2-2309 5 NH-CONHCO -iBuO 2-2310 5 NHCONHCO -sBuO 2-2311 5 NHCONH-CO -tBuO 2-2312 5 Ni-CONI-CO -HxO 2-2313 5 NH-CONHCO -PhO 2-23 14 5 1_NHCONH-CO BnO y:\wpdocs\d gt-mss\981 2\981 2cpd 2.doc -218- Table 2 (cont.) Cpd. k A B R No.

2-2315 5 NHCONHCO Z-1 2-2316 5 NHCONHCO Z-2 2-2317 5 NHCONHCO Z-3 2-2318 5 NHCONHCO Z-4 2-2319 5 NHCONCO 2-2320 5 NHCONHCO Z-6 2-2321 5 NHCONHCO Z-7 2-2322 5 NHCONICO Z-8 2-2323 5 NHCONHCO Z-9 2-2324 5 NHCONHCO Z-10 2-2325 5 NHCONICO Z-1 1 2-2326 5 NHCONHCO Z-12 2-2327 5 NHCONHCO 3-Py 2-2328 5 NHCONHCO 4-Py 2-2329 5 NHCONHS0 2

H

2-2330 5 NICONHS0 2 Ph 2-2331 5 N1-CONHSO2 2-Me-Ph 2-2332 5 N1-CON-SO- 4-Me-Ph 2-2333 5 NHCON-SO- 2,4-diMe-Ph 2-2334 5 NIHCONHSO? 3,4-diMe-Ph 2-2335 5 NHCONHSO 2 2-(CF 3 )Ph 2-2336 5 N-CONHSO 4-(CF 3 )Ph 2-2337 5 NHCONHSO 2 2-MeOPh 2-2338 5 NHCONHSO 2 4-MeOPh 2-2339 5 NHCONHS0 2 2-EtOPh y:\wpdocs\dgtmss\981 2\9812cpd2.doc Page(s).c? RP- were not lodged with this application 227 Table 2 (cont) Cpd. k A B R No. 2-2543 5 CO NMe BnO 2-2544 5 CO NMe Z-1 2-2545 5 CO W~e Z-2 2-2546 5 CO NMe Z-3 2-2547 5 CO NMe Z-4 2-2548 5 CO NMe 2-2549 5 CO NMe Z-6 2-2550 5 CO NMe Z-7 2-2551 5 CO NMe Z-8 2-2552 5 Co NMe Z-9 2-2553 5 CO NMe Z-10 2-2554 5 CO NWe Z-1 I 2-2555 5 CO NMe Z-12 2-2556 5 CO NMe 3-Py 2-2557 5 CO NMe 4-Py 2-2558 5 CO Thiad 2-2559 5 CO NH-Thiad 2-2560 5 NH-CO Thiad 2-2561 5 Ni-CO NI{Thiad 2-2562 5 CONi-CO Thiad 2-2563 5 CONHCO Ni-Thiad 2-2564 5 CONHSO2) Thiad 2-2565 5 CONHS02 NHThiad 2-2566 5 Ni-CS NH-

H

2-2567 5 NHCS NH- Me 2-2568 5 NHCS Ni- Et 2-2569 5 NHCS NiH Ph y:\wpdocs\dgt~rrss\981 2\981 2cpd2.doc -228- Tale2 cot.

Cpd. k A B R No. 2-2570 5 NHCS NH HOOCCH 2 2-257 1 5 NHCS NH MeOOCCH 2 2-25 72 5 NHCS NH- MeCH(COOH) 2-2573 5 NIICS NH HOOC-(CH 2 2 2-2574 5 NHCS NH MeCH(COOMe) 2-2575 5 Co NH HOOC-(CH 2 3 2-2576 5 NHCO NE HOOC-(CH 2 3 2-2577 5 NilCO HOOC-(CH 2 3 2-2578 5 NHCS NH HOOC-(CH 2 3 2-2579 5 Co NH MeSO 2 NHCOCH(Me) 2-2580 5 NHCO NH MeSO 2 NHICOCH(Me) 2-2581 5 NH-CO -MeSO 2 NHCOCH(Me) 2-2582 5 NH-CS NH MeSO 2 NHCOCH(Me) 2-2583 5 NH HOOCCH 2 2-2584 5 NH MeOOCCH 2 2-2585 7 NH- MeCH(COOH) 2-2586 7 NiH HOOC-(CH 2 )2 2-2587 5 NH- MeCH(COOMe) 2-2588 7 NH HOOC-(CH 2 )3- 2-2589 5 NHCOCO

OH

2-2590 7 NHCOCO MeO 2-2591 5 N-COCO EtO 2-2592 7 NH-COCO Pro 2-2593 7 NH-COCO iPrO 2-2594 5 NHCOCO -BuO y:\wpdocs\dgtmss\981I2\981I2cpd2.doc 229 Cpd. k A B Rl 2-2595 5 NHCOCO iBuG 2-2596 5 NHCOCO sBuO 2-2597 5 NIRCOCO tBuO 2-2598 5 NHCOCO -HxO 2-2599 5 NHCOCO -PhO 2-2600 5 NHCOCO BnO 2-2601 0 1,3-diox-llnd 2-2602 1 1,3-diox-Ind 2-2603 2 1,3-diox-llnd 2-2604 3 1,3-diox-lInd 2-2605 4 -1 ,3-diox-Ilnd 2-2606 5 -1 ,3-diox-Ind 2-2607 6 -1 ,3-diox-Ilnd 2 -26 08 7 -1 ,3-diox-I~nd 2-2609 8 -1 ,3-diox-Ilnd 2 -2 610 9 -1 ,3-diox-I~nd 2211 101 1,3-diox-Ilnd 2-2612 11 1 ,3-diox-llnd 2-26 13 121 1 ,3-diox-Ilnd 2 -26 14 4 NH-CONHS0 2 NH-CO NH Z-4 2-2615 4 NHCONHSO2)NHCO NH Pn 2-2616 2 0 -H 2-2617 4 0 -H 2)-2618 5 0 H 2-2619 5 0 -Ph 2-2620 5 0 -2-Py 2-262 1 5 0 3-Py a a a a a a. a a a. a a a. a a.

a a a y:\wpdocs\dgt-mss\981 2 98 1 2cpd2.doc Page($. vei-e not lodged with this application -231 Cpd. k A B

R

2-2648 5 NIICO NE

H

2

NSO

2

NHCOCH,

2-2649 4 Co NH 1-(MeSO 2 NHCO)-Et 2-2650 5 Co NH 1-(MeSO 2 NHCO)-Et 2-2651 4 NHCO NH 1-(MeSO 2 NHCO)-Et 2-2652 5 NHCO NH 1-(MeSO 2 NHCO)-Et 2-2653 4 Co NH 1-(H 2

NSO

2 NHCO)-Et 2-2654 5 Co NH 1-(H 2

NSO

2 NHCO)-Et 2-2655 4 NHCO NH 1-(H 2 NS0 2 NECO)-Et 2-2656 5 NECO NHl I -(H 2

NSO

2 NHCO)-Et 2-2657 4 CO NH

HOOC-(CH

2 4 2-265 8 5 CO NH HOOC-(CH 2 4 2-2659 4 NE-CO NH

HOOC-(CH

2 4 2-2660 5 NHCO NH

HOOC-(CH

2 4 2-2661 4 CO NH-

HO-(CH

2 2 2-2662 5 Co NH-

HO-(CH

2 2 2-2663 4 NE-CO NH

HO-(CH

2 2 2-2664 5 NHCO NH HO-(CH 2 2 2-2665 4 CO NH HO-CH 2

-CH(CH

3 2-2666 5 CO NHT HO-CH,-CH(CH 3 2-2667 4 N-HCO NH HO-CH 2

-CH(CH

3 2-2668 5 NH-CO NH HO-CH 2

-CH(CH

3 2-2669 4 CO NWe HOOC-(CH 2 3 2-2670 4 NHCO NWe

HOOC-(CH

2 3 2-267 1 5 NE-CO NWe HOOC-(CH 2 3 2-2672 4 CONMeSO 2 y:\wdocs\dgtmss\981I2\981 2cpd2.doc 232 Table2 (ont Cpd. k A BR No.

2-2673 5 CONMeSO 2 Me 2-2674 4 CO 1-Indn 2-2675 5 CO 1-Indn 2-2676 4 NHCO 1-Indn 2-2677 5 NHCO 1-Lndn 2-2678 4 CO 2-(HOOC)-l-Indn 2-2679 5 CO 2-(HOOC)- I-Indn 2-2680 4 NI-CO 2-(HOOC)-1I-Indn 2-2681 5 NH-CO 2-(HOOC)-1I-Indn 2-2682 4 -3,4-diMe-2,5-diox- I -Imdd 2-2683 5 -3 ,4-diMe-2,5-diox- I -Imdd e..

00*0 0.* y:\wpdacs\dgtmss\981I2\981I2cpd2.doc 233 r~lr(CH 2

A-B-RI

s-s Tabl (1-3) Cpd. k A B

R

No. 3-1 4 CO NH

H

3-2 4 CO NH Ph 3-3 4 CO Nil 2-Me-Ph 3-4 4 CO NH 4-Me-Ph 4 CO NiH 2,4-diMe-Ph 3-6 4 CO NH 3,4-diMe-Ph 3-7 4 CO NIH 2-(CF 3 )-Ph 3-8 4 CO Nil 4-(CF 3 )-Ph 3-9 4 CO Nil 2-MeOPh 3-10 4 CO NH 4-MeOPh 3-11 4 CO NH 2-EtOPh 3-12 4 CO NH 4-EtOPh 3-13 4 CO NH 2-HOPh 3-14 4 CO NH 4-HOPh 3-15 4 CO NH 2-(HOOC)-Ph 3-16 4 CO NH 4-(HOOC)-Ph 3-17 4 CO NH 2-(MeOOC)-Ph 3-18 4 CO NH 4-(MeOOC)-Ph 3-19 4 CO NH 2-(EtOOC)-Ph 3-20 4 CO N-H 4-(EtOOC)-Ph 3-21 4 CO NH 2-(tBuOOC)-Ph 3-22 4 CO NH 4-(tBuOOC)-Ph 3-23 4 CO H 2-Cl-Ph 3-24 4 CO N 4-Cl-Ph 0@ 0 0

*SSS

0

S

*SSS

55*5

S

S S 55 5ee* S OS S 5850

SO

55 0 0* 0 9 eSSOS.

S

y:\wpdocs\dgtjnss\981I2\981I2cpd3 .doc -234 Table 3(con Cpd. k A -B Rl 3-25 4 CO NH 2-Br-Ph 3-26 4 CO NH 4-Br-Ph 3-27 4 CO NH 2-I-Ph 3-28 4 CO NH 4-I-Ph 3-29 4 CO NH 2-N0 2 -Ph 3-30 4 CO NH 4-N0 2 -Ph 3-31 4 CO NH 2-NH 2 -Ph 3-32 4 CO NH 4-NH 2 -Ph 3-33 4 CO NH 2-(HO 3 S)-Ph 3-34 4 CO NH 4-(HO 3 S)-Ph 3-35 4 CO NH 2-(NH 2 0 2 S)-Ph 3-36 4 CO NH 4-(NH 2 0 2 S)-Ph 3-37 4 CO NH 2-CN-Ph 3-38 4 CO NH 4-CN-Ph 3-39 4 CO NH 2-(HOCH 2 )-Ph 3-40 4 CO NH 4-(HOCH 2 )-Ph 3-41 4 CO NH Me 3-42 4 CO NH Et 3-43 4 CO NH Pr 3-44 4 CO NH iPr 3-45 4 CO NH Bu 3-46 4 CO NH HOOCCH 2 3-47 4 CO NH MeOOCCH2- 3-48 4 CO NH MeCH(COOH)- 3-49 4 CO NH HOOC-(CH 2 )2- 3-50 4 CO NH MeCH(COOMe)y:\wpdocs\dgtrflss\981I2\981I2cpd3 .do -235- Table (cnt.

Cpd. k A B

R

No. 3-51 4 CO NiH 1-HOOC-iBu 3-52 4 CO NHl 1-MeOOC-iBu 3-53 4 CO NH 1-HOOC-iPn 3-54 4 CO Nil I-MeOOC-iPn 3-55 4 CO Nil 1-HOOC-2-Me-Bu 3-56 4 CO NiH 1-MeOOC-2-Me-Bu 3-57 4 CO NH

CH

2

CH

2

SO

3

H

3-58 4 CO NH

OH

*3-59 4 CO Nil MeO 3-60 4 CO NH EtO .0:3-61 4 CO NH- Pro 0003-62 4 CO Nil iPrO 00000 3-63 4 CO NH BuO oooeoo 3-64 4 CO NH iBuO 3-65 4 CO NIH sBuO 03-66 4 CO NH tBuO 3-67 4 CO NH HxO 0:*3-68 4 CO NH PhO 00 3-69 4 CO NH- BnO 3-70 4 CO NH- Z-1 3-71 4 CO N-H Z-2 3-72 4 CO NH Z-3 3-73 4 CO NH Z-4 3-74 4 CO NH- 3-75 4 CO NI-I Z-6 3-76 4 CO NH Z-7 3-77 4 CO NH Z-8 3-78 4 CO NH Z-9 y: \wPdocs\dgtmrss\981 2\9 81 2cpd 3.doc 236 Tabl 3(cnt.) Cpd. k A B

R

No. 3-79 4 CO NH 3-80 4 CO NH Z-11 3-81 4 CO NiH Z-12 3-82 4 CO NiH 3-Py 3-83 4 CO NH 4-Py 3-84 4 CO N(Ac)

H

3-85 4 CO N(Ac) Ph 3-86 4 CO N(Ac) 2-Me-Ph 3-87 4 CO N(Ac) 4-Me-Ph 3-88 4 CO N(Ac) 2,4-diMe-Ph 3-89 4 CO N(Ac) 3,4-diMe-Ph 3-90 4 CO N(Ac) 2-(CF 3 )Ph 3-91 4 CO N(Ac) 4-(CF 3 )Ph 3-92 4 CO N(Ac) 2-MeOPh 3-93 4 CO N(Ac) 4-MeOPh 3-94 4 CO N(Ac) 2-EtOPh 3-95 4 CO N(Ac) 4-EtOPh 3-96 4 CO N(Ac) 2-HOPh 3-97 4 CO N(Ac) 4-HOPh 3-98 4 CO N(Ac) 2-(HOOC)Ph- 3-99 4 CO N(Ac) 4-(HOOC)Ph 3-100 4 CO N(Ac) 2-(MeOOC)Ph 3-101 4 CO N(Ac) 4-(MeOOC)Ph 3-102 4 CO N(Ac) 2-(EtOOC)Ph 3-103 4 CO N(Ac) 4-(EtOOC)Ph 3-104 4 CO N(Ac) 2-(tBuOOC)Ph 3-105 4 CO N(Ac) 4-(tBuOOC)Ph 3-106 T CO N(Ac) 2-Cl-Ph y:\wpdocs\dgtmnss\981 2\9812cpd3.doc 237 Table 3(cont Cpd. k A B

R

3-107 4 CO N(Ac) 4-Cl-Ph 3-108 4 CO N(Ac) 2-Br-Ph 3-109 4 CO N(Ac) 4-Br-Ph 3-110 4 CO N(Ac) 2-I-Ph 3-111 4 CO N(Ac) 4-I-Ph 3-112 4 CO N(Ac) 2-N0 2 -Ph 3-113 4 CO N(Ac) 4-N0 2 -Ph 3-114 4 CO N(Ac) 2-NH 2 -Ph 3-115 4 CO N(Ac) 4-NH- 2 -Ph 3-116 4 CO N(Ac) 2-(HO 3 S)Ph 3-1 17 4 CO N(Ac) 4-(HO 3 S)Ph 3-118 4 CO N(Ac) 2-(NH 2

O

2 S)Ph 3-1 19 4 CO N(Ac) 4-(NH 2 0 2 S)Ph 3-120 4 CO N(Ac) 2-CN-Ph 3-121 4 CO N(Ac) 4-CN-Ph 3-122 4 CO N(Ac) 2-(HOCH 2 )Ph 3-123 4 CO N(Ac) 4-(HOCH 2 )Ph 3-124 4 CO N(Ac) Me 3-125 4 CO N(Ac) Et 3-126 4 CO N(Ac) Pr 3-127 4 CO N(Ac) iPr 3-128 4 CO N(Ac) Bu 3-129 4 CO N(Ac) HOOCCH 2 3-130 4 CO N(Ac) MeOOCCH2- 3-13 1 4 CO N(Ac) MeCH(COOH) 3-132 4 CO N(Ac) HOOC-(CH2)2y:\wpdocs\dgtmss\981 2\9812cpd3.dAm -238- Tabe 3(nt.) Cpd. k A B Bl 3-133 4 CO N(Ac) MeCH(COOMe) 3-134 4 CO N(Ac) 1-HOOC-iBu 3-135 4 CO N(Ac) 1-MeOOC-iBu 3-136 4 CO N(Ac) 1-HOOC-iPn 3-137 4 CO N(Ac) 1-MeOOC-iPn 3-138 4 CO N(Ac) 1-HOOC-2-Me-Bu 3-139 4 CO N(Ac) I-MeOOC-2-Me-Bu 3-140 4 CO N(Ac) CH 2

CH

2

SO

3

H

3-141 4 CO N(Ac)

OH

3-142 4 CO N(Ac) MeG 3-143 4 CO N(Ac) EtO 3-144 4 CO N(Ac) Pro 3-145 4 CO N(Ac) iPrO 3-146 4 CO N(Ac) BuO 3-147 4 CO N(Ac) iBuO 3-148 4 CO N(Ac) sBuO 3-149 4 CO N(Ac) tBuO 3-150 4 CO N(Ac) HxO 3-151 4 CO N(Ac) PhO 3-152 4 CO N(Ac) BnO 3-153 4 CO N(Ac) Z-1 3-154 4 CO N(Ac) Z-2 3-155 4 CO N(Ac) Z-3 3-156 4 CO N(Ac) Z-4 3-157 4 CO N(Ac) 3-158 4 CO N(Ac) Z-6 3-159 4 CO N(Ac) Z-7 3 -16 t 4 CO N(Ac) Z-8 y:\wpdocs\dgtmnss\9B I2\98 I2cpd3 .do -239- Table (cnt.) a Cpd. k A BR No. 3-161 4 CO N(Ac) Z-9 3-162 4 CO N(Ac) 3-163 4 CO N(Ac) Z-1 1 3-164 4 CO N(Ac) Z-12 3-165 4 CO N(Ac) 3-Py 3-166 4 CO N(Ac) 4-Py 3-167 4 COO

-H

3-168 4 COO -Ph 3-169 4 COO -2-Me-Ph 3-170 4 COO -4-Me-Ph 3-171 4 COO 2,4-diMe-Ph 3-172 4 COO 3,4-diMe-Ph 3-173 4 COO 2-(CF 3 )Ph 3-174 4 COO 4-(CF 3 )Ph 3-175 4 COO 2-MeOPh 3-176 4 COO 4-MeOPh 3-177 4 COO 2-EtOPh 3-178 4 COO 4-EtOPh 3-179 4 COO 2-HOPh 3-180 4 COO 4-HOPh 3-181 4 COO 2-(HOOC)Ph 3-182 4 COO 4-(HOOC)Ph 3-183 4 COO 2-(MeOOC)Ph 3-184 4 COO 4-(MeOOC)Ph 3-185 4 COO 2-(EtOOC)Ph 3-186 4 COO 4-(EtOOC)Ph 3-187 4 COO 2-(tBuOOC)Ph 3-188 4 COO 4-(tBuOOC)Ph y:\wpdocs\dgtmss\98I 2\981 2cpd3.doc 240 Table3(cont.) Cpd. k A B

R

3-189 4 coo -2-Cl-Ph 3-190 4 coo 4-Cl-Ph 3-191 4 coo 2-Br-Ph 3-192 4 coo 4-Br-Ph 3-193 4 coo 2-I-Ph 3-194 4 coo 4-I-Ph 3-195 4 coo 2-NO 2 -Ph 3-196 4 COO 4-N0 2 -Ph 3-197 4 COO 2-NH 2 -Ph 3-198 4 COO 4-NH 2 -Ph 3-199 4 COO 2-(HO 3 S)Ph 3-200 4 COO 4-(HO 3 S)Ph 3-201 4 COO 2-(NH 2

O

2 S)Ph 3-202 4 COO 4-(NH 2

O

2 S)Ph 3-203 4 COO 2-CN-Ph 3-204 4 COO 4-CN-Ph 3-205 4 COO 2-(HOCH 2 )Ph 3-206 4 COO 4-(HOCH 2 )Ph 3-207 4 COO -Me 3-208 4 COO -Et 3-209 4 COO -Pr 3-210 4 coo iPr 3-211 4 coo Bu 3-2 12 4 coo HOOCCH2- 3-213 4 coo-

HOOC-(CH

2 )2- 3-214 4 coo- MeCH(COOMe) y:\wpdocs\dgtmffss\981I2\981I2cpd3 .doc 241 Table (cnt.) Cpd. k A BR 3-215 4 coo 1 I-HOOC-iBu 3-216 4 coo 1-HOOC-iPn 3-217 4 coo Z-1 3-218 4 coo Z-2 3-219 4 coo Z-3 3-220 4 COO -Z-4 3-22 1 4 coo 3-222 4 coo Z-6 3-223 4 coo -Z-7 .3-224 4 coo

Z-

**3-225 4 coo -Z-9 :3-226 4 coo 3-227 4 COO Z-1 I *3-228 4 coo 12 3-229 4 COO- 3-Py **3-230 4 coo -4-Py *3-231 4 COiNmCO

H

3-232 4 CONE-CO Ph .:3-233 4 COM-ICO- 2-Me-Ph 3-234 4 coM-Ico- 4-Me-Ph 3-235 4 CONECO 2,4-diMe-Ph 3-236 4 CONHCO 3,4-diMe-Ph 3-237 4 CON}iCO 2-(CF 3 )Ph 3-238 4 CONECO 4-(cF 3 )Ph 3-239 4 CONHCO 2-MeOPh 3-240 4 CONHCO 4-MeOPh 3-241 4 CONHCO 2-EtOPh y:\wpdocs\dgtmss\981I2\981I2cpd3 .doc 242 Tabl-(cont.) Cpd. k A B

R

3-242 T CONHCO -th 3-243 4 CONHCO 2H~ 3-244 4 CONHCO 4H~ 3-245 4 CONIHCO 2-(HOOC)Ph 3-246 4 CONi-CO 4-(HOOC)Ph 3-247 4 CONHCO 2-(MeOOC)Ph 3-248 4 CONH-CO 4-(MeOOC)Ph 3-249 4 CONHCO 2-(EtOOC)Ph 3-250 4 CONHCO 4-(EtOOC)Ph 3-251 4 CONHCO 2-(tBuOOC)Ph 3-252 4 CONIICO 4-(tBuOOC)Ph 3-253 4 CONHCO 2-Cl-Ph 3-254 4 CONHCO

P

3-255 4 CONHCO 2-rP 3-256 4 CON}HCO 4-rP 3-257 4 CONH-CO -21P 3-258 4 CONHCO -4-I-Ph 3-259 4 CONHCO 2-N0 2 -Ph 3-260 4 CONHCO 3-261 4 CONHCO 2-NH 2 -Ph 3-262 4 CONHCO 4-NH- 2 -Ph 3-263 4 CONE-CO 2-(HO 3 S)Ph 3-264 4 CONHCO 4-(HO 3 S)Ph 3-265 4 CONHCO 2-(NH 2

O

2 S)Ph 3-266 4 CONH-CO 4-(NH 2

O

2 S)Ph 3-267 4 CONHCO 2-CN-Ph 3-268 4 CONi-CO 4-CN-Ph y:\wpdocs\dgtmnss\981 2\981I2cpd3.doc 243 Table 3 (cont.) Cpd. k A B

R

3-269 4 CONHCO 2-(HOCH 2 )Ph 3-270 4 CONHCO 4-(HOCH 2 )Ph 3-271 4 CONIICO Me 3-272 4 CONH-CO Et 3-273 4 CONHCO Pr 3-274 4 CONIICO iPr 3-275 4 CONH-CO Bu 3-276 4 CONE-CO

HOOCCH

2 3-277 4 CONIICO MeOOCCH2- 3-278 4 CONI-CO MeCH(COOH) 3-279 4 CONH-CO HOOC-(CH2)2- 3-280 4 CONHCO MeCH(COOMe) 3-281 4 CONE-CO I -HOOC-iBu 3-282 4 CONHCO I-MeOOC-iBu 3-283 4 CONE-CO 1-HOOC-iPn 3-284 4 CON-HCO 1-MeOOC-iPn 3-285 4 CONHCO 1-HOOC-2-Me-Bu 3-286 4 CONH-CO 1-MeOOC-2-Me-Bu 3-287 4 CONHCO

CH

2

CH

2 SO3Ui 3-288 4 CONHCO Z-1 3-289 4 CONH-CO Z-2 3-290 4 CONI-CO Z-3 3-291 4 CONIICO Z-4 3-292 4 CONHCO 3-293 4 CONHCO Z-6 3-294 4 CONHiCO Z-7 3-295 4 CONI-CO -Z-8 y:\wpdocs\d gtjlss\9812\981 2cpd 3.Am 244 Tabl (ont.) Cpd. k A B R 3-296 T CONHCO Z-9 3-297 4 CONHCO 3-298 4 CONHCO Z-11 3-299 4 CONHCO Z-12 3-300 4 CONHCO 3-Py 3-301 4 CONI-CO 4-Py 3-302 4 CON(Ac)CO

H

3-3 03 4 CON(Ac)CO -Ph 3-304 4 CON(Ac)CO 2-Me-Ph 3-305 4 CON(Ac)CO 4-Me-Ph .0:3-306 4 CON(Ac)CO 2,4-diMe-Ph :3-307 4 CON(Ac)CO 3,4-diMe-Ph 3-308 4 CON(Ac)CO 2-(CF 3 )Ph 0003-309 4 CON(Ac)CO 4-(CF 3 )Ph 3-310 4 CON(Ac)CO 2-MeOPh 3-311 4 CON(Ac)CO 4-MeOPh 3-312 4 CON(Ac)CO 2-th 3-313 4 CON(Ac)CO 4-th :3-314 4 CON(Ac)CO -2H~ 3-315 4 CON(Ac)CO -4H~ 3-316 4 CON(Ac)CO 2-(HOOC)Ph 3-317 4 CON(Ac)CO 4-(HOOC)Ph 3-318 4 CON(Ac)CO 2-(MeOOC)Ph 3-319 4 CON(Ac)CO 4-(MeOOC)Ph 3-320 4 CON(Ac)CO 2-(EtOOC)Ph 3-32 1 4 CON(Ac)CO 4-(EtOOC)Ph 3-322 4 CON(Ac)CO -2-(tBuOOC)Ph y \wpdocs\d gt mss\981I2\981I2cpd3.doc 245 Table3 (ont) 3-323 T CON(Ac)CO -4-(tBuOOC)Ph 3-324 4 CON(Ac)CO -lP 3-325 4 CON(Ac)CO 4-Cl-Ph 3-326 4 CON(Ac)CO 2-Br-Ph 3-327 4 CON(Ac)CO 4-Br-Ph 3-328 4 CON(Ac)CO 2-I-Ph 3-329 4 CON(Ac)CO 4-I-Ph 3-330 4 CON(Ac)CO 2-N0 2 -Ph 3-331 4 CON(Ac)CO 4-N0 2 -Ph 3-332 4 CON(Ac)CO 2-N11 2 -Ph 3-333 4 CON(Ac)CO 4-NH 2 -Ph 3-334 4 CON(Ac)CO 2-(HO 3 S)Ph 3-335 4 CON(Ac)CO 4-(HO 3 S)Ph 3-336 4 CON(Ac)CO 2-(NHi 2 0 2 S)Ph 3-337 4 CON(Ac)CO 4-(NH 2

O

2 S)Ph 3-338 4 CON(Ac,)CO 2-NP 3-339 4 CON(Ac.)CO 4-NP 3-340 4 CON(Ac)CO 2-(HOCH 2 )Ph 3-341 4 CON(Ac)CO 4-(HOCH 2 )Ph 3-342 4 CON(Ac)CO -Me 3-343 4 CON(Ac)CO -Et 3-344 4 CON(Ac)CO

-P

3-345 4 CON(Ac)CO ir 3-346 4 CON(Ac)CO

-B

3-347 4 CON(Ac)CO -HOC2 3-348 4 CON(Ac)CO MeOOCCI 2 y:\wpdocs\dgt-mss\981I2\981 2cpd3.-doc 246 Table 3 (cont) Cpd. k A B

R

3-4 T CON(Ac)CO MeCH(COOH) 3-3 50 4 CON(Ac)CO

HOOC-(CH

2 2 3-35 1 4 CON(Ac)CO MeCH(COOMe) 3-352 4 CON(Ac)CO 1-HOOC-iBu 3-353 4 CON(Ac)CO 1-MeOOC-iBu 3-354 4 CON(Ac)CO 1-HOOC-iPn 3-355 4 CON(Ac)CO 1-MeOOC-iPn 3-356 4 CON(Ac)CO 1-HOOC-2-Me-Bu 3-357 4 CON(Ac)CO I-MeOOC-2-Me-Bu 3-358 4 CON(Ac)CO

CH

2

CH

2

SO

3

H

3-359 4 CON(Ac)CO -Z-1I 3-360 4 CON(Ac)CO -Z-2 3-361 4 CON(Ac)CO -Z-3 3-362 4 CON(Ac)CO -Z-4 3-363 4 CON(Ac)CO 3-364 4 CON(Ac)CO -Z-6 3-365 4 CON(Ac)CO -Z-7 3-366 4 CON(Ac)CO -Z-8 3-367 4 CON(Ac)CO -Z-9 3-368 4 CON(Ac)CO 3-369 4 CON(Ac)CO -Z-1 1 3-370 4 CON(Ac)CO 12 3-371 4 CON(Ac)CO 3-Py 3-372 4 CON(Ac)CO 4-Py 3-373 4 CONH-CO NH

H

3-374 4 CONI-CO NHl Ph 3-375 4 CONHCO NHl 2-Me-Ph 3-376 4 CONHCO NHl 4-Me-Ph y:\WPdocs\dgt mss\9812\98I2cpd3.doc 247 Tabl 3(cat) Cpd. k A B

R

3-3 77 4 CONHCO NH 2,4-diMe-Ph 3-378 4 CONi-CO NH 3,4-diMe-Ph 3-379 4 CONHCO NH 2-(CF 3 )Ph 3-380 4 CONIICO NH- 4-(CF 3 )Ph 3-381 4 CONHCO NIH 2-MeOPh 3-3 82 4 CONI-CO NH 4-MeOPh 3-383 4 CONHCO NEl 2-EtOPh 3-384 4 CONHCO NH 4-EtOPh 3-8 4 COHONH2H* *3-386 4 CONH-CO NH 2-HOPh 3-8 4 3-386 4 CONHCO NH 4-HOOPh 3-387 4 CONI-CO NH 2-(HeOOC)Ph 3-388 4 CONH-CO NH 4-(HeOOC)Ph 3-391 4 CONH-CO NHl 2-(MEOOC)Ph 3-9 4.OHON

-EOCP

3-390 4 CONHCO NH 4-(MeuOOC)Ph *3-391 4 CONHCO NH 2-OCPh 3-392 4 CONHCO NE 4-OCPh 3-393 4 CONHCO NHl 2-BOOPh :3-394 4 CONHCO NH- 4-BOOPh 3-399 4 CONHCO Nil 2-Cl-Ph 3-396 4 CONHCO Nil 4-Cl-Ph 3-397 4 CONHCO NH 2-Br-Ph 3-402 4 CONHCO NH 4-N0 2 -Ph 3-403 4CONHCO NH 2-NH 2 -Ph y:\wpdocs\dgtmnss\98 I 2\981 I cpd3.dAm 248 Table3cnt.) 00 0 0 0 0* 0:0.

Cpd. k A B R No. 3-404 4 CONHCO NH 4-NH 2 -Ph 3-405 4 CONIICO NH 2-(HO 3 S)Ph 3-406 4 CONHCO NH 4-(HO 3 S)Ph 3-407 4 CONHCO NH 2-(NH 2

O

2 S)Ph 3-408 4 CON'HCO NH 4-(NH- 2 0 2 S)Ph 3-409 4 CONI-CO NH 2-CN-Ph 3-410 4 CONHCO NH 4-CN-Ph 3-411 4 CONH-CO NIH 2-(HOCH 2 )Ph 3-412 4 CONHCO NH 4-(HOCH 2 )Ph 3-413 4 CONHCO NH Me 3-414 4 CONE-CO NH Et 3-415 4 CONHCO NH Pr 3-416 4 CONE-CO NIH iPr 3-417 4 CONE-CO NE- Bu 3-418 4 CONI-CO NH HOOCCH 2 3-419 4 CONI-CO NiE MeOOCCH 2 3-420 4 CONHCO NH MeCH(COOH) 3-42 1 4 CONJ-ICO NiE HOOC-(CH 2 2 3-422 4 CONHCO Nil MeCH(COOMe) 3-423 4 CONilCO NHl I-HOOC-iBu 3-424 4 CONilCO NHl I-MeOOC-iBu 3-425 4 CONHCO NIH I -HOOC-iPn 3-426 4 CONilCO Ni-I 1-MeOOC-iPn 3-427 4 CONE-CO NI-I I-HOOC-2-Me-Bu 3-428 4 CONHCO NiH 1-MeOOC-2-Me-Bu 3-429 T CONIICO Nil CH 2

CH

2 SO3H 3-430 4 CONI-ICO NH HO Y:\-pdocs\dgt-mss\981I2\981I2cpd3.doc -249- Table 3 (cont.)

S

6S** 00 @0 *0 0 0 S. 000@

S.

Cpd. k A B R No.

3-431 4 CONHCO NH MeO 3-432 4 CONHCO NH EtO 3-433 4 CONHCO NH PrO 3-434 4 CONHCO NH iPrO 3-435 4 CONICO NH BuO 3-436 4 CONiCO NH iBuO 3-437 4 CONHCO NH sBuO 3-438 4 CONHCO NH tBuO 3-439 4 CONHCO NH HxO 3-440 4 CONHCO NH PhO 3-441 4 CONHCO NH BnO 3-442 4 CONHCO NH Z-1 3-443 4 CONCO NH Z-2 3-444 4 CON-CO NH Z-3 3-445 4 CON-CO NH Z-4 3-446 4 CONHCO NH 3-447 4 CONHCO NH Z-6 3-448 4 CONHCO NH Z-7 3-449 4 CONHCO NH Z-8 3-450 4 CONECO NH Z-9 3-451 4 CONTHCO NH 3-452 4 CONHCO NB Z-1I 3-453 4 CON-CO NH Z-12 3-454 4 CONBCO NH 3-Py 3-455 4 CON-CO NB 4-Py 3-456 4 CONHS02

H

3-457 4 CONHS0 2 Ph 3-458 4 CONHS0 2 2-Me-Ph y:\wpdocs\dgt~mss\981 2\9812cpd3.doc 000* 0

S

0 *o*Q 0506 00 0 -250- Table (cnt) Cpd. k A B R No. T CONHIS0 2 4-Me-Ph 3-460 4 CONHS0 2 2,4-diMe-Ph 3-461 4 CONH~S0 2 3,4-diMe-Ph 3-462 4 CONH{S02 2-(CF 3 )Ph 3-463 4 CONH-S0 2 4-(CF 3 )Ph 3-464 4 CONHS0 2 2-MeOPh 3-465 4 CONHS02 4-MeOPh :*3-466 4 CONH-S0 2 2-EtOPh .3-467 4 CONH-S0 2 4-EtOPh *3-468 4 CONH-S02 2-HOPh *3-469 4 CONH-S0 2 4-HOPh 3-470 4 CONH-S0 2 2-(HOOC)Ph *3-471 4 CONHS0 2 4-(HOOC)Ph 3-472 4 CONH-S02 2-(MeOOC)Ph 3-473 4 CONHSO2 4-(MeOOC)Ph 3-474 4 CONJ-{S09 2-(EtOOC)Ph 3-475 4 CONHS0 2 4-(EtOOC)Ph 3-476 4 CONE-S0 2 2-(tBuOOC)Ph 3-477 4 CONI-1S0 2 4-(tBuOOC)Ph 3-478 4 CONH-S0 2 -2-Cl-Ph 3-479 4 CONH-S0 2 -4-Cl-Ph 3-480 4 CONH-S0 2 -2-Br-Ph 3-481 4 CONHS02 -4-Br-Ph 3-482 4 CONH-S02 -2-I-Ph 3-483 4 CONHS02 4-I-Ph Y:\wpdocs\dgtmnss\ 981 2\981 2cpd3.doc -251 Table 3 (cont.) Cpd. k A B R No.

3-484 4 CONHS0 2 2-N0 2 -Ph 3-485 4 CONHSO 2 4-N0 2 -Ph 3-486 4 CONIHS0 2 2-NH 2 -Ph 3-487 4 CONISO 2 4-NH 2 -Ph 3-488 4 CONHSO 2 2-(HO 3 S)Ph 3-489 4 CONHS0 2 4-(HO 3 S)Ph 3-490 4 CONHS02 2-(NH 2

O

2 S)Ph 3-491 7 CONHSO 2 4-(NH 2

O

2 S)Ph 3-492 4 CONHS0 2 2-CN-Ph 3-493 4 CONHSO 2 4-CN-Ph 3-494 4 CONHSO 2 2-(HOCH 2 )Ph 3-495 4 CONHSO 2 4-(HOCH 2 )Ph 3-496 4 CONHSO2 Me 3-497 7 CONHSO2 Et 3-498 4 CONHSO-, Pr 3-499 7 CONHSO9 iPr 3-500 7 CONHSO', Bu 3-501 7 CON-S02 HOOCCH 2 3-502 7 CON-HS0 2 MeOOCCH 2 3-503 7 CON-S0 2 MeCH(COOH) 3-504 7 CONHS0 2

HOOC-(CH

2 2 3-505 7 CONHS0 2 MeCH(COOMe) 3-506 7 CON1-S0 2 1-HOOC-iBu 3-507 7 CONISO9 1-MeOOC-iBu 3-508 7 CONHS0 2 1-HOOC-iPn y:\wpdocs\dgtmss\98 12\9812cpd3 .doc

_IT

252 Table 3(cont) Cpd. k A B

R

No.

3-509 T CONHS0 2 -MeOOC-iPn 3-510 4 CONHS02 -1-HOOC-2-Me-Bu 3-511 4 CONHS0 2 -I -MeOOC-2-Me-Bu 3-512 4 CON-HS0 2

-CH

2

CH

2

SO

3

H

13 4 CONHS0 2

-OH

3-514 4 CONES02 -MeO 3-515 4 CONH-S02 -EtO 3-516 4 CONH1S0 2 -Pro :3-517 4 CONE-S02 -pr 18 4 CONE-S0 2 BuO **3-519 4 CONE-S02 iBuO 3-520 4 CONHS0 2 sBuO 3-521 4 CON-S02 -u 3-522 4 CONH-S02, HxO 3-523 4 CONIHSS02 PhO 3-524 4 CONHS0 2 BnO 3-525 4 CONBS02 1 3-526 4 CONHS0 2 -Z-2 3-527 4 CONH-S0 2 -Z-3 3-528 4 j CONHS0 2 -Z-4 3-529 4 CONES0 2 3-530 4 CONHS0 2 -Z-6 3-531 4 CONHS0 2 -Z-7 3-532 4 CONHIS0 2 -Z-8 3-53 3 4 CONH-S0 2 Z-9 y:\wpdocs\dgtmnss\98 I 2\981I2cpd3 Ado -253- Cpd. k A

R

3-534 4 CONHS02 3-535 4 CONHS02 -Z-1

I

3-53 4 ONHS2 -Z-12 3-536

CONHS

2 -3-Py 3-538 4

CONHIS

2 -4-Py 3-538 4 CONHS0 2

N

3-540 4 CONH-S0 2 NH

PH

3-540 4 CONH{S02 NH- 2-Ph 3-542 4 CONHS-1S0 NH 4-Me-Ph 3-543 4 CONHS0 2 NH 24-dMe-Ph 3-544 4 CONH-S02 NH 3,4-diMe-Ph 3-545 4 CONH-S02 NH 2,-(CF 3 )Ph 3-546 4 CONH-S0 2 NH 4-(CF 3 )Ph 3-547 4 CONE-S02 NH 2-MeOPh 3-548 4 CONHSO 2 NH- 4-MeOPh 3-549 4 CONHS02 NIH 2-EtOPh 3-550 4 CONHSO2) NE- 4-EtOPh 3-551 4 CONHSO 2 NH 2-HOPh 3-552 4 CONH-S0 2 NH 4-HOPh 3-553 4 CONHSO? NH 2-(HOOC)Ph 3-554 4 CONIS-1S0 NH 4-(HOOC)Ph 3-555 4 CONHS02 NH 2-(MeOOC)Ph 3-556 4 CONHS02 NH 4-(MeOOC)Ph 3-557 4 CONHS02 NH 2-(EtOOC)Ph 3-558 4CONHS02 NH 4-(EtOOC)Ph y:\wpdocs\dgt~mss\ 98 1I2\981I2cpd3 .doc -254- Table 3 (omnL Cpd. k A l B R No.

3-559 4 CONHS0 2 NH 2-(tBuOOC)Ph 3-560 4 CONHS02 NH 4-(tBuOOC)Ph 3-561 4 CONHS0 2 Ni 2-Cl-Ph 3-562 4 CONHS0 2 NH 4-Cl-Ph 3-563 4 CONHS0 2 NH 2-Br-Ph 3-564 4 CONHS02 Ni 4-Br-Ph 3-565 4 CONHS02 NH 2-I-Ph 3-566 4 CONHS02 NH 44Ph 3-567 4 CONHS0 2 NH 2-N0 2 -Ph 3-568 4 CONHS0 2 NH 4-N0 2 -Ph 3-569 4 CONHS0 2 NH 2-NH 2 -Ph 3-570 4 CONHS0 2 NH 4-NH 2 -Ph 3-571 4 CONHS02 NH 2-(HO 3 S)Ph 5 3-572 4 CONHSO2 NH 4-(HO 3 S)Ph 3-573 4 CONlS02 NH 2-(NH 2 0 2 S)Ph 3-574 4 CONHS02 NH 4-(NH 2

O

2 S)Ph 3-575 4 CONHS0 2 NH 2-CN-Ph 3-576 4 CON1S0 2 NH 4-CN-Ph 3-577 4 CONHSO- NH 2-(HOCH 2 )Ph 3-578 4 CONESO2 NH 4-(HOCH 2 )Ph 3-579 4 CONHSO 2 NH Me 3-580 4 CONHS0 2 NH Et 3-581 4 CONHS0 2 NH Pr 3-582 4 CONHS0 2 NH iPr 3-583 4 CONHS0 2 NH Bu y:\wpdocs\dgtmss\981 2\9812cpd3.doc 255 Table3(cnt.) Cpd. k A B R No. 3-584 T CONHS0 2

HOOCCH

2 3-585 4 CONHS0 2 NiH MeOOCCH 2 3-586 4 CONHS0 2 NiH MeCH(COOH) 3-587 4 CONHS0 2 NHl HOOC-(CH 2 )2- 3-588 4 CONHlS0 2 NH MeCH(COOMe) 3-589 4 CONHSO02 NHl 1-HOOC-iBu 3-590 4 CONHS0 2 Nil 1-MeOOC-iBu 3-591 4 CONHS0 2 Nil 1-HOOC-iPn 3-592 4 CONHlS0 2 Nil 1-MeOOC-iPn 3-593 4 CONH-S0 2 NH 1 -HOOC-2-Me-Bu 3-594 4 CONHS0 2 Nil 1-MeOOC-2-Me-Bu 3-595 4 CONHS0 2 Nil CH 2

CH

2 SO3H 3-596 4 CONH-S0 2 Nil

OH

3-597 4 CONH-S02 NH MeG 3-598 4 CONHSO-, NH EtO 3-599 4 CONE-S0 2 NH Pro 3-600 4 CONHS0 2 NH iPro 3-601 4 CONHS', NE BuG 3-602 4 CONH-S0 2 NH- iBuG 3-603 4 CGNHSG2) NH sBuG 3-604 4 CONB-S0 2 NH tBuO 3-605 4 CONH-S0 2 NH HxG 3-606 4 CONHS02 NH PhO 3-607 4 CONHSG2 NH BnO 3-608 4 CONHlS02 NH Z-1 y:\wpdocs\dgtmss\981I2\98 I2cpd3 .doc -256- Table 3 (cont.) Cpd. k A B R No.

3-609 4 CONHS0 2 NH Z-2 3-610 4 CONHSO 2 NH Z-3 3-611 4 CONHS02 NH Z-4 3-612 4 CONHS02 NH 3-613 4 CONHS02 NH Z-6 3-614 4 CONHS0 2 NH Z-7 3-615 4 CONHS0 2 Ni Z-8 3-616 4 CONHS0 2 Ni Z-9 3-617 4 CONHSO2 Ni 3-618 4 CONHSO 2 Ni Z-11 3-619 4 CONHSO2 NH Z-12 3-620 4 CONES02 Nil 3-Py 3-621 4 CONHSO 2 NH 4-Py 3-622 4 N-CO

H

3-623 4 NHCO Ph 3-624 4 NHCO 2-Me-Ph 3-625 4 NHCO 4-Me-Ph 3-626 4 NICO 2,4-diMe-Ph 3-627 4 NHCO 3,4-diMe-Ph 3-628 4 NiCO 2-(CF 3 )Ph 3-629 4 NHCO 4-(CF 3 )Ph 3-630 4 NHCO 2-MeOPh 3-631 4 NHCO 4-MeOPh 3-632 4 NiCO 2-EtOPh 3-633 4 NHCO 4-EtOPh 3-634 4 NHCO 2-HOPh y:\wpdocs\dgtrnss\ 9 8 I2\9812cpd3.doc -257- Tabl3(cnt.) Cpd. k ABR No. 3-635 4 NHCO -4H~ 3-636 4 NIICO,

-HOCP

3-63 7 4 NIICO -4-(HOOC)Ph 3-63 8 4 NHCO -2-(MeOOC)Ph 3-63 9 4 NHCO -4-(MeOOC)Ph 3-640 4 NI-CO -2-(EtOOC)Ph 3-641 4 NHCO -4-(EtOOC)Ph 3-642 4 NHCO -2-(tBuOOC)Ph 3-643 4 NHCO -4-(tBuOOC)Ph 3-644 4 NIICO -2-Cl-Ph 3-645 4 NI-CO -4-Cl-Ph 3-646 4 NI-CO -2-Br-Ph *3-647 4 NHCO 4-Br-Ph *3-648 4 NH-CO 2-I-Ph 3-649 4 NHcO 4-I-Ph 3-650 4 NHCO 2-N0 2 -Ph 3-651 4 NH-CO -4-N0 2 -Ph :3-652 4 NIICO -2-NH 2 -Ph 3-653 4 NHCO -4-NI- 2 -Ph 3-654 4 NECO 2-(HO 3 S)Ph 3-655 4 NHCO -4-(HO 3 S)Ph 3-656 4 NHCO 2-(NH 2

O

2 S)Ph 3-657 4 NHCO 4-(N11 2 0 2 S)Ph 3-658 4 NH-CO 2-CN-Ph 3-659 4 NHCO 4-CN-Ph 3-660 4 NHCO 2-(HOCH 2 )Ph 3-661 4 NH-CO 4-(HOCH 2 )Ph y:\wpdocs\dgtmffss\9812\981I2cpd3.doc -258- Table 3(cont) Cpd. k A B

R

3-662 4 NHCO Me 3-663 4 NH-CO -Et 3-664 4 NHCO -Pr 3-665 4 NIICO iPr 3-666 4 NIICO Bu 3-667 4 Ni-CO

HOOCCH

2 3-668 4 NI-CO MeOOCCH 2 3-669 4 NH-CO MeCH(COOH) 3-670 4 NH-CO

HOOC-(CH

2 2 3-671 4 NH-CO MeCH(COOMe) 3-672 4 N-CO 1-HOOC-iBu 3-673 4 NHCO 1-HOOC-iPn 3-674 4 NHCO 1-HOOC-2-Me-Bu 3-675 4 NH-CO

CH

2

CH

2

SO

3

H

3-676 4 NHCO -MeO 3-677 4 NI-CO -EtO 3-678 4 NHCO -Pro 3-679 4 NHCO 1 3-680 4 NHCO -Z-2 3-68 1 4 NBCO -Z-3 3-682 4 NHCO -Z-4 3-683 4 NHCO 3-684 4 NHCO -Z-6 3-685 4 NH-CO -Z-7 3-686 4 Ni-CO -Z-8 3-687 4 NI-CO -Z-9 3-698 4 NH-CO Z- y:\wpdacs\dgt-mss\ 9 8 1I2\981I2cpd3 .doc -259- Tabl 3(cont.) Cpd. k A B

R

3-689 4 NHCO Z-1l1 3-690 4 NI-CO Z-12 3-691 4 NHCO 3P 3-692 4 NHCO -4P 3-693 4 NIICO NH

H

3-694 4 NHCO NH

P

3-695 4 Ni-CO NH 2-Me-Ph 3-696 4 NI-CO NEl 4-Me-Ph :3-697 4 NHCO NH 2,4-diMe-Ph 3-698 4 NHCO NH 3,4-diMe-Ph .003-699 4 NHCO NH 2-(CF 3 )Ph 3-700 4 NHCO NH 4-(CF 3 )Ph 0000 3-701 4 NHCO Nil 2-MeOPh 3-702 4 NH-CO NH 4-MeOPh .0 3-703 4 NH-CO NH 2-EtOPh alCONH2H 3-704 4 NH-CO NIH 4-EtOPh 3-707 4 N-HCO NIH 2-HOPh *3-706 4 NHCO NH 4-HOPh 3-707 4 NHCO NHl 2-(HeOOC)Ph 3-710 4 NHCO NH 4-(HeOOC)Ph 3-709 4 NHCO NH 2-(EOOC)Ph 3-7 10 4 NHCO NEl 4-(MEOOC)Ph 3-711 4 NHCO NH 2-(tuOOCPh 3-712 4 NHCO NH 4-(tuOOC)Ph 3-715 4 Ni-CO NHl 2-Cl-Ph 3-7 16 4 NHCO NH- 4-Cl-Ph y:\wpdocs\d gtmrss\981 2\981 2cpd3.doc 260 Table3(cont.) Cpd. k A

BR

3-717 T NHCO NiH 2-Br-Ph 3-718 4 NHCO NHl 4-Br-Ph 3-719 4 NIICO Nil 2-I-Ph 3-720 4 NH-CO NH 4-I-Ph 3-721 4 NHCO NH 2-N0 2 -Ph 3-722 4 NHCO NH 4-N0 2 -Ph 3-723 4 NH-CO Nil 2-NH 2 -Ph 3-724 4 NHCO NI- 4-NH 2 -Ph 3-725 4 NH-CO NE 2-(HO 3 S)Ph 3-726 4 NHCO NE- 4-(HO 3 S)Ph 3-727 4 NHCO NI- 2-(NH 2

O

2 S)Ph 3-728 4 NH-CO NE 4-(NI- 2 0 2 S)Ph 3-729 4 NH-CO N-H 2-CN-Ph 3-730 4 NH-CO NE- 4-CN-Ph 3-73 1 4 NH-CO NE 2-(HOCH 2 )Ph 3-732 4 NI-CO N-H 4-(HOCH 2 )Ph 3-733 4 Ni-CO NH Me 3-734 4 NHCO NI- Et 3-735 4 NB-CO NH- Pr 3-736 4 NHCO NH- iPr 3-737 4 NBCO NH B u 3-738 4 NI-CO NH HOOCCH2- 3-739 4 NHCO NH MeOOCCH2- 3-740 4 NH-CO NH MeCH(COOH) 3-741 4 NH-CO NH HOOC-(CH2)2- 3-742 4NH-CO NH MeCH(COOMe) y:\wpdocs\dgtrnss\ 98 I 2\981I2cpd3.doc -261- Table 3 (cont.)

C

.;CC.

C C C. C 0b c

SC

S

C.

Cpd. k A B R No.

3-743 4 NHCO NH 1-HOOC-iBu 3-744 4 NHCO NH 1-MeOOC-iBu 3-745 4 NHCO Ni 1-HOOC-iPn 3-746 4 NHCO NH 1-MeOOC-iPn 3-747 4 NICO Ni 1-HOOC-2-Me-Bu 3-748 4 NHCO NH 1-MeOOC-2-Me-Bu 3-749 4 NHCO Ni CH 2

CH

2

SO

3

H

3-750 4 NHCO Ni OH 3-751 4 NHCO Ni MeO 3-752 4 NHCO NH EtO 3-753 4 NiCO NH PrO 3-754 4 NiCO NH iPrO 3-755 4 NICO Ni BuO 3-756 4 NHCO NH iBuO 3-757 4 NHCO NH sBuO 3-758 4 NHCO NH tBuO 3-759 4 NECO NH HxO 3-760 4 NHCO NH PhO 3-761 4 NHCO NH BnO 3-762 4 NHCO NH Z-1 3-763 4 NHCO NH Z-2 3-764 4 NHCO NH Z-3 3-765 4 NHCO NH Z-4 3-766 4 N-CO NH 3-767 4 NHCO NH Z-6 3-768 4 NHCO NH Z-7 3-769 4 NHCO NH Z-8 3-770 4 NHCO NH Z-9 y:\wpdocs\dgtmss\981 2\981 2cpd3.doc 262 Table 3 (cont.) Cpd. k A B R No.

3-771 T NHCO NH 3-772 4 NH-CO NH Z-11 3-773 4 NHCO NiH Z-12 3-774 4 NHCO NH 3-Py 3-775 4 NHCO NH 4-Py 3-776 4 NHCO NMe Ph 3-777 4 NI{CO NMe 2-Me-Ph 3-778 4 NHCO NMe 4-Me-Ph .3-779 4 NH-CO NMe 2,4-diMe-Ph :3-780 4 NI-CO NMe 3,4-diMe-Ph 3-781 4 NHiCO NMe 2-(CF 3 )Ph 3-782 4 NH-CO NMe 4-(CF 3 )Ph 3-783 4 NHCO W~e 2-MeOPh 3-784 4 NI-CO NWe 4-MeOPh 3-785 4 NI-CO NMe 2-EtOPh *3-786 4 NHCO NMe 4-EtOPh 3-787 4 NHCO N-Me 2-HOPh ~3-788 4 NiCO NMe 4-HOPh 3-789 4 NHCO N-Me 2-(HOOC)Ph 3-790 4 NH-CO W~e 4-(HOOC)Ph 3-791 4 NH-CO N-Me 2-(MeOOC)Ph 3-792 4 NH-CO NMe 4-(MeOOC)Ph 3-793 4 NE-CO NMe 2-(EtOOC)Ph 3-794 4 NI-CO NMe 4-(EtOOC)Ph 3-795 4 NE-CO NMe 2-(tBuOOC)Ph 3-796 4 NH-CO NMe 4-(tBuOOC)Ph 3-797 4 NI-CO NMe 2-Cl-Ph 3-798 4 NH-CO NMe 4-Cl-Ph y:\wpdocs\dgtmss\981I2\981 2cpd3.doc 263 Tabl3(cnt.) Cpd. k A B

R

3-799 4 NHCO NMe 2-Br-Ph 3-800 4 NIICO NMe 4-Br-Ph 3-801 4 NIICO NMe 2-I-Ph 3-802 4 NHCO NWe 4-I-Ph 3-803 4 NH-CO NMe 2-N0 2 -Ph 3-804 4 NIICO NMe 4-N0 2 -Ph 3-805 4 NHCO NMe 2-NH- 2 -Ph 3-806 4 NH-CO NWe 4-NH 2 -Ph 3-07 4 HC Ne -(O 3 AP 3-808 4 NHCO NWe 3 S)Ph 3-809 4 NI-CO NMe 2-(NHi 2

O

2 S)Ph 3-8 10 4 NHCO NMe 4-(NE- 2 0 2 S)Ph 3-811 4 Ni-CO Ne 2-CN-Ph 3-812 4 NHCO NMe 4-CN-Ph 3-813 4 NHiCO NMe 2-(HOCH 2 )Ph 3-814 4 NH-CO NMe 4-(HOCH 2 )Ph 3-815 4 NE-CO NMe Me 3-816 4 NHCO NMe Et 3-817 4 N-CO NMe Pr 3-8 18 4 NHCO NMe iPr 3-8 19 4 NE-CO NMe Bu 3-820 4 NH-CO NMe HOOCCH 2 3-821 4 NHCO NMe MeOOCCH 2 3-822 4 NI-CO NMe MeCH(COOH) 3-823 4 NH-CO W~e HOOC-(CH 2 2 3-824 4 NH-CO NMe MeCH(COOMe) y:\wpdocs\dgtniss\98I2\981 2cpd3.doc 264 Table 3 (cont.) Cpd. k A B Rl 3-825 4 NIICO W~e 1-HOOC-iBu 3-826 4 NIICO NMe I-MeOOC-iBu 3-827 4 NI-ICO NMe 1-HOOC-iPn 3-828 4 Ni-CO NMe I-MeOOC-iPn 3-829 4 Ni-CO NMe 1-HOOC-2-Me-Bu 3-830 4 NIICO NMe 1-MeOOC-2-Me-Bu 3-83 1 4 NI-CO NMe CH 2

CH

2

SO

3

H

3-832 4 NH-CO NMe

OH

3-833 4 NH-CO NMe MeO 3-834 4 NHCO NMe EtO 3-835 4 NHCO NMe Pro 3-836 4 NHCO NMe iPrO 3-837 4 Ni-CO W~e BuO 3-838 4 NHCO NMe iBuO 3-839 4 NHCO NMe sBuO 3-840 4 NHCO NMe tBuO 3-84 1 4 NHCO NWe HxO 3-842 4 NHCO NWe PhO 3-843 4 Ni-CO NWe BnO 3-844 4 NHCO NWe Z-1 3-845 4 NHCO NMe Z-2 3-846 4 NI-CO NMe Z-3 3-847 4 NHCO NMe Z-4 3-848 4 NH-CO NMe 3-849 4 NHCO NMe Z-6 3-850 4 NHCO NMe Z-7 3-85 1 4 Ni-CO NWe Z-8 3-852 4 NI-CO NMe Z-9 y:\wpdocs\dgt-nmss\981I2\981 2cpd3.doc -V W-- 265 Table 3 (cont.) 0** 0 0** Cpd. k A B Rl No. 3-853 4 NH-CO W~e 3-854 4 NIHCO NWe Z-1 1 3-855 4 NHCO NMe Z-12 3-856 4 NIICO NMe 3-Py 3-857 4 NHCO NMe 4-Py 3-858 4 NI-CO NHN1H H 3-859 4 N-CO NHNH Me 3-860 4 NHClO NHNH Et 3-861 4 NI-CO NHI4Me Me 3-862 4 NH-CO NHNMe Et 3-863 4 NI-CO NHNMe Pr 3-864 4 NH-CONHNHCO NiH H 3-865 4 NJ-CON1-NHCO NH Ph 3-866 4 N1-CONHNHCO NiH 2-Me-Ph 3-867 4 NHCONHN1ICO NH 4-Me-Ph 3-868 4 NHCONH-NI-CO NH 2,4-diMe-Ph 3-869 4 N\HCONHNH-CO NE- 3,4-diMe-Ph 3-870 4 NHCONHNI-CO NiH 2-(CF 3 )Ph 3-87 1 4 NBI-CONH-N-CO NE- 4-(CF 3 )Ph 3-872 4 N-CONl-INHCO NH 2-MeOPh 3-873 4 NHCON1{NH-CO NH 4-MeOPh 3-874 4 NH-CON1*41-CO NH 2-EtOPh 3-875 4 NHCONHN-CO NH 4-EtOPh 3-876 4 NH-CONHN}ICO NE 2-HOPh 3-877 4 N1-CONHNHCO NIH 4-HOPh 3-878 4 NH-CONI{NHCO NH 2-(HOOC)Ph 3-879 4 NHCONHNHCO NH 4-(HOOC)Ph 3-88.0 4 NHCONHMICO NH 2-(MeOOC)Ph y:\wpdocs\dgtmss\981I2\981I2cpd3 .doc 266 Tabl 3(cnt) Cpd. k A

BR

No. 3-881 T NHCONHNIICO NH 4-(MeOOC)Ph 3-882 4 NHCONIINHCO NIL 2-(EtOOC)Ph 3-883 T NHCONHNHCO NH 4-(EtOOC)Ph 3-884 4 NIICONILNICO NH 2-(tBuOOC)Ph 3-885 4 NHCONHNHCO NH 4-(tBuOOC)Ph 3-886 4 NI-CONI{NHCO. NH 2-Cl-Ph 3-887 4 Nl-CONHNHCO NH 4-Cl-Ph 3-888 4 NHCONHNHCO NH 2-Br-Ph 3-889 4 NIICONHNHCO NH 4-Br-Ph 3-890 4 NHCON1-NIICO NH 2-I-Ph 3-89 1 4 NI-CONHNHCO

NHE-IP

3-892 4 NIICONl-NHCO NH 2-N0 2 -Ph 3-893 4 NEHCONl-INl-CO NI-I 4-N0 2 -Ph 3-894 4 NHCON1-NHCO NH 2-NH 2 -Ph 3-895 4 NHCONHNH-CO NiH 4-NH- 2 -Ph 3-896 4 Ni-CON1-NHCO NEH 2-(HO 3 S)Ph 3-897 4 NHCON{N HCO NH- 4-(HO 3 S)Ph 3-898 4 NE-CONl{NE-CO NI 2-(N- 2 0 2 S)Ph 3-899 4 NH-CONE-Nl-CO NH 4-(NH 2

O

2 S)Ph 3-900 4 NI-ICONH-NHiCO Ni-H 2-CN-Ph 3-901 4 NiICONI-NI-CO NI-I 4-CN-Ph 3-902 4 NH-CONi-NH-CO Ni- 2-(HOCH 2 )Ph 3-903 T NHCONI{NHCO NEl 4-(HOCH 2 )Ph 3-904 4 NIICONHNHCO Nil Me 3-905 4 NilCONILNECO Nil Et 3-906 4 NH-CONHNHCO Nil Pr 3-907 4 NHCONI-NHCO NHl iPr y:\wpdocs\dgtmnss\981I2\981I2cpd3 .doc 267 Tabl(cnt.) Cpd. k A B R 3-908 T NiiCOiNiHCO NH Bu 3-909 4 NHCONH-NHCO NH HOOCCH 2 3-910 4 NIHCONHNHCO NH MeOOCCH 2 3-911 4 NHCONHNHCO NH MeCH(COOH) 3-9 12 4 NHCONI-NHCO NH HOOC-(CH 2 2 3-913 4 NI{CONHNH-CO NH MeCH(COOMe) 3-9 14 4 N1-CONHNHCO NH 1-HOOC-iBu 3-915 4 NI-CONHN1-CO NH 1-MeOOC-iBu 3-916 4 NHCONHNH-CO NH 1-HOOC-iPn 3-917 4 NHCONHN-ICO NE I-MeOOC-iPn 3-918 4 NI{CONHNIICO NH 1-HOOC-2-Me-Bu 3-919 4 NHqCON1-NHCO NH I-MeOOC-2-Me-Bu 3-920 4 NHCON1{NH-CO NH CH 2

CH

2

SO

3

H

3-921 4 N1-CONHN1-CO NH OH 3-922 4 NI{CONHNHCO NH MeO 3-923 4 NH-CONH-NHCO NH DtO 3-924 4 NB-CONH-NHCO NE Pro 3-925 4 NI-CONI*41-CO NIH iPrO 3-926 4 N1-ICONIIN}iCO N-H BuO 3-927 4 NHCON1-NHCO NE iBuO 3-928 4 NHCONH-NIHCO NH sBuO 3-929 4 NHCONHNHCO NH tBuO 3-930 4 NH-CONHN-HCO NH HxO 3-931 4 NH-CONHNHCO NH PhO 3-932 4 NHCONHiNHCO NH BnO 3-933 4 NHCONHNHCO NH Z-1 3-934 4 NHCONHNI4CO NH Z-2 3-935 4 NHCONHNHCO NH Z-3 Y:\-pdocs\dgtniss\9812\981 2cpd3.doc 268 Tabl3(cnt.) 3-936 T NHCONHNHCO NHl Z-4 3-937 4 NI{CONI{M{CO NHl 3-93 8 4 N}ICONHfNHCO NiH Z-6 3-939 4 NI{CONHNHCO NH Z-7 3-940 4 NHCONHINI{CO NH Z-8 3-941 4 NHCONHM{CO NH Z-9 3-942 4 NI-CONHMICO NH 3-943 4 NHCONHNHCO NH Z-11I 3-944 4 NHCONHNHCO NH Z-12 3-945 4 NHCONIINH-CO NH- 3-Py 3-946 4 NHCONI-NH-CO NHl 4-Py 3-947 4 NH-CONi-CO

H

3-948 4 NHCONHCO Ph 3-949 4 NE-CONE-CO 2-Me-Ph 3-950 4 NHCONHCO 4-Me-Ph 3-951 4 NHCONHCO 2,4-diMe-Ph 3-952 4 N HCONH-CO 3,4-diMe-Ph 3-953 4 NI-CONHCO 2-(CF 3 )Ph 3-954 4 NH-CONHCO 4-(CF 3 )Ph 3-955 4 NH-CONHCO 2-MeOPh 3-956 4 Ni-CONI-CO 4-MeOPh 3-957 4 NIICONHCO 2-EtOPh 3-958 4 NE-CONH-CO 4-EtOPh 3-959 4 NHCONH-CO 2-HOPh 3-960 4 NH-CONi-CO 4-HOPh 3-961 4 NH-CONIICO 2-(HOOC)Ph 3-962 4 NH-CONH-CO 4-(HOOC)Ph 3-963 4 NH-CONI-CO 2-(MeOOC)Ph y:\wpdocs\dgtmss\981I2\981I2cpd3 .doc -269- Table 3 (co Cpd. k A B Rl No.

3-964 4 NHCONHCO 4-(MeOOC)Ph 3-965 4 NHCONHCO 2-(EtOOC)Ph 3-966 4 NHCONHCO 4-(EtOOC)Ph 3-967 4 NHCONIICO 2-(tBuOOC)Ph 3-968 4 NH-CONH-CO 4-(tBuOOC)Ph 3-969 4 NH-CONHCO -2-Cl-Ph 3-970 4 NHCONHCO -4-Cl-Ph 3-971 4 NHCON7HCO -2-Br-Ph 3-972 4 NHCONHCO -4-Br-Ph 3-973 4 Nli-CONHCO -2-I-Ph -3-974 4 N HCONH-CO -4-I-Ph 3-975 4 NHCONH-CO 2-N0 2 -Ph 3-976 4 NHCONHCO 4-N0 2 -Ph 3-977 4 NHCONE-CO 2-NH 2 -Ph 3-978 4 NHCONHCO 4-NH- 2 -Ph 3-979 4 NHCONH-CO 2-(HO 3 S)Ph 3-980 4 NiCONH-CO 4-(HO 3 S)Ph 3-981 4 NHCONHCO 2-(NH 2

O

2 S)Ph 3-982 4 Ni-CONH-CO 4-(NI- 2 0 2 S)Ph 3-983 4 NH-CONHCO -2-CN-Ph 3-984 4 N}ICONHCO -4-CN-Ph 3-985 4 N-HCONH-CO 2-(HOCH 2 )Ph 3-986 4 NHCOM-ICO -4-(HOCH 2 )Ph 3-987 4 NHCONH-CO

M

3-988 4 Ni-CONI-CO Et* 3-989 4 Ni-CONI-CO

P

3-990 4 NH-CONIICO iPr y:\wpdocs\dgt_mfss\981I2\981I2cpd3 .doc 270 Table 3 (cont.A S. S

S

*5 Cpd. k A B

R

No. 3-99 1 T NHuCONHCO Bu 3-992 4 NIICONHCO

HOOCCH

2 3-993 4 N}{CONHCO MeOOCCH2~- 3-994 4 NHCONHCO MeCH(COOH) 3-995 4 NHCONIICO HOOC-(CH2) 2 3-996 4 NHCONHCO MeCH(COOMe) 3-997 4 NH-CONHCO 1-HOOC-iBu 3-998 4 NI-CONI-CO 1-MeOOC-iBu 3-999 4 NHCONHiCO 1-HOOC-iPn 3-1000 4 NHCONHCO I-MeOOC-iPn 3-100 1 4 NH-CONH-CO 1-HOOC-2-Me-Bu 3-1002 4 NIICONi-CO 1-MeOOC-2-Me-Bu 3-1003 4 NH-CONHCO

CH

2

CH

2

SO

3

H

3-1004 4 NH-CONi-CO -MeO 3-1005 4 NH-CONH-CO EtO 3-1006 4 NHCONHCO -Pro 3-1007 4 NHCOM-ICO -iPrO 3-1008 4 NHCONHCO -BuO 3-1009 4 NH-CONI-CO iBuO 3-1010 4 N1-CONHCO sBuO 3-10l1 4 NH-CONH-CO tBuO 3-1012 4 NH-CONHCO HxO 3-1013 4 Ni-CONI-CO PhO 3-1014 4 NIICONHCO BnO 3-1015 4 NHCONHCO Z-1 3-1016 4 NHCONHCO Z-2 3-1017 4 NHCONHMCO Z-3 y:\wpdocs\d gtmss\981I2\98 I 2cpd 3.doc -271 Table 3 (cont.

r r r r r Cpd. k A B R No.

3-1018 4 NHCONHCO Z-4 3-1019 4 NHCONHCO 3-1020 4 NHCONHCO Z-6 3-1021 4 NHCON-CO Z-7 3-1022 4 NHCONHCO Z-8 3-1023 4 N-CONHCO Z-9 3-1024 4 NHCONHCO 3-1025 4 NHCONHCO Z- 11 3-1026 4 N-CONHCO -Z-12 3-1027 4 NI-CONHCO 3-Py 3-1028 4 NHCONHCO 4-Py 3-1029 4 NHCONHSO2

H

3-1030 4 N-CONHSO 2 Ph 3-1031 4 NHCONHSS02 2-Me-Ph 3-1032 4 NHCONHSO 2 4-Me-Ph 3-1033 4 NHCONHS02 2,4-diMe-Ph 3-1034 4 NHCONHS0 2 3,4-diMe-Ph 3-1035 4 NHCONHS02 2-(CF 3 )Ph 3-1036 4 NI-CONI-S02 4-(CF 3 )Ph 3-1037 4 N HCONHS020 2-MeOPh 3-1038 4 NHCONHS02 4-MeOPh 3-1039 4 NHCONHS02 2-EtOPh 3-1040 4 NHCONHS02 4-EtOPh 3-1041 4 NHCONHSO2 2-HOPh 3-1042 4 NHCONHSO2 4-HOPh y:\wpdocs\dgt~mss\9BI 2\981 2cpd3.doc -272- Table 3 (cont) 0 0 0 0 0 c 0 0 0 go 0 0 0 0 *O 0 0 0 0 0 0 0 *O 0 0 00 Cpd. k A B

R

No.

3-1043 T NHCONHS02 2-(HOOC)Ph 3-1044 4 NHCONHSO2 4-(HOOC)Ph 3-1045 4 NHCONHS02 2-(MeOOC)Ph 3-1046 4 NHCONHS02 4-(MeOOC)Ph 3-1047 4 NHCONHS02 2-(EtOOC)Ph 3-1048 4 NHCONHS0 2 4-(EtOOC)Ph 3-1049 4 NHCONHSO 2 2-(tBuOOC)Ph 3-1050 4 NHCONHS02 4-(tBuOOC)Ph 3-1051 4 NHCONHSO2 2-Cl-Ph 3-1052 4 NHCONHSS02 -4-Cl-Ph 3-1053 4 NHCONHSO 2 2-Br-Ph 3-1054 4 NHCONHS0 2 4-Br-Ph 3-1055 4 NHCONI-S02 2-I-Ph 3-1056 4 NHCONHS0 2 4-I-Ph 3-1057 4 NHCONHS0 2 2-N0 2 -Ph 3-1058 4 N-CON1-S02 4-N0 2 -Ph 3-1059 7 NHCONHS0 2 2-N1 2 -Ph 3-1060 4 NHCONHSO2 4-NH 2 -Ph 3-1061 4 NHCONHSO2 2-(-0 3 S)Ph 3-1062 7 NHCONHS0 2 4-(HO 3 S)Ph 3-1063 4 NECONHSO2 2-(NH 2

O

2 S)Ph 3-1064 7 NHCONHSO 2 4-(NH 2 0 2 S)Ph 3-1065 7 NHCONHS02 2-CN-Ph 3-1066 4 NHCONHS02 4-CN-Ph y:\wpdocs\dgt~mss\9812\981 2cpd3.doc 274 Table 3 (cont.) S.

S..

S

*5*S S. SS**

S

*5*S S. S S *5 Cpd. k A B

R

3-1091 4 NHCONHS02 -BuG 3-1092 4 NIICONHSO2 -iBuG 3-1093 4 NHCONH-S02 -sBuO 3-1094 4 NHCONHIS02 -tBuO 3- 1095 4 NHCONHS02 -HxO 3-1096 4 NHICONHiS02 -PhO 3-1097 4 NH-CONHSO2 -BnO 3-1098 4 NHCONHSO2 1 3-1099 4 NHCONHS02 -Z-2 3-1100 4 NHCONHS0 2 -Z-3 3-1101 4 NHCONH-S02 -Z-4 3-1102 4 NHCONHS0 2 3-1103 4 NH4CONH-S02 -Z-6 3-1104 4 NHCONES02 -Z-7 3-1105 4 NH-CONH1S02 -Z-8 3-1106 4 NHCOM-1S02 Z-9 3-1107 4 NE-CONH-S02 -Z-1 0 3-1108 4 NHCONH-S02 -Z-1 1 3-1109 4 NH-CONHLS02 -Z-12 3-1110 4 NHCONHS02 3-Py 3-1111 4 NH-CONHS02 4P 3-1112 4 NH-CONES02

N

3-1113 4 NHCONH{S02

NHIM

3-1114 4 NHCONHS02NHE y:\wpdocs~.dgt_mss\981I2\9B1 2cpd3.doc 00

S.

S.

0 5 00

S

@55.

5 *5555 -275- Table 3 (cont.

Cpd. k A B

R

No.

3-1115 4 NHCONHSO2 NH Pr 3-1116 4 NHCONHSO2 NH iPr 3-1117 4 NHCONHSO2 NH Bu 3-1118 4 NHCONHSO2 NMe Me 3-1119 4 NHCONHSO2 NMe Et 3-1120 4 NHCONHS02 NMe Pr 3-1121 4 NHCONHS02 NMe iPr 3-1122 4 NHCONHS02 NMe Bu 3-1123 4 NH

H

3-1124 4 NH Me 3-1125 4 NH Et 3-1126 4 NH Pr 3-1127 4 NH iPr 3-1128 4 NH Bu 3-1129 4 CO Pyr 3-1130 4 CO Pipri 3-1131 4 co Pipra 3-1132 4 Co Mor 3-1133 4 CO Thmor 3-1134 4 CO NHPyr 3-1135 4 co NHPipri 3-1136 4 CO NHPipra 3-1137 4 CO NHMor 3-1138 4 CO NHThmor 3-1139 4 NHCO Pyr 3-1140 4 NHCO Pipri y:\wpdocs\dgtmss\981 2\9812cpd3.doc -276- Table 3 (co-nt

S

S

S

r Cpd. k A B R No.

3-1141 4 NHCO Pipra 3-1142 4 NHCO Mor 3-1143 4 NHCO Thmor 3-1144 4 NHCO NHPyr 3-1145 4 NHCO NHPipri 3-1146 4 NICO NHPipra 3-1147 4 NHCO NHMor 3-1148 4 NHCO NHThnor 3-1149 4 CONHCO Pyr 3-1150 4 CONHCO Pipri 3-1151 4 CONHCO Pipra 3-1152 4 CONHCO Mor 3-1153 4 CONHCO Thmor 3-1154 4 CONHCO NHPyr 3-1155 4 CON-CO NHPipri 3-1156 4 CONHCO NHPipra 3-1157 4 CONHCO NHMor 3-1158 4 CONHCO NHThmor 3-1159 4 CONHSO, Pyr 3-1160 4 CONHS0 2 Pipri 3-1161 4 CONHS0 2 Pipra 3-1162 4 CONHSO 2 Mor 3-1163 4 CONHS02 Thmor 3-1164 4 CONHS0 2 NHPyr 3-1165 4 CONHSO 2 NHPipri 3-1166 4 CONHSO 2 NHPipra y:\wpdocs\dgt_ms\98 12\981 2cpd3.doc 277 Table3-CoIJ Cpd. k A B R No. 3-1167 4 CONHS02 NHMor 3-1168 4 CONHS02 N7HThmor 3-1169 4 NH-S02 NH Z-4 3-1170 4 NHS0 2 -Me 3-1171 4 Ni-SO 2 -Et 3-1172 4 NH-SO 2 -Pr 3-1173 4 NH-SO 2 -CH2-.CI 3-1174 4 Ni-SO 2 -Ph 3-1 175 4 j NH-S02 4-Me-Ph 3-1176 4 CO NMe Ph 3-1177 4 CO NMe 2-Me-Ph 3-1178 4 CO NMe 4-Me-Ph 3-1 179 4 CO NMe 2,4-diMe-Ph 3-1180 4 CO NMe 3,4-diMe-Ph 3-1181 4 CO NMe 2-(CF 3 )Ph 3-1182 4 CO NMe 4-(CF 3 )Ph 3-1183 4 CO NMe 2-MeOPh 3-1184 4 CO NMe 4-MeOPh 3-1185 4 CO NMe 2-EtOPh 3-1186 4 CO NMe 4-EtOPh 3-1187 4 CO NMe 2-HOPh 3-1188 4 CO NMe 4-HOPh 3-1189 4 CO NMe 2-(HOOC)Ph 3-1190 4 CO NMe 4-(HOOC)Ph 3-1191 4 CO NMe 2-(MeOOC)Ph 3-1192 4 CO NMe 4-(MeOOC)Ph y:\wpdocs\dgt_mss\ 9 8 I 2\981I2cpd3.dAm 278 Table 3 (cont.

Cpd. k A B

R

3-1193 4 CO NMe 2-(EtOOC)Ph 3-1194 4 CO NMe 4-(EtOOC)Ph 3-1195 4 CO NMe 2-(tBuOOC)Ph 3-1196 4 CO NMe 4-(tBuOOC)Ph 3-1197 4 CO NMe 2-Cl-Ph 3-1198 4 CO NMe 4-Cl-Ph 3-1199 4 CO NMe 2-Br-Ph 3-1200 4 CO NMe 4-Br-Ph 3-1201 4 CO NMe 2-I-Ph 3-1202 4 CO NMe 4-I-Ph 3-1203 4 CO NMe 2-N0 2 -Ph 3-1204 4 CO NMe 4-N0 2 -Ph 3-1205 4 CO NMe 2-NH 2 -Ph 3-1206 4 CO NMe 4-NH 2 -Ph 3-1207 4 CO NMe 2-(HO 3 S)Ph 3-1208 4 CO NMe 4-(HO 3 S)Ph 3-1209 4 CO NMe 2-(NHi 2

O

2 S)Ph 3-1210 T CO NMe 4-(NIH 2

O

2 S)Ph 3-1211 4 CO NMe 2-CN-Ph 3-1212 4 CO NMe 4-CN-Ph 3-1213 4 CO NMe 2-(HOCH 2 )Ph 3-1214 4 CO NMe 4-(H-OCH 2 )Ph 3-1215 4 CO NMe Me 3 -1216 4 CO NMe Et 3-1217 4 CO NMe Pr 3-1218 4 CO NMe iPr y:\wpdocs\dgtms\981I2\98 I 2cpd3.dAm -279- Table3 contJ

S

S

Cpd. k A B

R

No.

3-1219 4 CO NMe Bu 3-1220 4 CO NMe HOOCCH 2 3-1221 4 CO W~e MeOOCCH 2 3-1222 4 Co NMe MeCH(COOH) 3-1223 4 CO NMe HOOC-(CH 2 2 3-1224 4 Co NMe MeCH(COOMe) 3-1225 4 Co NWe 1-HOOC-iBu 3-1226 4 CO NMe 1-MeOOC-iBu 3-1227 4 Co NMe 1-HOOC-iPn 3-1228 4 Co NMe I-MeOOC-iPn 3-1229 4 CO NMe 1-HOOC-2-Me-Bu 3-1230 4 CO NMe 1-MeOOC-2-Me-Bu 3-1231 4 CO W~e

CH

2

CH

2

SO

3

H

3-1E232 4 CO NMe

OH

3-1233 4 CO NMe MeO 3-1234 4 CO W~e EtO 3-1235 4 CO W~e Pro 3-1236 4 CO NMe iPrO 3-1237 4 CO NMe BuO 3-1238 4 CO NMe iBuO 3-1239 4 CO NMe sBuO 3-1240 4 CO NWe tBuO 3-1241 4 CO NMe x 3-1242 4 CO NMe h 3-1243 4 CO NMe n 3-1244 4 CO W~e 1 [3-1245 4 CO NMeZy:\wpdocs\dgt_ms\981I2\98 I2cpd3.doc -280- Table3 -cnLJ 9* Cpd. k A B Rl No. 3-1246 4 co NMe Z-3 3-1247 4 CO NMe Z-4 3-1248 4 CO NMe 3 -124 9 4 CO NMe Z-6 3-1250 4 CO NMe Z-7 3-1251 4 CO NMe Z-8 3-1252 4 CO NMe Z-9 3-1253 4 Co NMe 3-1254 4 CO NMe Z-1 1 3-1255 4 CO NMe Z-12 3-1256 4 CO NMe 3-Py 3-1257 4 CO NMe 4-Py 3-1258 4 CO Thiad 3-1259 4 CO NHThiad 3-1260 4 NH-CO Thiad 3-1261 4 NHCO NHThiad 3-1262 4 CONHCO Thiad 3-1263 4 CONHCO NIIThiad 3-1264 4 CONH-S02 Thiad 3-1265 4 CONHIS02 NHThiad 3-1266 4 NI-CS NH

H

3-1267 4 NHCS NH Me 3-1268 4 NI4CS NHl Et 3-1269 4 NHSNH Ph 3-1270 4 NHNl HOOCCH2- 3-1271 4 NH-CS NE MeOOCCH2- 3-1272 4T NIICS NH- MeCH(COOH) y:\wpdocs\dgt_m-ss\981I2\981I2cpd3.doc -281 Tabl3(cnt.) *09*@9 0 S 9 9. 9 9.

9 9 9* 9909 9 99 9 9 9*99 *599 9*99 9 Cpd. k A B R 3-1273 T NHCS NH- HOOC-(CH 2 2 3-1274 4 MACS NH MeCH(COOMe) 3-1275 4 CO NH- HOOC-(CH 2 3 3-1276 4 NHCO NH HOOC-(CH 2 3 3-1277 4 NH-CO -HOOC-(CH 2 3 3-1278 4 MACS NH HOOC-(CH 2 3 3-1279 4 CO NH. MeSO 2 NHCOCH(Me) 3-1280 4 NHCO NH MeSO 2 NHCOCH(Me) 3-1281 4 NHCO -MeSO 2 NHCOCH(Me) 3-1282 4 MACS NH MeSO 2 NHCOCH(Me) 3-1283 4 -NH HOOCCH 2 3-1284 4 -NH- MeOOCCH2- 3-1285 4 -NH MeCH(COOH) 3-1286 4 NH HOOC-(CH 2 2 3-1287 4 -NH MeCH(COOMe) 3-1288 4 -NH HOOC-(CH 2 3 3-1289 4 NHCOCO -OH 3-1290 4 NE-COCO -MeO 3-1291 4 NHCOCO -EtO 3-1292 4 NH-COCO -Pro 3-1293 4 Ni-ICOCO -iPrO 3-1294 4 NH-COCO -BuO 3-1295 4 NI-COCO -iBuO 3-1296 4 NHCOCO -sBuO 3-1297 4 NH-COCO -tBuO 3-1298 4 NHCOCO HxO y:\wpdocs\dgt_mss\981 2\981 2cpd3.doc 282 Table 3 (cont.

S

50055O

S

0OSS S 5* 0

S.

S 0 S S 000*

SO

0

S

0

S

S

0S@@ 5@ S 0s 56 Cpd. kA B Rl No. 3-1299 4 NI-COCO PhO 3-1300 4 NHCOCO BnO 3-1301 5 CO NH H 3-1302 5 Co NH Ph 3-1303 7 Co NIH 2-Me-Ph 3-1304 7 Co Nil 4-Me-Ph 3-1305 5 Co NI 2,4-diMe-Ph 3-1306 5 Co NH 3,4-diMe-Ph 3-1307 5 CO NH 2-(CF 3 )Ph 3-1308 5 Co NH 4-(CF 3 )Ph 3-1309 5 CO NH 2-MeOPh 3-1310 5 Co NH 4-MeOPh 3-1311 5 CO NH 2-EtOPh 3-1312 5 CO NH 4-EtOPh 3-1313 5 CO NH 2-HOPh 3-1314 5 CO NH 4-HOPh 3-1315 7 CO NH 2-(HOOC)Ph 3-1316 7 CO NH 4-(HOOC)Ph 3-1317 5 CO NH 2-(MeOOC)Ph 3-1318 5 CO NH 4-(MeOOC)Ph 3-1319 5 CO NH 2-(EtOOC)Ph 3-1320 5 CO NH 4-(EtOOC)Ph 3-1321 7 CO NH 2-(tBuOOC)Ph 3-1322 5 CO NiH 4-(tBuOOC)Ph 3-1323 5 CO NH 2-Cl-Ph 3-1324 5 CO NH 4-Cl-Ph 3-1325 5 CO NH 2-Br-Ph y:\wpdocs\dgtmffss\981I2\981I2cpd3.doc 283 Table 3 (cont.) Cpd. k A B

R

No.

3-1326 5 CO NH- 4-Br-Ph 3-1327 5 CO NH{ 2-I-Ph 3-1328 5 CO NH 4-I-Ph 3-1329 5 CO NH 2-N0 2 -Ph 3-1330 5 CO NH 4-N0 2 -Ph 3-1331 5 CO NH 2-NH 2 -Ph 3-1332 5 CO0 NH- 4-NI-1 2 -Ph 3-1333 5 CO NH 2-(HO 3 S)Ph :3-1334 5 CO NH 4-(HO 3 S)Ph 3-1335 5 CO NH 2-(NIH 2

O

2 S)Ph 3-1336 5 CO0 NH 4-(NIH 2 0 2 S)Ph *3-1337 5 CO0 NH 2-CN-Ph 3-1338 5 CO0 NH 4-CN-Ph 3-1339 5 CO0 NH 2-(HOCH 2 )Ph 3-1340 5 CO0 NH 4-(HOCH 2 )Ph 3-1341 5 CO NH Me *3-1342 5 CO NH Et 3-1343 5 CO NH Pr 3-1344 5 CO NH iPr 3-1345 5 CO NH Bu 3-1346 5 CO NIH HOOCCH 2 3-1347 5 CO NH MeOOCCH2- 3-1348 5 CO NH MeCH(COOH) 3-1349 7 CO NH HOOC-(CH2)2- 3-1350 5 CO NH MeCH(COOMe) 3-1351 5 CO NiH I-HOOC-iBu y:\wpdocs\dgt_mfss\981I2\981I2cpd3 .doc 284 Cpd. k A B

R

No. 3-1352 5 Co NH 1-MeOOC-iBu 3-1353 5 Co NH 1-HOOC-iPn 3-1354 5 CO NH 1-MeOOC-iPn 3-1355 7 CO NIH 1-HOOC-2-Me-Bu 3-1356 7 CO NH 1-MeOOC-2-Me-Bu 3-1357 5 CO NH

CH

2

CH

2 SO3H 3-1358 5 Co- NH

OH

3-1359 5 co NH MeG 3-1360 5 CO NH

EDO

3-1361 5 CO NH Pro 3-1362 5 CO N-H iPrO 3-1363 7 CO NH BuO 3-1364 7 CO NH iBuG 3-1365 7 CO NH sBuO 3-1366 5 CO NH tBuO 3-1367 5 CO NH HxO 3-1368 5 CO NH PhO 3-1369 7 CO NH- BnO 3-1370 5 CO NH Z-1 317 5 oNH- Z-7 317 oNHl Z-8 -17 oNH Z-9 y:\wpdocs\dgt_mfss\981I2\981I2cpd3 .doc 285 Table 3 (conQ.

Cpd. k A B

R

No. 3-1379 5 Co NH 3-1380 5 CO NH Z-11 3-1381 5 CO NH Z-12 3-1382 5 CO NH 3-Py 3-1383 5 CO NH 4-Py 3-1384 5 CO N(Ac)

H

3-1385 5 Co N(Ac) Ph 3-1386 5 Co N(Ac) 2-Me-Ph 3-1387 5 CO N(Ac) 4-Me-Ph 3-1388 5 Co N(Ac) 2,4-diMe-Ph 3-1389 5 CO N(Ac) 3,4-diMe-Ph 3-1390 5 CO N(Ac) 2-(CF 3 )Ph 3-1391 5 CO N(Ac) 4-(CF 3 )Ph 3-1392 5 CO N(Ac) 2-MeOPh 3-1393 5 CO N(Ac) 4-MeOPh 3-1394 5 CO N(Ac) 2-EtOPh 3-1395 5 CO N(Ac) 4-EtOPh 3-1396 5 CO N(Ac) 2-HOPh 3-1397 5 CO N(Ac) 4-HOPh 3-1398 5 CO N(Ac) 2-(HOOC)Ph 3-1399 5 CO N(Ac) 4-(HOOC)Ph 3-1400 5 CO N(Ac) 2-(MeOOC)Ph 3-1401 5 CO N(Ac) 4-(MeOOC)Ph 3-1402 5 CO N(Ac) 2-(EtOOC)Ph 3-1403 5 lCO N(Ac) 4-(EtOOC)Ph 3-1404 5 CO N(Ac) 2-(tBuOOC)Ph 3-1405 5 CO N(Ac) 4-(tBuOOC)Ph y:\wpdocs\dgt~fmss\981I2\981I2cpd3 .do 286 Tabl 3 cont Cpd. k A B

R

No.

3-1406 5 CO N(Ac) 2-Cl-Ph 3-1407 5 CO N(Ac) 4-Cl-Ph 3-1408 5 CO N(Ac) 2-Br-Ph 3-1409 5 CO N(Ac) 4-Br-Ph 3-1410 5 CO N(Ac) 2-I-Ph 3-1411 7 CO N(Ac) 4-I-Ph 3-1412 7 CO N(Ac) 2-N0 2 -Ph 3-1413 5 CO N(Ac) 4-N02)-Ph 3-1-414 5 CO N(Ac) 2-NH 2 -Ph 3-1415 5 CO N(Ac) 4-NH- 2 -Ph 3-1416 5 CO N(Ac) 2-(HO 3 S)Ph 3-1417 5 CO N(Ac) 4-(HO 3 S)Ph 3-1418 7 CO N(Ac) 2-(N11 2 0 2 S)Ph 3-1419 5 CO N(Ac) 4-(NH 2

O

2 S)Ph 3-1420 5 CO N(Ac) 2-CN-Ph 3-1421 5 CO N(Ac) 4-CN-Ph 3-1422 7 CO N(Ac) 2-(HOCH 2 )Ph 3-1423 7 CO N(Ac) 4-(HOCH 2 )Ph 3-1424 5 CO N(Ac) Me 3-1425 5 coNA)Et 3-1426 57oN(c Pr 3-1427 5 coNA)iPr 3-148 5co NAc)Bu 3-1429 5 CO N(Ac) FOCCH2- 3-1430 5 CO N(Ac) MeOOCCH2- 3-143 1 5 CO N(Ac) MeCH(COOH) y:\wpdocs\dgtLss\981I2\981I2cpd3 .doc 287 TabIl cont.) Cpd. k A B R 3-1432 5 Co N(Ac) HOOC-(CH 2 )2- 3-1433 5 CO N(Ac) MeCH(COOMe) 3-1434 5 CO N(Ac) 1-HOOC-iBu 3-1435 7 Co N(Ac) 1-MeOOC-iBu 3-1436 7 CO N(Ac) 1-HOOC-iPn 341437 7 CO N(Ac) 1-MeOOC-iPn 3-1438 7 Co N(Ac) 1-HOOC-2-Me-Bu 3-1439 5 CO N(Ac) 1-MeOOC-2-Me-Bu 3-1440 5 CO N(Ac) CH 2

CH

2

SO

3

H

3-1441 5 CO N(Ac)

OH

3-1442 5 CO N(Ac) MeO 3-1443 5 CO N(Ac) EtO 3-1444 5 CO N(Ac) Pro 3-1445 7 Co N(Ac) iPrO 3-1446 7 CO N(Ac) BuO 3-1447 5 Co N(Ac) iBuO 3-1448 5 CO N(Ac) sBuO 3-1449 5 Co N(Ac) tBuO 3-1450 5 CO N(Ac) HxO 3-1451 7 CO N(Ac) PhO 3-1452 7 Co N(Ac) BnO 3-1453 5 CO N(Ac) Z-1 3-1454 5 CO N(Ac) Z-2 3-1455 7 CO N(Ac) Z-3 3-1456 5 CO N(Ac) Z-4 3-1457 5 CO N(Ac) 3-1458 5 CO N(Ac) Z-6 y:\wpdocs\dgtmffss\981I2\981 2cpd 3.doc 288 Tabl 3tcnL) Cpd. k A B R No. 3-1459 5 CO N(Ac) Z-7 3-1460 5 CO N(Ac) Z-8 3-1461 5 CO N(Ac) Z-9 3-1462 5 CO N(Ac) 3-1463 5 Co N(Ac) Z-11I 3-1464 5 CO N(Ac) Z-12 3-1465 5 Co N(Ac) 3-Py 3-1466 5 CO N(Ac) 4-Py 3-1467 5 COO -H 3-1468 5 COO -Ph 3-1469 5 COO 2-Me-Ph 3-1470 5 COO 4-Me-Ph 3-1471 5 COO 2,4-diMe-Ph 3-1472 5 COO 3,4-diMe-Ph 3-1473 5 COO 2-(CF 3 )Ph 3-1474 5 COO 4-(CF 3 )Ph 3-1475 5 COO 2-MeOPh 3-1476 5 COO 4-MeOPh 3-1477 5 COO -2-EtOPh 3-1478 5 COO -4-EtOPh 3-1479 5 COO 2-HOPh 3-1480 5 COO -4-HOPh 3-1481 7 COO 2-(HOOC)Ph 3-1482 5 COO 4-(HOOC)Ph 3-1483 5 COO 2-(MeOCPh 3-1484 7 COO 4-(MeOOC)Ph 3-1485 7 COO -2-(EtOOC)Ph y:\wpdocs\dgt_mfss\981 2\981I2cpd 3dAm 289 Table 3 (coot) Cpd. k A B R No. 3-1486 5 coo 4-(EtOOC)Ph 3-1487 5 coo 2-(tBuOOC)Ph 3-1488 5 coo 4-(tBuOOC)Ph 3-1489 7 coo -2-Cl-Ph 3-1490 7 coo -4-Cl-Ph 3-149 1 7 coo -2-Br-Ph 3-1492 5 coo -4-Br-Ph 3-1493 5 coo -2-I-Ph 3-1494 7 coo -4-I-Ph 3-1495 5 coo -2-N0 2 -Ph 3-1496 7 coo -4-N0 2 -Ph 3-1497 7 coo -2-NI- 2 -Ph 3-1498 5 coo -4-NH- 2 -Ph 3-1499 5 coo 2-(HO 3 S)Ph 3-1500 5 coo 4-(HO 3 S)Ph 3-1501 5 coo 2-(NH 2 0 2 S)Ph 3-1502 7 coo 4-(NlH 2

O

2 S)Ph 3-1503 5 coo -2-CN-Ph 3-1504 5 coo -4-CN-Ph 3-1505 5 coo 2-(HOCH 2 )Ph 3-1506 5 coo 4-(HOCH- 2 )Ph 3-1507 5 coo -Me 3-1508 5 coo -Et 3-1509 5 coo Pr 3-1510 5 coo iPr 3-1511 5 coo Bu y:\wpdocs\dgtmss\981I2\981I2cpd3 .doc 290 Table (cnt.) Cpd. k A B

R

No. 3-1512 5 coo HOOCCH2- 3-1513 5coo

HOOC-(CH

2 2 3-1514 5 COO MeCH(COOMe) 3-1515 5 coo 1-HOOC-iBu 3-1516 5 coo I1-HOOC-iPn 3-1517 5 coo -Z-1I 3-1518 5 coo Z-2 3-1519 5 coo Z-3 3-1520 5 coo -Z-4 3-1521 5 coo 3-1522 5 coo -Z-6 3-1523 5 coo -Z-7 3-1524 5 coo -Z-8 3-1525 5 coo -Z-9 3-1526 7 coo 3-1527 5 coo -Z-1 1 3-1528 5 coo 12 3-1529 5 coo -3-Py 3-1530 5 coo -4-Py 3-1531 5 CONBCO

H

3-1532 5 CONHCO Ph 3-1533 5 CONH-CO 2-Me-Ph 3-1534 5 CONHCO 4-Me-Ph 3-1535 5 CONHCO 2,4-diMe-Ph 3-1536 5 CONHCO 3,4-diMe-P r-3-1537 5 CONi-ICO- 2-(CF 3 )Ph y:\wpdocs\dgt.msS\98I 2\981 2cpd3.doc -291 Table 3 (cont.) a a. a a a.

a Cpd. k A B

R

No. 3-1538 5 CONHCO -4-(CF 3 )Ph 3-1539 5 CONHCO 2-MeOPh 3-1540 5 CONFICO -4-MeOPh 3-1541 5 CONHCO 2-EtOPh 3-1542 5 CONH-CO 4-EtOPh 3-i543 5 CONHCO 2-HOPh 3-1544 5 CONI-CO 4-HOPh 3-1545 5 CONFICO 2-(HOOC)Ph 3-1546 5 CONFICO 4-(HOOC)Ph 3-1547 5 CONH-CO 2-(MeOOC)Ph 3-1548 5 CONHCO 4-(MeOOC)Ph 3-1549 5 CONH-CO 2-(EtOOC)Ph 3-1550 5 CONH-CO 4-(EtOOC)Ph 3-1551 5 CONHCO 2-(tBuOOC)Ph 3-1552 5 CON14CO 4-(tBuOOC)Ph 3-1553 5 CONI-CO -2-Cl-Ph 3-1554 5 CONH-CO -4-Cl-Ph 3-1555 5 CONH-CO -2-Br-Ph 3-1556 5 CONHCO -4-Br-Ph 3-1557 5 CONH-CO -2-I-Ph 3-1558 5 CONH-CO -4-I-Ph 3-1559 5 CONFICO -2N2P 3-1562 5 CONIICO -4N2P 3-1563 5 CONH-CO I 2-(HO 3 S)Ph y:\wpdocs\dgt_rnss\981I2\981I2cpd3.-doc 292 Table 3 (cont.

4. 0 ~0 Cpd. k A BR 3-1564 5 CONHCO -4-(HO 3 S)Ph 3-1565 5 CONI-CO 2-(NI- 2 0 2 S)Ph 3-1566 5 CONHCO 4-(NH 2

O

2 S)Ph 3-1567 5 CONIICO 2-CN-Ph 3-1568 5 CONHCO 4-CN-Ph 3- 1569 5 CONI-CO 2-(HOCH 2 )Ph 3-1570 5 CONHCO 4-(HOCH 2 )Ph 3-1571 5 CONH-CO -Me 3-1572 5 CONI-CO -Et 3-1573 5 CONHCO -Pr 3-1574 5 CONHCO -iPr 3-1575 7 CONHCO -Bu 3-1576 5 CONHCO HOOCCH 2 3-1577 5 CONI-CO MeOOCCH2- 3-1578 5 CONI-CO MeCH(COOH) 3-1579 5 CONB-CO HOOC-(CH 2 )2- 3-1580 5 CONH-CO MeCH(COOMe) 3-1581 5 CONHCO 1-HOOC-iBu 3-1582 5 CONH-CO -MeOOC-iBu 3-1583 5 CONH-CO -1-HOOC-iPn 3-1584 5 CONHCO -MeOOC-iPn 3-1585 7 CONH-CO -1-HOOC-2-Me-Bu 3-1586 5 CONHCO -MeOOC-2-Me-Bu 3-1587 5 CONI-CO -CH 2 )CH)SO3AH 3-1588 5 CONHCO 1 3-1589 5 COiNiCOZy:\wpdocs\dgt_mss\9812\981 2cpd3.doc 293 Table 3 (cont.) a0**$S boo* 0 eoS**: *040 .0 6 00 Cpd. k A B Rl 3-1590 5 CONIICO -Z-3 3-1591 5 j CONHCO -Z-4 3-1592 5 CONHCO 3-1593 5 CONHCO -Z-6 3-1594 5 CONHCO -Z-7 3-1-595 5 COMICO -Z-8 3-1596 5 CONIICO -Z-9 3-1597 5 CONI-CO 3-1598 5 CONHCO -Z-1 1 3-1599 5 CONIICO 12 3-1600 5 CONHCO -3-Py 3-1601 5 CONH-CO -4-Py 3-1602 5 CON(Ac)CO

-H

3-1603 5 CON(Ac)CO -Ph 3-1604 5 CON(Ac)CO -2-Me-Ph 3-1605 5 CON(Ac)CO -4-Me-Ph 3-1606 5 CON(Ac)CO 2,4-diMe-Ph 3-1607 5 CON(AcCO 3,4-diMe-Ph 3-1608 5 CON(Ac)CO -2-(CF 3 )Ph 3-1609 5 CON(Ac)CO -4-(CF 3 )Ph 3-1610 5 CON(Ac)CO 2-MeOPh 3-16 11 5 CON(Ac)CO 4-MeOPh 3-1612 5 CON(Ac)CO 2-EtOPh 3-1613 5 CON(Ac)CO 4-EtOPh 3-1614 5 CON(Ac)CO ~,2-HOPh 3-1615 5 CON(Ac)CO 4-HOPh 3-1616 7 CON(Ac)CO -2-(I-OOC)Ph y:\wpdocs\dgt_mss\981 2\981 2cpd3.dAm 294 Table 3(cont) Cpd. k A B

R

No.

3-1617 5 CON(Ac)CO 4-(HOOC)Ph 3-1618 5 CON(Ac)CO 2-(MeOOC)Ph 3-1619 5 CON(Ac)CO 4-(MeOOC)Ph 3-1620 5 CON(Ac)CO 2-(EtOOC)Ph 3-1621 5 CON(Ac)CO 4-(EtOOC)Ph 34t622 5 CON(Ac)CO 2-(tBuOOC)Ph 3-1623 5 CON(Ac)CO 4-(tBuOOC)Ph 3-1624 5 CON(Ac)CO 2-Cl-Ph 3-1625 5 CON(Ac)CO -4-Cl-Ph 3-1626 7 CON(Ac)CO 2-Br-Ph 3-1627 7 CON(Ac)CO 4-Br-Ph 3-1628 5 CON(Ac)CO -2-I-Ph 3-1629 5 CON(Ac)CO -4-I-Ph 3-1630 5 CON(Ac)CO 2-N0 2 -Ph 3-1631 5 CON(Ac)CO 4-N0 2 -Ph 3-1632 5 CON(Ac)CO 2-NH 2 -Ph 3-1633 5 CON(Ac)CO 4-NH 2 -Ph 3-1634 5 CON(Ac)CO 2-(HO 3 S)Ph 3-1635 7 CON(Ac)CO 4-(HO 3 S)Ph 3-1636 5 CON(Ac)CO 2-(N11 2 0 2 S)Ph 3-1637 5 CON(Ac)CO 4-(NH 2

O

2 S)Ph 3-1638 5 CON(Ac)CO 2-CN-Ph 3-1639 5 CON(Ac)CO 4-CN-Ph 3-1640 5 CON(Ac)CO -2-(HOCH 2 )Ph 3-1641 7 CON(Ac)CO -4-(HOCH 2 )Ph 3-1642 5 CON(Ac)CO Me y:\wpdacs\dgt-rmss\981 2\981 2cpd3.-doc 295 Tabkslei L)cot.

Cpd. k A B

R'

No. 3-1643 5 CON(Ac)CO Et 3-1644 5 CON(Ac)CO -Pr 3-1645 5 CON(Ac)CO -iPr 3-1646 5 CON(Ac)CO -Bu 3-1647 5 CON(Ac)CO

HOOCCH--

3-'1648 5 CON(Ac)CO MeOOCCH 2 3-1649 5 CON(Ac)CO MeCH(COOH) 3-1650 7 CON(Ac)CO HOOC-(CH2)2- 3-1651 7 CON(Ac)CO MeCH(COOMe) 3-1652 5 CON(Ac)CO 1-HOOC-iBu 3-1653 5 CON(Ac)CO l-MeOOC-iBu 3-1654 5 CON(Ac)CO 1-HOOC-iPn 3-1655 5 CON(Ac)CO 1-MeOOC-iPn 3-1656 5 CON(Ac)CO 1-HOOC-2-Me-Bu 3-1657 7 CON(Ac)CO 1-MeOOC-2-Me-Bu 3-1658 5 CON(Ac)CO

CH

2

CH

2

SO

3

H

3-1659 5 CON(Ac)CO Z-1I 3-1660 5 CON(Ac)CO Z-2 3-1661 7 CON(Ac)CO Z-3 3-1662 5 CON(Ac)COZ- 3-1663 5 CON(Ac)COZ- 3-1664 5 CON(Ac)COZ- 3-1665 5 CON(Ac)COZ- 3-1666 5 CON(Ac)CO Z-8 3-1667 5 CON(Ac)CO Z-9 3-1668 5 CON(Ac)CO y:\wpdocs\dgtmss\981I2\9812 cpd3 .doc 296 Table 3 (cont.) Cpd. k A B

R

No. 3-1669 5 CON(Ac)CO -Z-1 1 3-1670 5 CON(Ac)CO 12 3-167 1 5 CON(Ac)CO -3-Py 3-1672 5 CON(Ac)CO -4-Py 3-1673 5 CONHiCO NH

H

3-1674 5 CONH-CO NH Ph 3-1675 5 CONHCO NH 2-Me-Ph 3-1676 5 CONH-CO NHL 4-Me-Ph 3-1677 5 CONH-CO NH- 2,4-diMe-Ph 3-1678 5 CONHCO NH 3,4-diMe-Ph 3-1679 5 CONI-CO N -C3P 3-1680 7 CONHCO NH 4-(CF 3 )Ph 3-1681 7 COiN.mCO N -e 3-1682 7 CONI-CO NH 4-MeOPh 3-1683 5 CONH-CO NH 2-EtOPh 3-1684 5 CONH-CO NH 4-EtOPh 3-1685 5 CONI-CO NH 2-HOPh 3-1686 5 CONHCO NH 4-HOPh 3-1687 5 CON-HCO NH 2-(HOOC)Ph 3-1688 5 CONH-CO NIL 4-(HOOC)Ph 3-1689 7 CONBCO NE 2-(MeOOC)Ph 3-1690 5 CONILCO NH 4-(MeOOC)Ph 3-1691 5 CONH-CO NH 2-(EtOOC)Ph 3-1692 5 CONH-CO NH 4-(EtOOC)Ph 3-1693 5 CONHCO NH 2-(tBuOOC)Ph 3-1694 5 CONHCO NH 4-(tBuOOC)Ph 3-1695 5 CONHCO NH 2-Cl-Ph y:\wpdocs\dgt_mss\981I2\981I2cpd 3.doc 297 Table 3 (cont.) Cpd. k A B R 3-1696 5 CONHlCO NH 4-Cl-Ph 3-1697 5 CONHCO NH 2-Br-Ph 3-1698 5 CONHCO NH 4-Br-Ph 3-1699 5 CONHCO NH 2-I-Ph 3-1700 5 CONHCO NH 4-I-Ph 3-1701 5 CONHCO NH 2-N0 2 -Ph 3-1702 5 CONHCO NH- 4-N0 2 -Ph 3-1703 5 CONHCO NH 2-N1- 2 -Ph 3-1704 5 CONHCO NH 4-NH2-Ph 3-1705 5 CONH-CO NH 2-(HO 3 S)Ph 3-1706 5 CONHCO NH 4-(HO 3 S)Ph 3-1707 5 CONHCO NH 2-(NH 2

O

2 S)Ph 3-1708 5 CONH-CO NH 4-(NH 2 0 2 S)Ph 3-1709 5 CONHCO NH 2-CN-Ph 3-1710 5 CONHCO NIH 4-CN-Ph 3-1711 5 CONHCO NH 2-(HOCH 2 )Ph 3-1712 5 CON-HCO NH 4-(HOCH 2 )Ph 3-1713 5 CONHCO NH Me 3-1714 5 CONHCO NH Et 3-1715 5 CONHCO NH Pr 3-1716 5 CONHCO NH iPr 3-1717 5 CONHCO NH Bu 3-1718 5 CONHCO NH HOOCCH 2 3-1719 5 CONHCO NH MeO OCCH 2 3-1720 5 CONHCO NH MeCH(COOH) 3-1721 5 CONHCO NH HOOC-(CH 2 2 y:\wpdocs\dgt_mfss\9812\981 2cpd3.doc 298 Table 3 (cont) Cpd. k A B

R

No. 3-1722 5 CONIICO NH MeCH(COOMe) 3-1723 5CONH-CO NiE 1-HOOC-iBu 3-1724 5CONIICO NH 1-MeOOC-iBu 3-1725 5 CONTICO NIH 1-HOOC-iPn 3-1726 5 CONHCO NH- I1-MeOOC-iPn 3-1727 5 CONi-CO NiH 1-HOOC-2-Me-Bu 3-1728 5 CONH-CO Nil 1-MeOOC-2-Me-Bu 3-1729 5 CONHCO NH CH 2

CH

2

SO

3

H

3-1730 5 CONHCO NH

HO

3-1731 5 CONHCO NH MeO 3-1732 5 CONHCO NH EtO 3-1733 5 CONHCO NH Pro 3-1734 5 CONHCO NH iPrO 3-1735 5 CONHCO NH BuG 3-1736 5 CONHCO NH iBuG 3-1737 5 CONHCO NH sBuO 3-1738 5 CONHCO NH tBuO 3-1739 5 CONHCO NH HxO 3-1740 5 CONHCO NH PhO 3-1741 5 CONH-CO NH BnO 3-1742 5 CONI-ICO NH Z-1 3-1743 5 CONI-CO NH Z-2 3-1744 5 CONHCO NH Z-3 3-1745 5 CONHCO NH Z-4 3-1746 7 CONHCO NH 3-1747 5 CONHCO NH Z-6 3-1748 5 CONHCO NH Z-7 y:\wpdocs\dgt-fmss\9812\9 8 I 2cpd3.-doc 299 Table 3 (cont.) 4 *5 Cpd. k A B

R

No.

3-1749 5 CONIICO NH- Z-8 3-1750 5 CONHCO NH Z-9 3-1751 5 CONIICO Nil 3-1752 5 CONIICO NHl Z-1 1 3-1753 5 CONHCO NHl Z- 12 3-1754 5 CONHCO NHl 3-Py 3-1755 5 CONHCO NH 4-Py 3-1756 5 CONH-S0 2

-H

3-1757 5 CONHS0 2 -Ph 3-1758 5 CONH-S0 2 -2-Me-Ph 3-1759 5 CONH-S02 -4-Me-Ph 3-1760 5 CONI-SO-, 2,4-diMe-Ph 3-1761 5 CONH-S02 3,4-diMe-Ph 3-1762 5 CONHS0 2 2-(CF 3 )Ph 3-1763 5 CONHS02, 4-(CF 3 )Ph 3-1764 5 CONH-S0 2 -2-MeOPh 3-1765 5 CONH-S0 2 -4-MeOPh 3-1766 5 CONES0 2 -2-EtOPh 3-1767 5 CONHS0 2 -4-EtOPh 3-1768 5 CONHS0 2 -2-HOPh 3-1769 5 CONH-S0 2 -4-HOPh 3-1770 5 CONHS0 2 2-(HOOC)Ph 3-1771 5 CONHS0 2 4-(HOOC)Ph 3-1772 5 CONHS0 2 2-(MeOOC)Ph 3-1773 5 CONHS0 2 -4-(MeOOC)Ph y:\wpdocs\dgtmss\981 2\9812cpd 3 doc -300- Table 3 (coWt.

Cpd. k A B

R

No.

3-1774 5 CONHS0 2 2-(EtOOC)Ph 3-1775 5 CONHS0 2 4-(EtOOC)Ph 3-1776 5 CONHS0 2 2-(tBuOOC)Ph 3-1777 5 CONHSO 2 4-(tBuOOC)Ph 3-1778 5 CONHSO 2 2-Cl-Ph 3-1779 5 CONHS02 4-CI-Ph 3-1780 5 CONHS0 2 2-Br-Ph 3-1781 5 CONHS0 2 4-Br-Ph 3-1782 5 CONHS0 2 2-I-Ph 3-1783 5 CONHS02 4-I-Ph 3-1784 5 CONS02- 2-N0 2 -Ph 3-1785 5 CON S0 2 4-N0 2 -Ph 3-1786 5 CON S02 2-NI 2 -Ph 3-1787 5 CONHS02 4-NH 2 -Ph 3-1788 5 CONHS0 2 2-(HO 3 S)Ph 3-1789 5 CONHSO2 4-(HO 3 S)Ph 3-1790 5 CONHS0 2 2-(N- 2 0 2 S)Ph 3-1791 5 CONHS0 2 4-(NI 2 0 2 S)Ph 3-1792 5 CON-S0 2 2-CN-Ph 3-1793 5 CONHS0 2 4-CN-Ph 3-1794 7 CONHS0 2 2-(HOCH 2 )Ph 3-1795 5 CONHSO 2 4-(HOCH 2 )Ph 3-1796 5 CONHS0 2 Me 3-1797 5 CONHS02 Et y:\wpdocs\dgtniss\98 12\9812cpd3.doc 301 Table 3 (cont.J Cpd. k A B

R

No. 3-1798 5 CONHS0 2

P

3-1799 5 CONIHS02 -iPr 3-1800 5 CONHS02 -Bu 3-1801 5 CONH-S02

HOOCCH

2 3-1802 5 CONHS02 MeOOCCH2- 3-1803 5 CONHS02 MeCH(COOH) 3-1804 5 CONHS02 -HOOC-(CH 2 )2- :3-1805 7 CONH-S02 MeCH(COOMe) 3-1806 7 CONHS0 2 1-HOOC-iBu 3-1807 5 CONH4S02 I-MeOOC-iBu *3-1808 5 CON-S02 1-HOOC-iPn 3-1809 5 CONH-S0 2 1-MeOOC-iPn 3-1810 5 CONHS0 2 1-HOOC-2-Me-Bu 3-1811 7 CONHS0 2 1-MeOOC-2-Me-Bu *:3-1812 5 CONHS02

CH

2

CH

2 SO3H 3-1813 5 CONHSO2

OH

3-1814 5 CONH-S02 -MeG 3-1815 7 CONH-S02 -EtO 3-1816 5 CONH-S02 Pro 3-1817 5 CONHS0 2 iPrO 3-1818 5 CONH-S02 BuG 3-1819 5 CONHS02 iBuG 3-1820 5 CONE-S02 sBuO 3-1821 5 CONHS0 2 tBuO y.\wpdocs\dgt mss\9 8 1 2\981I2cpd 3.Am 302 Tabe (gqnlJ Cpd. k A B

R

3-1822 5 CONHS02 HxO 3-1823 5 CONH1S0 2 -PhO 3-1824 5 CONHlS02 -BnO 3-1825 5 CONHS02 -Z-1 3-1826 5 CONHS0 2 -Z-2 3-1827 5 CONHS0 2 -Z-3 3-1828 5 CONH-S02 -Z-4 3-1829 5 j CONHS0 2 3-1830 5 CONHS0 2 -Z-6 3-1831 5 CONHlS02 -Z-7 3-1832 5 CONHS02 -Z-8 3-1833 5 CONHS0 2 -Z-9 3-1834 5 CONHS0 2 3-1835 5 CONHSO 2 7 Z 1 3-1836 5 CONHS0 2 12 3-1837 5 CONH-S0 2 -3-Py 3-1838 5 CONH-S02 -4-Py 3-1839 5 CONHS02 NEl

H

3-1840 5 CONHlS02 NI-I Ph 3-1841 5 CONH-S02 NH 2-Me-Ph 3-1842 5 CONHS0 2 NE 4-Me-Ph 3-1843 5 CONHlS02 NHl 2,4-diMe-Ph 3-1844 5 CONHIS02 NH 3,4-diMe-Ph 3-1845 5 CONHS0 2 NiH 2-(CF 3 )Ph y:\wpdocs\dgt_mss\981I2\981I2cpd3 .doc -303 Table 3 (cont.) Cpd. k A B R No. 3-1846 5 CONHS0 2 NH 4-(CF 3 )Ph 3-1847 5 CONHS02 NHl 2-MeOPh 3-1848 5 CONHSO2) NHl 4-MeOPh 3-1849 5 CONHS02 NHl 2-EtOPh 3-1850 7 CONHS0 2 NHl 4-EtOPh 3-1851 7 CONHS02 NH 2-HOPh 3-1852 5 CONHSO-, NHl 4-HOPh 3-1853 5 CONHSO2) NH 2-(HOOC)Ph 3-1854 5 CONHSO2) Nil 4-(HOOC)Ph 3-1855 5 CONHSO-, NHl 2-(MeOOC)Ph 3-1856 5 CONilSO-, NH 4-(MeOOC)Ph 3-1857 5 CONHS0 2 NH 2-(EtOOC)Ph 3-1858 5 CONH-S0 2 NH 4-(EtOOC)Ph 3-1859 7 CONHS0 2 NHi 2-(tBuOOC)Ph 3-1860 5 CONH-S02 NE 4-(tBuOOC)Ph 3-1861 5 CONHSO', NiE 2-Cl-Ph 3-1862 5 CONHSO-) NH 4-Cl-Ph 3-1863 7 CONH-S0 2 NHi 2-Br-Ph 3-1864 5 CONHS0 2 NH 4-Br-Ph 3-1865 5 CON'HSO 2 NH 2-I-Ph 3-1866 7 CONHS0 2 NH 4-I-Ph 3-1867 5 CONHS0 2 Nil 2-N0 2 -Ph 3-1868 5 CONHS0 2 Nil 4-N0 2 -Ph 3-1869 5 CONHS0 2 NH 2-NH 2 -Ph y:\wpdocs\dgt mss\98 12\981I2cpd3 .doc -304- Table3(cont.) S. S S S S *5

S

S

Cpd. k A B R 3-1870 5 CONHS0 2 NH 4-NH- 2 -Ph 3-1871 5 CONHS0 2 NH 2-(HO 3 S)Ph 3-1872 5 CONHS02 NI- 4-(HO 3 S)Ph 3-1873 5 CONHS0 2 NH 2-(NI- 2 0 2 S)Ph 3-1874 5 CONHS0 2 NHl 4-(NH 2

O

2 S)Ph 3-1875 5 CONHS02 NH 2-CN-Ph 3-1876 5 CONHS02 NIH 4-CN-Ph 3-1877 5 CONHS0 2 NH 2-(HOCH 2 )Ph 3-1878 5 CONHS0 2 NH 4-(HOCH 2 )Ph 3-1879 5 CONHS0 2 NH Me 3-1880 5 CONHS0 2 NH Et 3-1881 5 CONHS0 2 NH Pr 3-1882 5 CONHS0 2 NH iPr 3-1883 5 CONHS0 2 NH Bu 3-1884 7 CONHS0 2 NH HOOCCH 2 3-1885 5 CONES0 2 NH MeOOCCH 2 3-1886 5 CONHS0 2 NH MeCH(COOH) 3-1887 5 CONHS0 2 NH HOOC-(CH 2 2 3-1888 5 CONHS02, NH MeCH(COOMe) 3-1889 5 CONES0 2 NH 1-HOOC-iBu 3-1890 5 CONHS0 2 NH 1-MeOOC-iBu 3-1891 5 CONHS0 2 NH l-HOOC-iPn 3-1892 7 CONHS0 2 NH 1-MeOOC-iPn 3-1893 5 CONHS0 2 NH 1-HOOC-2-Me-Bu y: \wpdocs\d gt-mss\9912\981 2cpd3.-doc -305- Table 3 (cnltj Cpd. k A B R No.

3-1894 5 CONHSO 2 Nl 1-MeOOC-2-Me-Bu 3-1895 5 CONHS 2 NH CH 2

CH

2

SO

3

H

3-1896 5 CONHS02 NH OH 3-1897 5 CONHS0 2 NH MeG 3-1898 5 CONHS0 2 NH EtO 3-1899 5 CONHSO NH PrO 3-1900 5 CONHSO NH iPrO 3-1901 5 CONHS02 NH BuG 3-1902 5 CONHS0 2 NH iBuG 3-1903 5 CGNHSG, NH sBuO 3-1904 5 CONHSG, NH tBuG 3-1905 5 CONHSO 2 NH HxG 3-1906 5 CONHSO2 NH PhO 3-1907 5 CONHSO-, NH BnG 3-1908 5 CONHS02 NH Z-1 3-1909 5 CONHSG 2 NH Z-2 3-1910 5 CONHS0 2 NH Z-3 3-1911 5 CONES0 2 NH Z-4 3-1912 7 CONHSO? NH 3-1913 5 CONHS02 NH Z-6 3-1914 5 CONHS0 2 NH Z-7 3-1915 7 CONHS0 2 NH Z-8 3-1916 5 CONHS02 .,NH Z-9 3-1917 5 CONHS02 NH y:\wpdocs\dgtrnss\98 12\981 2cpd3.doc 306 Table 3 (cont.)

S

5*

S

S *5 S S@ Cpd. k A B

R

No. 3-1918 5 CONH-S02 NH Z-1 1 3-1919 5 CONH1S02 NHl Z-12 3-1920 5 CONH-S0 2 NH 3-Py 3-1921 5 CONH-S0 2 NH 4-Py 3-.1922 5 NHCO

-H

3-1923 5 NHCO -Ph 3-1924 5 Ni-CO -2-Me-Ph 3-1925 5 NHCO -4-Me-Ph 3-1926 5 NH-CO 2,4-diMe-Ph 3-1927 5 NHCO 3,4-diMe-Ph 3-1928 5 NHCO 2-(CF 3 )Ph 3-1929 5 NH-CO 4-(CF 3 )Ph 3-1930 5 N-HCO 2-eh 3-1931 5 NHCO 4-eh 3-1932 5 NI-CO- Eth 3-1933 5 Ni-CO 4-th 3-1934 5 NH-CO -2-HOPh 3-1935 5 NHCO -4-HOPh 3-1936 5 Ni-CO 2-(HOOC)Ph 3-1937 5 NH-CO 4-(HOOC)Ph 3-1938 7 NH-CO -2-(MeOOC)Ph 3-1939 5 NHCO -4-(MeOOC)Ph 3-1940 7 NHCO -2-(EtOOC)Ph 3-1941 7 NHCO -4-(EtOOC)Ph 3-1942 7 NIICO -2-(tBuOOC)Ph 3-1943 5 NIICO -4-(tBuOOC)Ph y:\wpdocs~dgtmrrss\981I2\981I2cpd3 .doc 307 Tabf~le (o Cpd. k A B

R

No.

3-1944 5 NHCO 2-Cl-Ph 3-1945 5 NIHCO 4-C 1-Ph 3-1946 5 NHCO -2-Br-Ph 3-1947 5 NI-CO -4-Br-Ph 3-1948 5 NHCO -2-I-Ph 3-1949 5 NHCO -4-I-Ph 3-1950 5 NHCO 2-N0 2 -Ph 3-1951 5 NHCO 4-N0 2 -Ph 3-1952 5 NI-CO 2-NH 2 -Ph 3-1953 5 NI-CO 4-NH 2 -Ph 3-1954 5 NHCO 2-(HO 3 S)Ph 3-1955 5 Ni-CO 4-(HO 3 S)Ph 3-1956 5 NH-CO 2-(NH- 2 0 2 S)Ph 3-1957 5 NI-CO 4-(NH 2 0 2 S)Ph 3-1958 5 NI-CO -2-CN-Ph 3-1959 5 NH-CO -4-CN-Ph 3-1960 5 Ni-CO 2-(HOCH 2 )Ph 3-1961 5 NHCO 4-(HOCH 2 )Ph 3-1962 5 NH-CO -Me 3-1963 5 Ni-CO Et 3-1964 5 NI-CO Pr 3-1965 5 Ni-CO iPr 3-1966 5 NI-CO

B

3-1967 7 NHCO 10CH2 3-1968 5 NHCO -MeOOCCH2y:\wpdocs\dgtmss\98l2\98I 2cpd3.dAm 308 Table 3 (cont.

0* Cpd. k A B R No. 3-1969 5 NHCO MeCH(COOH) 3-1970 5 NHCO HOOC-(CH 2 2 3-1971 5 NHCO MeCH(COOMe) 3-1972 5 NHiCO 1-HOOC-iBu 3-1973 5 NHCO 1-HOOC-iPn 3-1974 5 NHTCO I1-HOOC-2-Me-Bu 3-1975 5 NHCO

CH

2

CH

2

SO

3

H

3-1976 5 NH-CO -MeO 3-1977 5 NHCO -EtO 3-1978 5 NHCO -Pro 3-1979 5 NHCO -Z-1I 3-1980 5 NH-CO -Z-2 3-1981 5 NH-CO -Z-3 3-1982 7 NI-CO -Z-4 3-1983 5 NI-CO 3-1984 5 NE-CO

Z-

3-1985 5 NHCO

Z-

3-1986 5 NHCO

Z-

3-1987 5 NE-CO Z9 3-1988 7 rmCO -Z1 3-1989 5 NHCO -Z-1 1 3-1990 5 NHCO -Z-12 3-1991 7 NHCO 3-Py 3-1992 7 Ni-CO 4-Py 3-1993 5 NHCO NH H 3-1994 5 NIICO NIH Ph 3-1995 7 NHCO NH 2-Me-Ph y:\wpdocs\dgtmffss\981 2\981 2cpd3.doc 309 Table (cnt.) 555 S5* Cpd. k A

BR

No. 3-1996 5 NIACO NH 4-Me-Ph 3-1997 5-T NHCO NH 2,4-diMe-Ph 3-1998 7 NH-CO NH 3,4-diMe-Ph 3-1999 7 NHCO NH 2-(CF 3 )Ph 3-2000 5 NHCO NH 4-(CF 3 )Ph 3-2001 5 Ni-CO NH 2-MeOPh 3-2002 5 NIICO NH 4-MeOPh 3-2003 5 NH-CO NiH 2-EtOPh 3-2004 5 NHCO NH 4-EtOPh 3-2005 5 NHCO NH 2-HOPh 3-2006 7 NHCO NH 4-HOPh 3-2007 7 NE-CO NH 2-(HOOC)Ph 3-2008 5 NE-CO NH 4-(HOOC)Ph 3-2009 5 NH-CO NH 2-(MeOOC)Ph 3-2010 5 NHCO NH 4-(MeOOC)Ph 3-2011 7 NHCO NH 2-(EtOOC)Ph 3-2012 7 NH-CO NH 4-(EtOOC)Ph 3-2013 5 NIICO NH 2-(tBuOOC)Ph 3-2014 5 NHCO NHl 4-(tBuOOC)Ph 3-201 5 NHO NH2-Cl-Ph 3-2016 5 NCNE4-Cl-Ph 3-2017 5 NCNE2-Br-Ph 3-2018 5 NCNH4-Br-Ph 3-2019 5 NHCO NH 2-I-Ph 3-2020 5 NH-CO NH 4-I-Ph 3-2021 5 NHCO N H 2 N 2

P

3-2022 5 NHCO Ni- 4-N0 2 -Ph y:\wpdocs\dgtmffss\981I2\981 2cpd3.-doc -310- Table 3 (conti S S

S.

S

Cpd. k A B R No. 3-2023 5 NI{CO NHl 2-NH 2 -Ph 3-2024 5 NHCO NH 4-Nil 2 -Ph 3-2025 5 NHCO NH 2-(HO 3 S)Ph 3-2026 5 NHCO NH 4-(HO 3 S)Ph 3-2027 5 NHCO NH 2-(NH 2

O

2 S)Ph 3-2028 5 NH-CO N-H 4-(NE 2 O2S)Ph 3-2029 5 NHCO NH 2-CN-Ph 3-2030 7 NH-CO NH 4-CN-Ph 3-2031 5 NilCO NH 2-(HOCH 2 )Ph 3-2032 5 NHCO NH 4-(HOCH 2 )Ph 3-2033 5 NH-CO NH Me 3-2034 5 NHCO NH Et 3-2035 5 Ni-CO NH Pr 3-2036 5 Ni-CO Nil iPr 3-2037 7 NHCO NH Bu 3-2038 5 NE-CONHOCH2 3-2039 5 NE-CO NH MeOOCCH2- 3-2040 5 NE-CO NH MeCH(COOH) 3-2041 7 NHCO Nil HOOC-(CH2)2- 3-2042 5 NHCO NH MeCH(COOMe) 3-2043 5 NHCO NHl 1-HOOC-iBu 3-2044 7 NilCO NH I-MeOOC-iBu 3-2045 5 NilCO Nil 1-HOOC-iPn 3-2046 5 NHCO Nil I-MeOOC-iPn 3-2047 5 NIICO Nil 1-HOOC-2-Me-Bu 3-2048 5 NHCO Nil I-MeOOC-2-Me-Bu

S

S

*4 y:\wpdocs\dgtjnss\981I2\98 12cpd3.doc -311- Table 3 (cont.) A

B

0* 5

S

Cpd. k No.

3-2049 5 3-2050 -5 3-2051 5 3-2052 5 3-2053 5 3-2054 5 3-2055 5 3-2056 5 3-2057 5 3-2058 5 3-2059 5 3-2060 5 3-2061 5 3-2062 5 3-2063 5 3-2064 5 3-2065 5 3-2066 5 3-2067 5 3-2068 5 3-2069 5

NHCO

NHCO

NHCO

NHCO

NHCO

NHCO

NHCO

NHCO

NHCO

NiCO

NHCO

Ni-CO

NHCO

NHCO

NHCO

NHCO

L C ~l C \I

NH

NH

NH

NH

NE

OH

MeO EtO PrO

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

iPrO BuO iBuO sBuO tBuO HxO PhO BnO Z-1 Z-2 I NH i Z-3 I

I

NHCO

NH

i I

NHCO

NH

NHCO

NH

Z-6 4

NHCO

NH I

NECO

NH

I

Z-zsr 3-2070 5 NHCO NH Z-9 3-2071 5 NiCO NH 3-2072 5 N-CO NH Z-11 3-2073 5 NHCO NH Z-12 3-2074 5 NHCO NH 3-Py 3-2075 5 NICO NH 4-Py y:\wpdocs\dgtmss\981 2 98 12cpd3.doc 312 Table 3 (coMt.

C

*600ee

C

OSSC

0S C. 0 *0

C

S.

0 S 0e

S

e.g.

ego, 0

OS@*

S

Ce..

C

*0*C

C

0@S SOS

C

Cpd. k A B

R

3-2076 5 NHCO NWe Ph 3-2077 7 NHCO W~e 2-Me-Ph 3-207 8 7 NHCO NMe 4-Me-Ph 3-2079 5 NI-CO W~e 2,4-diMe-Ph 3-2080 5 NIICO NMe 3,4-diMe-Ph 3-2081 5 NHCO NMe 2-(CF 3 )Ph 3-2082 5 NHCO W~e 4-(CF 3 )Ph 3-2083 5 NI-CO NMe 2-MeOPh 3-2084 5 NH-CO NMe 4-MeOPh 3-2085 5 NHCO NMe 2-EtOPh 3-2086 7 NHCO W~e 4-EtOPh 3-2087 5 NH-CO NMe 2-HOPh 3-2088 5 NH-CO Ne4-HOPh 3-2089 5 NHCO W~e 2-(HOOC)Ph 3-2090 5 NIICO We 4-(HOOC)Ph 3-2091 7 Ni-CO NMe 2-(MeOOC)Ph 3-2092 5 NiCO We 4-(MeOOC)Ph 3-2093 5 NHCO Me 2-(EtOOC)Ph 3-2094 5 NH-CO W-e 4-(EtOOC)Ph 3-2095 5 NHCO NMe 2-(tBuOOC)Ph 3-2096 5 N-HCO NMe 4-(tBuOOC)Ph 3-2097 5 NHCO We 2-Cl-Ph 3-2098 5 NHCO We 4-Cl-Ph 3-2099 5 NIICO NMe 2-Br-Ph 3-2 100 5 NI-CO NWe 4-Br-Ph 3-2101 5 NI-CO We 2-I-Ph 3-2102 5 Ni-CO We 4-I-Ph y:\wpdocs\dgtmss\98I 2\981 2cpd3.doc -313 Table (cnt.) Cpd. k A B

R

No.

3-2103 5 NHCO NMe 2-N0 2 -Ph 3-2104 5 NHCO NMe 4-N0 2 -Ph 3-2105 5 NHCO NMe 2-NH 2 -Ph 3-2 106 5 NHCO NMe 4-NH 2 -Ph 3-2107 5 NI-CO NMe 2-(HO 3 S)Ph 3-2108 5 NIICO NMe 4-(HO 3 S)Ph 3-2109 5 NH-CO NMe 2-(NH 2

O

2 S)Ph 3-2110 5 NHCO NMe 4-(NI- 2 0 2 S)Ph 3-2111 5 NI-CO NMe 2-CN-Ph 3-2112 5 NHCO NMe 4-CN-Ph 3-2113 5 NH-CO NMe 2-(HOCH 2 )Ph 3-2114 5 NI-CO NMe 4-(HOCH 2 )Ph 3-2115 5 Ni-CO NMe Me 3-2116 5 NHCO NMe Et 3-2117 5 NH-CO NMe Pr 3-2118 5 NHCO NMe iPr 3-2119 5 NHCO NMe Bu 3-2120 5 NH-CO NMe HOOCCH 2 3-2121 7 NHCO W~e MeOOCCH2- 3-2122 5 NHCO We MeCH(COOH) 3-14 5 HONMe MeCH(COOMe) 3-16 5NHCO NMe 1-MeOOC-iBu 3-2 127 5 NH-CO NMe 1-FIOOC-iPn 3-2128 5 NIICO W~e 1-MeOOC-iPn y:\wpdocs\dgt_rris\981I2\981I2cpd3.doc 314- Table-1con.) Cpd. k A B

R

No. 3-2129 5 NH-CO NMe 1-HOOC-2-Me-Bu 3-2 130 5 NHTCO NMe I-MeOOC-2-Me-Bu 3-2131 5 NHCO NMe

CH

2

CH

2 SO3H 3-2132 5 NHiCO NMe

OH

3-2 133 5 Ni-CO NMe MeO 3-2134 7 NHCO NMe EtO 3-2135 5 NI-CO NMe Pro 3-2136 7 NHCO NMe iPrO 3-2137 5 Ni-CO NMe BuG 3-2138 5 NH-CO W~e iBuG 3-2139 5 NHCO NMe sBuO 3-2 140 5 NH~CO NMe tBuO 3-2141 5 NHCO NMe HxO 3-2142 7 NH-CO NMe PhO 3-2143 5 NHCO NMe BnO 3-2144 5 Ni-CO W~e Z-1 3-2145 5 NHCO NMe Z-2 3-2146 7 NH-CO NMe Z-3 3-2147 5 NHCO W~e Z-4 3-2148 5 NH-CO NWe 3-2149 5 NHCO W~e Z-6 3-2150 7 NHCO W~e Z-7 3-2151 5 NHCO NMe Z-8 3-2152 5 Nli-CO eZ9 3-2153 5 NHCOWeZ1 3-2154 5YHOW F3-2155 5 NH-CO NeZ1 y:\wpdocs\dgt_rrss\981 2 98 i 2cpd3.doc 315 Table 3A(onti Cpd. k A

B

3-2156 5 NI-CO NMe 3-2157 5 NHCO NMe 3-2158 5 NCO0

NHN]

3-2159 5 N-CO0

NI{N

3-2160 5 NHCO

NHN]

3-2161 5 Ni-CO

NHNN

:3-2162 5 NHCO

NHN

3-2163 5 Ni-CO

NIINI

3-2164 5 NH-CONH-NHCO

NH

3 -2165 5 NHCONHNHCO

NH

3-2166 5 Ni-CONHNI-CO NHl 3)-2 167 5 NHCO1LHON 3-2168 5 NI-CONHNHCO

NH

1A T-rnNHII1C0 NHl y:\wpdocs\dgtjflss\ 98 1I2\981I2cpd3.doc 316 Table 3 (cont.

Cpd. k A B R No. 3-2 183 5 NILCONILNHCO NH 4-(EtOOC)Ph 3-2 184 5 NIICONHNIICO NHL 2-(tBuOOC)Ph 3-2185 7 NHCONILNHCO NHL 4-(tBuOOC)Ph 3-2 186 5 NHCONIINH-CO NHL 2-Cl-Ph 3-2 187 7 NIJCONIINILCO NHL 4-Cl-Ph 3-2 188 7 NHCONILNHCO NH 2-Br-Ph 3-2189 5 NHCONHNILCO NH 4-Br-Ph 3-2 190 5 NHTCONH-NHCO NH 2-I-Ph 3-2191 5 NHCONHNHCO NH 4-I-Ph 3-2192 5 NHCONH-NILCO NH 2-N0 2 -Ph 3-2193 5 Ni-CONH-IMCO NH 4-N0 2 -Ph 3-2194 5 NHCONHNHCO NH 2-NH 2 -Ph 3-2195 7 N'HCONI-N7HCO NH 4-NH 2 -Ph 3-2196 7 NHCONH-N1-CO NHL 2-(HO 3 S)Ph 3-2 197 7 NILCONI-NHCO NIH 4-(HO 3 S)Ph 3-2 198 5 N1-CONI{NHCO NH 2-(NIL 2

O

2 S)Ph 3-2199 5 N1-CONH-NI-CO NH 4-(NH 2

O

2 S)Ph 3-2200 7 NHCONHNI-CO NIL 2-CN-Ph 3-220 1 7 N1-CONHN7HCO NE 4-CN-Ph 3-2202 5 NH-CONHNE-CO NiL 2-(HOCH 2 )Ph 3-2203 5 NIICONILNICO NIH 4-(HOCH 2 )Ph 3-2204 7 NI-CONi-NILCO NIL Me 3-2205 5 NHCONHNE-CO NHL Et 3-2206 5 NHCON1{NHCO NHl Pr 3-2207 5 NHCONILNICO'N iPr 3-2208 5 NILCONHNHCO NEL Bu y:\wpdocs\dgtmnss\9812\98I 2cpd3.doc 317- Table 3 (coot.

Cpd. k A B

R

No.

3-2209 5 NI-CONHNHCO NiH HOOCCH 2 3-2210 5 NI-CONH-NHCO NHl MeOOCCH 2 3-2211 5 NHCONIHNHCO NHl MeCH(COOH) 3-22 12 5 NHCONilNHCO NH HOOC-(CH 2 2 3-22 13 5 N1-CONHNHCO NHl MeCH(COOMe) 3-2214 5 NHCON1-NHCO NIH 1-HOOC-iBu 3-2215 5 NHCONI{NHCO Nil l-MeOOC-iBu 3-2216 5 NilCONHNHCO Nil 1-HOOC-iPn 3-2217 5 NIICONIINi-CO Nil 1-MeOOC-iPn 3-2218 5 NHCON14NHCO Nil 1-HOOC-2-Me-Bu 3-2219 5 NHCONHNHCO NH 1-MeOOC-2-Me-Bu 3-2220 5 N1-CONI4NHCO NH CH 2

CH

2

SO

3

H

3-222 1 5 M-ICONHNHCO NH

OH

3-2222 5 NHCONHNHCO NH MeO 3-2223 5 NHCONHN-ICO NH EtO 3-2224 5 N-HCON}INHCO NH Pro 3-2225 5 NHCONHN-ICO NH iPrO 3-2226 5 N1-CONHN1-CO NH BuO 3-2227 5 Ni-CONINi-HCO NH iBuO 3-2228 7 NHCONIINHCO NH sBUO 3-2229 5 NHCONI-N-HCO NHtBuO 3-2230 5 NHCONHNHCO NH HxO 3-2231 5 NH-CONHNHCO NH PhO 3-2232 5 NHCONHNHCO NH BnO 3-2233 5 NH-CONH-NHCO NH Z-1 3-2234 7 NHCONHNilCQ. .NH -Z-2 3-2235 7 NHCONHNHCO NH Z-3 y:\wpdocs\dgt miss\9 8 1I2\981I2cpd3.doc -318 Table 3 (cont)

S.

S

Cpd. k A B R No. 3-2236 5 NilCONHNI-CO NiH Z-4 3-2237 5 NHCONHNHCO NHl 3-2238 5 NHCONilNHCO NHl Z-6 3-2239 5 NHCONilNHCO Nil Z-7 3-2240 5 NilCONilNHCO NHl Z-8 3-224 1 5 NilCONHNHCO Nil Z-9 3-2242 5 NilCONI{NiCO NH 3-2243 5 NlcoNI-NilCO Nil Z-1 1 3-2244 5 NilCONilNilCO Nil Z-12 3-2245 5 NHCONH-NHCO Nil 3-Py 3-2246 5 NHCONilNHCO Nil 4-Py 3-2247 5 NHCONH-CO

-H

3-2248 5 NH-CONilCO -Ph 3-2249 5 NHCONilCO -2-Me-Ph 3-2250 5 NHCONilCO -4-Me-Ph 3-2251 5 NHCONH-CO 2,4-diMe-Ph 3-2252 5 Ni-CONH-CO 3,4-diMe-Ph 3-2253 5 NilCONE-CO 2-(CF 3 )Ph 3-2254 5 NE-CONE-CO 4-(CF 3 )Ph 3-225 5 5 NH-COM-ICO 2-MeOPh 3-2256 5 NHCONilCO -4-MeOPh 3-2257 5 NHCONIICO -2-EtOPh 3-2258 5 NIHCONHCO -4-EtOPh 3-2259 5 N-HCONilCO -2-HOPh 3-2260 5 NHCONilCO 4-HOPh 3-2261 5 NHCONHCO -2-(HOOC)Ph 3-2262 5 NilCONHCO -4-(HOOC)Ph y:\wpdocs\dgtmffss\981 2\981 2cpd3.dAm 319 Table 3 (cont.) .0.0 0 00.0 0 .:040: Cpd. k A lB Rl No. 3-2263 5 NIICONIICO -2-(MeOOC)Ph 3-2264 5 NHCONHCO -4-(MeOOC)Ph 3-2265 7 NHCONHCO -2-(EtOOC)Ph 3-2266 7 NHCONHCO -4-(EtOOC)Ph 3-2267 7 NHCONI{CO 2-(tBuOOC)Ph 3-2268 5 NI-CONEiCO 4-(tBuOOC)Ph 3-2269 7 NHCONHiCO -2-Cl-Ph 3-22 70 5 NHCONH-CO -4-Cl-Ph 3-2271 5 NHCONHCO -2-Br-Ph 3-2272 5 NI-CONH-CO -4-Br-Ph 3-2273 5 NH-CONHCO -2-I-Ph 3-2274 5 NHCONH-CO -4-I-Ph 3-2275 5 NHCONHCO 2-N0 2 -Ph 3-2276 5 NHCONHCO 4-N0 2 -Ph 3-2277 5 NHCONHCO 2-NH 2 -Ph 3-2278 5 NH-CONI-CO 4-NHi 2 -Ph 3-2279 5 NH-CONIICO 2-(HO 3 S)Ph 3-2280 5 NHCONHCO 4-(HO 3

SP

3-2281 5 NHCONH-CO 2-(NH 2

O

2

SP

3-2282 7 NlICONH-CO 4-(NIH 2

O

2 S)Ph 3-2283 5 NI-CONHCO -2-CN-Ph 3-2284 5 NIICONIICO -4-CN-Ph 3-2285 5 NH-CONHCO 2-(HOCH 2 )Ph 3-2286 7 NHCONHCO 4-(HOCH 2 )Ph 3-2287 5 NH-CONIICO -Me 3-2288 5 NIICONIICO I IEt y:\wpdocs\dgtmffss\981I2\9812cpd3 .doc -320- Table 3 (cont.

S 5 5 *5S* Cpd. k A

BR

No. 3-2289 5 NHCONHCO -Pr 3-2290 5 N HCONHCO -iPr 3-2291 5 NHCONIICO -Bu 3-2292 5 N}ICONHCO

HOOCCH

2 3-2293 5 NHCONIHCO MeOOCCH 2 3-2294 5 M-{CONIICO MeCH(COOH) 3-2295 5 N HCONH-CO

HOOC-(CH

2 2 3-2296 5 NHCONIHCO MeCH(COOMe) 3-2297 5 N HCONHiCO 1-HOOC-iBu 3-2298 5 NH-CONI-CO 1-MeOOC-iBu 3-2299 5 NHCONIHCO 1-HOOC-iPn 3-2300 5 NHCONHCO 1-MeOOC-iPn 3-2301 5 NHCONHCO 1-HOOC-2-Me-Bu 3-2302 5 NHiCONHCO 1-MeOOC-2-Me-Bu 3-2303 5 NI-CONHCO

CH

2

CH

2

SO

3

H

3-2304 5 NH-CONHCO Me 3-2305 5 NH-CONi-CO -EtO 3-2306 5 NH-CONH-CO -Pro 3-2307 5 NH-CONHCO iPrO 3-2308 5 NHCONHCO BuO 3-2309 5 NHCONHCO iBuG 3-2310 5 NH-CONHCO sBuO 3-2311 5 NH-CONHCO tBuO 3-2312 5 NHCONHCO HxO 3-2313 5 NHCONHCO PhO 3-23 14 5 NH-CONHCO BnO y:\wpdocs\dgtmffss\981I2\981I2cpd3 .doc 321 Cpd. k A B R No. 3-23 15 5 NHCONHCO Z- 1 3-2316 5 NH-CONHCO -Z-2 3-23 17 5 NHCONHCO -Z-3 3-23 18 5 NHCONIICO -Z-4 3-2319 5 NHCONHCO 3-2320 5 NH-CONHCO -Z-6 3-232 1 5 NHCONHCO -Z-7 3-2322 5 NHCONH-CO -Z-8 3-2323 5 NH-CONHCO -Z-9 3-2324 5 NHCONHCO 3-2325 5 NHCONHCO -Z-1 1 3-2326 5 NH-CONI-CO -Z-12 3-2327 5 Nli-CONH-CO -3-Py 3-2328 5 M-LCONHCO -4-Py 3-2329 5 NB-CONHS0 2

-H

3-2330 5 NH{CONH-S0 2 -Ph 3-2331 5 NE-CONH-S02) 2-Me-Ph 3-2332 5 NHCON1-S0 2 -4-Me-Ph 3-2333 5 NH-CONH-S0 2 2,4-diMe-Ph 3-2334 5 NECONHS0 2 3,4-diMe-Ph 3-2335 5 NHCONH-S0 2 2-(CF 3 )Ph 3-2336 5 NHCONHS0 2 4-(CF 3 )Ph 3-2337 5 NH-CONHS0 2 -2-MeOPh 3-2338 5 NHCONHIS0 2 -4-MeOPh 3-2339 5 NHCONHS0 2 2-EtOPh y:\wpdocs\dgtmss\98I 2\981 2cpd3.-doc -322- Table 3 (contJ

S

S

0SO*

S@

S S

S

0 0 .605 Cpd. k A B R No.

3-2340 5 NHCONHSO 2 4-EtOPh 3-2341 5 NHCONHS0 2 2-HOPh 3-2342 5 NHCONHS0 2 4-HOPh 3-2343 5 NHCONHSO 2 2-(HOOC)Ph 3-2344 5 NHCONHS0 2 4-(HOOC)Ph 3-2345 5 NHCONISO2 2-(MeOOC)Ph 3-2346 5 NHCONHS0 2 4-(MeOOC)Ph 3-2347 5 NHCONHSO 2 2-(EtOOC)Ph 3-2348 5 NHCONHSO2 4-(EtOOC)Ph 3-2349 5 NHCONHS02 2-(tBuOOC)Ph 3-2350 5 NHCONHS0 2 4-(tBuOOC)Ph 3-2351 5 NICONHS0 2 2-Cl-Ph 3-2352 5 NHCONHS0 2 4-Cl-Ph 3-2353 5 NHCONHSO 2 2-Br-Ph 3-2354 5 NHCONHSO 2 4-Br-Ph 3-2355 5 NHCONHS0 2 2-I-Ph 3-2356 5 N-CONHSO2 4-I-Ph 3-2357 7 NICONIS02 2-N0 2 -Ph 3-2358 5 NHCONHS02 4-N0 2 -Ph 3-2359 5 NHCONHSO2 2-NH 2 -Ph 3-2360 7 NHCONHSO2 4-NH 2 -Ph 3-2361 7 N-CONHSO2 2-(HO 3 S)Ph 3-2362 5 NHCONHSO 2 4-(HO 3 S)Ph 3-2363 5 NHCONHS0 2 2-(NH 2

O

2 S)Ph y:\wpdocs\dgtfss\9812\9812cpd3doc -323- Table 3 (cont.) Cpd. k A B R No.

3-2364 5 NHCONHS02 4-(NH 2

O

2 S)Ph 3-2365 5 NHCONHS02 2-CN-Ph 3-2366 5 NHCONHS 2 4-CN-Ph 3-2367 5 NHCONHS02 2-(HOCH 2 )Ph 3-2368 5 NHCONHS02 4-(HOCH 2 )Ph 3-2369 5 NHCONHS02 Me 3-2370 5 NHCONHS0 2 Et 3-2371 5 NHCONHSO 2 Pr 3-2372 5 NICONHSO 2 iPr 3-2373 5 NECONHSO-) Bu 3-2374 5 NHCONHSO2 HOOCCH 2 3-2375 5 NHCONHSO-, MeOOCCH2 3-2376 5 NHCONHSO2 MeCH(COOH) 3-2377 5 N1CONHSO2 HOOC-(CH 2 2 3-2378 5 NHCONHS0 2 MeCH(COOMe) 3-2379 5 NHCONHS02 1-HOOC-iBu 3-2380 5 NHCONHSO9 1-MeOOC-iBu 3-2381 5 NHCONHSO2 1-HOOC-iPn 3-2382 5 NHCONES02 1-MeOOC-iPn 3-2383 5 NHCONES02 1-HOOC-2-Me-Bu 3-2384 5 NHCON-HS0 2 1-MeOOC-2-Me-Bu 3-2385 5 NHCONHS0 2

CH

2

CH

2

SO

3

H

3-2386 5 NHCONES02

OH

3-2387 5 NHCONHSO 2 MeO y:\wpdocs\dgtms\9812\981 2cpd3 .doc -324- Table 3 (cont) Cpd. k A B Rl No. 3-2388 5 NHCONHS02 -EtO 3-23 89 5 NH-CONHS02 -Pro 3-2390 5 NHCONHS02 PrO 3-2391 5 NHICONHS02 -BuO 3-2392 5 NHCONHIS02 -iBuO 3-23 93 5 NH{CONHS0 2 -sBuO 3-2394 5 NHCONH{S0 2 -tBuO 3-2395 5 NHCONHS0 2 -HxO 3-2396 5 NHiCONHSO2 -PhO 3-2397 5 NHCONHSO 2 BnO 3-2398 5 Nli-CON1S-1S02 Z-1 3-2399 5 Nli-CONHSO2) Z-2 3-2400 5 NHCONE-102 Z-3 3-2401 5 N-HCONILSO2) Z-4 3-2402 5 NHCONHiSO 2 3-2403 5 NE-CONI-S0 2 -Z-6 3-2404 5 NHCONHS02 -Z-7 3-2405 5 N1ICONE-S0 2 -Z-8 3-2406 5 NBICONHS02 -Z-9 3-2407 5 NHCONI-{S0 2 3-2408 5 NHICONHS0 2 -Z-1 1 3-2409 5 NHiCONHSO2 -Z-12 3-2410 5 N-HCONHS0 2 3-Py 3-2411 5 N-HCONHS0 2 I4-Py y:\wpdocs\dgtnss\981I2\981I2cpd3.-doc 325 Table 3 (co-nti Cpd. k A B R No. 3-2412 5 NHCONHS0 2 NE H 3-2413 5 NHICONHIS02 NEl Me 3-2414 5 NH-CONHS0 2 NH Et 3-2415 5 NHCONHIS02 NHl Pr 3-2416 5 NH{CONHS0 2 NiH iPr 3-2417 5 NHlCONHS0 2 NHl Bu 3-2418 5 NHCONHS0 2 NMe Me 3-2419 5 NH-CONHS0 2 NMe Et 3-2420 5 NHCONHS0 2 NMe Pr 3-2421 5 NHCONH-S0 2 NMe iPr 3-2422 5 NHCONH-S0 2 NMe Bu 3-2423 5 -NH

H

3-2424 5 -NH Me 3-2425 5 -NH Et 3-2426 5 -N-H Pr 3-2427 5 NH- iPr 3-2428 5 NH Bu 3-2429 5 CO Pyr 3-2430 5 CO Pipn 3-2431 7 CO Pipra 3-2432 5 CO Mor 3-2433 5 CO Thmor 3-2434 5 CO NI-Pyr 3-243 5 5 CO NilPipri 3-2436 5 CO NHPipra 3-2437 5 CO NHMor y:\wpdocs\dgt_mfss\981I2\98 12cpd3 .doc -326- Table 3 (coaW.

Cpd. k A

BR

No.

3-2438 5 CO Hho 3-243 9 5 NHCO y 3-2440 5 NHCO Pipri 3-244 1 5 Ni-CO Pipra 3-2442 5 NHCO Mor 3-2443 5 NHCO Thmor 3-2444 5 NHCO NHPyr 3-2445 5 NH-CO NBIpri 3-2446 5 NI-CO NHPipra 3-2447 5 NHCO NHMor 3-2448 5 NH-CO NHThmor 3-2449 5 CONHCO Pyr 3-2450 5 CONH-CO Pipri 3-2451 5 CONHCO Pipra 3-2452 5 CONH-CO Mor 3-2453 5 CONH-CO Thmor 3-2454 5 COM-ICO NHPyr 3-2455 5 CONI-CO NHPipri 3-2456 5 CONHCO NHPipra 3-245 7 5 COM-ICO NHMor 3-2458 5 CONH-CO NI{Thmor 3-2459 5 CONH-S0 2 Pyr 3-2460 5 CONH-S0 2 Pipri 3-2461 5 CONH-S0 2 Pipra 3-2462 5 CONES0 2 Mor 3-2463 5 CONHS0 2 Thmor y:\wpdocs\dgtmffss\981I2\98 12cpd3.doc 327 Table 3 (co-nt.

0 Cpd. k A BR No.

3-2464 5 CONHS0 2 NHPyr 3 -2465 7 CONHS02 NI-Pipri 3-2466 7 CONHIS0 2 NilPipra 3-2467 5 CONHS0 2 NHMor 3-2468 5 CONHS0 2 NHlThmor 3-2469 5 NHS0 2 NH Z-4 3-2470 5 NI-SO 2 -Me 3-2471 5 NH-SO 2 -Et 3-2472 7 NH-SO 2 -Pr 3-2473 5 NH-S02 -CH2..CI 3-2474 5 NH-SO 2 -Ph 3-2475 5 NH-S02) 4-Me-Ph 3-2476 5 CO NWe Ph 3-2477 5 CO NMe 2-Me-Ph 3-2478 5 CO NMe 4-Me-Ph 3-2479 7 CO NMe 2,4-diMe-Ph 3-2480 5 CO NMe 3,4-diMe-Ph 3-2481 5 CO NMe 2-(CF 3 )Ph 3-2482 5 CO NWe 4-(CF 3 )Ph 3-2483 7 CO NMe 2-MeOPh 3-2484 7 CO NWe 4-MeOPh 3-2485 5 CO NMe 2-EtOPh 3-2486 5 CO NMe 4-EtOPh 3-2487 7 CO NWe 2-HOPh 3-2488 7 CO NMe 4-HOPh 3-2489 5 CO NMe 2-(HOOC)Ph y:\wpdocs\d gt mss\9812\981 2cpd 3.doc 328 Table 3 (cont.) Cpd. k A B R No. 3-2490 5 Co We 4-(HOOC)Ph 3-249 1 5 Co NMe 2-(MeOOC)Ph 3-2492 5 CO NMe 4-(MeOOC)Ph 3-2493 5 Co NMe 2-(EtOOC)Ph 3-2494 5 Co NMe 4-(EtOOC)Ph 3-2495 5 CO NMe 2-(tBuOOC)Ph 3-2496 5 Co NMe 4-(tBuOOC)Ph 3-2497 5 co We 2-Cl-Ph 3-2498 5 CO We 4-Cl-Ph 3-2499 5 CO We 2-Br-Ph 3-2500 5 CO We 4-Br-Ph 3-2501 5 CO We 2-I-Ph 3-2502 5 CO We 4-I-Ph 3-2503 5 CO We 2-N0 2 -Ph 3-2504 5 CO We 4-N0 2 -Ph 3-2505 5 CO W~e 2-NH 2 -Ph 3-2506 5 CO We 4-NH 2 -Ph 3-2507 5 CO We 2-(HO 3 S)Ph 3-2508 5 CO We 4-(HO 3 S)Ph 3-2509 5 CO We 2-(NH 2 0 2 S)Ph 3-25 10 5 CO We 4-(NH 2

O

2 S)Ph 3-2511 5 CO We 2-CN-Ph 3-2512 5 CO We 4-CN-Ph 3-25 13 5 CO We 2-(HOCH 2 )Ph 3-25 14 5 CO We 4-(HOCH 2 )Ph 3-2515 5 CO We Me y:\wpdocs\dgtmrrss\981I2\981I2cpd3.doc 329 Table 3 (cont.

S

*5

S

S.

S S

S.

S S Cpd. k A B R 3-2516 5 CO NMe Et 3-2517 5 CO NMe Pr 3-2518 5 CO NMe iPr 3-2519 5 CO NMe Bu 3-2520 7 CO NMe HOOCCH2) 3-2521 7 CO NMe HOOC-(CH 2 2 3-2522 5 CO NMe MeCH(COOH) 3-2523 5 CO NMe HOOC-(CH 2 3 3-2524 5 CO NMe MeCH(COOMe) 3-2525 5 CO NMe 1-HOOC-iBu 3-2526 5 co NMe 1-MeOOC-iBu 3-2527 7 CO NMe 1-HOOC-iPn 3-2528 7 CO We 1-MeOOC-iPn 3-2529 5 CO We 1-HOOC-2-Me-Bu 3-2530 5 CO We 1-MeOOC-2-Me-Bu 3-2531 5 CO We CH 2

CH

2

SO

3

H

3-2532 5 CO NMe 01- 3-2533 7 CO We MeO 3-2534 7 CO We EtO 3-2535 7 CO We Pro 3-2536 5 CO We iPrO 3-2537 5 CO We BuO 3-2538 5 CO We iBuO 3-2539 7 CO NMe sBuO 3-2540 5 CO We tBuO 3-2541 5 CO We HxO 3-2542 5 CO We PhO

S

Y:\wpdocs\dgt~mss\981I2\981I2cpd3 .doc -330- Table 3 (cont.) Cpd. k A B

R

No. 3-2543 5 Co NMe BnO 3-2544 5 CO NMe Z-1 3-2545 5 Co NMe Z-2 3-2546 5 CO NMe Z-3 3-2547 5 Co NMe Z-4 3-2548 5 CO NMe 3-2549 5 CO NMe Z-6 5'3-2550 5 CO NMe Z-7 3-2551 5 CO NMe Z-8 3-2552 5 CO NMe Z-9 3-2553 5 CO NMe 3-2554 5 CO NMe Z-11I .003-2555 5 CO NMe Z-12 00003-2556 5 CO NMe 3-Py 3-2557 5 CO NMe 4-Py 3-2558 5 CO Thiad :3-2559 5 CO NH-Thiad 3-2560 5 NH-CO Thiad 3-2561 5 NI-CO NH-Thiad 3-2562 5 CONE-CO Thiad 3-2563 5 CONHCO NHThiad 3-2564 5 CONHS0 2 Thiad 3-2565 5 CONH-S0 2 NHThiad 3-2566 5 N-HCS NH-

H

3-2567 5 Ni-CS NHL Me 3-2568 5 NH-CS NH- Et 3-2569 5 Ni-CS NH Ph y:\wpdocs\dgt_ms\981I2\981 I cpd3.-doc 331 Table 3 (cont.) C Cpd. k A B

R

3-2570 5 NHCS NiH HOOCCH 2 3-257 1 5 NIICS NE MeOOCCH 2 3-2572 5 NHCS NiH MeCH(COOH) 3-2573 5 NiICS NiH HOOC-(CH 2 2 3-25 74 5 NilCS Nil MeCH(COOMe) 3-2575 5 CO NH HOOC-(CH 2 3 3-2576 5 NHCO N-H HOOC-(CH 2 3 3-2577 5 NH-CO -HOOC-(CH 2 )3- 3-2578 5 NilCS NH HOOC-(CH 2 3 3-2579 5 CO N-H MeSO 2 NHlCOCH(Me) 3-2580 7 NHCO NH MeSO 2 NHICOCH(Me) 3-2581 5 NilCO -MeSO 2 NHCOCH(Me) 3-2582 5 NHCS N-H MeSO 2 NiICOCH(Me) 3-2583 5 -N-H HOOCCH 2 3-2584 5 -Nil MeOOCCH 2 3-2585 7 NH MeCH(COOH) 3-2586 57 NH HOOC-(CH 2 2 3-2587 5 NH MeCH(COOMe) 3-2588 5 NH HOOC-(CH 2 3 3-2589 5 NHCOCO

OH

3-2590 7 NHCOCO MeO 3-2591 5 NHCOCO EtO 3-2592 5 HCOCO Pr-o 3-2593 5 NHCOCO iPrO 3-2594 5 NHCOCO BuO y:\wpdocs\dgt_mss\981 2\981 2cpd 3.doc 332 Table 3 (cont.

Cpd. k A B

R

No. 3 -2595 5 NRCOCO -iBuO 3-2596 5 NI-COCO -sBuO 3-2597 5 NH-COCO -tBuO 3-2598 5 NHCOCO -HxO 3-2599 5 NH-COCO -PhO 3-2600 5 NHiCOCO -BnO 3-2601 0 1 ,3-diox-Ilnd 3-2602 1 1 ,3-diox-Ilnd 3-2603 2 1 ,3-diox-IInd 3-2604 3 ,-ixln 3-2605 4 ,-ixIn 3-2606 57,-ixIn 3-2607 6 1 ,3-diox-Ilnd 3-2608 7 1 ,3-diox-Ilnd 3-2609 8 1 ,3-diox-IInd 3-2610 9 1 ,3-diox-Ilnd 3-26 11 101 1 ,3-diox-Ilnd 3-2612 11 1 ,3-diox-Ilnd 3-2613 12 1 ,3-diox-Ilnd 3-26 14 4 NIHCONH-S0 2 NI-CO NHZ- 3-2615 4 NHICONH{S0 2 NHCO NH

P

3-2616 2 0H 3-261 0Ph 3-262 02-Py 3-2621 5 03-Py y:\wpdocs\dgtmrss\981I2\981I2cpd3.-doc 333 Table 3 (cont.) Cpd. k A B

R

3-2622 5 0 -4-Py 3-2623 5 0 -Z-1 3-2624 5 0 -Z-2 3-2625 5 0 Z-3 3-2626 5 0 -Z-4 3-2627 5 0 3-2628 5 0 -Z-6 3-2629 5 0 -Z-7 3-2630 5 0 -Z-8 3-2631 5 0 -Z-9 3-2632 5 0 3-2633 5 0 -Z-11 3-2634 5 0 -Z-12 3-2635 4 NHCO 3-Py 3-2636 5 NHCO -3-Py 3-263 7 4 Co NH- HOCH 2

CH(CH

3

)CH

2 3-2638 5 Co NE HOCH 2

CH(CH

3

)CH

2 3-2639 4 NHCO NiH HOCH 2

CH(CHI)CH

2 3-2640 5 NHCO NH- HOCH 2

CH(CH

3

)CH

2 3-2641 4 CO NiH MeSO 2

NHCOCH

2 3-2642 5 Co NiH MeSO 2

NHCOCH

2 3-2643 4 NH-CO NH MeSO 2 NHlCOCH 2 3-2644 5 NilCO NiH MeSO 2

NH-COCH

2 3-2645 4 CO NH H 2

NSO

2

NHCOCH

2 3-2646 5 Co NH H 2

NSO

2 NiICOCH 2 3-2647 4- NHCO NilT H 2

NSO

2 NilCOCH 2 y:\wpdocs\dgt_mss\ 98 1 2\981 Zcpd3.doc -334- Table 3 (cont.) Cpd. k A B

R

No.

3-2648 5 NHCO NH H 2

NSO

2

NIICOCH

2 3-2649 4 CO NH 1-(MeSO 2 NHCO)-Et 3-2650 5 CO NH 1-(MeSO 2 NHCO)-Et 3-2651 4 NHCO NH 1 -(MeSO2NHCO)-Et 3-2652 5 NECO NH 1-(MeSO 2 NHCO)-Et 3-2653 4 CO NH 1-(H 2

NSO

2 NHCO)-Et 3-2654 5 CO NH I1-(H 2

NSO

2 NHCO)-Et 3-2655 4 NHCO NH 1-(H 2

NSO

2 NHCO)-Et 3-2656 5 NHCO NH I1-(H2NSO 2 NHiCO)-Et 3-2657 4 CO NH HOOC-(CH 2 4 3-265 8 5 CO NH HOOC-(CH 2 4 3-2659 4 NI-CO NH HOOC-(CH 2 4 3-2660 5 Ni-CO NH HOOC-(CH 2 4 3-2661 4 CO NH HO-(CH 2 2 3-2662 5 CO NH HO-(CH 2 2 3-2663 4 NH-CO NiH HO-(CH 2 2 3-2664 5 Ni-CO NH HO-(CH 2 2 3-2665 4 CO NH- HO-CH 2

-CH(CH

3 3-2666 5 coNH

HO-CH

2

-CH(CH

3 3-2667 4 NI-CO NH HO-CH 2

-CH(CH

3 3-2668 5 NHCO NH HO-CH 2

-CH(CH

3 3-2669 4 CO NMe HOOC-(CH 2 3 3-2670 4 NHCO NMe HOOC-(C1 2 3 3-2671 5 NHCO NMe HOOC-(CH 2 3 3-2672 4 CONMeSO 2 Me y:\wpdocs\dgt_mss\9812\ 981 2cpd3.doc 335 Cpd. k

A

No. 3-2673 5 CONMeSO 2 3-2674 4

CO

3-2675 5

CO

3-2676 4

NHCO

3-2677 5

NHCO

3-2678 4

CO

3-2679 5

CO

3-2680 4

NHCO

3-268 1 5

NI-CO

3-2682 4 3-2683

BRI

a a a I1-Indn I -Indn 2-(HOOC)-lI-Indn 2-(HOOC)-lI-Indn 2-(HOOC)- 1 -Indn 3 -ie-dO I -Idd 3 ,4-diMe-2,5-diox- I -Imdd y:\wpdocs\dgtms\981 2\981 2cpd 3.doc 336 Of the above compounds, preferred compounds are Compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-34, 1-49, 1-64, 1-79, 1-20, 1-3 5, 1-50, 1-65, 1-80, 1-21, 1-22, 1-36, 1-37, 1-5 1, 1-52, 1-66, 1-67, 1-81, 1-82, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-83, 1-232, 1-233, 1-234, 1-235, 1-236, 1-237, 1-238, 1-239, 1-240, 1-252, 1-264, 1-276, 1-288, 1-300, 1-312, 15 1-324, 1-336, 1-348, 1-360, 1-3 72, 1-384, 1-396, 1-408, 1-24 1, 1-25 3, 1-265, 1-277, 1-289, 1-301, 1-313, 1-325, 1-33 7, 1-349, 1-361, 1-3 73, 1-3 85, 1-397, 1-409, 1-242, 1-254, 1-266, 1-278, 1-243, 1-25 5, 1-267, 1-279, 1-244, 1-245, 1-246, 1-247, 1-256, 1-257, 1-258, 1-259, 1-268, 1-269, 1-270, 1-271, 1-280, 1-28 1, 1-282, 1-283, 1-292, 1-293, 1-294, 1-295, 1-248, 1-249, 1-260, 1-261, 1-272, 1-273, -290, 1-291, -302, 1-303, [-314, 1-3 15, -326, 1-327, 1-338, 1-339, 1-350, 1-351, 1-362, 1-363, 1-374, 1-375, 1-386, 1-387, 1-398, 1-399, 1-410, 1-411, 1-422, 1-423, 1-304, 1-305, 1-316, 1-317, 1-328, 1-329, 1-306, 1-318, 1-330, 1-307, 1-319, 1-331, 1-340, 1-3 52, 1-364, 1-3 76, 1-388, 1-400, 1-4 12, 1-424, 1-341, 1-342, 1-343, 1-353, 1-354, 1-355, 1-365, 1-366, 1-367, 1-377, 1-378, 1-379, 1-389, 1-390, 1-391, 1-401, 1-402, 1-403, 1-413, 1-414, 1-415, 1-425, 1-426, 1-427, 1-284, 1-296, 1-308, 1-320, 1-332, 1-344, 1-3 56, 1-368, 1-3 80, 1-392, 1-404, 1-285, 1-297, 1-309, 1-321, 1-333, 1-345, 1-3 57, 1-369, 1-381, 1-393, 1-405.

1-250, 1-262, 1-2 74, 1-286, 1-298, 1-3 10, 1-322, 1-334, 1-346, 1-3 58, 1-370, 1-3 82, 1-394, ,1-406, 9l-418, ,1-430, 1-25 1, 1-263, 1-275, 1-287, 1-299, 1-311, 1-323, 1-3 1-347, 1-3 59, 1-37 1, 1-3 83, 1-395, 1-407, 1-419, 1-431, 1-416, 1-417.

1-428, 1-429 1-420, 1-421, 1-432, 1-444, 1-456, 1-43 3, 1-445, 1-45 7, 1-434, 1-435, 1-446, 1-447, 1-458, 1-459, 1-436, 1-448, 1-460, 1-437, 1-438, 1-449, 1-450, 1-461, 1-462, 1-439, 1-45 1, 1-463, 1-440, 1-452, 1-464, 1-441, 1-45 3, 1-465, 1-442, 1-454, 1-466, 1-443, 1-455, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-480, 1-48 1, 1-482, 1-483, 1-484, 1-485, 1-492, 1-493, l-494, l-495, 1-496, 1-497, 1-504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-516, 1-517, 1-518, 1-519, 1-520, 1-521, 1-528, 1-529, 1-530, 1-531, 1-532, 1-533, 1-474, 1-475, 1-476, 1-477, 1-478, 1-479, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491, 1-498, 1-499, 1-500, 1-501, 1-502, 1-503, 1-510, 1-511, 1-512, 1-513, 1-514, 1-515, 1-522, 1-523, 1-524, 1-525, 1-526, 1-527, 1-534, 1-535, 1-536, 1-537, 1-538, 1-539, y:\wpdocs\dgtrniss\981 2\usa\98 I2sp I .doc 337 1-540, 1-552, 1-564, 1-576, 1-588, 1-600, 1-6 12, 1-678, 1-690, 1-702, 1-7 14, 1-726, 1-73 8, 1-750, 15 1-762, 1-774, 1-786, 1-79 8, 1-810, 1-822, 1-834, 1-846, 1-54 1, 1-5 53, 1-565, 1-5 77, 1-5 89, 1-60 1, 1-6 13, 1-679, 1-69 1, 1-703, 1-715, 1-727, 1-739, 1-75 1, 1-763, 1-775, 1-787, 1-799, 1-8 11, 1-823, 1-83 5, 1-847, 1-542, 1-543, 1-554, 1-555, 1-566, 1-567, 1-578, 1-579, 1-590, 1-591, 1-602, 1-603, 1-614, 1-615, 1-680, 1-681, 1-692, 1-693, 1-704, 1-705, 1-716, 1-717, 1-728, 1-729, 1-740, 1-741, 1-752, 1-753, 1-544, 1-556, 1-568, 1-580, 1-592, 1-604, 1-616, 1-682, 1-694, 1-706, 1-718, 1-730, 1-742, 1-754, 1-545, 1-55 7, 1-569, 1-58 1, 1-593, 1-605, 1-6 17, 1-683, 1-695, 1-707, 1-719, 1-731, 1-743, 1-755, 1-767, 1-779, 1-791, 1-803, 1-594, 1-595, 1-606, 1-607, 1-618, 1-619, 1-684, 1-685, 1-696, 1-697, 1-708, 1-709, 1-720, 1-721, 1-732, 1-733, 1-744, 1-745, 1-756, 1-757, 1-768, 1-769, 1-780, 1-781, 1-792, 1-793, 1-804, 1-805, 1-596, 1-608, 1-620, 1-686, 1-698, 1-7 10, 1-722, 1-734, 1-746, 1-75 8, 1-770, 1-782, 1-794, 1-806, 1-8 18, 1-830, 1-842, 1-546, 1-547, 1-548, 1-558, 1-559, 1-560, 1-570, 1-571, 1-572, 1-582, 1-583, 1-584, 1-549, 1-550, 1-55 1, 1-561, 1-562, 1-563, 1-573, 1-574, 1-575, 1-585, 1-586, 1-587, 1-597, 1-598, 1-599, 1-609, 1-610, 1-611, 1-621, 1-676, 1-677, 1-687, 1-688, 1-689, 1-699, 1-700, 1-701, 1-711, 1-712, 1-713, 1-723, 1-724, 1-725, 1-735, 1-736, 1-737, 1-747, 1-748, 1-749, 1-759, 1-760, 1-761, 1-771, 1-772, 1-773, 1-783, 1-784, 1-785, 1-795, 1-796, 1-797, 1-807, 1-808, 1-809, 1-819, 1-820, 1-821, 1-83 1, 1-832, 1-833, 1-843, 1-844, 1-845, 1-764, 1-765, 1-776, 1-777, 1-788, 1-789, 1-800, 1-801, 1-812, 1-813, 1-824, 1-825, 1-836, 1-837, 1-848, 1-849, 1-766, 1-778, 1-790, 1-802, 1-814, 1-826, 1-83 8, 1-815, 1-816, 1-817, 1-827, 1-828, 1-829, 1-839, 1-840, 1-841, 1-850, 1-851, 1-852, 1-853, 1-854, 1-855, 1-856, 1-857, 1-858, 1-859, 1-860, 1-861, 1-862, 1-863, 1-1112, 1-1113, 1-1114, 1-1115, 1-1116, 251-1 127, 1-1128, 1-1129, 1-1130, 1-1 131, 1-1132, 1-1133, 1-1134, 1-1125, 1-1136, 1-1137, 1-1138, 1-1139, 1-1140, 1-1141, 1-1142, 1-1143, 1-1144, 1-1145, 1-1146, 1-1147, 1-1148, 1-1149, 1-1150, 1-1151, 1-1142, 1-1143, 1-1154, 1-1155, 1-1146, 1-1157, 1-1148, 1-1159, 1-1160, 1-1161, 1-1162, 1-1163, 1-1164, 1-1165, 1-1166, 1-1167, 1-1168, 1-1169, 1-1224, 1-1268, 1-112, 1-1260, 1-1261, 1-1262, 1-1266, 1-1264, 1-1265, 1-1266, 1-1267, 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1-1274, 1-1275, 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1281, 1-1282, 1-1283, 1-1284, 1-1285, 1-1286, 1-1287, 1-1278, 1-1279, 1-1290, 1-1291, 1-1292, 1-1293, y:\wpdocs\dgtms\981 2\usa\981I2sp I .doc 338 1-1294, 1-1295, 1 1-1304, 1-1305, 1 1-1314, 1-1315, 1 1-1324, 1-1325, 1 1-1334, 1-1335, 1 1-1344, 1-1345, 1 1-1354, 1-1355, 1 1-1364, 1-1365,1 1-1374, 1-1375, 1 -1532, 1-1533, 1-1542, 1-1543, 1-1552, 1-1553, 1-1562,141563, 1-1572, 1-1573, 1-1582, 1-1583, 1-1592, 1-1593, 1-1602, 1-1603, 1-1612, 1-1613, 1-1622, 1-1623, 1-1632, 1-1633, -1296, 1-1297, 1-1298, 1-1299, -1306, 1-1307, 1-1308, 1-1309, -1316, 1-1317, 1-1318, 1-1319, 1-1300, 1-13 1-1320, 1-1301, 1-1302, 1-1303, 1-1321, 1-1322, 1-1323, -1326, 1-1327, -1336, 1-1337, -1346, 1-1347, [-1356, 1-1357, [-1366, 1-1367, [-1376, 1-1377, 1-1534, 1-1544, 1-15 54, 1-1564, 1-1574, 1-1584, 1-1594, 1-1604, 1-16 14, 1-1535, 1-1545, 1-1555, 1-1565, 1-15 75, 1-1585, 1-1595, 1-1605, 1-1615.

1-1328, 1-1329, 1-1330, 1-1331, 1-1332, 1-1333, 1-1338, 1-1339, 1-1340, 1-1341, 1-1342, 1-1343, 1-1348, 1-1349, 1-1350, 1-1351, 1-1352, 1-1353, 1-1358, 1-1359, 1-1360, 1-1361, 1-1362, 1-1363, 1-1368, 1-1369, 1-1370, 1-1371, 1-1372, 1-1373, 1-1378, 1-1379, 1-1380, 1-1381, 1-1382, 1-1383, 1-1536, 1-1537, 1-1538, 1-1539, 1-1540, 1-1541, 1-1546, 1-1547, 1-1548, 1-1549, 1-1550, 1-1551, 1-1556, 1-1557, 1-1558, 1-1559, 1-1560, 1-1561, 1-1566, 1-1567, 1-1568, 1-1569, 1-1570, 1-1571, 1-1576, 1-1577, 1-1578, 1-1579, 1-1580, 1-1581, 1-1586, 1-1587, 1-1588, 1-1589, 1-1590, 1-1591, 1-1596, 1-1597, 1-1598, 1-1599, 1-1600, 1-1601, 1-1606, 1-1607, 1-1608, 1-1609, 1-1610, 1-1611, 1-1616, 1-1617, 1-1618, 1-1619, 1-1620, 1-1621, ,1-1626, 1-1627, 1-1628, 1-1629, 1-1630, 1-163 1, 1-1624, 1-1625 1-1634, 1-1635, 1-1636, 1-1637, 1-1638, 1-1639, 1-1640, 1-1641, 1-1642, 1 1-1652, 1 1-1662, 1 1-1672, 1 1-1682, 1-1692, 1-1702, 1-1712, 1-1722, 1-1732, 1-1742, 1-1752, -1643, -1653, -1663, -1673, 1-1683, 1-1693, 1-1703, 1-1713, 1-1723.

1-1733 1-1743 1-1753 1-1644, 1-1645, 1-1646, 1-1647, 1 1-1654, 1-1655, 1-1656, 1-1657, 1 1-1664, 1-1665, 1-1666, 1-1667, 1 1-1674, 1-1675, 1-1676, 1-1677, 1 1-1684, 1-1685, 1-1686, 1-1687, 1 1-1694, 1-1695, 1-1696, 1-1697, 1-1704, 1-1705, 1-1706, 1-1707, 1-1714, 1-1715, 1-1716, 1-1717, 1-1724, 1-1725, 1-1726, 1-1727, 11-1734, 1-1735, 1-1 736, 1-1737, 11-1744, 1-1745, 1-1746, 1-1747, ,1-1754, 1-1755, 1-1756, 1-1757, -1648, 1-1649, 1-1650, 1-1651, -1658, 1-1659, 1-1660, 1-1661, -1668, 1-1669, 1-1670, 1-1671, -1678, 1-1679, 1-1680, 1-1681, 1688, 1-1689, 1-1690, 1-1691, 1-1698, 1-1699, 1-1700, 1-1701, 1-1708, 1-1709, 1-1710, 1-1711, 1-1718, 1-1719, 1-1720, 1-1721, 1- 1728, 1-1729, 1-1730, 1-173 1, 1-1738, 1-1739, 1-1740, 1-1741, 1-1748, 1-1749, 1-1750, 1-1751, 1-1758, 1-1759, 1-1760, 1-1761, y:\wpdocs\dgtjntIss\981I2\usa\981I2sp I .doc 339 1-1762, 1-1763, 1-1772,1-1773, 1-1782,1-1783, 1-1792, 1-1793, 1-1802, 1-1803, 1-1812, 1-1813, 1-1822, 1-1823, 1-1832, 1-1833, 1-1842, 1-1843, 1-1852, 1-1853, 1-1862, 1-1863, 1-1872, 1-1873, 1-1882,1-1883, 1-1764, 1-1774, 1-1784, 1-1794, 1-1804, 1-1814, 1-1824, 1-1834, 1-1844, 1-1854, 1-1864, 1-1874, 1-1884, 1-1765, 1-1766, 1-1767, 1-1775,1-1776,1-1777, 1-1785,1-1786,1-1787, 1-1795,1-1796,1-1797, 1-1805, 1-1806, 1-1807, 1-1815, 1-1816, 1-1817, 1-1825, 1-1826, 1-1827, 1-1835, 1-1836, 1-1837, 1-1845, 1-1846, 1-1847, 1-1855, 1-1856, 1-1857, 1-1865,1-1866,1-1867, 1-1768, 1-1778, 1-1788, 1-1798, 1-1808, 1-1818, 1-1828, 1-1838, 1-1848, 1-1858, 1-1868, 1-1878, 1-1888, 1-1898, 1-1908, 1-1769, 1-1779, 1-1789, 1-1799, 1-1809, 1-1819, 1-1829, 1-1839, 1-1849, 1-1770, 1-1771, 1-1780 1-1781, 1-1790, 1-1791, 1-1800, 1-1801, 1-1810, 1-1811, 1-1820, 1-1821, 1-1830,1-1831, 1-1840, 1-1841, 1-1850, 1-1851, 1-1859, 1-1860, 1-1861, 1-1869, 1-1870, 1-1871, 1-1875, 1-1885, 1-1895, 1-1905, 1-1892, 1 1-1902, 1-1912, 1-1962, 1-1972, 1-1982, 1-1992, 1-2002, 1-2012, 1-2022, 1-2032, 1-2042, [-1893,1-1894, 1-1903, 1-1904, 1-1913, 1-1963, 1-1973, 1-1983, 1-1993, 1-2003, 1-2013, 1-2023, 1-2033, 1-2043, 1-1914,1-1915, 1-1964,1-1965, 1-1876, 1-1877, 1-1886, 1-1887, 1-1896, 1-1897, 1-1906, 1-1907, 1-1916, 1-1917, 1-1966,1-1967, 1-1976,1-1977, 1-1986, 1-1987, 1-1996, 1-1997, 1-2006, 1-2007, 1-2016, 1-2017 1-2026, 1-2027 1-1879, 1-1889, 1-1899, 1-1909, 1-1918,1-1919, 1-1968, 1-1969, 1-1880, 1-1881, 1-1890,1-1891, 1-1900, 1-1901, 1-1910, 1-1911, 1-1920,1-1921, 1-1970,1-1971, 1-1980, 1-1981, 1-1990, 1-1991, 1-2000, 1-2001, 1-2010, 1-2011, 1-2020, 1-2021, 1-1974, 1-1984, 1-1994, 1-2004, 1-2014, 1-2024, 1-2034, 1-2044, 1-1975, 1-1985, 1-1995, 1-2005, 1-2015, 1-2025, 1-2035, 1-2045.

1-1978, 1-1988, 1-1998, 1-2008, 1-2018, 1-2028, 1-2038, 1-1979, 1-1989, 1-1999, 1-2009, 1-2019,

I

1-2036, 1-2037, 1-2029, 1-2030, 1-2031, 1-2039, 1-2040, 1-2041, 1-2049, 1-2050, 1-2051, 1-2046, 1-2047, 1-2048, 1-2052, 1-2053, 1-2054, 1-2055, 1-2056, 1-2057, 1-2058, 1-2059, 1-2060, 1-2061, 1-2062, 1-2063, 1-2072, 1-2073, 1-2082,1-2083, 1-2092,1-2093, 1-2102, 1-2103, 1-2112,1-2113, 1-2064, 1-2074, 1-2084, 1-2094, 1-2104, 1-2114, 1-2065, 1-2066, 1-2067, 1-2068, 1-2069, 1-2070, 1-2071, 1-2075, 1-2076, 1-2077, 1-2078, 1-2079, 1-2080, 1-2081, 1-2085, 1-2086, 1-2087, 1-2088, 1-2089, 1-2090, 1-2091, 1-2095, 1-2096, 1-2097, 1-2098, 1-2099, 1-2100, 1-2101, 1-2105, 1-2106, 1-2107, 1-2108, 1-2109, 1-2110, 1-2111, 1-2115, 1-2116, 1-2117, 1-2118, 1-2119, 1-2120, 1-2121, y:\wpdocs\dgt mss\9812\usa\9812sp I .doc 340 1-2122, 1-2123, 1-2124, 1-2125, 1-2126, 1-2127, 1-2128, 1-2129, 1-2130,.1-213 1, 1-2132, 1-2133, 1-2142, 1-2143, 1-2152, 1-2153, 1-2162, 1-2163, 1-2437, 1-2438, 1-2447, 1-2448, 1-2457, 1-2458, 1-2467, 1-2468, 1-2477, 1-2478, 1-2487, 1-2488, 1-2134, 1-2135, 1-2136, 1-2144, 1-2145, 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3-2125, 3-2126, 3-2127, 3-2038, 3-2039, 3-2040, 3-2041, 3-2042, 3-2048, 3-2049, 3-2050, 3-2051, 3-2052, 3-2043, 3-2044, 3-2053, 3-2054, 3-2058, 3-2059, 3-2060, 3-2068, 3-2069, 3-2070, 3-2078, 3-2079, 3-2080, 3-2088, 3-2089, 3-2090, 3-2098, 3-2099, 3-2100, 3-2108, 3-2109,3-2110, 3-2118, 3-2119, 3-2120, 3-2128, 3-2129, 3-2130, 3-2061, 3-2071, 3-2081, 3-2091, 3-2101, 3-2111, 3-2121, 3-2131, 3-2062, 3-2063, 3-2064, 3-2072, 3-2073, 3-2074, 3-2082, 3-2083, 3-2084, 3-2092, 3-2093, 3-2094, 3-2102, 3-2103, 3-2104, 3-2112,3-2113,3-2114, 3-2122, 3-2123, 3-2124, 3-2132, 3-2133, 3-2134, 3-2142, 3-2143, 3-2144, 3-2135, 3-2136, 3-2137, 3-2138, 3-2139, 3-2140, 3-2141, 3-2145, 3-2146, 3-2147, 3-2148, 3-2149, 3-2150, 3-2151, 3-2152, 3-2153, 3-2154, 3-2155, 3-2156, 3-2157, 3-2158, 3-2159, 3-2160, 3-2161, 3-2162, 3-2163, 3-2429, 3-2430, 3-2431, 3-2432, 3-2433, 3-2434, 3-2435, 3-2436, 3-2437, 3-2438, 3-2439, 3-2440, 3-2441, 3-2442, 3-2443, 3-2444, 3-2445, 3-2446, 3-2447, 3-2448, 3-2449, 3-2450, 3-2451, 3-2452, 3-2453, 3-2454, 3-2455, 3-2456, 3-2457, 3-2458, 3-2459, 3-2460, 3-2461, 3-2462, 3-2463, 3-2464, 3-2465, 3-2466, 3-2467, 3-2468, 3-2469, 3-2470, 3-2471, 3-2472, 3-2473, 3-2474, 3-2475, 3-2476, 3-2477, 3-2478, 3-2479, 3-2480, 3-2481, 3-2482, 3-2483, 3-2484, 3-2485, 3-2486, 3-2487, 3-2488, 3-2489, 3-2490, 3-2491, 3-2492, 3-2493, 3-2494, 3-2495, 3-2496, 3-2497, 3-2498, 3-2499, 3-2500, 3-2501, 3-2502, 3-2503, 3-2504, 3-2505, 3-2506, 3-2507, 3-2508, 3-2509, 3-2510,3-2511,3-2512, 3-2513, 3-2514, 3-2515, 3-2516, 3-2517, 3-2518, 3-2519, 3-2520, 3-2521, 3-2522, 3-2523, 3-2524, 3-2525, 3-2526, 3-2527, 3-2528, 3-2529, 3-2530, 3-2531, 3-2532, 3-2533, 3-2534, 3-2535, 3-2536, 3-2537, 3-2538, 3-2539, 3-2540, 3-2541, 3-2542, 3-2543, 3-2544, 3-2545, 3-2546, 3-2547, 3-2548, 3-2549, 3-2550, 3-2551, 3-2552, 3-2553, 3-2554, 3-2555, 3-2556, 3-2557, 3-2558, 3-2559, 3-2560, 3-2561, 3-2562, 3-2563, 3-2564, 3-2565, 3-2566, 3-2567, 3-2568, 3-2569, 3-2570, 3-2571, 3-2572, 3-2573, 3-2574, 3-2575, 3-2576, 3-2577, 3-2578, 3-2579, y:\wpdocs\dgt-mss\9812\usa\9812sp I .doc 350 3-2580, 3-2581, 3-2582, 3-2583, 3-2584, 3-2585, 3-2586, 3-2587, 3-2588, 3-2589, 3-2590, 3-2591, 3-2592, 3-2593, 3-2594, 3-2595, 3-2596, 3-2597, 3-2598,'3-2599, 3-2600, 3-2601, 3-2602, 3-2603, 3-2604, 3-2605, 3-2606, 3-2607, 3-2608, 3-2609, 3-2610, 3-2611, 3-2612, 3-2613, 3-2614, 3-2657, 3-2665, 3-2667 and 3-2669.

The following compounds are more preferred, that is Compounds No.: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-271, 1-272, 1-273, 1-274, 1-275, 1-276, 1-277, 1-278, 1-279, 1-280, 1-28 1, 1-282, 1-283, 1-284, 1-285, 1-286, 1-287, 1-288, 1-289, 1-290, 1-291, 1-292, 1-293, 1-294, 1-295, 1-296, 1-297, 1-298, 1-299, 1-300, 1-301, 1-302, 1-303, 1-304, 1-305, 1-306, 1-307, 1-308, 1-309, 1-310, 1-311, 1-312, 1-313, 1-314, 1-315, 1-316, 1-317, :*15 1-318, 1-319, 1-320, 1-321, 1-322, 1-323, 1-324, 1-325, 1-326, 1-327, 1-328, 1-329, *1-330, 1-331, 1-332, 1-333, 1-334, 1-335, 1-336, 1-337, 1-338, 1-339, 1-340, 1-341, 1-342, 1-343, 1-344, 1-345, 1-346, 1-347, 1-348, 1-349, 1-350, 1-351, 1-352, 1-353, 1-354, 1-355, 1-356, 1-357, 1-358, 1-359, 1-360, 1-361, 1-362, 1-363, 1-364, 1-365, 1-366, 1-367, 1-368, 1-369, 1-370, 1-371, 1-372, 1-373, 1-374, 1-375, 1-376, 1-377, 1-378, 1-379, 1-380, 1-381, 1-382, 1-383, 1-384, 1-385, 1-386, 1-387, 1-388, 1-389, 1-390, 1-391, 1-392, 1-393, 1-394, 1-395, 1-396, 1-397, 1-398, 1-399, 1-400, 1-401, 1-402, 1-403, 1-404, 1-405, 1-406, 1-407, 1-408, 1-409, 1-410, 1-411, 1-412, 1-413, 1-414, 1-415, 1-416, 1-417, 1-418, 1-419, 1-420, 1-421, 1-422, 1-423, 1-424, 1-425, 1-426, 1-427, 1-428, 1-429, 1-430, 1-431, 1-432, 1-433, 1-434, 1-435, 1-436, 1-437, 1-438, 1-439, 1-440, 1-441, 1-442, 1-443, 1-444, 1-445, 1-446, 1-447, 1-448, 1-449, 1-450, 1-451, 1-452, 1-453, 1-454, 1-455, 1-456, 1-457, 1-458, 1-459, 1-460, 1-461, 1-462, 1-463, 1-464, 1-465, 1-466, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-474, 1-475, 1-476, 1-477, 1-478, 1-479, 1-480, 1-481, 1-482, 1-483, 1-484, 1-485, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491, 1-492, 1-493, 1-494, 1-495, 1-496, 1-497, 1-498, 1-499, 1-500, 1-501, 1-502, 1 503, 1-504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1-513, 1-514, 1-515, 1-516, 1-517, 1-518, 1-519, 1-520, 1-521, 1-522, 1-523, 1-524, 1-525, 1-526, 1-527, 1-528, 1-529, 1-530, 1-531, 1-532, 1-533, y:\wpdocs\dgtmffss\981 2\usa\9S1 2SPI .do -351 1-534, 1-682, 1-694, 1-706, 1-718, 1-730, 1-742, 1-754, 1-766, 1.-778, 1-790, 1-802, 1-8 14, 1-826, 1-838, 1-535, 1-536, 1-537, 1-683, 1-684, 1-685, 1-695, 1-696, 1-697, 1-707, 1-708, 1-709, 1-719, 1-720, 1-721, 1-73 1, 1-732, 1-733, 1-743, 1-744, 1-745, 1-755, 1-756, 1-757, 1-767, 1-768, 1-769, 1-779, 1-780, 1-781, 1-791, 1-792, 1-793, 1-803, 1-804, 1-805, 1-815, 1-816, 1-817, 1-827, 1-828, 1-829, 1-839, 1-840, 1-841, 1-538, 1-539, 1-686, 1-687, 1-676, 1-688, 1

I

1 1-698, 1-699, 1-700, 1-710, 1-722, 1-734, 1-746, 1-75 8, 1-770, 1-782, 1-794, 1-806, 1-8 18, 1-830, 1-723, 1-724, 1 1-735, 1-736, 1 1-747, 1-748, 1 1-759, 1-760, 1 1-771, 1-772, 1 1-783, 1-784, 1 1-795, 1-796, 1 1-807, 1-808, 1 1-819, 1-820, 1 -677, -689, -701, -713, -725, -737, -749, -761, -773, -785, -797, -809, -821, 1-678, 1-679, 1-680, 1-681, 1-702, 1-703, 1-704, 1-705, 1-714, 1-715, 1-716, 1-717, 1-726, 1-727, 1-728, 1-729, 1-738, 1-739, 1-740, 1-741, 1-750, 1-75 1, 1-752, 1-753, 1-762, 1-763, 1-764, 1-765, 1-774, 1-775, 1-776, 1-777, 1-786, 1-787, 1-788, 1-789, 1-798, 1-799, 1-800, 1-801, 1-810, 1-811, 1-812, 1-813, 1-822, 1-823, 1-824, 1-825, 1-834, 1-835, 1-836, 1-837, 1-846, 1-847, 1-848, 1-849, .000 *000.

1-83 1, 1-832, 1-833, 1-842, 1-843, 1-844, 1-845, 0000 90 00 1-850, 1-851, 1-852, 1-853, 1-854, 1-855, 1-856, 1-857, 1-858, 1-859, 1-860, 1-861, 1-112, 1-112, 1-112, 1-113, 1-114, 1-115, 1-116, 1-117, 1-118, 1-119, 1-1130, 1-1131, 1-1132, 1-1133, 1-1134, 1-1135, 1-1136, 1-1137, 1-1138, 1-1139, 20 1-1140, 1-1 141, 1-1 142, 1-1143, 1-1144, 1-1 145, 1-1 146, 1-1147, 1-1 148, 1-1224, 1-1258, 1-1259, 1-1260, 1-1261, 1-1262, 1-1263, 1-1264, 1-1265, 1-1266, 1-1267, 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1-1274, 1-1275, 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1962, 1-1963, 1-1964, 1-1965, 1-1966, 1-1967, 1-1968, 1-1969, 1-1970, 1-1971, 1-1972, 1-1973, 1-1974, 1-1975, 1-1976, 1-1977, 1-1978, 1-1979, 1-1980, 1-1981, 1-1982, 1-1983, 1-1984, 1-1985, 1-1986, 1-1987, 1-1988, 1-1989, 1-1990, 1-1991, 1-1992, 1-1993, 1-2470, 1-2471, 1-2472, 1-2473, 1-2474, 1-2475, 1-2476, 1-2477, 1-2478, 1-2479, 1-2480, 1-2481, 1-2482, 1-2483, 1-2484, 1-2485, 1-2486, 1-2487, 1-2488, 1-2489, 1-2490, 1-2491, 1-2492, 1-2493, 1-2494, 1-2495, 1-2496, 1-2497, 1-2498, 1-2499, 1-2500, 1-2501, 1-2502, 1-2503, 1-2504, 1-2505, 1-2506, 1-2507, 1-2508, 1-2509, 1-2510, 1-2511, 1-2512, 1-2513, 1-2514, 1-2515, 1-2516, 1-2517, 1-2518, 1-2519, 1-2520, 1-2521, 1-2522, 1-2523, 1-2524, 1-2525, 1-2526, 1-2527, 1-2528, 1-2529, 1-2530, 1-2531, 1-2532, 1-2533, 1-2534, y:\wpdocs\dgtms\981 2\usa\981 2sp I.doc 352 1-2535, 1-2536, 1-2537, 1-2538, 1-2539, 1-2545, 1-2546, 1-2547, 1-2548, 1-2549, 1-2555, 1-2556, 1-2557, 1-2558, 1-2559, 1-2565, 1-2566, 1-2567, 1-2568, 1-2569, 1-2575, 1-2576, 1-2577, 1-2578, 1-2579, 1-2585, 1-2586, 1-2587, 1-2588, 1-2589, 1-2595, 1-2596, 1-2597, 1-2598, 1-2599, 1-2605, 1-2606, 1-2607, 1-2608, 1-2609, 1-2657, 1-2665, 1-2667 and 1-2669.

1-2540, 1-2550, 1-2560, 1-25 70, 1-2580, 1-2590, 1-2600, 1-26 10, 1-2541, 1-255 1, 1-256 1, 1-257 1, 1-258 1, 1-259 1, 1-260 1, 1-26 11, 1-2542, 1-2543,-1-2544, 1-2552, 1-2553, 1-2554, 1-2562, 1-2563, 1-2564, 1-2572, 1-2573, 1-2574, 1-2582, 1-2583, 1-2584, 1-2592, 1-2593, 1-2594, 1-2602, 1-2603, 1-2604, 1-2612, 1-2613, 1-2614, 0* 0@ S

S.

S

*5@S *5*S

S

*5*S 0

OS@S

S* S C 0O The following compounds are still more preferred, that is Compounds No.: 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-7 1, 1 -72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-271, 1-272, 1-273, 1-274, 1-275, 1-276, 15 1-458, 1-470, 1-482, 1-494, 1-506, 20 1-518, 1-530, 1-735, 1-747, 1-823, 1-835, 1-847, 1-277, 1 1-459, 1-471, 1-483, 1-495, 1-507, 1-5 19, 1-531, 1-736, 1-748, 1-824, 1-836, 1-848, -278, 1-279, 1-460, 1-461, 1-472, 1-484, 1-496, 1-508, 1-520, 1-532, 1-737, 1-749, 1-825, 1-473, 1-48 5, 1-497, 1-509, 1-521, 1-53 3, 1-73 8, 1-750, 1-826, 1-280, 1-462, 1-474, 1-486, 1-498, 1-5 10, 1-522, 1-534, 1-739.

1-815 1-281, 1-463, 1-475, 1-487, 1-499, 1-511, 1-523, 1-535, 1-740, 1-816, 1-464, 1-476, 1-488, 1-500, 1-5 12, 1-524, 1-536, 1-74 1, 1-8 17, 1-465, 1-466, 1-477, 1-478, 1-489, 1-490, 1-501, 1-502, 1-513, 1-514, 1-525, 1-526, 1-537, 1-538, 1-282, 1-283, 1-284, 1-285, 1-467, 1-479, 1-491, 1-503, 1-5 15, 1-527, 1-539, 1-286, 1-457, 1-468, 1-469, 1-480, 1-481, 1-492,1-493, 1-504, 1-505, 1-5 16, 1-5 17, 1-528, 1-529, 1-733, 1-734, 1-742, 1-8 18, 1-830, 1-743, 1-744, 1-819, 1-820, 1-83 1, 1-832, 1-745, 1-82 1, 1-833, 1-746, 1-822, 1-834, 1-827, 1-828, 1-829, 1-837, 1-849, 1-838, 1-850, 1-839, 1-851, 1-840, 1-841, 1-852, 1-853, 1-842, 1-854, 1-843, 1-844, 1-855, 1-856, 1-845, 1-857, 1-846, 1-858, 1-859, 1-860, 1-861, 1-862, 1-863, 1-1129, 1-1130, 1-1131, 1-1132, 1-1133, 1-1134, 1-1135, 1-1136, 1-1 137, 1-1138, 1-1139, 1-1140, 1-1141, 1-1142, 1-1143, 1-1144, 1- 1145, 1-1146, 1-1 147, 1-1148, 1-1224, 1-125 8, 1-1259, 1-1260, 1-1261, 1-1262, 1- 1263, 1-1264, 1-1265, 1-1266, 1-1267, 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1-1274, 1-1275, 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1962, 1-1963, 1-1964, 1-1965, 1-1966, 1-1967, 1-1968, 1-1969, 1-1970, 1-1971, 1-1972, 1-1973, y:\wpdocs\dgtmnss\9812\usa\98 1 ZspI .do 353 1- 1974, 1-1984, 1-2470, 1-2480, 1-2490, 1-2500, 1-2510, 1-2520, 1-2530, 1-2540, 1-2550, 1-2560, 1-2570, 1-1975, 1-1976, 1-1977, 1-1985, 1-1986, 1-1987, 1-2471, 1-2472, 1-2473, 1-2481, 1-2482, 1-2483, 1-249 1, 1-250 1, 1-2511, 1-252 1, 1-253 1, 1-254 1, 1-255 1, 1-256 1, 1-257 1, 1-2492, 1-2493, 1-2502, 1-2503, 1-25 12, 1-25 13, 1-2522, 1-2523, 1-2532, 1-2533, 1-2542, 1-2543, 1-2552, 1-2553, 1-2562, 1-2563, 1-1978, 1-1988, 1-2474, 1-2484, 1-2494, 1-2504, 1-25 14, 1-2524, 1-2534, 1-2544, 1-2554, 1-2564, 1-1989, 1-1990, 1-2475, 1-2476, 1-2485, 1-2486, 1-2495, 1-2496, 1-2505, 1-2506, 1-2515, 1-2516, 1-2525, 1-2526, 1-2535, 1-2536, 1-2545, 1-2546, 1-2555, 1-2556, 1-2565, 1-2566, 1-1991, 1-1992, 1-2477, 1-2478, 1-2487, 1-2488, 1-2497, 1-2498, 1-2507, 1-2508, 1-25 17, 1-2518, 1-2527, 1-2528, 1-2537, 1-2538, 1-2547, 1-2548, 1-2557, 1-2558, 1-2567, 1-2568, 1-2577, 1-2578, 1- 1979, 1-1980, 1-1981, 1-1982, -1-1983, 1-1993, 1-2479, 1-2489, 1-2499, 1-2509, 1-25 19, 1-2529, 1-2539, 1-2549, 1-25 59, 1-2569, 1-2657, 1-2572, 1-2573, 1-2574, 1-2575, 1-2576, 1-2665, 1-2667 and 1-2669.

The following compounds are even more preferred, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, that is Compounds No.: 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-271, 1-272, 1-273, 1-274, 1-286, 1-468, 1-480, 1-492, 1-504, 1-516, 1-528, 1-275, 1-276, 1-457, 1-458, 1-469, 1-470, 1-481, 1-482, 1-493, 1-494, 1-505, 1-506, 1-517, 1-518, 1-529, 1-530, 1-277, 1-459, 1-47 1, 1-483, 1-495, 1-507, 1-519, 1-531, 1-278, 1-279, 1-280, 1-460, 1-472, 1-484, 1-496, 1-508, 1-520, 1-532, 1-461, 1-473, 1-485, 1-497, 1-509, 1-52 1, 1-533, 1-462, 1-474, 1-486, 1-498, 1-5 10, 1-522, 1-534, 1-28 1, 1-463, 1-475, 1-487, 1-499, 1-5 11, 1-523, 1-535, 1-282, 1-464, 1-476, 1-488, 1-500, 1-512, 1-524, 1-536, [-283, 1-465, 1-477, 1-489, 1-50 1, 1-5 13, 1-525, 1-537, 1-284, 1-285, 1-466, 1-467, 1-478, 1-479, 1-490, 1-491, 1-502, 1-503, 1-514, 1-515, 1-526, 1-527, 1-538, 1-539, 1-733, 1-734, 1-735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1-747, 1-748, 1-749, 1-750, 1-815, 1-820, 1-861, 1-1134, 1-1135, 1-1136, 1-1137, 1-1 138, 1-1139, 1-1140, 1-1141, 1-1142, 1-1143, 1-1144, 1-1145, 1-1146, 1-1147, 1-1148, 1-1224,1-1258, 1-1259, 1-1260, 1-1261, 1-1262, 1-1263, 1- 1264, 1-1265, 1-1266, 1-1267, 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1- 1274, 1-1275, 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1963, 1-1993, 1-2470, y:\wpdocs\dg~lmss\981I2\usa\981I2spI .doc -354- 1-2520, 1-2566, 1-2567, 1-2568, 1-2569, 1-2570, 1-2571, 1-2572, 1-2573, 1-2574, 1-2575, 1-2576, 1-2577, 1-2578, 1-2657, 1-2665, 1-2667 and 1-2669.

The following compounds are further preferred, that is Compounds No.: 1-46, 1-47, 1-48, 1-49, 1-50, 1-71, 1-271, 1-496, 1-539, 1-733, 1-738, 1-739, 1-740, 1-741, 1-742, 1-815, 1-820, 1-861, 1-1 135, 1-1 145, 1-1224, 1-1258, 1-1260, 1-1275, 1-1276, 1-1280, 1-1963, 1-1993, 1-2470, 1-2520, 1-2567, 1-2657, 1-2665, 1-2667 and 1-2669.

The following compounds are particularly preferred, that is Compounds No.: 1-49, 1-271, 1-496, 1-539, 1-733, 1-738, 1-739, 1-740, 1-741, 1-742, 1-820, 1-861, 1-1135, 1-1224, 1-1258, 1-1260, 1-1275, 1-1963, 1-2470, 1-2520, 1-2567, 1-2657, 1-2665, 1-2667 and 1-2669.

The most preferred compounds are [5 1,2D ithio lan 3 yl)pentanoyl]methanesulfonaide (Compound No. 1-496); Methyl 3 1,2-dithiolan-3-yl)buty1]ureidoacetate (Compound No. 1-739); 1,2-Dithiolan-3-yl)butyllureido} propionic acid (Compound No. 1-740); 15 Methyl 3-[4-(1I,2-dithiolan-3-yl)butyllureido }propionate (Compound No.

1-742); Ethyl 3-[4-(1I,2-dithiolan-3-yl)butyl]- I -methylureidoacetate (Compound No. 1-820 ethyl ester); and N-[5-(1I,2-Djthiolan-3-yl)pentyl]methaInesulfonamide (Compound No. 1-2470); and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared by a variety of methods well known for the preparation of compounds of this general type. For example, they may be prepared by the following Methods A to G.

y:\wpdocs\dgt.mss\98 12\usa\98 12spl .doc t> f- 4 r- -355- Method A In this Method, a compound of formula (II) is reacted with a compound of formula (III), to give a compound of formula which is a compound of formula (I) in which the meanings of A and B are somewhat restricted.

Reaction Scheme A: /(CH2)k-A 1 B l

H

S I* ,1 Step Al

Y-R

1

S-S

)m

(II)

(CH

2 )k-A 1

-B

1

-R

S-S

(Ia) (0)m (0)n In the above formulae: k, m and n are as defined above; A' represents any of the groups defined above for A, other than the groups of formula -CO-O- and -N(R 2 [wherein R 2 is as defined above]; B' represents a group of formula -N(R or -N(R [wherein R 5 and R 6 are as defined above]; and Y represents a group to be eliminated.

y:\wpdocs\dgtmss\9812\usa\981 2spl.doc -356- There is no particular restriction on the group to be eliminated, provided that it can be eliminated as a nucleophilic residue, and examples of such groups are well known to those skilled in the art. Specific examples of such groups include: halogen atoms, such as the chlorine, bromine and iodine atoms trihalomethyl groups, such as the trichloromethyl group; lower alkanesulfonyloxy groups, such as the methanesulfonyloxy and ethanesulfonyloxy groups; lower haloalkanesulfonyloxy groups, such as the trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; and 10 arylsulfonyloxy groups, such as the benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy groups.

Of these, a halogen atom or an alkanesulfonyl group is preferred.

Step Al In this Step, a dithiolan derivative of formula (Ia) is prepared by reacting a 15 compound of formula (II) with a compound of formula (III) in a solvent in the presence of a base.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, N,N-dimethyly:\wpdocs\dgtms\98 12\usa\9812sp I .doc -357acetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; and sulfones, such as sulfolane. Of these, we prefer the ketones, ethers and amides, more preferably acetone, tetrahydrofuran, dimethylformamide and N,N-dimethylacetarnide.

There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: inorganic bases, such as alkali metal carbonates (for example sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate), alkali metal hydrogencarbonates (for example sodium hydrogencarbonate, potassium *i 10 hydrogencarbonate or lithium hydrogencarbonate), alkali metal hydrides (for example lithium hydride, sodium hydride or potassium hydride), alkali metal or alkaline earth metal hydroxides (for example sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) and alkali metal fluorides (for example sodium fluoride or potassium fluoride); and alkali metal alkoxides, such as sodium methoxide, 15 sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or o lithium methoxide. Of these, the alkali metal carbonates, alkali metal hydrides and alkali metal alkoxides are preferred, and potassium carbonate, sodium hydride and potassium t-butoxide are most preferred.

The reaction can take place over a wide range of temperatures, and the precise 20 reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20°C to 100 0 C, more preferably from 0°C to 50 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 24 hours, more preferably from 30 minutes to 12 hours, will usually suffice.

y:\wpdocs\dgt_mss\9812\usa\9812sp I.doc 358 This demonstrates the preparation of a compound of formula that is a compound of formula in which A represents an oxygen atom, or a group of formula -N(R 2)CO-, -N(R 2)S0 2 -ON(R2)CO-, -ON(R )S02-, -N(R 2)N(R )CO-, -N(R 2)N(R')S0 2 -N(R )CON(R 3)N(R 4 -N(R2)CON(R 3)CO- or -N(R )CON(R )S0 2 [wherein R R 3 and R 4 are as defined above].

Reaction Scheme B:

(CH

2 )k-Y Step B I

H-A

2

-B-R

1

S-SM

0 )m (O)n (IV) (CHA-A -B-Rl

S-S

In the above formulae: B, R Y, k, mn and n are as defined above; and A 2represents an oxygen atom, or a group of formula -N(R2)CO-, -N(R -ON(R 2)CO-, -ON(R )S02-, -N(R2)N(R )CO-, -N(R 2)N(R 3 )S0 2 -N(R 2)CON(R )N(R 4 -N(R2 )CON(R3)CO- or -N(R 2)CON(R 3)S02- [wherein R2, R 3and R4 are as defined above].

y:\wpdocs\dgt~mss\98 12\usa\981I2sp I .do -359- In this Step, a dithiolan derivative of formula (Ib) is prepared by reacting a compound of formula (IV) with a compound of formula in a solvent in the presence of a base. The reaction is essentially the same as that described above in Step Al, and may be carried out using the same solvents, bases and reaction conditions.

Method C This demonstrates the preparation of a compound of formula that is a compound of formula in which A represents a group of formula -N(R 2

)CO-,

-CON(R 2)N(R -CON(R 2)CO_, -CON(R 2)S02-, -0-C0% .10 -ON(R 2 -ON(R 2 )S0 2 _,-0.O.CON(R 2

)NQR

3 O0CON(R 2

)CO_'

~~-O-CON(R

2 )S0 1 -CO-CON(Rh)N(R' -CO-CON(R C-

-CO-CON(R

2 ')S0 2 -N(R 2 )CO-CO-, -N(R 2)N(R -N(R )N(R )S02-, -N(R 2)CON(R )N(R 4 -N(R 2)CON(R )CO- or -N(R 2)CON(R 3)S02- [wherein R 2, R 3and R 4are as defined above], and B represents a single bond.

Reaction Scheme C: H k D H Y E R S t e p C l I S-S (VII) (O)m (VI)

(CH

2 'I 0) (Ic) (O)m (O n y:\wpdocs\dgtmffss\981 2\usa\981 2spI .doc -360- In the above formulae: R k, m and n are as defined above, D' represents an oxygen atom, or a group of formula -N(R 2

-CON(R

2

-ON(R

2

-O-CON(R

2

-N(R

2

)N(R

3 or -N(R 2

)CON(R

3 [wherein

R

2 and R 3 are as defined above], E' represents a carbonyl group, a sulfonyl group or a group of formula -COCO-, and Y' represents a group to be eliminated, as in the definition ofY; however, the imidazolyl group, or an active ester residue, including acyloxy groups, such as 10 the acetoxy group, or alkoxyacyloxy groups, such as the methoxyacetoxy group, are preferred.

Step C1 In this Step, a dithiolan derivative of formula (Ic) is prepared by acylating or o sulfonylating a compound of formula (VI) with a compound of formula (VII) in a 15 solvent in the presence of a base.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Of these, the aromatic hydrocarbons, halogenated y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -361hydrocarbons, ethers and amides are preferred, and halogenated hydrocarbons, ethers and amides are more preferred.

There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methyldicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo- 10 [2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), of these, triethylamine and diisopropylethylamine are preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or 15 reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 0 C to 100 0 C, more preferably from 0°C to 80 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a 20 period of from 5 minutes to 2 days, more preferably from 20 minutes to 1 day, will usually suffice.

As an alternative, where the compound of formula (VI) is reacted with a compound of formula (VII) in which E' represents a carbonyl group, the reaction may also be accomplished using a compound of formula HOOC-R' (wherein R' is as defined above) by reacting the compound of formula (VI) with the compound of formula (VII) using a condensing agent in a solvent in the presence or absence of a base.

There is no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type may equally be used here. Examples of such condensing agents include: y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc 362 a combination of a phosphoric acid ester, such as diethyl cyanophosphate or diphenyiphosphoryl azide, and the base described below; a carbodlimide, such as I ,3-dicyclohexylcarbodiimide, 1 ,3-diisopropylcarbodiimide or I -ethy1-3(3dimethylaminopropyl)carbodiimide; a combination of one or more of the above carbodimides and the base described below; a combination of one or more of the above carbodiimides and an N-hydroxy compound, such as N-hydroxysuccinimide, 1 -hydroxybenzotfiazole or N-hydroxy-5 -norbomnene- 2,3-dicarboxyimide; a combination of a disulfide, such as 2,2'-dipyridyl disulfide or 2,2'-dibenzo- 00000: 10 thiazolyl disulfide, and a phosphine, such as triphenyiphosphine or tributyiphosphine; 0 a carbonate, such as N,N'-disuccinimidyl carbonate, di-2-pyridyl carbonate or SS-bis( 1 -phenyl- I H-tetrazol-5-y1)dithiocarbonate; a phosphinic chloride, such as N,l' -bis(2-oxo-3 -oxazolidinyl)phosphinic ,chloride; an oxalate, such as N'-dsuccinimidyl oxalate, Nl,N'-diphthalimide oxalate, N,N' -bis(5-norbornene-2,3-dicarboxyimidyl) oxalate, 1,1' -bis(benzotriazolyi) oxalate, 1,1 '-bis(6-chlorobenzotniazolyl) oxalate or 1,1' -bis(6-trifluoromethylbenzotriazolyl) 0: 0.oxalate; a combination of one or more of the above phosphines and an azodicarboxylic acid ester, such as diethyl azodicarboxylate, or an azodicarboxylic amide, such as 1,1 '-(azodicarbonyl)dipiperidine; a combination of one or more of the above phosphines and the base described below; an N-lower alkyl-5-arylisoxazolium-3'-sulfonate, such as N-ethyl-5-phenylisoxazolium-3 '-sulfonate; a diheteroaryldiselenide, such as di-2-pyridyl diselenide; an arylsulfonyltriazolide, such as p-nitrobenzenesulfonyltriazolide; y:\wpdocs\dgtrniss\981 2\usa\981I2spl .doc -363- (11) a 2-halo-i-lower alkylpyridinium halide, such as 2-chloro-1-methylpyridinium iodide; (12) an imidazole, such as 1,1'-oxalyldiimidazole or N,'-carbonyldiimidazole; (13) a 3-lower alkyl-2-halobenzothiazolium fluoroborate such as 3-ethyl-2-chloro-benzothiazolium fluoroborate; (14) a 3-lower alkyl-benzothiazole-2-serone, such as 3-methyl-benzothiazol-2-serone; a phosphate, such as phenyldichlorophosphate or polyphosphate ester; (16) a halosulfonyl isocyanate, such as chlorosulfonyl isocyanate; (17) a halosilane, such as trimethylsilyl chloride or triethylsilyl chloride; 4* 10 (18) a combination of a lower alkanesulfonyl halide, such as methanesulfonyl chloride and the base described below; (19) an N,N,N',N'-tetra lower alkylhaloformamidium chloride, such as N,N,N',N'-tetramethylchloroformamidium chloride; and (20) a combination of a lower alkyloxycarbonyl halide, such as ethyl chlorocarbonate and the base described below; preferably the above (12) and The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aliphatic hydrocarbons, such as hexane and heptane; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and y:\wpdocs\dgt_mss\9812\usa\9812sp I.doc SW 364 isobutyronitrile; and amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(Nh -dimethylamino)pyridine, 2;6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.

If desired, 4-(N,N-dimethylamino)pyridine and 4-pyrrolidinopyridine can be *combined with other bases and used in a catalytic amount. Also, in order to carry out the reaction more effectively, a dehydrating agent such as a molecular sieve, a quaternary ammonium salt (for example benzyltriethylammonium chloride or 15 tetrabutylammonium chloride), a crown ether, such as dibenzo-18-crown-6, or an acid trapping agent, such as 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one, can be added to the reaction mixture.

The reaction can take place over a wide range of temperatures, and the precise •reaction temperature is not critical to the invention. The preferred reaction temperature 20 will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 0 C to 80 0 C, more preferably from 0 C to room temperature.

The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 3 days, more preferably from 30 minutes to 1 day, will usually suffice.

Method D This demonstrates the preparation of a compound of formula that is a compound of formula in which A represents a carbonyl group, or a group of y:\wpdocs\dgtmss\9812\usa\9812spl.doc 365 formula -CON(R 2

)N(R

3

-CON(R

2

)CO-,

-CO-CON(R 2

)N(R

3 -CO-CON(R 2

)CO-

and R 3 are as defined above].

-CON(R 2 )S0 2

-CO-O-,

or -CO-CON(R 2)S02- [wherein R 2 Reaction Scheme D: (CH2

D

2

-Y'

S-S

0 )m (O)n (VIII)

H-E

2

-B-R

1

(IX)

Step DlI (CH 2 )k-D 2

-E

2 -B-Rl

S-S

In the above formulae: B, R 1, k' M and ]a are as defined above, D2represents a carbonyl group or a group of formula -CO-GO-, and E 2 represents an oxygen atom, or a group of formula -N(R 2

)N(R

3

)CO-,

-N(R 2 )CO- or -N(R 2)S02- [wherein R 2and R 3are as defined above].

Ste1D In this Step, a dithiolan derivative of formula (Id) is prepared by acylating a compound of formula (IX) with a compound of formula (VIII) in a solvent in the presence of a base. The reaction is essentially the same as that described above in Step Cl1, and may be carried out using the same solvents, bases and reaction conditions.

y:\wpdocs\dgtms\981I2\usa\9 8 12 sp I .do -366- Alternatively, the dithiolan derivative of formula (Id) can be prepared by reacting a compound of formula (VIII') with the compound of formula (IX) using a condensing agent in a solvent in the presence or absence of a base.

(CH 2 )k-D 2

-OH

S-S

(0)m (O)n (VIII') (wherein D k, m and n are as defined above.) The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: 10 aliphatic hydrocarbons, such as hexane and heptane; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 15 dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.

y:\wpdocs\dgt_mss\9812\usa\9812sp I.doc -367- If desired 4-(N,N-dimethylamino)pyridine and 4-pyrrolidinopyridine can be combined with other bases and used in a catalytic amount. Also, in order to carry out the reaction more effectively, a dehydrating agent, such as a molecular sieve, a quaternary ammonium salt (for example benzyltriethylammonium chloride or tetrabutylammonium chloride), a crown ether, such as dibenzo-18-crown-6, or an acid trapping agent, such as 3,4-dihydro-2H-pyrido[ 1,2-a]pyrimidin-2-one, can be added to the reaction mixture.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 0 C to 80 0 C, more preferably from 0°C to room temperature.

The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 3 days, more preferably from 30 minutes to 1 day, will usually suffice.

Method

E

*oooo This demonstrates the preparation of a compound of formula that is a compound of formula in which: A represents a group of formula -N(R 2 )CO- [wherein R 2 represents a hydrogen atom], and B represents a group of formula -N(R 5 or -N(R )N(R 6 [wherein R 5 and R 6 are as defined above].

y:\wpdocs\dgt_nss\9812\usa\981 2 spI .doc -368- Reaction Scheme E:

(CH

2 )k-COOH

S-S

(0) m (X) Step El

(CH

2 )k-NCO

S-S

(0)m (O)n (XI) Step E2

H-B

1

-R

1

(XII)

HO

(CH

2 )k-N-C-B

-R

S-S

(Ie) (O)m (O)n In the above formulae: R 1 k, m and n are as defined above.

Step El In this Step, an isocyanic acid ester of formula (XI) is prepared by azidating the carboxy group of a compound of formula in a solvent in the presence or absence of a catalyst to obtain an acid azide compound and then heating it.

The azidation reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride and chloroform; ethers, such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; nitriles, such as acetonitrile; and amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

y:\wpdocs\dgtmss\981 2\usa\9812sp .doc -369- Of these, we prefer the aromatic hydrocarbons, the halogenated hydrocarbons and the ethers.

There is likewise no particular restriction on the nature of the azidation agents used, and any azidation agent commonly used in reactions of this type may equally be used here. Examples of such azidation agents include: diarylphosphoryl azide derivatives, such as diphenylphosphoryl azide; trialkylsilyl azides, such as trimethylsilyl azide or triethylsilyl azide; and alkali metal salt azides, such as sodium azide, potassium azide or lithium azide. Of these, we prefer the diarylphosphoryl azide derivatives.

10 There is likewise no particular restriction on the nature of the catalysts used, and any catalyst commonly used in reactions of this type may equally be used here.

Examples of such catalysts include: Lewis acids, such as trialkylsilyl triflates (e.g.

trimethylsilyl triflate and triethylsilyl triflate), trifluoroborane etherate, aluminum chloride and zinc chloride; and organic bases, such as N-methylmorpholine, 15 triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di-t-butyl-4-methylpyidine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.

The reaction can take place over a wide range of temperatures, and the precise 20 reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from 20°C to 180 0 C, more preferably from 50 0 C to 150 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 24 hours, more preferably from 30 minutes to 8 hours, will usually suffice.

y:\wpdocs\dgt.mss\981 2\usa\981 2sp I.doc -370- Step E2 In this Step, a dithiolan derivative of formula (Ie) is prepared by reacting an isocyanic acid ester (XI) with a compound of formula (XII) in a solvent.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 10 dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, 15 h,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; and sulfones, T. *such as sulfolane. Of these, we prefer the aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles and amides, more preferably the aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles and amides.

20 The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 0 C to 100 0 C, more preferably from 0°C to 80 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 2 days, more preferably from 10 minutes to 1 day, will usually suffice.

y:\wpdocs\dgt_mss\9812\usa\9812spl.doc -371 Alternatively, the compound of formula in which A represents a group of formula -N(R2)CON(R )N(R 4 -N(R2)CON(R3)CO- or -N(R )CON(R )SO,- [wherein R 2 represents a hydrogen atom, and R 3 and R 4 are as defined above] can be prepared by reacting the above isocyanic acid ester of formula (XI) with a compound of formula: H-D 3 {wherein B and R' are as defined above, and D 3 represents a group of formula -N(R 3

)N(R

4

-N(R

3 )CO- or -N(R 3

)SO

2 [wherein R 3 and

R

4 are as defined above]}, following the same procedure as described above.

A compound of formula in which A represents a group of formula -N(R )CO- (wherein R 2 represents a hydrogen atom), B represents a single bond, and R' represents a group OR 7 (wherein R 7 is as defined above) can be prepared by reacting the above isocyanic acid ester of formula (XI) with a compound of formula: HOR 7 (wherein R is as defined above), following the same procedure as described above.

A hydrogen atom of an amino, amide or imide group can be replaced by another group by reacting a compound of formula in which R 2 R R 4 R and/or R 6 represent a hydrogen atom with a compound of formula Y-R s (in which Y is as defined above and R 8 represents a group other than a hydrogen atom in the definition of R 2

R

3

R

4 and R 6 according to the above Method A, or by alkylation using a combination of an alcohol and a carbodiimide, such as dicyclohexylcarbodiimide. For example, after the dithiolan derivative of the present invention is synthesized according S. 20 to the above Method E, a hydrogen atom of an amide group in the compound can be replaced by another group by these processes.

Method F This demonstrates the preparation of a compound of formula that is a compound of formula in which: A represents a group of formula -N(R 2

-N(R

2

)CS-,

-CON(R2)CO-, -CON(R2)CS-, -ON(R2)CO-, -O-CON(R 2

)CO-,

-N(R

2

)N(R

3 )CO- or -N(R 2

)CON(R

3 )CO- [wherein R 2 and R 3 are as defined above], y:\wpdocs\dgtmss\98 12\usa\981 2sp I .doc -372- B represents a single bond or a group of formula -N(R 5 [wherein R represents the groups other than hydrogen in the definition of R and R' represents a group as defined above other than hydrogen.

Reaction Scheme F: (CH2)k-D 1

-H

1' Step F1

G=CN-E

3

R

1 S-S (XIII) I 0 )m (O)n (V) G G

(CH

2 )k-D-C-N-E 3

R

1

H

S-S

(O)n (If) (0)m (0)n In the above formulae: D k, m and n are as defined above,

E

3 represents a single bond or a group of formula [wherein R5 is as defined above], G represents an oxygen atom or a sulfur atom, and

R

1 represents a group as defined above for R 1 other than hydrogen.

Step F1 In this Step, a dithiolan derivative of formula (If) is prepared by reacting an isocyanic acid ester or an isothiocyanic acid ester of formula (XIII) with a compound y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -373of formula The reaction is essentially the same as that described above in Step E2, and may be carried out using the same solvents, bases and reaction coAditions.

The compound of formula (If) wherein E 3 represents a single bond and R' represents a hydrogen atom can also be prepared by carrying out the reaction using a compound of formula G=CN-R 9 [wherein G is as defined above and R 9 represents a silyl group, such as a tri-lower alkylsilyl group, e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl or triisopropylsilyl, or a tri-lower alkylsilyl group substituted with 1- or 2 aryl groups, such as a diphenylmethylsilyl, diphenylbutylsilyl, 10 diphenylisopropylsilyl or phenyldiisopropylsilyl group] instead of the isocyanic acid ester or the isothiocyanic acid ester of formula (XIII).

Where the dithiolan ring is subjected to ring-opening in the course of carrying out the reactions described in Methods A to F to produce a dithiol compound, a dithiolan derivative can be obtained by oxidizing the ring-opened compound to form a 15 disulfide bond. The oxidation reaction is usually carried out using an oxidizing agent in the presence of a solvent.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Preferred solvents include watercontaining organic solvents. Such organic solvent include: ketones, such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; nitriles, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; and alcohols, such as methanol or ethanol.

There is likewise no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type may equally be used here provided it can form a disulfide bond. Examples of such oxidizing agents include ferric chloride.

y:\wpdocs\dgt_mss\9812\usa\9812sp .doc -374- The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from 0 to 150 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 24 hours will usually suffice.

Method G This illustrates the preparation of a compound of formula in which at least one ofm and n is 1 or 2, that is a compound of formula (Ig) from a compound of formula in which m and n are both zero, that is a compound of formula Reaction Scheme G: SCH 2 )k-A B-R 1

(CH

2 k

A-B-R

1" r 1 -Step G--s

S-S

S-S (Ig) (O)n In the above formulae: A, B, R' and k are as defined above; and m' and n' are as defined above for m and n provided that at least one is not 0.

Step G1 In this Step, a dithiolan derivative of formula (Ig) is prepared by oxidizing a compound of formula [a compound of formula wherein n and m are 0].

y:\wpdocs\dgt~mss\98 12\usa\981 2 sp .doc -375- There is no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type may equally be used here.

provided that it is capable of oxidising a sulfide to a sulfoxide or a sulfone. Examples of such oxidizing agents include: hydroperoxides, such as hydrogen peroxide, t-butyl hydroperoxide or pentyl hydroperoxide; dialkyl peroxides, such as di-t-butyl peroxide; peracids, such as perbenzoic acid, m-chloroperbenzoic acid or peracetic acid; peracid esters, such as methyl perbenzoate; and diacyl peroxides, such as benzoyl peroxide. Of these, we particularly prefer hydrogen peroxide, m-chloroperbenzoic acid and t-butyl hydroperoxide.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: *fe aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated 15 hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and 20 isobutyronitrile; amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane; alcohols, such as methanol and ethanol; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; and water. Of these, we prefer the aromatic hydrocarbons, halogenated hydrocarbons, ketones, amides, alcohols and water, more preferably the halogenated hydrocarbons, ketones, amides, alcohols and water.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the ifnvention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a y:\wpdocs\dgt_mss\9 8 12\usa\9812sp I .doc -376temperature of from -50 to 100 0 C, more preferably from -20 to 50 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 2 days, more preferably from 30 minutes to 12 hours, will usually suffice.

After completion of each of the above reactions, the desired compound may be recovered from the reaction mixture by conventional methods.

For example, the desired compound may be obtained by: suitably neutralising the 10 reaction mixture; removing insolubles by filtration if insolubles exist; adding a water-immiscible organic solvent, such as ethyl acetate to the reaction mixture; washing with water or another suitable solvent; separating the organic layer containing the desired compound; drying it over a drying agent, such as anhydrous sodium sulfate or anhydrous magnesium sulfate; and removing the solvent, e.g. by evaporation.

The compound thus obtained can be separated and purified, if necessary, by appropriately combining conventional methods, for example, recrystallization, reprecipitation or other methods commonly used in the separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina or magnesium-silica gel type Florisil; a method using a synthesized adsorbent such as partition column chromatography using a carrier such as Sephadex LH-20 (trade mark, manufactured by Pharmacia Co, Ltd.), Amberlite XAD-11 (trade mark, manufactured by Rohm and Haas Co. Ltd.) and Diaion (trade mark, manufactured by Mitsubishi Kasei Corporation), a method using an ion exchange chromatogram, or normal phase-or reverse phase column chromatography using silica gel or alkylated silica gel (preferably high performance liquid chromatography), and eluting with a suitable eluent.

The starting materials in Methods A to G are known compounds or are compounds synthesized from known compound by conventional methods. For example, the amino derivative of formula which is a starting material in Method A, Method C and Method F can be prepared by the following Method H.

y:\wpdocs\dgtmss\98 1 2\usa\981 2sp I.doc -377- Method H Reaction Scheme H: (CH2)--OH

S-S

(XIV)

(0)m (0)n Step H1

(XV)

o ((CH2)k

S-S

(0)m (0)n Step H2

(XVI)

(CH

2 )k-NH 2

S-S

m (Ih) In the above formulae: k, m and n are as defined above.

Step H1 In this Step, a phthalimide derivative of formula (XVI) is prepared by carrying out a Mitsunobu reaction between a compound of formula (XIV) and phthalimide of formula (XV).

There is no particular restriction on the nature of the reagents used in the Mitsunobu reaction, and any reagent commonly used in reactions of this type may equally be used here. Examples of such reagents include: a combination of an azo compound, such as a di-lower alkyl azodicarboxylate (for example dimethyl y:\wpdocs\dgt_mss\9812\usa\9812spI.doc t.~,-tflr'tAt2.~.. -378azodicarboxylate, diethyl azodicarboxylate or diisopropyl azodicarboxylate) or an azodicarboxamide [such as 1,l'-(azodicarbonyl)dipiperidine] and a phosphine, such as a triarylphosphine (for example triphenylphosphine) or a tri-lower alkyl phosphine (for example tributylphosphine), more particularly a combination of a di-lower alkyl azodicarboxylate and a triarylphosphine, most preferably a combination of dimethyl azodicarboxylate and triphenylphosphine.

The reaction is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can 10 dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl 15 ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; and sulfoxides, such as dimethyl sulfoxide and sulfolane. Of these, we prefer the aromatic hydrocarbons and 20 ethers.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 to 100 0 C, more preferably from 0 to 50 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 3 days, more preferably from 30 minutes to 12 hours, will usually suffice.

y:\wpdocs\dgtms\98 1 2\usa\981 2sp I .doc -379- Step H2 In this Step, an amino derivative of formula (Ih) is prepared by reacting the phthalimide derivative of formula (XVI) with butylamine or hydrazine in a solvent.

For example it may be accomplished by reacting the phthalimide derivative of formula (XVI) with butylamine in methanol at room temperature for 6 hours.

Since the dithiolan derivatives have the effect of increasing the activity of glutathione reductase, a composition which increases the activity of glutathione reductase, containing those compounds or pharmaceutically acceptable salts thereof can be used for the prevention or treatment of diseases resulting from oxidative stress.

10 Examples of diseases resulting from oxidative stress are disease or pathologic states including damage caused by alcohol abuse, exposure to xenobiotic agents or radiation; intracellular oxidative states caused by hepatic diseases; intoxication from drugs and chemical agents carcinostats including platinum chelate, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane); intoxication from heavy metals; disorders of the nervous system including brain and neurone degenerative disorders cerebral ischemia, cerebral ictus, hypoglycemia, epileptic attacks, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea); diseases related to an altered functionality of the immune system, in particular tumour immunotherapy; infertility, in particular male infertility; coronary heart disease; ophthalmologic disorders such as cataract, retinopathy of prematurity and siderosis; pulmonary diseases such as idiopathic pulmonary fibrosis, adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis; chronic renal failure; gastric ulcer; canceration and metastases of cancer including colorectal cancer; diabetes; hepatocyte necrosis and apoptosis including ethanol-induced hepatopathy; viral diseases including influenza, hepatitis B and HIV; abnormalities of blood or blood vessels such as Fanconi's anemia, septicemia, enhanced permeability through blood vessels and leukocyte adherence; various malformations such as Down's syndrome, Duchenne muscular dystrophy, Becker dystrophy, Dubin-Johnson-Spring syndrome and favism; and inflammatory diseases such as nephritis, pancreatitis, dermatitis, fatigue and rheumatism. In particular, the dithiolan derivatives and pharmaceutically acceptable y:\wpdocs\dgtmss\98 1 2\usa\981 2sp I.doc -380salts thereof of the present invention are useful for the prevention or treatment of diseases or pathologic states such as damage caused by radiation, intracellhlar oxidative states caused by hepatic diseases, intoxication side effects) from carcinostats including platinum chelate, disorders of the nervous system, cataract, diabetes, hepatocyte necrosis and apoptosis, viral diseases, and inflammatory diseases.

Among the above-described diseases resulting from oxidative stress, there are some diseases where the effects are irreversible, once they have occurred. A therapeutic agent for such a disease means a medicament which prevents or delays the progress of the disease.

10 The dithiolan derivatives of formula or pharmaceutically acceptable salts thereof of the present invention can be used together with a medicament which is known as a preventive agent or therapeutic agent for a disease listed above as the diseases resulting from oxidative stress and may show a synergistic effect.

Cyanamide, disulfiram, adenine and cysteine are known as medicaments for treating the damage caused by alcohol abuse, exposure to xenobiotic agents or radiation; aminoethylsulfonic acid, protoporphyrin disodium and diisopropylamine dichloroacetate are known as medicaments for treating intracellular oxidative states caused by hepatic diseases; glutathione, dimercaprol, and calcium disodium edetate are known as medicaments for treating intoxication from drugs and chemical agents (e.g.

carcinostats including platinum chelate, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane) or for treating intoxication from heavy metals; phenobarbital, phenytoin, bromocriptine mesylate, sulpiride, sodium valproate, haloperidol, levodopa-carbidopa, idebenone and aniracetam are known as medicaments for treating disorders of the nervous system including brain and neurone degenerative disorders cerebral ischemia, cerebral ictus, hypoglycemia, epileptic attacks, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea); cyclophosphamide, interferon-a and interferon-p are known as medicaments for treating diseases related to an altered functionality of the immune system, in particular tumour immuriotherapy; sildenafil is known as a medicament for treating infertility, in particular male infertility; digitoxin and digoxin are known as medicaments for treating coronary heart disease; pirenoxine is known as a medicament y:\wpdocs\dgtmss\981 2\usa\981 2sp I .doc -381 for treating ophthalmologic disorders such as cataract, retinopathy of prematurity and siderosis; theophylline, ketotifen fumarate, epinastine hydrochloride, pranrukast and suplatast tosylate are known as medicaments for treating pulmonary diseases such as idiopathic pulmonary fibrosis, adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis; furosemide, etacrynic acid and bumetanide are known as medicaments for treating chronic renal failure; teprenone, rebamipide, ecabet sodium, plaunotol, famotidine, ranitidine hydrochloride and lansoprazole are known as medicaments for treating gastric ulcer; BB-2516 and AG3340 are known to be useful against canceration and metastases of cancer including colorectal cancer; epalrestat, voglibose, acarbose, insulin, glibenclamide and troglitazone are known as medicaments for treating diabetes; aminoethylsulfonic acid, protoporphyrin disodium and diisopropylamine dichloroacetate are known as medicaments for treating hepatocyte necrosis and apoptosis including ethanol-induced hepatopathy; acyclovir, zidovudine, interferon-a, interferon-p and interferon-y are known as medicaments for treating viral diseases including influenza, hepatitis B and HIV; erythropoietin derivatives are known as medicaments for treating abnormalities of the blood or blood vessels such as Fanconi's anemia, septicemia, enhanced permeability through blood vessels and leukocyte adherence; fenipentol, camostat mesylate, indomethacin, loxoprofen sodium and 20 diclofenac sodium are known as medicamenst for treating inflammatory diseases such as nephritis, pancreatitis, dermatitis, fatigue and rheumatism.

The compounds of the present invention can be administered in any conventional pharmaceutical formulation, the nature of which will depend on the patient and the intended route of administration. For example for oral administration, suitable formulations include tablets, capsules, granules, powders or syrups. For parenteral administration suitable formulations include injections or suppositories. These formulations can be prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrating agents, stabilizers, corrigents and diluents.

Examples of suitable excipients include organic excipients, for example: sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives y:\wpdocs\dgtmss\98 1 2\usa\981 2sp I .doc -382such as corn starch, potato starch, a-starch, dextrin or carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally bridged carboxymethylcellulose sodium; gum arabic; dextran; and Pullulan; inorganic excipients including silicate derivatives such as light silicic acid anhydride, synthetic aluminium silicate or magnesium meta-silicic acid aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.

Examples of suitable lubricants include stearic acid, metal stearates such as 10 calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic acid anhydride or silicic acid hydrate; and the foregoing starch derivatives.

Examples of suitable binders include polyvinylpyrrolidone, Macrogol, and similar compounds to the excipients described above.

Examples of suitable disintegrating agents include similar compounds to the excipients described above; and chemically modified starches or celluloses such as crosscarmelose sodium, sodium carboxymethylstarch or bridged polyvinylpyrrolidone.

Examples of suitable stabilisers include paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of suitable corrigents include sweeteners, vinegar or perfumes such as those conventionally used.

Moreover, since the dithiolan derivative or the pharmaceutically acceptable salt thereof of the present invention is less stimulating for the eyes, it can be topically administered to the eyes. Suitable formulations for the topical administration to the eyes include solutions, suspensions, gels, ointments and solid inserting agents.

y:\wpdocs\dgtmss\981 2\usa\981 2sp I .doc -383 The formulation of these compositions for topical administration may contain the dithiolan derivative or the pharmaceutically acceptable salt thereof at a level of from 0.001% (preferably 0.01%) as a lower limit to 10% (preferably as an upper limit.

The pharmaceutical formulation containing an active compound can, if desired, be mixed with a non-toxic inorganic or organic carrier for pharmaceuticals.

Typical pharmaceutically acceptable carriers include water, a mixture of water and a water-miscible solvent such as a lower alkanol or aralkanol, a vegetable oil, polyalkylene glycol, a jelly using a petroleum as a base material, ethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other acceptable carriers which can be preferably used. The formulation may contain nontoxic auxiliary substances such as an emulsifier, a preservative, a wetting agent and an excipient, for example, polyethylene glycol 200, 300, 400 and 600, carbowax 1000, .1500, 4000, 6000 and 10000, p-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, a quaternary ammonium compound (for 15 example, benzetonium chloride or benzalkonium chloride) which are known as compounds having anti-fungal properties at low temperatures and are non-toxic when used, an anti-fungal agent such as a phenyl mercury salt, a buffering component such *.ooo as thimerosal, methyl- and propylparaben, benzyl alcohol, phenylethanol, sodium chloride, sodium borate and sodium acetate, a gluconic acid buffering agent and 20 sorbitan monolaurate, triethanolamine, polyoxyethylenesorbitan monopalmitate, sodium dioctyl sulfosuccinate, monothioglycerol, thiosorbitol and ethylenediaminetetraacetic acid.

Ophthalmological excipients can be used as a desired support medium for the compounds of the present invention and examples include the usual phosphoric acid buffering excipients (for example, a sodium phosphate buffer or a potassium phosphate buffer), isotonic boric acid excipients, isotonic sodium chloride excipients and isotonic sodium borate excipients.

As a further alternative, the pharmaceutical formulation may have the form of a solid insert which remains almost intact after the formulation has been administered, or y:\wpdocs\dgt~nmss\981 2\usa\981 2sp I.doc -384it may also be formulated as a disintegrating insert which dissolves in the tear fluid or is disintegrated by other methods.

The dose of the dithiolan derivative of formula or the pharmaceutically acceptable salt thereof of the present invention will vary, depending upon the condition and age of the patient and the form and route of administration. However, for example, in the case of oral administration, for an adult human patient, it is desirable to administer from 0.1 mg (preferably 1 mg) as a lower limit to 10000 mg (preferably 5000 mg) as an upper limit per day. In the case of intravenous administration, it is desirable to administer from 0.01 mg (preferably 0.1 mg) as a lower limit to 5000 mg 10 (preferably 2000 mg) as an upper limit per day. In the case of topical administration to the eyes, it is desirable to administer from 0.001 mg (preferably 0.01 mg) as a lower limit to 500 mg (preferably 200 mg) as an upper limit per day. All of the above may be administered as a single dose or in divided doses. The dose and dosage regime will depend on the condition of the patient.

15 Pharmaceutical preparations of the present invention are illustrated by the following non-limiting Formulation Examples.

FORMULATION EXAMPLE 1 Powder g of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (the compound of Example 2 hereafter), 895 g of lactose and 100 g of corn starch are mixed by means of a blender to obtain a powder.

FORMULATION EXAMPLE 2 Granules g of N-[5-(1,2-dithiolan-3-yl)pentanoyl]sulfamide (the compound of Example 7 hereafter), 865 g of lactose and 100 g of low substituted hydroxypropylcellulose are mixed. 300 g of a 10% w/v aqueous solution of hydroxypropyl cellulose are then added to the mixture, and then the resulting mixture is kneaded. The mixture is then y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -385granulated using an extruding granulator, after which it is dried to obtain a granule formulation.

FORMULATION EXAMPLE 3 Capsules 5 g of N-[4-(1,2-dithiolan-3-yl)butyl-N'-methylurea (the compound of Example 8 hereafter), 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate are mixed using a V-type mixer. 180 mg of the mixture are then encapsulated in a No. 3 capsule to obtain a capsule formulation.

FORMULATION EXAMPLE 4 S 10 Tablet g of ()-N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (the compound of Example 40 hereafter), 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed by means of a blender.

The mixture is then pelletised by means of a tablet making machine to obtain tablets.

FORMULATION EXAMPLE f Eve drops The following components are mixed: y:\wpdocs\dgt_mss\9812\usa\9812sp .doc -386- (R)-N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (the Compound of Example 0.2 g r r Disodium phosphate 0.716 g Sodium phosphate 0.728 g Sodium chloride 0.400 g Methyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Sterilised purified water q.s.

Sodium hydroxide q.s.

Total 100 ml The pH of the mixture is adjusted to 7.0 and eye drops are prepared by a conventional method.

FORMULATION EXAMPLE 6 Eve drops The following components are mixed: y:\wpdocs\dgtmss\9812\usa\9812sp I .doc -387- (R)-N-[5-(1,2-dithiolan-3-yl)pentanoyl]methane- 0.2 g sulfonamide (the Compound of Example Disodium phosphate 0.716 g Sodium phosphate 0.728 g Sodium chloride 0.400 g Methyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Sterilised purified water q.s.

Ascorbic acid q.s.

Sodium hydroxide q.s.

Total 100 ml The pH of the mixture is adjusted to 7.0 and eye drops are prepared by a conventional method.

BIOLOGICAL ACTIVITY The biological activity of the compounds of the present invention is illustrated by the following Test Examples.

y:\wpdocs\dgt_mss\9812\usa\9812sp I .doc -388- TEST EXAMPLE 1 Measurement of Glutathione Reductase Activity Lens Tissue Culture The test animals were 6 to 8 week old male SD rats (supplier: Nippon SLC). The animals were sacrificed by suffocation by inhalation of carbon dioxide. Both eyeballs of each test animal were then excised. An incision was made in the sclera on the back of the eyeballs, and then the vitreous body and iris-ciliary body were removed, followed by removal of the lens.

a Each lens obtained in this manner was cultured by immersing it in 3 ml of the 10 culture solution described below in a 6-well tissue culture plate (FALCON). Culturing was performed for 72 hours in a CO2 incubator maintained at 37 0 C and 100% humidity in the presence of 5% CO 2 (in air).

Medium 199 (Gibco) containing penicillin (20 units/ml) and streptomycin (20 pg/ml) was used as the control culture solution.

o 15 The test culture solution contained the test compound added to the abovementioned culture solution. The cultured lenses were placed in frozen storage until the time of the test.

Measurement of Glutathione Reductase Activity After homogenising each frozen rat lens in 2 ml of distilled water, the resulting homogenate was separated by centrifugation (10,000 g, 20 minutes) after which the resulting supernatant was used as the enzyme sample.

400 pl of enzyme sample were added to 0.6 ml of phosphate buffer containing 1 mM oxidized glutathione (GSSG) and 100 P.M NADPH. After the mixture had reacted at 25 0 C for 6 minutes, the absorbance of the reaction mixture (at 340 nm: i.e.

OD

34 0nm) was measured. The difference (AOD 340 on between the OD340n m value before reaction and the OD34on, value after completion of the reaction was used as an indicator of glutathione reductase activity.

y:\wpdocs\dgtnmss\98 1 2\usa\981 2sp I.doc -389- The results for the compound of Example 2 are shown in the following Table 4.

Concentration of the compound of AOD 34 o/min/g protein Example 2 (|pM) 06060.

c S 066.

0 0 0 0 0 000 -old 0 0 0 0660 00.: 6060 0 @604 @006 9 6.6.

06t6 6 O 0 66 6 @6 0@ 3.10±0.11 3.24±0.10 3.20±0.09 3.59±0.05 (p<0.05) 3.70±0.08 (p<0.05) 4.16±0.18 (p<0.05) 300 1000 The dithiolan derivatives of the present invention exhibited excellent glutathione 5 reductase activity enhancing effects.

TEXT EXAMPLE 2 Anti-cataract Test The test animals were 6 week old male SD rats (supplier: Nippon SLC). The animals were sacrificed by suffocation by inhalation of carbon dioxide. Both eyeballs of each test animal were then excised. The excised lenses were cultured at 37 0 C for 24 hours in Medium 199 (Gibco) containing 0.05 mg/ml of the test compound and 5 mM hydrogen peroxide. For the control test, excised lenses were cultured at 37 0 C for 24 hours in normal culture liquid (Medium 199, Gibco) or Medium 199 (Gibco) containing 5 mM hydrogen peroxide.

After culturing for 24 hours, the lenses were washed with physiological saline.

Surface moisture was removed by placing the lenses on a piece of filter paper, and then the lenses were placed on a slide glass after which lens turbidity was scored under y:\wpdocs\dgtmss\9812\usa\ 9 812sp I .doc 390 stereomnicroscope from (turbidity degree of the lens cultured in a normal culture medium) to '++"(turbidity degree of the lens cultured in a medium containing hydrogen peroxide). The results are shown in Table Tal Compound of Rat Lens turbidity in 5 m.M Example No. H 2 0 2 24 hours 1 2 2+ 7 :8 4+ 21 43 4+ y:\wpdocs\dgtjniss\981I2\usa\981I2spl .doc 00.

0 0 0:0.

o 391 Table 5 (cont.

Compound of Rat Lens turbidity in 5 mM Example No. H 2 0 2 24 hours

-H-

74 79

-H

86

-H-

103 106 109 118

-H-

123 lipoic acid normal lens without drug HH As can be seen from the above results, the compounds of the present invention substantially improve the opacity of the lens.

y:\wpdocs\dgtmss\981I2\usa\981I2sp I .do 392

EXAMPLES

The present invention is further illustrated by reference to the following nonlimiting Examples.

EXAMPLE 1 N-Acetyl-a-thioctamide (Compound No. 1-271) 0 0 N CH 3 S-S H A mixture of 0.76 g of D,L-tx-thioctamide, 1.5 g of acetic anhydride and 10 ml of pyridine was heated under reflux for 20 hours. The pyridine was then removed from the reaction mixture by distillation under reduced pressure, and water was added to the residue, which was then extracted with ethyl acetate. The extraction solution was washed twice with water and dried over anhydrous magnesium sulfate. 0.76 g of the icrude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography, using a 2 1 by volume mixture ofhexane and ethyl acetate as eluent, to obtain 0.45 g of 3-(4-cyanobutyl)-1,2-dithiolan having [an Rf value of 0.84 (silica gel thin layer chromatography, using a 1 1 by volume mixture of hexane and ethyl acetate as the developing solvent)] as a first component and 0.17 g of the title compound, melting at 67 0 C to 69 0 C as a second component.

EXAMPLE 2 N-15-(1.2-Dithiolan-3-vl)pentanovllmethanesulfonamide (Compound No. 1-496) 0

N-S-CH

3 S-SI II S-S HO y:\wpdacs\dgt.mss\981 2\usa\9812ex .doc 393 0.88 g of sodium hydride (as a 55% by weight dispersion in mineral oil) was washed with hexane, and 20 ml of dimethylformamide and 1.96 g of methanesulfonamide were added to the dispersion at room temperature. The resulting mixture was subjected to ultrasonic treatment for three hours and then left to stand at room temperature overnight, to give reaction mixture Separately, 2.06 g of D,L-a-lipoic acid were dissolved in 20 ml of dimethylformamide, and 1.63 g of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The resulting mixture was then left to stand at room temperature overnight. At the end of this time, the reaction mixture was added 10 dropwise to the above reaction mixture at room temperature, and the mixture was stirred for 7 hours. The reaction mixture was then heated at 130 0 C for 3 hours, after which it was left to cool, and then poured into ice-water. Diluted aqueous hydrochloric acid was added to the mixture to adjust the pH to 5, and the mixture was extracted with ethyl acetate. The extraction solution was washed three times with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 4 1 by volume mixture of ethyl acetate and hexane and then ethyl acetate alone as the eluent, to obtain 0.12 g of the title compound, melting at 87 0 C to 88 0

C.

20 25.0 g of D,L-a-lipoic acid were dissolved in 500 ml of anhydrous dimethylformamide, and 21.57 g of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling, after which the resulting mixture was stirred at room temperature for 2 hours and 30 minutes. 12.65 g of methanesulfonamide and 5.80 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were then added, whilst icecooling, to the reaction mixture, and the mixture was stirred at room temperature for 4 hours and then left to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate.

The extraction solution was washed.with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed y:\wpdocs\dgt.mss\9812\usa\98i2ex .doc 394 by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 1, 2 1 and 3 1 by volume mixtures of ethyl acetate and hexane as eluent, to obtain 19.85 g of the title compound, melting at 0 C to 88 0

C.

EXAMPLE 3 N-[5-(1-Oxo-1.2-dithiolan-3-vl)pentanovllmethanesulfonamide (Compound No. 2-496) *0 0

III

""N-S-CH3 S-S HO '500 mg of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (prepared as described in Example 2) were dissolved in 10 ml of acetone, and 0.44 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the solution, whilst ice-cooling.

The mixture was stirred and then left to stand at room temperature overnight. At the end of this time, a further 0.2 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the reaction mixture, and then the mixture was stirred at room temperature for 30 minutes, and then stirred on an oil bath at 50 0 C for 1 hour. The mixture was then left to stand at room temperature for 3 days, after which it was stirred on an oil bath at 50 0 C for 10 hours; it was then left to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by reverse phase preparative silica gel column chromatography, using 1 3 and 2 3 by volume mixtures of acetonitrile and water as the eluent. The solvent was evaporated from the eluted fraction thus obtained under reduced pressure, and the fraction was lyophilised, to obtain 0.15 g of the title y:\wpdocs\dgtmss\98 12\usa\981 2cx I .doc 395 compound (diastereomer mixture) as a colorless oil having an Rf value of 0.43 (silica gel thin layer chromatography, using a 10 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

EXAMPLE 4 N-[5-(1.2-Dithiolan-3-vl)pentanoyll methanesulfonamide sodium salt (Compound No. 1-496.sodium salt) 750 mg of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (prepared as described in Example 2) were dissolved in 15 ml of ethyl acetate, and 482 mg of sodium 2-ethylhexoate was added to the mixture at room temperature. The mixture 10 was stirred for 2 hours, after which it was left to stand for 2 days at room temperature.

The crystals which precipitated from the reaction mixture were collected by filtration, to obtain 550 mg of the title compound, melting at 202 0 C to 204 0

C.

EXAMPLE Ethyl 5-(1-oxo-1.2-dithiolan-3-yl)pentanoate and ethyl 5-(2-oxo-1.2-dithiolan-3- 15 yl)pentanoate (Compound No. 2-208 and Compound No. 3-208) -0 0 OEt OEt S-S S-S O 0 1.00 g of ,L-a-lipoic acid was dissolved in 20 ml of acetone, and 0.58 g of a 31% w/v aqueous solution of hydrogen peroxide was added to the solution on a dry ice-acetone bath. The mixture was stirred for 2 hours, and it was then left to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under y:\wpdocs\dgtmnss\98 1 2\usa\981 2ex I.doc 396 reduced pressure. 16 ml of anhydrous ethanol and 4 ml of a 4 N solution of hydrogen chloride in ethyl acetate were added to the residue thus obtained, and the mixture was stirred for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography, using 1 1, 2 1 and 3 1 by volume mixtures of ethyl acetate and hexane as eluent, to obtain 0.26 g of ethyl 5-(2-oxo-1,2-dithiolan-3yl)pentanoate having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as the developing solvent) and 0.67 g of ethyl 5-(l-oxo- 1,2-dithiolan-3-yl)pentanoate having an Rf value of 0.29 10 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 6 2-Dithiolan-3-yl)butvll-N'.N'-dimethylurea (Compound No. 1-815) H Me I N N Me S-S 0 1.00 g of D,L-a-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution at room temperature, and then the mixture was stirred on an oil bath at for 2 hours. 0.47 g of dimethylamine hydrochloride was then added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of anhydrous tetrahydrofuran and 0.52 ml of a 50% v/v aqueous solution of dimethylamine were added to the residue thus obtained; the mixture was then left to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate.

The extraction solution was washed with a saturated aqueous solution of sodium y:\wpdocs\dgtmss\9812\usa\981 2exI.doc 397 chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a 9 1 by volume mixture of ethyl acetate and methanol as eluent. The solvent was evaporated from the fraction including the title compound under reduced pressure, and the residue thus obtained was dissolved in dioxane. The solution was lyophilised, to obtain 832 mg of the title compound, melting at 52 0 C to 53 0

C.

EXAMPLE 7 N-[5-(1.2-Dithiolan-3-vl)pentanovylsulfamide (Compound No. 1-539) 0

N-S-NH

2 I II S-S HO mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 421 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling, and then the mixture was stirred at room temperature for 3 hours. 461 mg of sulfamide and 113 mg of sodium hydride (as a 55% w/w dispersion 15 in mineral oil) were then added to the reaction mixture, whilst ice-cooling, and the mixture was stirred for 4 hours and then left to stand at room temperature overnight.

At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 5 to 6, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using a 3 2 and then a 2 1 by volume mixture of ethyl acetate and hexane as the eluent, and the resulting fraction was then recrystallized from a 1 2 1 by volume mixture of ethanol, y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 398 diisopropyl ether and hexane, to obtain 119 mg of the title compound, melting at 141 0 C to 142 0

C.

EXAMPLE 8 N-[4-(1.2-Dithiolan-3-vl)butvl-N'-methylurea (Compound No. 1-733) H

H

I N NMe S-S O 1.00 g of D,L-a-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting .solution at room temperature, after which the resulting mixture was stirred on an oil bath at 80 0 C for 3 hours. The solvent was then removed from the reaction mixture by 10 evaporation under reduced pressure, and 20 ml of tetrahydrofuran and 0.45 ml of a v/v aqueous solution of methylamine were added to the residue thus obtained, whilst ice-cooling, and the mixture was stirred at room temperature for 3 hours and then left to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the 15 residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then 20 1 and 10 1 by volume mixtures of ethyl acetate and methanol as the eluent, to obtain 425 mg of the title compound, melting at 89 0 C to y:\wpdocs\dgt_mss\9812\usa\9812cx I .doc 399 EXAMPLE 9 N-[4-(1.2-Dithiolan-3-vl)butyllurea (Compound No. 1-693)

H

I

NH

2 S-S O 1.00 g of D,L-ao-lipoic acid was dissolved in 20 ml of toluene, and 0.80 ml of 5 triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the solution at room temperature, after which the resulting mixture was stirred on an oil bath at *ooo for 4 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of tetrahydrofuran and 0.49 ml of 28% w/v aqueous ammonia were added to the residue thus obtained. The mixture was then stirred at 10 room temperature for 4 hours, after which it was left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the mixture to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous 9 15 sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 10 1, 4 1 and 3 1 by volume mixtures of ethyl acetate and methanol as eluent, to obtain 340 mg of the title compound, melting at 110 0 C to 113 0

C.

EXAMPLE N-15-(1.2-Dithiolan-3-yl)pentanoyllbenzenesulfonamide (Compound No. 1-457) 0 0O

II

N-S

\I II S-S

HO

y:\wpdocs\dgtmss\9812\usa\9812ex I .doc 400 1.00 g of D,L-a-lipoic acid was dissolved in 20 ml of anhydrous dimethylformamide, and 0.86 g of N,N'-carbonyldiimidazole was added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 2 hours and 30 minutes. 0.83 g of benzenesulfonamide and 0.23 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst icecooling, and the mixture was stirred for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed 10 with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 2, 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as eluent, and then by reverse phase preparative silica gel column chromatography, using 3 7, 1 1 and 7 3 15 by volume mixtures of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure from the fraction containing the title compound, and the '.residue thus obtained was dissolved in dioxane. The resulting solution was oo lyophilised, to obtain 0.61 g of the title compound having an Rf value of 0.51 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and 20 hexane as the developing solvent).

EXAMPLE 11 N-15-(1.2-Dithiolan-3-yl)pentanoyllbenzenesulfonamide sodium salt (Compound No. 1-457.sodium salt) 492 mg of N-[5-(1,2-dithiolan-3-yl)pentanoyl]benzenesulfonamide (prepared as described in Example 10) were dissolved in a mixture of 8 ml of ethyl acetate and 1 ml of tetrahydrofuran, and 283 mg of sodium 2-ethylhexoate were added to the mixture at room temperature. The resulting mixture was stirred for 1 hour and 30 minutes, after which it was left to stand for 2 days. The crystals which precipitated from the reaction y:\wpdocs\dgtss\98 1 2\usa\91 2cx I.doc 401 mixture were collected by filtration to obtain 349 mg of the title compound, melting at 213 0 C to 215 0

C.

EXAMPLE 12 2-Dithiolan-3-vl)pentanoll-N--but arbonlhistidin methyl ester (Compound No. 1-70) 0 COOCH 3 IN N S-S H Boc (Boc is t-butoxycarbonyl) 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 422 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 2 hours. At the end of this time, 629 mg of L-histidine methyl ester dihydrochloride salt foe and 0.70 ml of triethylamine were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred for 1 hour whilst ice-cooling, and then stirred at room temperature for a further 1 hour. The solvent was then removed from the reaction 15 mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then 20 1, 10 1 and 5 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was evaporated from the fraction containing the product under reduced pressure, and then 5 ml of ethyl acetate were added to the residue thus obtained. 0.55 ml of di-t-butyl dicarbonate, 0.33 ml of triethylamine and a catalytic amount of N,N-dimethylaminopyridine were added to the resulting solution, and the mixture was stirred for 1 hour. The reaction mixture was then purified by silica gel column chromatography, using a 2 1 by volume mixture of y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 402 ethyl acetate and hexane and then ethyl acetate alone as eluent. The solvent was evaporated from the fraction containing the title compound under reduced pressure and the residue thus obtained was dissolved in dioxane. The solution was lyophilised, to obtain 844 mg of the title compound having an Rf value of 0.41 (silica gel thin layer chromatography; using ethyl acetate as the developing solvent).

EXAMPLE 13 Na-f5-(1.2-Dithiolan-3-vl)pentanovll histidine (Compound No. 1-71) 0 COOH N N S-S H H 006., 764 mg of N a -[5-(1,2-dithiolan-3-yl)pentanoyl]- "-t-butoxycarbonylhlstidine fee* 10 methyl ester (prepared as described in Example 12) were dissolved in 5 ml of methanol, and 5.1 ml of a 1 N aqueous solution of sodium hydroxide were added to the *9* solution at room temperature, after which the resulting mixture was stirred for 2 hours and 30 minutes. 2.60 ml of 2 N aqueous hydrochloric acid were then added to the mixture, and the resulting mixture was stirred and then left to stand overnight. The 15 solvent was removed from the reaction mixture by evaporation under reduced pressure and the residue thus obtained was purified by reverse phase preparative silica gel column chromatography, using a 3 7 by volume mixture of acetonitrile and water as eluent, to obtain 0.51 g of a mixture of the title compound melting at 122 0 C to 126 0 C, and sodium chloride y:\wpdocs\dgtmss\98 1 2\usa\982 2ex .doc 403 EXAMPLE 14 5-[5-(1.2-Dithiolan-3-vl)pentanovlamino-l .2.4-dithiazole-3-thione (Compound No. 1-72) 0 N-S N S

S

S-S H 500 mg of D,L-ca-lipoic acid were dissolved in 10 ml of anhydrous S•dimethylformamide, and 428 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 3 hours, after which 391 mg of 3-amino-1,2,4-dithiazole-5-thione were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred for 1 hour and minutes. It was then left to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate.

The extraction solution was washed with a saturated aqueous solution of sodium Schloride and dried over anhydrous sodium sulfate, and then the solvent was removed 15 by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 2, 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as eluent, and then recrystallized from a mixture of ethyl acetate and hexane, to obtain 372 mg of the title compound, melting at 158°C to 161°C.

EXAMPLE 4-(1.2-Dithiolan-3-yl)butylamine diphenylphosphate (Compound No. 1-1123 diphenylphosphate) 0NH 2 S-S diphenylphosphate y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I.doc 404 1.00 g of D,L-a-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the solution at room temperature, after which the resulting mixture was stirred on an oil bath at for 2 hours and 30 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of tetrahydrofuran and 1.21 ml of a w/v aqueous solution of Q-methylhydroxylamine hydrochloride were added to the residue thus obtained, whilst ice-cooling. 2 ml of methanol were then added to the mixture, after which the mixture was stirred at room temperature for 6 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a 3 1 by volume mixture of ethyl acetate and methanol as eluent, followed by reverse phase preparative silica gel column chromatography (using 1 4 and 1 1 by volume mixtures of acetonitrile and water as the eluent). The solvent was then removed from the fraction containing the title compound by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted S: e. with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. Ethyl acetate was added to the residue thus obtained to recrystallise it, giving 116 mg of the title compound, melting at 100 0 C to 103 0

C.

y:\wpdocs\dgtfss\98 12\usa\ 9 8 1 2ex I .doc 405 N.N'-Bis[4-(1.2-dithiolan-3-yl)butvllurea (Compound No. 1-765) H H I I N N S-S O

S-S

g of D,L-c-lipoic acid were dissolved in 60 ml of toluene, and 2.40 ml of triethylamine and 3.70 ml of diphenylphosphoryl azide were added to the resulting solution at room temperature, after which the resulting mixture was stirred on an oil bath at 80 0 C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 60 ml of t-butanol were added at room temperature to the residue thus obtained. The mixture was then stirred and then left to stand for 5 days. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography, using 1 5 and 1 3 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was then removed by evaporation under reduced pressure, and 5 ml of dioxane were added to the resulting residue. The solvent was then removed by evaporation under reduced pressure. 5 ml of 2 N aqueous hydrochloric acid and 10 ml of methanol were added to the residue thus obtained, and the mixture was stirred on an oil bath at 60 0 C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure.

Water was added to the residue and the mixture was neutralized with triethylamine, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 260 mg of a crude product.

160 mg of this crude product were purified by reverse phase preparative silica gel column chromatography, using 2 3, 1 1, 3 2 and 7 3 by volume mixtures of y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 406 acetonitrile and water as the eluent. The solvent was then evaporated from the fraction containing the title compound under reduced pressure, to obtain 87 mg of the title compound, melting at 115 0 C to 116 0

C.

EXAMPLE 17 5-(1.2-Dithiolan-3-vl)pentanohydroxamic acid (Compound No. 1-58) 0 N "OH S-S H S500 mg of D,L-at-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 428 mg of N,N'-c-rbonyldiimidazole were added to the solution, whilst ice-cooling, and then the mixture was stirred at room temperature for 2 hours and 30 minutes. 0.67 ml oftriethylamine and 334 mg ofhydroxylamine hydrochloride were then added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours and then left to stand overnight.

0 At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 6 to 7, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using a 4 1 by volume mixture of ethyl acetate and hexane, followed by a 20 1 by volume mixture of ethyl acetate and methanol, as eluent, and then by reverse phase preparative silica gel column chromatography, using 3 7 and 1 1 by volume mixtures of acetonitrile and water as eluent. The product thus obtained was lyophilised, to obtain 0.38 g of the title compound, melting at 63 0 C to 64 0

C.

y:\wpdocs\dgt..mss\98 I 2\usa\9812ex I.doc 407 N-[4-(1.2-Dithiolan-3-yl)butyl-N'-[1-methoxvcarbonyl-2-(4methoxybenzvlthio)ethyllurea (Compound No. 1-766) H H I I N N

S

S-S O COOCH 3 OCH3 300 mg of D,L-a-lipoic acid were dissolved in 6 ml of toluene, and 0.24 ml of triethylamine and 0.37 ml of diphenylphosphoryl azide were added to the solution at room temperature. The mixture was then stirred on an oil bath at 80°C for 2 hours. At the end of this time, a solution of 434 mg of S-(4-methoxybenzyl)-L-cysteine methyl ester in 3 ml of anhydrous tetrahydrofuran was added to the reaction mixture, whilst 10 ice-cooling, and the mixture was stirred at room temperature for 3 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and the mixture was recrystallized from ethyl acetate, to obtain 434 mg of the title compound, melting at 105 0 C to 107°C.

EXAMPLE 19 S" 15 Hvdrazine-N.N'-dicarboxvlic acid bis[4-(1.2-dithiolan-3-yl)butylamide (Compound No. 1-936) H HH H I I I I N N-N N S-S O O S-S 1.00 g of D,L--lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution. The mixture was then stirred on an oil bath at 70C for 2 hours. 0.19 ml of anhydrous hydrazine was then added to the reaction mixture, whilst ice-cooling, and y:\wpdocs\dgt_mss\9812\usa\9812ex .doc 408 the mixture was stirred at room temperature for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and the residue thus obtained was washed with water and with ethyl acetate. The insolubles were then collected by filtration. The insolubles thus obtained were washed with a 5 2 1 by volume mixture of methanol, tetrahydrofuran and dimethylformamide, to obtain 401 mg of the title compound, melting at 205 0 C to 207°C.

EXAMPLE N-[5-(1.2-Dithiolan-3-l)pentanoyllethanesulfonamide (Compound No. 1-497) 0 O I

N-S-C

2

H

I II S-S H O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 428 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. At the end of this time, a solution of 284 mg of ethanesulfonamide in 3 ml of dimethylformamide and 113 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture :was stirred at room temperature for 1 hour and then left to stand for 3 days. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water and 2 N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 3 7, 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent. The solvent was then removed from the eluted fraction thus obtained by evaporation under reduced pressure, and the residue thus obtained was dissolved in y:\wpdocs\dgt~mss\98 I 2\usa\981 2ex I .doc 409 dioxane. The solution was lyophilised, to obtain 30 mg of the title compound, melting at 98 0 C to 100 0

C.

EXAMPLE 21 1.1-Dimethyl-4-4-(1 .2-dithiolan-3-vl)butyllsemicarbazide (Compound No. 1-861) H H I I ,CH3 N N-N 'H3 Y^ CH 3 S-S 0 1.00 g of D,L-o-lipoic acid was dissolved in 10 ml of toluene, and 0.80 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour.

0.55 ml of 1,1-dimethylhydrazine was then added to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour and then left to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus *i obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using a 3 1 by volume mixture of ethyl acetate and hexane and then a 10 1 by volume mixture of ethyl acetate and methanol as eluent, followed by reverse phase preparative silica gel column chromatography, using 7 13 and 2 3 by volume mixtures of acetonitrile and water as eluent. The eluted fraction thus obtained was lyophilised, to obtain 0.99 g of the title compound, melting at 60°C to 61 0

C.

y:\wpdocs\dgt-mss\98 I 2\usa\981 2ex I.doc 410 EXAMPLE 22 Morpholine-4-carboxylic acid 4-(1.2-dithiolan-3-vl)butvlamide (Compound No. 1-1142)

H

NN O S-S O 500 mg of D,L-c-lipoic acid were dissolved in 10 ml of toluene, and 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the resulting i solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour and 30 minutes. 0.23 ml of morpholine was then added to the mixture, whilst icecooling, and the mixture was stirred at room temperature for 2 hours and then left to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a 10 1 by volume mixture of ethyl acetate and methanol as eluent, followed by reverse phase preparative silica gel column chromatography, using 3 7 and 2 3 by volume mixtures of acetonitrile and water as eluent. The solvent was evaporated from the eluted fraction thus obtained under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was dissolved in dioxane, and the solution was lyophilised, to obtain 0.51 g of the title compound, melting at 74 0 C to 77 0

C.

y:\wpdocs\dgtss\98 1 2\usa\981 2ex I.doc Page(s)..LA7?:.. were not lodged with this application 413 EXAMPLE N-l-15-(1.2-Dithiolan-3-yl)pentanoyllhistamine (Compound No. 1-75) 0 H

N

S-S H 500 mg of D,L-ac-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 422 mg of N,N'-carbonyldiimidazole were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at room temperature for 2 hours and 30 minutes. 0.73 ml of triethylamine and 479 mg of histamine dihydrochloride were then added to the reaction mixture at room temperature, and the mixture was stirred for 4 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 0, 5 1 and 3 1 by volume mixtures of ethyl acetate and ethanol as eluent. It was then recrystallized from a 1 2 by volume mixture of ethyl acetate and diisopropyl ether, to obtain 270 mg of the title compound, melting at 108 0 C to 110 0

C.

EXAMPLE 26 N.N'-Bis[4-(1.2-dithiolan-3-yl)butylcarbamoyllsulfamide (Compound No. 1-2614 H H H H I I II I I SNSN N-S-N S-S 0 O S-S y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I.doc 414 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the mixture, after which the resulting mixture was stirred on an oil bath at 80 0 C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 6 ml of anhydrous dimethylformamide were added to the residue thus obtained, to give a dimethylformamide solution.

Separately, 113 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were dispersed in 4 ml of dimethylformamide, and 252 mg of sulfamide were added to the suspension, whilst ice-cooling, after which the resulting mixture was stirred at 10 room temperature for 2 hours. The above dimethylformamide solution was then added to the reaction mixture on a bath containing ice and an aqueous solution of sodium chloride, and the mixture was stirred at the same temperature for 1 hour and minutes. The reaction mixture was then stirred at room temperature for 4 hours, after which it was left to stand at room temperature overnight. The solvent was then 15 removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was neutralized by the addition of 2 N aqueous hydrochloric acid. The crystals which precipitated were washed with ethyl acetate, with water and with ethanol, to obtain 223 mg of the title compound, melting at 154 0 C to 156 0

C.

20 EXAMPLE 2 Nl.Nim-Bis[4-(1.2-dithiolan-3-yl)butvlcarbamoylhistamine H H I I

N

N N H S-S OY O

S-S

500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 mi of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour y:\wpdocs\dgtmffss\98 12\usa\98I 2ex .doc 415 and 30 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran were added to the residue thus obtained, to give a tetrahydrofuran solution.

Separately, 479 mg of histamine dihydrochloride were dissolved in 2 ml of anhydrous dimethylformamide, and then 0.72 ml of triethylamine was added to the solution, after which the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. 5 ml of anhydrous tetrahydrofuran were then added to the reaction mixture, and then the above anhydrous tetrahydrofuran solution was added thereto, whilst ice-cooling. The mixture was stirred at room temperature for 3 hours and then 10 left to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation 15 under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using 1 0, 5 1 and 3 1 by volume mixtures of ethyl acetate and methanol as the eluent, after which it was subjected to reverse phase preparative silica •gel column chromatography, using 1 4, 3 7, 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure 20 from the fraction containing the title compound, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure, and the residue thus obtained was dissolved in dioxane and lyophilised, to obtain 52 mg of the title compound, melting at 115 0 C to 117 0

C.

y:\wpdocs\dgtrnss\98 1 2\usa\981 2ex I.doc 416 EXAMPLE 28 N-[4-(1.2-Dithiolan-3-yl)butyll-N'-methanesulfonlurea (Compound No. 1-1069) H HO I I 11 C^ N N-S -CH 3 S-S O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 2 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous dimethylformamide were added to the residue 10 thus obtained, to give a dimethylformamide solution.

Separately, 247 mg of methanesulfonamide were dissolved in 5 ml of anhydrous to todimethylformamide, and then 113 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the solution, after which the resulting mixture was stirred at room temperature for 2 hours. The above anhydrous dimethylformamide solution was then added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 3 hours and then left to stand at room temperature for 3 days.

The solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue thus obtained, and the mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate as eluent, and the active fraction was then recrystallized from ethyl acetate, to obtain 302 mg of the titlecompound, melting at 125 0 C to 127 0

C.

y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 417 EXAMPLE 29 4-[4-(1.2-Dithiolan-3-yl)butyllsemicarbazide diphenvlphosphate (Compound No. 1-858 diphenylphosphate) H H I I N YN'NH2 S-S 0 diphenylphosphate 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour and 30 minutes. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 3.5 ml of anhydrous tetrahydrofuran were added to the 10 residue thus obtained. The solution was added to 0.75 mg of hydrazine and then 2 ml of anhydrous dimethylformamide were added thereto. The mixture was stirred at room temperature for 5 hours and then left to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the residue thus 15 obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 0, 10 1 and 5 1 by volume mixtures of ethyl acetate and methanol as eluent, after which it was recrystallized from a 1 1 by volume mixture of ethyl acetate and diisopropyl ether, to obtain 125 mg of the title compound, melting at 134°C to 139 0

C.

y:\wpdocs\dgt..mss\98 1 2\usa\981 2ex I.doc 418 EXAMPLE N-14-(1.2-Dithiolan-3-vl)butvil-N'-aminosulfonylurea (Compound No. 1-1112) H HO I I II N -N N-S-NH 2 S-S O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 70 0 C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous dimethylformamide were added to the residue thus obtained, to give a dimethylformamide solution.

Separately, 1.15 g of sulfamide were dissolved in 10 ml of anhydrous dimethylformamide, and then 524 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the solution, whilst ice-cooling, after which the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The above dimethylformamide solution was then added to the reaction mixture, whilst ice- 15 cooling, and the mixture was stirred at room temperature for 4 hours and then left to stand for 2 days. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 1, 2 1 and 4 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized from ethanol, to obtain 126 mg of the title compound, melting at 123 0 C to 125 0

C.

y:\wpdocs\dgtrmss\98 1 2\usa\981 2ex I.doc 419 EXAMPLE 31 Methyl N-14-(1.2-Dithiolan-3-yl)butvllcarbamate (Compound No. 1-676)

H

I

N

OCH

3 S-S O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour.

The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 10 ml of anhydrous methanol were added to the residue thus obtained.

The mixture was stirred at room temperature for 6 hours and then left to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 4 and 1 2 by volume mixtures of ethyl acetate and hexane o as eluent, after which it was subjected to reverse phase column chromatography, using 1 4, 3 7, 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure from the fraction containing the title compound, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and lyophilised, to obtain 324 mg of the title compound, melting at 31 0 C to 32 0

C.

y:\wpdocs\dgt_mss\98 I 2\usa\9812ex I .doc 420 EXAMPLE 32 N-[2-(5-Methoxy-1H-indol-3-vl)ethvlllipoamide (Compound No. 1-80)

OCH

3

NI

S-S H N

I

H

500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and 422 mg of NN'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 3 hours and 30 minutes. At the end of this time, 495 mg of 5-methoxytryptamine were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 3 hours and then left to stand at room temperature overnight. The S. 10 solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The residue was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The solvent was removed ooe* from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 2 1, 4 1 and 1 0 15 by volume mixtures of ethyl acetate and hexane as eluent, to obtain 515 mg of the title compound as a yellow oil having an Rf value of 0.26 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 421 EXAMPLE 33 N-14-(1.2-Dithiolan-3-y)butyl1-N'-12-(5-methoxyv-H-indol-3-vlethyl urea (Compound No. 1-772) H H I I N N OCH3 S-S o

N

500 mg of D,L--lipoic acid were dissolved in 10 ml of toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the *o solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour.

The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran were added to the residue thus 10 obtained, to give a tetrahydrofuran solution.

Separately, 1.37 mg of 5-methoxytryptamine were dissolved in a mixture of 10 ml of anhydrous tetrahydrofuran and 4 ml of anhydrous dimethylformamide, and the resulting solution was added to the above anhydrous tetrahydrofuran solution, whilst ice-cooling. The mixture was stirred, whilst ice-cooling, for 1 hour and then at S- 15 room temperature for 4 hours, after which it was left to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane and then a 10 1 by volume mixture of ethyl acetate and methanol as eluent, after which it was recrystallized from ethyl acetate, to obtain 674 mg of the title compound, melting at 100 0 C to 101*C.

y:\wpdocs\dgtmss\98 1 2\usa\981 2ex I .doc 422 N-[4-(1.2-Dithiolan-3-vylbutyllpyrrolidine-l-carboxamide (Compound No. 1-1139)

H

I

S-S O 500 mg of D,L--lipoic acid were dissolved in 10 ml of anhydrous toluene, and i then 0.56 ml of diphenylphosphoryl azide was added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour and 30 minutes. 0.22 ml ofpyrrolidine was then added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour and then left to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 0 and 10 1 by volume mixtures of ethyl acetate and methanol as eluent, after which it was recrystallized from a 1 1 1 by volume mixture of ethyl acetate, methanol and acetonitrile, to obtain 231 mg of the title compound, melting at 91 0 C to 93 0

C.

1-15-(1.2-Dithiolan-3-vlipentanoyllpyrrolidine (Compound No. 1-1129) 0

N

S-S

y:\wpdocs\dgt_ss\9812\usa\9812ex .doc 423 500 mg ofD,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and then 422 mg of NN'-carbonyldiimidazole were added to the solution. The resulting mixture was then stirred at room temperature for 1 hour and minutes. 0.22 ml ofpyrrolidine was added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time.

the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was 10 removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 2 1, 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilised, to obtain 364 mg of the title compound as a yellow oil having an Rf value of 0.15 (silica gel thin layer chromatography, using ethyl 15 acetate as the developing solvent).

EXAMPLE 36 N-14-(1.2-Dithiolan-3-yl)butyl piperidine-1-carboxamide (Compound No. 1-1140) o

H

S-S O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 hour. 0.26 ml of piperidine was then added to the reaction mixture, whilst ice-cooling, and the mixture was left to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 424 with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 2 1, 4 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized from a 1 1 by volume mixture of ethyl acetate and methanol, to obtain 252 mg of the title compound, melting at 90 0 C to 91 0

C.

EXAMPLE 37 1-[5-(1.2-Dithiolan-3-yl)pentanovllpiperidine (Compound No. 1-1130) No

S-S

500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and then 422 mg of N,N'-carbonyldiimidazole were added to the solution. The mixture was then stirred at room temperature for 3 hours. At the end of this time, 0.26 ml of piperidine was added to the reaction mixture, and the mixture was 15 stirred at room temperature for 4 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 3 2 and 3 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then dissolved in dioxane and lyophilised, to obtain 381 mg of the title compound as a yellow oil having an Rf value of 0.30 (silica gel thin layer chromatography, using a 3 2 by volume mixture of ethyl acetate and hexane Ps the developing solvent).

y:\wpdocs\dgtmss\98 1 2\usa\981 2ex I .doc 425 EXAMPLE 38 N-[4-(1.2-Dithiolan-3-vl)butvllthiomorpholine-4-carboxamide (Compound No. 1-1143)

H

N N S S-S o 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80 0 C for 1 .hour. 0.25 ml of thiomorpholine was then added to the reaction mixture at room temperature, and the mixture was stirred for 5 hours and then left to stand for 2 days.

At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed S* with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 3 2, 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. It was then dissolved in dioxane and lyophilised, to obtain 583 mg of the title compound, melting at 80 0 C to 81 0

C.

EXAMPLE 39 (S)-N-15-(1.2-Dithiolan-3-vl)pentanoyllmethanesulfonamide (Compound No. 1-496) 0

N-S-CH

3 SSI

I

H

S-S

HO

y:\wpdocs\dgtfmss\98 1 2\usa\981 2ex I.doc 426 300 mg of(S)-ct-lipoic acid were dissolved in 6 ml of anhydrous dimethylformamide, and 276 mg of N,N'-carbonyldiimidazole and 1 ml of anhydrous dimethylformamide were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour and 30 minutes. At the end of this time, 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour and then left to stand for 2 days.

The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The S residue thus obtained was purified by silica gel column chromatography, using I 1 and 3 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized from a 1 2 by volume mixture of ethyl acetate and hexane, to obtain 154 mg of the title compound, melting at 91 0 C to 92 0

C.

*(Compound No. 1-496) 0

N-S-CH

3 I II S-S

HO

100 mg of (R)-a-lipoic acid were dissolved in 2 ml of anhydrous dimethylformamide, and 97 mg of N,N'-carbonyldiimidazole were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 4 hours. At the end of this time, 57 mg of methanesulfonamide and 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours and y:\wpdocs\dgtmss\98 I 2\usa\98 I 2ex .doc 427 then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The resulting mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 1 and 3 1 by volume mixtures of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilised, to obtain 68 mg of the title compound, melting at 71 0 C to 73°C.

EXAMPLE 41 S4-5-(1,2-Dithiolan-3-vl)pentanoylithiomorpholine (Compound No. 1-1133) 0 N S -7"

S-S

s** 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous dimethylformamide, and then 422 mg of N,N'-carbonyldiimidazole were added to the solution. The mixture was then stirred at room temperature for 1 hour and 30 minutes, o* after which it was left to stand overnight. At the end of this time, 0.25 ml of thiomorpholine was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours and then left to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate.

The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then dissolved in y:\wpdocs\dgtmss\98 1 2\usa\981 2ex I.doc 428 dioxane and lyophilised, to obtain 385 mg of the title compound as a yellow amorphous substance, melting at 31°C to 32 0

C.

EXAMPLE 42 N-[4-(1,2-Dithiolan-3-vl)butyl] 1-piperazinvlcarboxamide (Compound No. 1-1141)

H

N N N-H S-S O 500 mg of D,L-a-lipoic acid were dissolved in 10 ml of anhydrous toluen-, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred on an oil bath at 80'C for 2 10 hours. A solution of 1.03 g of piperazine in 10 ml of anhydrous dimethylformamide was then added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 3 hours and 30 minutes and then left to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which 15 it was neutralised by the addition of 2 N aqueous hydrochloric acid. The crystals which precipitated were collected by filtration and washed with water and ethyl acetate, to obtain 107 mg of the title compound, melting at 175°C to 177 0

C.

EXAMPLE 43 3-[5-(1.2-Dithiolan-3-vy)pentanovllthiazolidine (Compound No. 1-1258) 0

N

S-S

422 mg of N,N'-carbonyldiimidazole were added to a solution of 500 mg of D,La-lipoic acid in 10 ml of anhydrous dimethylformamide,. The resulting mixture was y:\wpdocs\dgt_mss\9812\usa\9812ex .doc 429 stirred at room temperature for 1 hour and 30 minutes. 0.20 ml of thiazolidine was then added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for 4 hours. The reaction mixture was allowed to stand overnight at room temperature and then the solvent was removed by distillation under reduced pressure.

Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1 1, 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using a 2 3 by volume mixture of acetonitrile and water as eluent.

Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under ~reduced pressure, and the resulting residue was dissolved in dioxane. The resulting solution was lyophilised, to give 317 mg of the title compound as a pale yellow amorphous substance, melting at 40 to 41 0

C.

EXAMPLE 44 N-[4-(1.2-Dithiolan-3-yl)butyll-N'-(-piperidyl)urea (Compound No. 1-1145) H H N N N S-S O 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to a solution of 500 mg of D,L-a-lipoic acid in 10 ml of anhydrous toluene. The resulting mixture was stirred on an oil bath at 80 0 C for 1 hour and 30 minutes. 0.28 ml of 1-aminopiperidine was then added dropwise to the reaction mixture, whilst icecooling, and then the mixture was stirred at room temperature for 5 hours. The reaction mixture was then allowed to stand overnight at room temperature. The y:\wpdocs\dgtmss\981 2\usa\981 2ex I .doc 430 solvent was removed from the reaction mixture by distillation under reduced pressure.

Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 0 and 5 1 by volume mixtures of ethyl acetate and ethanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 593 mg of the title compound as a yellow amorphous substance, melting at 67 to 69'C.

10 EXAMPLE N-(1-Piperidyl)-5-(1,2-dithiolan-3-ylpentanamide (Compound No. 1-1135) No S-S

H

The reaction was effected as described in Example 43, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyl- 15 diimidazole and 0.28 ml of l-aminopiperidine. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, after which it was recrystallised from ethyl acetate, to give 298 mg of the title compound as a yellow needle-like crystals, melting at 108 to 109 0

C.

y:\wpdocs\dgtmss\98 I 2'usa'.,)8I2ex I .doc 431 EXAMPLE 46 Methyl 3-[4-(1.2-dithiolan-3-yl)butvllureidoacetate (Compound No. 1-739) H H N N COOCH3 S-S O 0.73 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to a solution of 500 mg of D,L-a-lipoic acid in 10 ml of anhydrous toluene. The resulting mixture was stirred on an oil bath at 80 0 C for 1 hour and 30 minutes. The solvent was then removed from the reaction mixture by distillation under reduced pressure. 10 ml of anhydrous dimethylformamide were then added to the residue, after .0 which 301 mg of L-glycine methyl ester hydrochloride were added, whilst ice-cooling.

The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the reaction mixture was allowed to stand overnight at room temperature.

after which the solvent was removed by distillation under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The extract was 0000 washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column 0@ 6 chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 3 17, 3 7 and 3 2 by volume mixtures ofacetonitrile and water as eluent.

Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 336 mg of the title compound as a pale yellow amorphous substance, melting at 62 to 64 0

C.

y:\wpdocs\dgtmss\98 I 2\usa\98I 2ex I.doc 432 EXAMPLE 47 Methyl f5-(1.2-dithiolan-3-vl)pentanovlaminoacetate (Compound No. 1-47) 0 N

COOCH

3 S-S H 422 mg of N,N'-carbonyldiimidazole were added to a solution of 500 mg of D,L-ca-lipoic acid in 10 ml of anhydrous dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which 0.36 ml oftriethylamine was added dropwise to the reaction mixture. 301 mg of glycine methyl ester hydrochloride were then added to the reaction mixture, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was allowed to stand at room 10 temperature for two days, and then the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with S ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to oeeo 15 silica gel column chromatography, using 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 1 4, 3 7 and 1 1 by volume mixtures of acetonitrile and Iwater as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was dissolved in dioxane, after which it was lyophilised, to give 320 mg of the title compound as a yellow oil having an Rf value of 0.26 (silica gel thin layer chromatography; using a 3 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

y:\wpdocs\dgtmss'98 I 2\usa\981 2ex I.doc 433 EXAMPLE 48 {3-[4-(1.2-Dithiolan-3-vl)butvl]ureido}acetic acid (Compound No. 1-738) H H I I N Y N -COOH S-S O 2.1 ml of a 1 N aqueous solution of sodium hydroxide were added dropwise to a solution of 218 mg of methyl {3-[4-(1,2-dithiolan-3-yl)butyl]ureido acetate (prepared as described in Example 46) in 4 ml of methanol, and then the mixture was stirred at room temperature for 5 hours. The reaction mixture was then allowed to stand overnight at room temperature, after which the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The o*O 10 resulting mixture was neutralized by the addition of2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from a 3 1 by volume mixture of ethyl 15 acetate and hexane, to give 64 mg of the title compound as a pale yellow powder, melting at 95 to 96 0

C.

o* EXAMPLE 49 [5-(1.2-Dithiolan-3-vl)pentanoylaminolacetic acid (Compound No. 1-46) 0 N 1COOH S-S H 0.28 g of methyl 5-(1,2-dithiolan-3-yl)pentanoylaminoacetate (prepared as described in Example 47) was dissolved in a mixture of 2 ml of methanol and 2 ml of tetrahydrofuran. 2.0 ml of a 1 N aqueous solution of sodium hydroxide were added y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I .doc 434 dropwise to the resulting solution, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was then allowed to stand overnight at room temperature, after which the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 156 mg of the title compound as a yellow oil having an Rf value of 0.12 (silica gel thin layer chromatography; using a 5 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

EXAMPLE Methyl 2(S)-{3-[4-(1.2-dithiolan-3-yl)butyllureido}propionate (Compound No. 1-742) I I s-s 0 CH3

*H

The reaction was effected as described in Example 46, but using 500 mg of D,Lat-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 335 mg of L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.

Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. Ethyl acetate was removed y:'\pdocs\dgtmss\98 I 2\usa\981 2ex I.doc 435 from the eluate by distillation under reduced pressure, and the residue was recrystallized from a 1 1 1 by volume mixture of ethyl acetate, diisopropyl ether and hexane, to give 142 mg of the title compound as yellow crystals, melting at 90 to 92 0

C.

EXAMPLE 51 Methyl 2(S)-[5-(1.2-dithiolan-3-yl)pentanoylaminolpropionate (Compound No. 1-50) O CH 3 N

COOCH

3

I

S-S H The reaction was effected as described in Example 47, but using 500 mg of *o D,L-ao-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole, 0.36 ml of triethylamine and 335 mg of L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of oo. sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using by volume 3 7 and 1 1 mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 271 mg of the title compound as a pale yellow amorphous substance, melting at 48 to 49 0

C.

y:\wpdocsdgtmss\98 I 2usa\98 2ex I.doc 436 EXAMPLE 52 2(S)-{3-f4-(1.2-Dithiolan-3-vl)butvllureido}propionic acid (Compound No. 1-740) H H N N ,COOH S-S O

CH

3 The reaction was effected as described in Example 46, but using 1.00 g of D,Lac-lipoic acid, 20 ml of anhydrous toluene, 1.47 ml of triethylamine, 1.14 ml of diphenylphosphoryl azide, 740 mg of L-alanine methyl ester hydrochloride and 20 ml of anhydrous dimethylformamide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it 10 was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, after which it was recrystallised from 15 ethyl acetate, to give 0.80 g of yellow crystals.

The resulting crystals were dissolved in a mixture of 10 ml of methanol and 3 ml of tetrahydrofuran, and then 16.8 ml of a 1 N aqueous solution of sodium hydroxide were added dropwise thereto. The resulting mixture was stirred at room temperature for 6 hours and 30 minutes. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was recrystallized from ethylacetate, to give 141 mg of the title compound as pale yellow crystals, melting at 128 to 130 0

C.

y:\wpdocs\dgtmss\98 I 2usa\981 2ex I .doc 437 EXAMPLE 53 2(S)-[5-(1.2-dithiolan-3-vl)pentanovlaminolpropionic acid (Compound No. 1-48) O

CH

3 N COOH S-S H The reaction was effected as described in Example 49, but using 153 mg of methyl 2(S)-[5-(1,2-dithiolan-3-yl)pentanoylamino]propionate (prepared as described in Example 51), 3 ml of methanol and 1.3 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of2 N aqueous hydrochloric acid, after which it was 10 extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 90 mg of the title compound as a yellow oil having an Rf value of 0.18 (silica gel thin layer 15 chromatography; using ethyl acetate as the developing solvent).

EXAMPLE 54 Methyl 3-{3-14-(1.2-dithiolan-3-yl)butyllureido}propionate (Compound No. 1-741 methyl ester) H H I I N N

COOCH

3 S-S O The reaction was effected as described in Example 46, but using 500 mg of D,La-lipoic acid, 10 ml of anhydrous toluene, 0.74 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 335 mg of p-alanine methyl ester hydrochloride and 10 ml y:\wpdocs\dgt_mss\9812\usa\982ex I .doc 438 of anhydrous dimethylformamide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 3 1 and I 0 by volume mixtures of ethyl acetate and hexane as eluent, after which it was recrystallised from a 1 2 by volume mixture of ethyl acetate and hexane, to give 213 mg of the title compound as yellow crystals, melting at 67 to 69 0

C.

EXAMPLE Methyl 3-[5-(1.2-dithiolan-3-vl)pentanovlaminolpropionate (Compound No. 1-49 methyl ester)

O

COOCH

S-S H The reaction was effected as described in Example 47, but using 500 mg of D,La-lipoic acid. 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole, 0.36 ml of triethylamine and 335 mg of p-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent, after which it was recrystallised from a 1 2 by volume mixture of ethyl acetate and hexane, to give 333 mg of the title compound as a yellow plate-like crystals, melting at 54 to 550C.

y:\wpdocs\dgtmss\98 12'.usa\98 I2ex .doc 439 EXAMNPLE 56 3-{3-(4-(1.2-Dithiolan-3-vl)butvilureido}propionic acid (Compound No. 1-741) H H I I S-S 0 The reaction was effected as described in Example 48, but using 115 mg of methyl 3- {3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 54), 3 ml of methanol, 2 ml of tetrahydrofuran and 1.40 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of2 N aqueous hydrochloric acid, after which 10 it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the crystals so precipitated were collected by filtration, to give 70 mg of the title compound as a yellow powder, melting at 108 to 110 0

C.

EXAMPLE 57 3-15-(l.2-Dithiolan-3-vlentanovlaminolpropionic acid (Compound No. 1-49) 0 YN ^COOH S-S H The reaction was effected as described in Example 49, but using 213 mg of methyl 3-[5-(1,2-dithiolan-3-yl)pentanoylamino]propionate (prepared as described in Example 55), 4 ml of methanol and 1.80 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was y \wpdocs\dgt~mss\981 2'usa\981 2ex I .doc 440 neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 0.11 g of the title compound as a pale yellow amorphous substance, melting at 74 to 76 0

C.

EXAMPLE 58 2-[5-(1.2-Dithiolan-3-vl)pentvllisoindole-1.3-dione (Compound No. 1-2606) 0

N

3.25 ml of dimethyl azodicarboxylate were added dropwise to a solution of 5.77 g of triphenylphosphine in 20 ml of tetrahydrofuran, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. 3.24 g of phthalimide were then added to the reaction mixture, after which a mixture of 20 mmol of 5-(1,2dithiolan-3-yl)pentanol (prepared as described in Preparation 1) in 30 ml of toluene and 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, after which 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added. The resulting mixture was stirred at room temperature for 7 hours and 30 minutes. 0.88 g of phthalimide, 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were then added to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 4 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 6 and 1 4 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate by distillation under reduced pressure, and 30 ml of toluene were added to the residue. 1 ml of the resulting mixture was weighed, and y:\wpdocs\dgtmss\98 I 2\usa981 2ex I .doc 441 the solvent was removed from it by distillation under reduced pressure, togive 165 mg of the title compound as an orange oil having an Rf value of 0.35 (silica gel thin layer chromatography; using a 1 4 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 59 N-[5-(1.2-Dithiolan-3-vl)pentvllmethanesulfonamide (Compound No. 1-2470)

O

N-S-CH

3 S-S H O 1 ml ofbutylamine was added to a solution of 0.24 g of 2-[5-(l,2-dithiolan-3yl)pentyl]isoindole-l,3-dione in 1 ml of methanol. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the o. residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium 15 sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 2 ml of tetrahydrofuran were added to the residue, and then 0.22 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added dropwise thereto, whilst ice-cooling. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using a 1 1 by volume mixture of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I .doc 442 under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was dissolved in dioxane, after which it was lyophilised, to give 100 mg of the title compound as a pale yellow amorphous substance, melting at 43 to 46 0

C.

EXAMPLE N-f5-(1.2-Dithiolan-3-vl)pentllacetamide (Compound No. 1-1962) *o

I

N

CH

3 SS-S H 1 ml of butylamine was added to a mixture of 1.3 mmol of 2-[5-(1,2-dithiolan-3yl)pentyl]isoindole-l,3-dione, 9 ml of toluene and 2 ml of methanol. The resulting mixture was stirred at room temperature for 3 hours, after which the reaction mixture was allowed to stand at room temperature for 2 days. 1 ml ofbutylamine was then added to the reaction mixture. The resulting mixture was stirred at room temperature 15 for 3 hours. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of anhydrous tetrahydrofuran were then added to the residue. 0.28 ml of triethylamine and 0.14 ml of acetyl chloride were then added dropwise to the resulting mixture, whilst icecooling, and then the mixture was stirred at room temperature for 1 hour and minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl y:\wpdocs\dgtmss98 I 2\usa\9812ex I .doc 443 acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1 0 and 10 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 161 mg of the title compound as yellow crystals, melting at 28 to 33 0

C.

EXAMPLE 61 N-[5-(1.2-Dithiolan-3-yl)pentvlpropionamide (Compound No. 1-1963) 0

CH

N 3 S-S H 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole- 1.3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of pyridine were then added to the residue. 0.31 ml of propionic anhydride was added dropwise to the resulting mixture, and then the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was thereafter subjected to silica gel column chromatography, using 2 1, 3 I and 1 0 by volume mixtures of ethyl acetate andy:\wpdocs\dgtmss\98 12'.usa\981 2ex I.doc 444 hexane as eluent, followed by reverse phase preparative silica gel column, chromatography, using 1 4, 3 7, 2 3 and 1 1 by volume mixtures ofacetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 125 mg of the title compound as a yellow oil having an Rf yalue of 0.45 (silica gel thin layer chromatography; using ethyl acetate as the developing solvent).

EXAMPLE 62 [5-(1.2-Dithiolan-3-vhpentvllurea (Compound No. 1-1993) 0 N NH 2 S-S H 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of tetrahydrofuran were added to the residue. 0.32 ml of trimethylsilyl isocyanate was then added dropwise to the resulting mixture, whilst ice-cooling, and then the mixture was stirred at room temperature for 3 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was y:\wpdocs\dgtmss\98 I 2usa',981I2ex I.doc 445 added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 1 0 and 5 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 80 mg of the title compound as yellow crystals, melting at 74 to 78 0

C.

EXAMPLE 63 10 1-5-(1.2-Dithiolan-3-vl)pentvl-3-methylthiourea (Compound No. 1-2567)

CH

o. S-S H H o The reaction was effected as described in Example 62, but using a solution of mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran and 0.12 ml 15 of methyl isothiocyanate. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1 0 and 20 1 by volume mixtures of ethyl acetate and methanol as eluent, followed by reverse phase preparative silica gel column chromatography, using 3 7 and 1 1 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was thereafter extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the y:\wpdocs\dgtmss\98 2\usa\98 I 2ex I .doc 446 extract by distillation under reduced pressure. The residue was recrystallized from a 1 1 by volume mixture of ethyl acetate and hexane, to give 183 mg of the title compound as yellow crystals, melting at 64 to 65 0

C.

EXAMPLE 64 Ethyl [5-(1.2-dithiolan-3-vl)pentyllcarbamate (Compound No. 1-1977) 0 N

OC,H

S-S H 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1.2-dithiolan-3-yl)pentyl]isoindole-l,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 7 hours. At the end of this time, the 10 reaction mixture was allowed to stand overnight at room temperature. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by 15 distillation under reduced pressure. 2 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.33 ml of triethylamine and 0.23 ml of ethyl chloroformate were added dropwise, whilst ice-cooling. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 3 and 1 2 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using a 1 1 by volume mixture of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation y: ,wpdocs'dgt_mss\9812i usa\9812ex .doc 447 under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 75 mg of the title compound as a red oil having an Rf value of 0.46 (silica gel thin layer chromatography; using a 1 2 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE Methyl N-[5-(1.2-dithiolan-3-yl)pentylloxalamidate (Compound No. 1-2590) N COOCH 3 S-S H 2 ml of methanol and 2 ml ofbutylamine were added to a solution of 1.5 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for one hour. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent 15 was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.32 ml of triethylamine and 0.21 ml of methyloxalyl acid chloride were added dropwise, whilst ice-cooling. The resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced y:\wpdocs'dgtmss\98 12\usa\981 2ex I .doc 448 pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using a 2 3 by volume mixture of acetonitrile and water as eluent.

Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was thereafter extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 154 mg of the title compound as a pale yellow amorphous substance, melting at 42 to 43 0

C.

10 EXAMPLE Methyl N-[5-(1.2-dithiolan-3-vl)pentvl]oxalamidate (Compound No. 1-2590) o 0 .N

COOCH

3 S-S H 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.5 mmol of 1.2-dithiolan-3-yl)pentyl]isoindole- 1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for one hour. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.32 ml of triethylamine and 0.21 ml of methyloxalyl acid chloride were added dropwise, whilst ice-cooling. The resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a y:\wpdocs\dgtmss\98 I 2\usa'98I 2ex i.doc 449 saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using a 2 3 by volume mixture of acetonitrile and water as eluent.

Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was thereafter extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 154 mg of the title compound as a pale yellow amorphous •substance, melting at 42 to 43 0

C.

EXAMPLE 66 N-[5-(1.2-Dithiolan-3-l)pentyllsuccinamic acid (Compound No. 1-1970) N COOH S-S H The reaction was effected as described in Example 61, but using a solution of mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 4 ml of pyridine and 230 mg of succinic anhydride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using 2 3, 1 1 and 3 2 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution y:\wpdocs\dgtmss\9812 I2usa\982ex I .doc 450 of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 166 mg of the title compound as a pale yellow amorphous substance, melting at 74°C.

EXAMPLE 67 4-[5-(1.2-Dithiolan-3-vl)pentylcarbamoyl]butanoic acid (Compound No. 1-2577)

COOH

N

SS-S H The reaction was effected as described in Example 61, but using a solution of 1.5 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 4 ml of pyridine and 262 mg of glutaryl anhydride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using a 2 3 by volume mixture of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure. The residue was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 132 mg of the title compound as a pale yellow amorphous substance, melting at 60 to 62 0

C.

y:\'wpdocs'detmss\98 1 2'usa\98 I 2ex .doc 451 EXAMPLE 68 Methyl [5-(1.2-dithiolan-3-yl)pentylaminolacetate (Compound No. 1-2584) N COOCH 3 S-S H 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was allowed to stand overnight at room temperature. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The ~extract was washed with a saturated aqueous solution of sodium chloride and then 10 dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.33 ml of triethylamine and 0.17 ml of methyl bromoacetate were added dropwise, whilst ice-cooling. The resulting mixture was stirred for one hour, whilst ice-cooling and then for 5 hours at room temperature. The reaction mixture was then allowed to stand at room temperature for 2 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 0 and 20 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 195 mg of the title compound as a yellow oil having an Rf value of 0.55 (silica gel thin layer chromatography; using a 4 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

y:\wpdocs\dgtmss\98 I 2'usa\981 2ex I .doc 452 EXAMPLE 69 Methyl 3-[5-(1.2-dithiolan-3-vl)pent'laminolpropionate (Compound No. 1-2586 methyl ester) 1/N

C

O O C H 3 S-S H The reaction was effected as described in Example 68, but using a solution of mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione, 2 ml of methanol, 2 ml of butylamine, 4 ml of anhydrous tetrahydrofuran, 0.24 ml of triethylamine and 0.19 ml of methyl bromopropionate. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after 10 which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.

Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1 0, 20 1 and 4 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed I 15 from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 161 mg of the title compound as a yellow oil having an Rf value of 0.21 (silica gel thin layer chromatography, using a 4 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

EXAMPLE Methyl 3-(4-(1.2-dithiolan-3-ylbutvllureido)propionate (Compound No. 1-742) H H N COOCH 3 S-S O C CH3 y:\wpdocs\dgtmss\98 I 2.usa,98 2ex I .doc 453 The reaction was effected as described in Example 46, but using 0.51 g of D,La-lipoic acid, 10 ml of anhydrous toluene, 0.75 ml of triethylamine, 0.59 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 0.34 g of Dalanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.

Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 0.27 g of the title ee compound as a yellow powder, melting at 72 to 82 0

C.

EXAMPLE 71 2(R)-{3-(4-(1.2-Dithiolan-3-vl)butyllureido}propionic acid (Compound No. 1-740) H H sS -S O i S m 0

.CH

3 The reaction was effected as described in Example 48, but using 1.74 g of methyl 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 70), 30 ml of methanol, 22 ml of tetrahydrofuran and 17.0 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2 N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized y:\wpdocs\dgtmss,98 1 2'usa981 2ex .doc 454 from ethyl acetate, to give 0.56 g of the title compound as yellow crystals, melting at 131 to 134 0

C.

EXAMPLE 72 N-(2-{3-[4-(1.2-Dithiolan-3-vl)butvllureido}propionyl)methanesulfonamide (Compound No. 1-1280 H H 0 I I H O N N HN-S-CH I II II S-S 0 0

CH

3 3 127 mg of N,N'-carbonyldiimidazole were added to a solution of 208 mg of {3-[4-(1,2-dithiolan-3-yl)butyl]ureido propionic acid (prepared as described in Example 71) in 2 ml of anhydrous dimethylformamide, and then the mixture was stirred at room temperature for 3 hours and 10 minutes.

Meanwhile, 34 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were washed with hexane, and then 3 ml of anhydrous dimethylformamide were added. 74 mg of methanesulfonamide were added to the resulting mixture, whilst icecooling, and then the mixture was stirred at room temperature for 3 hours and minutes. At the end of this time, the solution prepared as described in step above was added dropwise to the reaction mixture, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then allowed to stand overnight at room temperature. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2 N aqueous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from methanol, to give 77 mg of the title compound as a pale yellow powder, melting at 140 to 150 0

C.

y \wpdocs\dgt_mss\9812 .usa\9812ex I.doc 455 EXAMPLE 73 Methyl 4-15-(1.2-dithiolan-3-vl)pentanovlaminobutanoate (Compound No. 1-1275 methyl ester) 0 N

COOCH

3 S-S H 0.86 g of N,N'-carbonyldiimidazole was added to a solution of 1.00 g of D,L-clipoic acid in 20 ml of anhydrous dimethylformamide, whilst ice-cooling. The resulting mixture was stirred at room temperature for 1 hour and 25 minutes.

Meanwhile, 0.23 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed with hexane, after which 20 ml of anhydrous dimethylformamide were added. 0.82 g of methyl 4-aminobutanoate hydrochloride was then added, whilst icecooling, and then the resulting mixture was stirred at room temperature for 1 hour and minutes. The solution prepared as described in step above was then added dropwise to the reaction mixture, whilst ice-cooling, and then the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was allowed to stand overnight at room temperature, after which the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2 N aqueous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. The ethyl acetate was removed from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 0.83 g of the title compound as a yellow powder, melting at 30 to 32 0

C.

y:\wkpdocs\dgtmss 981 2,usa\8912ex I .doc 456 EXAMPLE 74 4-[5-(1.2-Dithiolan-3-yl)pentaynolaminobutanoic acid (Compound No. 1-1275) 0 N COOH S-S H The reaction was effected as described in Example 49, but using 0.65 g of methyl 4-[5-(1,2-dithiolan-3-yl)pentanoylamino]butanoate (prepared as described in Example 73), 13 ml of methanol and a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2 N aqueous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0.28 g of the title compound as yellow crystals, melting at 56 to 58 0

C.

EXAMPLE Methyl 4-{3-f4-(1.2-dithiolan-3-yl)butyllureido}butanoate (Compound No. 1-1276 methyl ester) H H I I N rN

COOCH

3 S-S 0 The reaction was effected as described in Example 46, but using 1.00 g of D,La-lipoic acid, 20 ml of anhydrous toluene, 1.48 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.74 g of methyl 4-aminobutanoate hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure.

y:\wpdocs\dgtmss\98 12usa\981 2ex I .doc 457 Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using ethyl acetate as eluent. The ethyl acetate was removed from the eluate so obtained by distillation under reduced pressure, to give 1.18 g of the title compound as yellow crystals, melting at 63 to EXAMPLE 76 N-[5-(1.2-Dithiolan-3-vl)pentvyloxalamic acid (Compound No. 1-2589)

O

N COOR The reaction was effected as described in Example 49, but using 92 mg of methyl N-[5-(1,2-dithiolan-3-yl)pentyl]oxalamidate (prepared as described in Example 4 ml of methanol, 1 ml of tetrahydrofuran and 0.6 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 64 mg of the title compound as a pale yellow amorphous substance, melting at 75 to 79 0

C.

y:\wpdocsddgt_mss981 2'usa\9812exI doc 458 EXAMPLE 77 Methyl N-[5-(1.2-dithiolan-3-yl)pentyllsuccinamidate (Compound No. 1-1970 methyl ester) 0 Y N COOCH S-S H 0.25 ml of a hexane solution containing 2.0 M of (trimethylsilyl)diazomethane was added dropwise to a mixture of 89 mg ofN-[5-(1,2-dithiolan-3-yl)pentyl]succinamic acid, 1 ml of methanol and 1.5 ml of toluene, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using 1 1 and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. Ethyl acetate and hexane were removed from the eluate so obtained by distillation under reduced pressure. The resulting residue was dissolved in dioxane, after which it was lyophilised, to give 77 mg of the title compound as a pale yellow amorphous substance, melting at 46 to 48 0

C.

EXAMPLE 78 Methyl 4-[5-(1.2-dithiolan-3-v)pentylcarbamoyvlbutanoate (Compound No. 1-2577 methyl ester) 0 N COOCH 3 S-S H The reaction was effected as described in Example 77, but using 68 mg of (l,2-dithiolan-3-yl)pentylcarbamoyl]butanoic acid (prepared as described in Example 67), 1 ml of methanol, 1 ml of toluene and 0.40 ml of a hexane solution containing y:'\pdocs\dgtmss\98 I 2\usa\ 9 8I2ex I.doc 459 M of(trimethylsilyl)diazomethane. The solvent was then removed frpm the reaction mixture by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 3 I and 1 0 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 62 mg of the title compound as a pale yellow amorphous substance, melting at 69 to 71'C.

EXAMPLE 79 Ethyl {N-[5-(1.2-dithiolan-3-vl)pentanoyll-N-methylamino}acetate 10 (Compound No. 1-2520 ethyl ester) N COOC2H S-S

CH

3 The reaction was effected as described in Example 47, but using 500 mg of D,La-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole, 0.36 ml of triethylamine and 399 mg of sarcosine ethyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 558 mg of the title compound as a yellow oil having an Rf value of 0.39 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

y:\wpdocs\dgtmss18 I 2\usa\9812ex I.doc 460 EXAMPLE Methyl 4-{N-[5-(1.2-dithiolan-3-yl)pentanoyll-N-methvlamino}butanoate (Compound No. 1-2669 methyl ester) 0 N

COOCH

3 S-S

CH

3 The reaction was effected as described in Example 47, but using 500 mg of D,Lc -lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole, 0.36 ml of triethylamine and 486 mg of methyl 4-(methylamino)butanoate hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of o sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 4 1 by volume mixtures of ethyl acetate and hexane as eluent, followed by reverse phase preparative silica gel column chromatography, using 2 3 and 9 11 by volume mixtures of acetonitrile and water as eluent. Acetonitrile was removed from the eluate so obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was then dissolved in dioxane, after which it was lyophilised, to give 229 mg of the title compound as a yellow oil having an Rf value of 0.37 (silica gel thin layer chromatography; using a 4 1 by volume mixture of ethyl acetate and hexane developing solvent).

y:\wpdocs\dgt_mss\9812\usa\982ex I .doc 461 EXAMPLE 81 2-[4-(2.4-Dioxothiazolidin-5-ylmethyl phenoxvmethyll-2.5,7.8tetramethvlchroman-6-yl 5-(1.2-dithiolan-3-vl)pentanoate CH3

CH

0 3

CR

3 3

II

CH3 1 0 O N-H 0 S O S-S

CH

3 5 0.36 ml of triethylamine and then 0.25 ml of ethyl chloroformate were added dropwise to 10 ml of a solution of 500 mg of D,L-c-lipoic acid in anhydrous dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, 1.06 g of tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione were added to the 10 reaction solution, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours, after which it was left to stand at room temperature overnight. The mixture was then stirred on an oil bath at 50 0 C for 1 hour, and then the solvent was

S

removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction *o 15 solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 3 2 by volume mixture of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 3 1 and 4 1 by volume mixtures of acetonitrile and water as eluent. The acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the y:\wpdocs\dgtmss\9812'.usa 9812e1 I doc 462 residue was dissolved in dioxane and then lyophilised, to obtain 0.57 g of the title compound as a yellow oil having an Rf value of 0.42 (silica gel thin layer chromatography; using a 1 2 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 82 2-(3.4-Dibenzvloxy-5-oxo-2.5-dihydrofuran-2-l)-2-hydroxvethyl 5-(1.2-dithiolan-3-yl)pentanoate

O

0 o i *S OHOBz S-S OH BzO is benzyl) 276 mg of N,N'-carbonyldiimidazole were added, whilst ice-cooling, to 6 ml of a solution of 300 mg of D,L-a-lipoic acid in anhydrous dimethylformamide and the •mixture was stirred at room temperature for I hour and 30 minutes. At the end of this time, 0.24 ml of triethylamine and 536 mg of 2,3-Q-dibenzylascorbic acid were added, whilst ice-cooling, to the reaction solution, and the mixture was stirred at room temperature for 1 hour, after which the reaction mixture was left to stand at room temperature for 2 days. The solvent was then removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 3 and 1 1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 11 9, 3 2 and 13 7 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation y:'.wpdocs\dgt_mss'9812\usa\9812ex I .doc 463 under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 321 mg of the title compound as a yellow oil having an Rf value of 0.34 (silica gel thin layer chromatography; using a 1 2 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 83 5-(1.2-Dithiolan-3-vy-l-(imidazol-l-yl)pentan-l-one eN

N

0.86 g of N,N'-carbonyldiimidazole was added, whilst ice-cooling, to 20 ml of a solution of 1.00 g of D,L-c-lipoic acid in anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour. At the end of this time, 311 mg of chloromethanesulfonamide and 104 mg of sodium hydride (as a 55% w/w dispersion in 15 mineral oil) were added, whilst ice-cooling, to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1, 4 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 464 evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 245 mg of the title compound as a pale yellow amorphous substance, melting at 37 to 39 0

C.

EXAMPLE 84 t-Butvl 4-15-(1,2-dithiolan-3-vl)pentanoyllpiperazine-l-carboxvlate .(Compound No. 1-1131 t-butoxycarbonyl derivative) 0 N N-Boc

S-S

("Boc" is t-butoxycarbonyl) The reaction was carried out as described in Example 43, but using 500 mg of D,L-c(-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole and 484 mg of N-t-butoxycarbonylpiperazine. The solvent was removed 15 from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was dissolved in dioxane and then lyophilised, to obtain 520 mg of the title compound as a pale yellow amorphous substance, melting at to 71 0

C.

y:,%wpdocs\dgtmss\98 12' usa\98 i 2ex I .doc 465 EXAMPLE 5-(1.2-Dithiolan-3-vy)- 1-(piperazin-l-vl)pentan-l-one hydrochloride (Compound No. 1-1131 hvdrochloride) 0 N N-H .HCI

S-S

3 ml of a 4 N solution of hydrogen chloride in ethyl acetate were added dropwise to 5 ml of a solution of 260 mg of t-butyl 4-[5-(1,2-dithiolan-3-yl)pentanoyl]piperazine-l-carboxylate (prepared as described in Example 84) in ethyl acetate, and the mixture was stirred at room temperature for 3 hours. The crystals which precipitated were then collected by filtration, to obtain 217 mg of the title compound as a pale yellow powder, melting at 84 to 86 0

C.

EXAMPLE 86 Thiazolidine-3-carboxvlic acid 14-(1.2-dithiolan-3-yl)butvllamide (Compound No. 1-1260) H

S

N

N

S-S O The reaction was carried out as described in Example 44, but using 500 mg of D,L-at-lipoic acid, 10 ml of anhydrous toluene, 0.36 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide and 0.20 ml of thiazolidine. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel y:\wpdocs\dgtmss\98 I 2\usa98I 2ex I .doc 466 column chromatography, using 2 1 and 1 0 by volume mixtures ofethyj acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from a 1 1 by volume mixture of ethyl acetate and hexane, to obtain 386 mg of the title compound as yellow crystals, melting at 76 to 77 0

C.

EXAMPLE 87 5-(1.2-Dithiolan-3-vl)pentanoic acid (1-methyl-2-nitroxyethyl)amide (Compound No. 1-2665 nitrate)

CH

3 N N S-S H The reaction was carried out as described in Example 47, but using 300 mg of D,L-cL-lipoic acid, 9 ml of anhydrous dimethylformamide, 259 mg of N,N'-carbonyldiimidazole, 0.22 ml of triethylamine and 251 mg of 1-methyl-2-nitroxyethylamine hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was 15 extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3 2 and 2 1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 3 7, 2 3 and 7 3 by volume mixtures ofacetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 467 dissolved in dioxane and then lyophilised, to obtain 119 mg of the title compound as a yellow oil having an Rf value of 0.39 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 88 1-[4-(1.2-Dithiolan-3-yl)butvll-3-(2-nitroxyethyl)urea (Compound No. 1-2661 nitrate) H H N N N NONO2 S-S O The reaction was carried out as described in Example 46, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous toluene, 0.72 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 342 mg of 2-nitroxyethylamine hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from a 1 2 by volume mixture of ethyl acetate and hexane, to obtain 58 mg of the title compound as a pale yellow powder having an Rf value of 0.31 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

y:\wpdocs\dgtmss\98 I 2\usa\98I2ex I .doc 468 EXAMPLE 89 3-(1,2-Dithiolan-3-yl)propionic acid

COOH

s-S 1.3 ml of 2 N aqueous hydrochloric acid were added to a solution of 500 mg of 4,6-dithioxyhexanoic acid in 5 ml of a 1 N aqueous solution of sodium hydroxide.

drops of a 1% w/v aqueous solution of ferric chloride were then added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 1 hour while air was blown through the mixture. Water was then added to the reaction solution, which was then washed with ethyl acetate. The aqueous layer was neutralized by the addition of 2 N aqueous hydrochloric acid and then extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 388 mg of the title compound as a yellow oil having an Rf value of 0.59 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 2-[5-(1.2-Dithiolan-3-yl)pentanoylaminolacetamide (Compound No. 1-46 amide) 0 N 1CONH 2 S-S H The reaction was carried out as described in Example 47, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyly:\wpdocs\dgtms\98 I 2'usa\981 2ex I .doc 469 diimidazole, 0.36 ml of triethylamine and 265 mg of glycinamide hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure.

and water was added to the residue, after which it was extracted with ethyl acetate.

The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the crystals which precipitated were collected by filtration, to obtain 330 mg of the title compound as yellow crystals, melting at 105 to 108 0

C.

EXAMPLE 91

S

10 2-{3-[4-(1.2-Dithiolan-3-vl)butvllureido}acetamide (Compound No. 1-738 amide) H H I I N N CONH 2 S-S O *4o. The reaction was carried out as described in Example 46, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous toluene, 0.56 ml of triethylamine, 0.72 ml of 15 diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 265 mg of

S

t* glycinamide hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 149 mg of the title compound as a yellow powder, melting at 141 to 143 0

C.

y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I.doc 470 EXAMPLE 92 1-(Indolin- -vl-5-(1.2-dithiolan-3-yl)pentan-I -one (Compound No. 1-2674) 0 s-s The reaction was carried out as described in Example 43, but using 1.00 g of D,L-a-lipoic acid, 30 ml of anhydrous dimethylformamide, 0.86 g of N,N'-carbonyl- Sdiimidazole, 0.73 ml of triethylamine and 1.13 g of methyl indoline-2-carboxylate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 4 and 1 2 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using a 3 2 by volume mixture ofacetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 0.84 g of the title compound as a pale yellow powder, melting at 65 to 66 0

C.

y\\pdocs\dgt_mss'98 I 2\usa\981 2ex I.doc 471 EXAMPLE 93 Methyl 1-[4-(1.2-dithiolan-3-yl)butlcarbamovllindoline-2-carboxvlate (Compound No. 1-2676 methyl ester)

COOCH

3

H

NsN S-S O 5 The reaction was carried out as described in Example 44, but using 1.00 g of D,L-a-lipoic acid. 25 ml of anhydrous toluene, 0.73 ml of triethylamine, 1.14 ml of diphenylphosphoryl azide and 0.94 g of methyl indoline-2-carboxylate. The reaction solution was washed with water, and the toluene layer was separated and washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium 10 sulfate. The toluene was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 2, 1 1 and 2 1 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 485 mg of the 15 title compound as yellow crystals, melting at 86 to 89 0

C.

EXAMPLE 94 1-[4-(1.2-Dithiolan-3-vl)butylcarbamoyllindoline-2-carboxylic acid (Compound No. 1-2676)

COOH

H

I

NSS N S-S O y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 472 The reaction was carried out as described in Example 48, but using 200 mg of methyl 1-[4-(1,2-dithiolan-3-yl)butylcarbamoyl]indoline-2-carboxylate (prepared as described in Example 93), 4 ml of methanol, 2 ml of tetrahydrofuran and 1.0 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 98 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.12 (silica gel thin layer chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 15 Methyl 3-13-(1.2-dithiolan-3-yl)propionylaminopropionate 0 "N COOCH 3 S-S H 5 ml of anhydrous tetrahydrofuran were added to 6 ml of a mixture of 2.5 mmol of 3-(l,2-dithiolan-3-yl)propionic acid in a mixture of ethyl acetate and dimethylformamide. 0.6 ml of triethylamine, 349 mg of p-alanine methyl ester hydrochloride and 0.38 ml ofdiethyl cyanophosphate were added to the reaction solution, whilst ice-cooling, and the resulting mixture was stirred, whilst ice-cooling for 1 hour. At the end of this time, the reaction mixture was stirred at room temperature for 30 minutes, and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation y:\wpdocs\dgtmss\981 2\usa\981 2ex I.doc 473 under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1, 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using a 2 3 by volume mixture of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 229 mg of the title compound as a yellow oil having an Rf value of 0.24 (silica gel thin layer chromatography; using a 3 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 96 1.2-Dithiolane-4-carboxylic acid

S

I COOH 40 ml of 5 N aqueous hydrochloric acid were added to 20 ml of a solution of 3.60 g of methyl (l,3-diacetylthio)propyl-2-carboxylate in methanol, and the mixture was heated under reflux for 5 hours and 30 minutes. At the end of this time, the reaction mixture was left to stand at room temperature overnight, and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a dilute aqueous solution of sodium hydrogencarbonate, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 150 ml of a saturated aqueous solution of sodium hydrogencarbonate and a catalytic amount of ferric chloride 6 hydrate were added to the residue, and then the mixture was stirred at room temperature for 8 hours. The reaction mixture was then left to y:\wpdocs\dgtmss\98 I 2\usa\981 2ex I .doc 474 stand at room temperature overnight, after which the solvent was removed. from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the resulting mixture was washed with ethyl acetate. The pH of the aqueous layer was adjusted to a value of 2 by the addition of aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 0.25 g of the title compound as yellow crystals having an Rf value of 0.56 (silica gel thin layer chromatography; using a 5 1 by volume mixture of ethyl acetate and methanol as developing solvent).

EXAMPLE 97 Methyl 1.2-dithiolan-4-vlcarbonylaminoacetate 0 I N COOCH 3 S I

H

5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine and 398 mg of glycine methyl ester hydrochloride were added to 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, and 0.55 ml ofdiethyl cyanophosphate was then added to the resulting mixture, whilst ice-cooling, after which the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was left to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column y:\wpdocs'dgtmss\98 I 2\usa\982ex I .doc 475 chromatography, using a 2 1 by volume mixture of ethyl acetate and hex.ane as the eluent. The solvent was then removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 1 2 by volume mixture of ethyl acetate and hexane, to obtain 54 mg of the title compound as pale yellow crystals, melting at 73 to 75 0

C.

EXAMPLE 98 Methyl 3-(1.2-dithiolan-4-ylcarbonyl)aminopropionate S N

COOCH

3

I

g S H The reaction was carried out as described in Example 97, but using 5 ml of a 10 solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine, 502 mg of p-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2 1 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 476 EXAMPLE 99 C-Chloro-N-[5-(1.2-dithiolan-3-vl)pentyl methanesulfonamide (Compound No. 1-2473) 0 N-S Cl I II S-S HO The reaction was carried out as described in Example 60, but using 3 ml of a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline- 1,3-dione (prepared as described in Example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.21 ml of chloromethanesulfonyl chloride. The solvent was removed from the reaction mixture by evaporation 10 under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated .aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using o 15 2 5 and 2 3 by volume mixtures of ethyl acetate and hexane as the eluent. The ethyl acetate was removed from the eluate solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 42 mg of the title compound as a brown oil having an Rf value of 0.29 (silica gel thin layer chromatography; using a 2 5 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 100 N-15-(1.2-Dithiolan-3-yl)pentvlbenzamide (Compound No. 1-1923)

O

S-S H y:\wpdocs\dgtmss\98 12'usa\981 2ex I .doc 477 2 ml of methanol and 2 ml of butylamine were added to 3 ml of a sqlution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline- 1,3-dione (prepared as described in Example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature for 2 days.

after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.28 ml of benzoyl chloride were added to the residue. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by 99 evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1 8, 1 4 and 1 2 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 56 mg of the title compound as a yellow amorphous substance, melting at 58 to 59 0

C.

y \wpdocs\dgtmss\98 12\usa\981 2ex I .doc 478 EXAMPLE 101 N-[5-(1.2-Dithiolan-3-vl)pentyllnicotinamide (Compound No. 1-1991) 0 S-S H

N

The reaction was carried out as described in Example 100, but using 3 ml of a 5 solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline- 1,3-dione (prepared as described in Example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 427 mg of nicotinoyl chloride hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was 10 extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane and a 20 1 by volume 15 mixture of ethyl acetate and methanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 156 mg of the title compound as a yellow amorphous substance, melting at 41 to 44 0

C.

y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 479 EXAMPLE 102 N-Butyl-N'-[5-(1.2-dithiolan-3-yl)pentvllphthalamide (Compound No. 1-1936 N-butvlamide) 0 0 N N S-S H H 4 ml of methanol and 4 ml ofbutylamine were added to 6 ml of a solution of 3.0 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline-1,3-dione (prepared as described in Example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under 10 reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, to give a residue.

584 mg of N,N'-carbonyldiimidazole were added to 5 ml of a solution of 770 mg of N-t-butoxycarbonylthiazolidine in anhydrous dimethylformamide, and the mixture was stirred at room temperature for 3 hours. A solution of the residue prepared as described in step above in 3 ml of anhydrous dimethylformamide was then added to the reaction mixture, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours and 30 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to reverse phase preparative silica gel column chromatography, using a 1 1 by volume mixture of y:\wpdocs\dgtmss\98 I2\usa\982ex I.doc 480 acetonitrile and water as eluent. The acetonitrile was removed from the solution by evaporation under reduced pressure, and the precipitated insolubles were collected by filtration, to obtain 118 mg of the title compound as a white powder having an Rf value of 0.44 (silica gel thin layer chromatography; using a 1 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 103 N-[4-(1.2-Dithiolan-3-yl)butyl]-N'-(2-hydroxy-1-methylethyl)urea (Compound No. 1-2667) H H

OH

S-S 0 CH 3 The reaction was carried out as described in Example 46, but using 1.00 g of D,L-a-lipoic acid, 25 ml of anhydrous toluene, 0.74 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.39 ml of D,L-alaninol. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution 15 was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 40 1 and 20 1 by volume mixtures of ethyl acetate and ethanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from methanol to obtain 0.63 g of the title compound as yellow crystals, melting at 87 to 89 0

C.

y:\wpdocs\dgtmss\98 1 2\usa\9812ex I.doc 481 EXAMPLE 104 6-(1.2-Dithiolan-3-vl)hexanoic acid (Compound No. 1-1467)

COOH

s-s ml of water and 60 ml of aqueous hydrochloric acid were added to 7.16 g of 6-(2-oxo-1,3-dithian-4-yl)hexanenitrile, and the mixture was heated under reflux for hours. The reaction mixture was then left to stand at room temperature overnight, after which it was heated under reflux for 2 hours and 30 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, which was then extracted with ethyl acetate. The extraction 10 solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 150 ml of a 1 N aqueous solution of sodium hydroxide, 40 ml of 2 N aqueous hydrochloric acid and 10 drops of a 1% w/v aqueous solution of ferric chloride were added to the residue. The mixture was 15 then stirred at room temperature for 2 hours and 30 minutes while air was blown through it. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was washed with ethyl acetate. The aqueous layer was neutralized by the addition of 2 N aqueous hydrochloric acid, and ethyl acetate was added to the solution. The aqueous layer (a) and ethyl acetate layer were then separated from the mixture.

The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 1 1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in 40 ml of toluene.

y:\wpdocs\dgtmss' 9812\usa\9812exI .doc 482 The ethyl acetate was evaporated from the ethyl acetate layer liberated from the above aqueous layer and 90 ml of a 1 N aqueous solution of sodium hydroxide, 17 ml of 2 N aqueous hydrochloric acid and 5 drops of a 1% w/v aqueous solution of ferric chloride were added to the residue, and then the mixture was stirred at room temperature for 1 hour while air was blown through the mixture. The reaction mixture was left to stand at room temperature overnight, and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized by the addition of 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The extraction solution was combined with the above-mentioned toluene solution, and the solvent was removed from the solution by evaporation under reduced pressure The residue was subjected to reverse phase preparative silica gel column chromatography, using 2 3, 1 1 and 3 2 by volume mixtures of acetonitrile and water as eluent, and acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in 50 ml of toluene. The toluene was evaporated from 2 ml of the resulting toluene solution, and the residue was dissolved in dioxane and then lyophilised, to obtain 69 mg of the title compound as a yellow oil having an Rf value of 0.39 (silica gel thin layer chromatography; using a 1 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 105 Methyl 6-(1.2-dithiolan-3-yl)hexanoylaminoacetate (Compound No. 1-1347)

H

I

N __111 COOCH 3 S-S 0 y:\wspdocs\dgtmss\98 12'usa\981 2ex I .doc 483 The reaction was carried out as described in Example 47, but using ml of a solution of 1.6 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 373 mg of N,N'carbonyldiimidazole, 0.25 ml of triethylamine and 199 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 3 1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2 3 and 1 1 by volume mixtures ofacetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was S° dissolved in dioxane and then lyophilised, to obtain 61 mg of the title compound as a 20 pale yellow amorphous substance having an Rf value of 0.28 (silica gel thin layer chromatography; using a 2 1 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 106 Methyl 2(S)-{N-15-(1.2-dithiolan-3-ylpentanovll-N-methvlamino propionate (Compound No. 1-1224)

I

CH3 y:\wpdocs\dgtmss\98 I 2usa\981 2ex I .doc 484 The reaction was carried out as described in Example 47, but using 500 mg of D,L-a-lipoic acid, 13 ml of anhydrous dimethylformamide, 422 mg of N,N'-carbonyldiimidazole, 0.36 ml of triethylamine and 399 mg of N-methyl-L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was evaporated from the eluate, and the residue was dissolved in dioxane and then lyophilised, to obtain 374 mg of the title compound as a yellow oil having an Rf value of 0.29 (silica gel thin layer chromatography; using ethyl acetate as developing solvent).

15 EXAMPLE 107 N-16-(1.2-Dithiolan-3-vl)hexanovllmethanesulfonamide (Compound No. 1-1796)

HO

I II

N-S-CH

3 S-S 0 6 ml of anhydrous dimethylformamide and 276 mg of N,N'-carbonyldiimidazole were added to 10 ml of a solution of 1.5 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, and the mixture was stirred at room temperature for 4 hours and 30 minutes. 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were then added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature overnight, and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was washed with ethyl acetate and y:\wpdocs\dgtmss\98 I 2\usaW8 2ex I doc 485 neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane as the eluent). The solvent was evaporated from the eluate, and the residue was again subjected to silica gel column chromatography, using 2 3 and 3 2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 98 mg of the title compound as a yellow oil having an Rf value of 0.37 (silica gel thin layer chromatography; using a 3 2 by volume mixture of ethyl acetate and hexane as developing solvent).

o* EXAMPLE 108 15 Methyl 3-[5-(1.2-dithiolan-3-ylpentyllureidoacetate (Compound No. 1-2039) 0 N N COOCH 3 S-S H H The reaction was carried out as described in Example 46, but using 10 ml of a solution of 1.5 mmol of 6-(l,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 6 ml of anhydrous toluene, 0.42 ml of triethylamine, 0.39 ml of diphenylphosphoryl azide, 6 ml of anhydrous dimethylformamide and 254 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of.sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column y:\wpdocs\dgt mss\9812\usa\9812ex I.doc 486 chromatography, using 1 4 and 3 2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 16 mg of the title compound as yellow crystals having an Rf value of 0.62 (silica gel thin layer chromatography; using a 2 3 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 109 Ethyl 3-[4-(1.2-dithiolan-3-yl)butyll-1-methylureidoacetate (Compound No. 1-820 ethyl ester) N N .COOC 2

H

S-S 0 10 oo The reaction was carried out as described in Example 46, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous tetrahydrofuran and 399 mg of sarcosine ethyl ester hydrochloride. The solvent was removed from the reaction 15 mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 7 13, 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent, and acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the y:\wpdocs\dgtmss\98 I 2\usa\98 I2ex I .doc 487 residue was dissolved in dioxane and then lyophilised, to obtain 194 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.43 (silica gel thin layer chromatography, using ethyl acetate as developing solvent).

EXAMPLE 110 3-[4-(1,2-Dithiolan-3-yl)butyll-1.5(S)-dimethylimidazolidine-2.4-dione (Compound No. 1-2682) 0 CH 3 N -CH3 S-S O The reaction was carried out as described in Example 46, but using 500 mg of D,L-a-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of 10 diphenylphosphoryl azide, 5 ml of anhydrous tetrahydrofuran, 5 ml of anhydrous dimethylformamide and 399 mg of N-methyl-L-alanine methyl ester hydrochloride.

The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of 15 sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3 2 and 1 1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2 3 and 1 1 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 283 mg of the title compound as a yellow oil having an Rf value of 0.29 y:\wspdocs\dgt_mss\98 I 2\usax.98I2ex I.doc 488 (silica gel thin layer chromatography, using a 3 2 by volume mixture of ethyl acetate and hexane as developing solvent).

EXAMPLE 111 Methyl 4-{3-t4-(1.2-dithiolan-3-vl)butyl]-l-methylureido}butanoate (Compound No. 1-2670 methyl ester) H CH 3

I

N COOCH 3 S-S O The reaction was carried out as described in Example 46, but using 500 mg of D,L-ac-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 5 ml of anhydrous dimethylformamide and 477 mg of methyl 4-(methylamino)butanoate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column So* chromatography, using 1 0 and 20 1 by volume mixtures of ethyl acetate and methanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 589 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.47 (silica gel thin layer chromatography, using a 20 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

y:\wpdocs\dgtmss\98 1 2\usa\981 2ex I .doc 489 EXAMPLE 112 N-16-(1.2-Dithiolan-3-yl)hexanovll sulfamide (Compound No. 1-1839)

HO

I II

II

N-S-NH2 S-S O The reaction was carried out as described in Example 107, but using 5 ml of a solution of 1.6 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 308 mg of N,N'carbonyldiimidazole, 365 mg of sulfamide and 83 mg of sodium hydride (as a w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3 2 and 2 1 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from a 1 2 by volume mixture of ethyl acetate and hexane, to obtain 92 mg of the title compound as pale yellow crystals, melting at 130 to 132 0

C.

EXAMPLE 113 N-{3-14-(1.2-Dithiolan-3-vl)butvllureidoacetyl}methanesulfonamide (Compound No. 1-26431 H H 0 I I 0 N N 11

N-S-CH

3 II II S-S O H O y:\wpdocs\dgt_mss\9812\usa\9812ex I.doc 490 The reaction was carried out as described in Example 73, but using 201 mg of methyl 3-[4-(1,2-dithiolan-3-yl)butyl]ureidoacetate (prepared as described in Example 46), 4 ml of anhydrous dimethylformamide, 129 mg of N,N'-carbonyldiimidazole, 76 mg of methanesulfonamide and 35 mg of sodium hydride (as a 55% wiw dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from methanol, to obtain 150 mg of the title compound as white crystals, melting at 157 to 158 0

C.

EXAMPLE 114 N-{3-[4-(1,2-Dithiolan-3-yl)butyllureidoacetyl}sulfamide 15 (Compound No. 1-2647) H H 0 N N- S-NH2 S-S O H O The reaction was carried out as described in Example 73, but using 0.20 g of 3-[4-(l,2-dithiolan-3-yl)butyl]ureidoacetic acid (prepared as described in Example 48), 4 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole, 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was y:\wpdocs\dgtmss\98 I 2\usa\982ex I.doc 491 recrystallized from a mixture of methanol and ethyl acetate, to obtain 76 mg of the title compound as yellow crystals, melting at 143 to 145°C.

EXAMPLE 115 N-(2(R)-{3-[4-(1.2-Dithiolan-3-yl)butyllureido}propionvl)sulfamide (Compound No. 1-2655) H H 0 0 0 N I N I I N-S-NH7 /II I II S-S O CH 3 H O S* The reaction was carried out as described in Example 73, but using 0.21 g of 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionic acid (prepared as described in Example 71), 5 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole. 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 114 mg of the title compound as a pale yellow powder, melting at 156 to 157 0

C.

EXAMPLE 116 N-(2(S)-{3-(4-(1.2-Dithiolan-3-vylbutvllureido}propionyl)methanesulfonamide (Compound No. 1-2655) H H 0 I I CN

N-S-NH

2 S-S O CH 3

HO

y:\wrpdocsdgtmss\)8 2'.usa98 2ex I doc 492 The reaction was carried out as described in Example 73, but using 0. 13 g of {3-[4-(1,2-dithiolan-3-yl)butyl]ureido propionic acid (prepared as described in Example 52), 4 ml of anhydrous dimethylformamide, 0.08 g of N,N'-carbonyldiimidazole, 0.05 g of methanesulfonamide and 0.02 g of sodium hydride (as a w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced "pressure, and the residue was recrystallized from ethyl acetate, to obtain 80 mg of the title compound as a white powder, melting at 142 to 147°C.

EXAMPLE 117 4-{3-(4-(1.2-Dithiolan-3-yl)butvllureido}butanoic acid .15 (Compound No. 1-1276) H H 9* N N COOH S-S 0 The reaction was carried out as described in Example 48, but using 0.65 g of methyl 4- 3-[4-(1,2-dithiolan-3-yl)butyl]ureido butanoate (prepared as described in Example 75), 13 ml of methanol and 7.10 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the y:\wpdocsdgtmss9812 .usa9812ex I .doc 493 residue was recrystallized from ethyl acetate, to obtain 0.46 g of the title compound as a pale yellow powder, melting at 94 to 99 0

C.

EXAMPLE 118 Methyl 5-[5-(1.2-dithiolan-3-yl)pentanovlaminolpentanoate (Compound No. 1-2657 methyl ester) 0 N COOCH3 S-S H The reaction was carried out as described in Example 47, but using 1.00 g of D,L-a-lipoic acid, 40 ml of anhydrous dimethylformamide, 0.86 g of N,N'-carbonyldiimidazole, 0.74 ml of triethylamine and 0.89 g of methyl 10 hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced 15 pressure, and the residue was subjected to silica gel column chromatography, using 2 1 and 1 0 by volume mixtures of ethyl acetate and hexane as the eluent. It was then recrystallized from ethyl acetate, to obtain 1.10 g of the title compound as pale yellow crystals, melting at 60 to 62 0

C.

y:'wpdocs\dgtmss\98 I2'usa.9O 2ex I .doc 494 EXAMPLE 119 Methyl 5-{3-[4-(1.2-dithiolan-3-vl)butvl]ureido}pentanoate (Compound No. 1-2659 methyl ester) H H I I N N

COOCH

3 S-S 0 The reaction was carried out as described in Example 46, but using 1.00 g of •D,L-a-lipoic acid, 20 ml of anhydrous toluene, 1.48 ml oftriethylamine, 1.15 ml of diphenylphosphoryl azide and 0.81 g of methyl 5-aminopentanoate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate.

The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue Swas subjected to silica gel column chromatography, using a 2 1 by volume mixture of ethyl acetate and hexane. followed by a 9 1 by volume mixture of ethyl acetate and ethanol, as the eluent, to obtain 1.27 g of the title compound as a pale yellow powder.

S. melting at 90 to 92 0

C.

EXAMPLE 120 5-[5-(1.2-Dithiolan-3-vl)pentaolanolaminpentanoic acid (Compound No. 1-2657) 0

NCO

S-S H The reaction was carried out as described in Example 49, but using 0.65 g of methyl 5-[5-(1,2-dithiolan-3-yl)pentanoylamino]pentanoate (prepared as described in y:\wpdocs'dgtrmss'.98 I2\usa 9812ex I .doc 495 Example 118), 13 ml of methanol and 5.09 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.33 g of the title compound as pale yellowish green crystals, melting at 98 to 100 0

C.

10 EXAMPLE 121 5-{3-14-(1.2-Dithiolan-3-vl)butvllureido}pentanoic acid (Compound No. 1-2659) H H ^N N S-S 0 The reaction was carried out as described in Example 48, but using 0.30 g of methyl 5-13-[4-(1,2-dithiolan-3-yl)butyl]ureido}pentanoate (prepared as described in SExample 119), 10 ml of methanol and 3.14 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.23 g of the title compound as pale yellow crystals, melting at 125 to 132 0

C.

y:.wupdocs\dgtmss\98 I 2'usa'98I2ex I.doc 496 EXAMPLE 122 5-(1.2-Dithiolan-3-y-N-(2-hydroxyethyl)pentanamide (Compound No. 1-2661) 0 O

NH

S-S H 0.86 g of N,N'-carbonyldiimidazole was added to 20 ml of a solution of 1.00 g of D,L-a-lipoic acid in anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour and 20 minutes. 0.32 ml of 2-aminoethanol was then added to the reaction solution, and the resulting mixture was stirred at room temperature for 4 hours and 10 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 19 1 by volume mixture of ethyl acetate and ethanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 0.71 g of the title compound as a yellow amorphous substance having an Rf value of 0.38 (silica gel thin layer chromatography, using a 19 1 by volume mixture of ethyl acetate and ethanol as developing solvent).

y:'wpdocs'dgtmss\98 I 2usax19812ex I doc 497 EXAMPLE 123 5-(1.2-Dithiolan-3-vl)-N-(2-hydroxy-l-methvlethyl)pentanamide (Compound No. 1-2665) 0 CH3 N

OH

S-S H The reaction was carried out as described in Example 122, but using 1.00 g of D,L-a-lipoic acid, 20 ml of anhydrous dimethylformamide, 0.86 g of N,N'-carbonyldiimidazole and 0.42 ml of D,L-alaninol. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using ethyl acetate as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane 15 and lyophilised, to obtain 0.39 g of the title compound as a yellow amorphous substance, melting at 52 to 56 0

C.

EXAMPLE 124 N-14-(1.2-Dithiolan-3-ylbutyll-N'-(2-hydroxyethylurea (Compound No. 1-2663) H H I I

N

S-S O The reaction was carried out as described in Example 46, but using 1.00 g of D,L-ac-lipoic acid, 20 ml of anhydrous toluene, 0.74 ml of triethylamine, 1.15 ml of y:\wpdocs'dgtmss\98 I2'usa\')S I2ex I .doc 498 diphenylphosphoryl azide and 0.29 ml of 2-hydroxy-l-ethylamine. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 39:1 and 19 1 by volume mixtures of ethyl acetate and ethanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from methanol to obtain 352 mg of the title compound as yellow crystals, melting at 50 to 65 0

C.

EXAMPLE 125 N-15-(1.2-Dithiolan-3-vl)pentanoyl-N-methylmethanesulfonamide (Compound No. 1-2672) 0 I* I 0 v v -N-S-CH S-S 0

CH

3 mg of copper chloride were added to 20 ml of a solution of 1.36 g of dicyclohexylcarbodiimide in anhydrous methanol, and the mixture was left to stand at room temperature for one and one half hours. The solvent was then removed from the mixture by distillation under reduced pressure. 20 ml of anhydrous dimethylformamide and 1.00 g of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (prepared as described in Example 2) were then added to the residue, and the mixture was stirred at 70 0 C on an oil bath for an hour. The mixture was then left to stand at room temperature overnight, after which it was stirred at 70 0 C on an oil bath for 1 hour, and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. Insoluble material in the extract was removed by filtration, and the y:\wpdocs'dgt-mss\98 I 2'usa\982ex I.doc 499 filtrate was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2 3 and 1 1 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was subjected to reverse phase preparative silica gel column chromatography, using 1 1 and 3 2 by volume mixtures ofacetonitrile and water as eluent. The acetonitrile was then removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 660 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.27 (silica gel thin layer 15 chromatography, using a 2 3 by volume mixture of ethyl acetate and hexane as developing solvent).

c- EXAMPLE 126 Allyl N-14-(1.2-dithiolan-3-vl)butyllcarbamate

H

N YO CH2 s-s o S-S O The reaction was carried out as described in Example 31, but using 1.00 g of D,L-ac-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 1.14 ml of diphenylphosphoryl azide and 2 ml of allyl alcohol. The reaction mixture was washed with water, the water layer was washed with ethyl acetate, and the ethyl acetate washings were combined with the above-mentioned toluene solution. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extract by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, y:\wpdocs\dgt_mss\9812\usa\9812ex I .doc 500 using 1 4 and 1 2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 944 mg of the title compound as an oily yellow substance having an Rf value of 0.49 (silica gel thin layer chromatography, using a 1 2 by volume mixture of ethyl acetate and hexane as developing solvent).

PREPARATION 1 5-(1.2-Dithiolan-3-vl)pentanol

OH

s-s 10 44 ml of a hexane solution containing 2.0 M of (trimethylsilyl)diazomethane was added dropwise, whilst ice-cooling, to a mixture of 15.00 g ofD,L-a-lipoic acid in ml of methanol and 150 ml of toluene, and then the mixture was stirred at room temperature for one hour. 11 ml of a hexane solution containing 2.0 M of (trimethylsilyl)diazomethane were then added dropwise to the reaction mixture. The 15 resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then allowed to stand at room temperature for 2 days. The solvent was then removed by distillation under reduced pressure from the reaction mixture, to give ethyl 5-(1,2-dithiolan-3-yl)pentanoate as a yellow oil.

A solution of ethyl 5-(1,2-dithiolan-3-yl)pentanoate in 40 ml of anhydrous tetrahydrofuran was added dropwise, whilst cooling with ice and sodium chloride, to a suspension of 3.34 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 3 hours and minutes. Sodium sulfate decahydrate was then added, whilst cooling with ice and sodium chloride, to the reaction mixture, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and then insoluble matter was filtered off using a Celite (trade mark) filter aid. The solvent was removed from the filtrate by distillation under reduced pressure.

y:\wpdocs\dgt_mssI98 2'usa\98 I 2ex I .doc 501 ml of methanol, 25 ml of a I N aqueous solution of sodium hydroxide and 10 ml of 2 N aqueous hydrochloric acid were then added to the residue. Air was then blown into the resulting mixture. Five drops of a 1% aqueous solution of ferric chloride were added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, and then the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the 10 extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1: 2 and 1 1 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the resulting eluate by S: distillation under reduced pressure, and 30 ml of toluene were added to the residue.

1 ml was taken from the resulting solution, and the solvent was removed by distillation under reduced pressure, to give 0.13 g of the title compound as a yellow oil having an Rf value of 0.39 (silica gel thin layer chromatography; using a 1 1 by volume mixture of ethyl acetate and hexane as the eluent).

y: wpdocs dgt_mss98 I? 2usa.)8 I 2ex I .doc

Claims (24)

1. Compounds of formula (CH 2 )k-A-B-R 1 S-S (O)m (0)n in which: one of in and n represents 0, and the other represents 0, 1 or 2; k represents 0 or an integer of from 1 to 12; A represents a single bond, an oxygen atom, a carbonyl group or a group of formula -N(R2)CO-, -N(R2)CS-, -N(R2)SO2?- -CON(R2)N(R3)CO-, -CON(R 2 -CON(R 2 )CS -ON(R 2 )CO-, -ON(R 2 )SO2-, -O-CON(R 2 )N(R3)CO- -O-CON(R 2 )CO-, -O-CON(R 2 )SO2-, -CO-CO-, -CO-CON(R 2 )N(R3)CO- -CO-CON(R 2 -CO-CON(R 2 )SO2-, -N(R 2 -N(R 2 )COCO-, -N(R2)N(R3)CO-, -N(R2)N(R3)SO2-, -N(R2)CON(R3)N(R4)CO-, -N(R 2 )CON(R')CO-, -N(R 2 )CON(R3)S02- or -N(R 2 )CON(R3)SO2N(R4)CO- in which R 2 R 3 and R4 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group defined below the aryl moiety of which may optionally be substituted by from 1 to 3 of substituents P defined below, an acyl group defined below, or one of substituents a defined below; B represents a single bond, or a group of formula -N(R 5 or -N(R 6 )N(R 5 in which R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group defined below the -503- aryl moiety of which may optionally be substituted by from 1 to 3 of substituents P defined below, an acyl group defined below, or one of substituents a defined below, or R 5 together with R 1 and the nitrogen atom to which they are bonded, may form a heterocyclic ring having from 5 to 7 ring atoms defined below; R 1 represents: a hydrogen atom, one of substituents a, defined below, or an alkyl group having from 1 to 12 carbon atoms which is unsubstituted or is substituted by from 1 to 3 of substituents a defined below and/or substituents y defined below or such a *:***substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and/or a sulfur atom, or, where A represents a group of formula -N(R2)CO-, -N(R2)CS-, -CON(R2)N(R3)CO-, -CON(R 2 -CON(R 2 -ON(R 2 -O-CON(R 2 )N(R3)CO-, -O-CON(R 2 -CO-CON(R2)N(R 3 -CO-CON(R 2 -N(R2)N(R 3 )CO-, -N(R2)CON(R3)N(R 4 )CO- or -N(R 2 )CON(R3)CO- [in which R 2 R 3 and R 4 are as defined above] and B represents a single bond, R 1 may represent a group of formula -OR 7 (in which R 7 represents a lower alkyl group defined below, a lower alkenyl group defined below, an aralkyl group defined below of which the aryl moiety may optionally be substituted by from 1 to 3 of substituents P defined below, or one of substituents a defined below); or, where A represents a group of formula -ON(R2)SO 2 -O-CON(R 2 )SO2-, -CO-CO-, -CO-CON(R2)SO2-, -N(R 2 )COCO-, -N(R 2 )N(R 3 )S02- or -N(R 2 )CON(R3)SO2- [in which R 2 and R 3 are as defined above] and B represents a single bond, or, where A does not represent an oxygen atom, a group of formula -CO-O- or -N(R 6 and B represents -N(R 5 [in which R 5 is as defined above], R 1 may represent a hydroxy group or a group of formula -OR 7 (in which R 7 is as defined above); Substituents a are selected from aryl groups defined below, heterocyclic groups defined below, aryl groups defined below substituted with from 1 to 3 of substituents P, and heterocyclic groups defined below substituted with from 1 to 3 of substituents P; Substituents p are selected from lower alkyl groups defined below, halogenated lower alkyl groups defined below, lower alkoxy groups defined below, lower alkylthio groups defined -504- below, hydroxy groups, carboxy groups, optionally-substituted carbamoyl groups defined below, lower alkoxycarbonyl groups defined below, halogen atoms, nitro groups, amine residues defined below, sulfo groups, sulfamoyl groups, cyano groups, and hydroxy- substituted lower alkyl groups defined below; Substituents y are selected from lower alkoxy groups defined below, lower alkylthio groups defined below, hydroxy groups, nitrooxy groups, carboxy groups, lower alkoxycarbonyl groups defined below, halogen atoms, sulfo groups, sulfamoyl groups, amine residues defined below, and optionally-substituted carbamoyl groups defined below; PROVIDED THAT: where A represents an oxygen atom, B represents a single bond or a group of formula -N(R 5 [in which R 5 is as defined above], where A represents a group of formula -CO-O- or -N(R 2 [in which R 2 is as defined above], B represents a single bond, and where k represents 4, the group of formula -A-B-R 1 does not represent a carboxyl group; and pharmaceutically acceptable salts thereof; the aryl groups referred to in the definition of substituents a are carbocyclic aromatic hydrocarbons having from 6 to 14 ring carbon atoms in one or more aromatic carbocyclic rings which may be fused to a cycloalkyl group having from 3 to 10 ring carbon atoms; the aralkyl groups referred to in the definitions of R 2 R R 6 and R' are alkyl groups having from 1 to 6 carbon atoms which are substituted by from 1 to 3 aryl groups defined above; the acyl groups referred to in the definitions of R 2 R 5 and R 6 are selected from the group consisting of alkylcarbonyl groups having from 1 to 30 carbon atoms, halogenated alkylcarbonyl groups having from 2 to 6 carbon atoms, alkoxyalkylcarbonyl groups in which each of the alkoxy and alkyl moieties has from 1 to 4 carbon atoms, unsaturated alkylcarbonyl groups having from 3 to 6 carbon atoms, arylcarbonyl groups in which the aryl moiety is as defined above, halogenated arylcarbonyl groups in which the aryl moiety is as defined above, alkyl-substituted arylcarbonyl groups in which the aryl moiety is as defined above, hydroxy-substituted arylcarbonyl groups in which the aryl moiety is as defined above, (C 6) alkoxy-substituted arylcarbonyl groups in which the aryl moiety is as defined above, nitro- substituted arylcarbonyl groups in which the aryl moiety is as defined above, lower alkoxycarbonyl-substituted arylcarbonyl groups in which the aryl moiety is as defined above -505 and the alkoxycarbonyl substituents have from 2 to 7 carbon atoms, aryl-substituted arylcarbonyl groups in which each aryl moiety is as defined above, alkoxycarbonyl groups having from 2 to 7 carbon atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms in which the alkoxy moiety is substituted with a halogen atom or a tri-(C-6) alkyl silyl group, aralkylcarbonyl groups in which the alkyl moiety has from 1 to 6 carbon atoms and the aryl moiety is as defined above and may optionally be substituted by 1 or 2 alkoxy groups having from 1 to 6 carbon atoms or nitro groups, lower alkanesulphonyl groups in which the lower alkyl moiety has from 1 to 6 carbon atoms, halogenated lower alkanesulphonyl groups in which the lower alkyl moiety has from 1 to 6 carbon atoms and arylsulphonyl groups in which the aryl moiety is as defined above; the 5- to 7-membered heterocyclic rings which may be formed from a combination ofR', RR and the nitrogen atom to which they are attached have from 1 to 3 sulphur and/or oxygen and/or nitrogen atoms of which at least one must be a nitrogen atom, said groups being optionally substituted by 1 or 2 oxygen atoms and/or 1 to 3 of substituents P defined above, and further optionally being fused with a carbocyclic or heterocyclic group having from 3 to 6 ring atoms; the lower alkyl groups referred to in the definitions of R 7 and substituents 3 are straight or branched chain groups having from 1 to 6 carbon atoms; the lower alkenyl groups referred to in the definition of R 7 are straight or branched chain groups having from 2 to 6 carbon atoms; the heterocyclic groups referred to in the definition of substituents a have from 5 to 7 ring atoms of which from 1 to 3 are sulphur and/or oxygen and/or nitrogen atoms, said groups being saturated or unsaturated, optionally being substituted by 1 or 2 oxygen and/or sulphur atoms, and further optionally being fused with a carbocyclic or heterocyclic group having from 3 to 6 ring atoms; the halogenated lower alkyl groups referred to in the definition of substituents P comprise a lower alkyl group as defined above which is substitituted by 1 or more halogen atoms; the lower alkoxy groups referred to in the definitions of substituents P and substituents y are straight or branched chain groups having from 1 to 6 carbon atoms; the lower alkylthio groups referred to in the definitions of substituents P and substituents y are straight or branched chain groups having from 1 to 6 carbon atoms; -506- the amine residues referred to in the definitions of substituents P and substituents y are groups of formula -NRaRb wherein Ra and Rb are the same or different and each represents a hydrogen atom, a lower alkyl group as defined above, a cycloalkyl group having from 3 to 8 ring carbon atoms, an aryl group as defined above, a heterocyclic group as defined above, or R a and Rb together with the nitrogen atom to which they are attached represent a 5- to 7-membered nitrogen-containing heterocyclic group as defined above; the optionally-substituted carbamoyl groups referred to in the defintions of substituents P and substituents y are groups of formula -CONRa'Rb wherein Ra' and Rb' are the same or different and each represents any of the atoms or groups represented by R a and Rb defined above or one ofRa' and R b represents a hydrogen atom and the other represents an acyl group as defined above or an aminosulphonyl group; the lower alkoxycarbonyl groups referred to in the definitions of substituents P and substituents y comprise a carbonyl group which is substituted by a straight or branched chain alkoxy group having from 1 to 6 carbon atoms; and the hydroxy-substituted lower alkyl groups referred to in the definitions of substituents P and substituents y are lower alkyl groups as defined above which are substituted by 1 or more hydroxy groups.

2. A compound according to Claim 1, represented by the formula S* (CH 2 )k-A-B-R 1 S-S (0)m (O)n (in which A, B, R 1 k, m and n are as defined in Claim 1) and salts thereof.

3. A compound according to Claim 1 or Claim 2, in which one ofm and n is 0, and the other is 0 or 1.

4. A compound according to any one of Claims 1 to 3, in which k is 0 or an integer of from 1 to 8. -507- A compound according to any one of Claims 1 to 4, in which R 1 represents a heterocyclic group as defined in Claim 1, an alkyl group having from 1 to 12 carbon atoms which is unsubstituted or is substituted by from 1 to 3 of substituents a as defined in Claim 1 and substituents y as defined in Claim 1 or such a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and/or a sulfur atom.

6. A compound according to any one of Claims 1 to 4, in which R 1 represents a hydroxy group or an alkoxy group having from 1 to 5 carbon atoms. A compound according to any one of Claims 1 to 6, in which A represents a group of formula-CO-, -N(R 2 -N(R2)CS-,-CON(R 2 -N(R 2 )COCO- or -N(R 2 )S02-, in which R 2 represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group.

8. A compound according to any one of Claims 1 to 7, in which B represents a single bond, or a group of formula -N(R 5 or -N(R 5 )N(R 6 in which R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group.

9. A compound according to Claim 1 or Claim 2, in which: one ofm and n is 0, and the other is 0 or 1; k is 0 or an integer of from 1 to 8; R 1 represents a heterocyclic group as defined in Claim 1, a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 12 carbon atoms which is unsubstituted or is substituted by from 1 to 3 of substituents a as defined in Claim 1 and/or substituents y as defined in Claim 1 or such a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and/or a sulfur atom; A represents a group of formula -N(R 2 -N(R2)CS-,-CON(R2)CO-, -N(R 2 )COCO- or -N(R 2 )S0 2 in which R 2 represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group; and -508- B represents a single bond, or a group of formula -N(R 5 or -N(R 5 )N(R 6 in which R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group. A compound according to Claim 1 or Claim 2, in which both of m and n are 0.

11. A compound according to any one of Claims 1, 2 and 10, in which k is an integer of from 2 to 6.

12. A compound according to any one of Claims 1, 2, 10 and 11, in which R 1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group as defined in Claim 1, an alkoxy group having from 1 to 5 carbon atoms or a hydroxy group.

13. A compound according to any one of Claims 1, 2 and 10 to 12, in which A represents a group of formula-CO-, -N(R 2 -N(R 2 -CON(R 2 -N(R 2 )COCO- or -N(R 2 in which R 2 represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms.

14. A compound according to any one of Claims 1, 2 and 10 to 13, in which B represents a single bond, or a group of formula -N(R 5 or -N(R 5 )N(R 6 in which R 5 and R 6 are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms. A compound according to Claim 1 or Claim 2, in which: both of m and n are 0; k is an integer of from 2 to 6; R 1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group as defined in Claim 1, an alkoxy group having from 1 to carbon atoms or a hydroxy group; -509- A represents a group of formula-CO-, -N(R 2 -N(R 2 -CON(R 2 )CO-, -N(R 2 )COCO- or -N(R 2 )S0 2 in which R 2 represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms; and B represents a single bond, or a group of formula -N(R 5 or -N(R 5 )N(R 6 in which R 5 and R 6 are the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 12 carbon atoms.

16. A compound according to Claim 1 or Claim 2, in which k is 4 or

17. A compound according to any one of Claims 1, 2 and 16, in which R 1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group as defined in Claim 1 or an alkoxy group having from 1 to 5 carbon atoms. *go

18. A compound according to any one of Claims 1, 2, 16 and 17, in which A represents a group of formula -NHCO-, -NHCS-, -CONHCO-, -NHCO-, -NHCOCO-, -NHSO2- or -CO-.

19. A compound according to any one of Claims 1, 2 and 16 to 18, in which B represents a single bond, or a group of formula -NCH 3 or -NHNCH 3 A compound according to Claim 1 or Claim 2, in which: both ofm and n are 0; k is 4 or R 1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group as defined in Claim 1 or an alkoxy group having from 1 to 5 carbon atoms; -510- A represents a group of formula -NHCO-, -NHCS-, -CONHCO-, -NHCO-, -NHCOCO-, -NHSO 2 or and B represents a single bond, or a group of formula -NCH 3 or -NHNCH 3

21. Methyl 3-[4-(1,2-dithiolan-3-yl)butyl]ureidoacetate and pharmaceutically acceptable salts thereof.

22. 2(S)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionic acid and pharmaceutically 0 acceptable salts thereof.

23. Methyl 2(S)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate and pharmaceutically acceptable salts thereof. 0*0*

24. Ethyl 3-[4-(1,2-dithiolan-3-yl)butyl]-l-methylureidoacetate and pharmaceutically acceptable salts thereof.

25. N-[5-(1,2-dithiolan-3-yl)pentyl]methanesulphonamide and pharmaceutically acceptable salts thereof. 0*

26. The use of a compound according to any one of Claims 1 to 25 for the manufacture of a medicament for enhancing the activity of glutathione reductase in a mammal.

27. The use of a compound according to any one of Claims 1 to 25 for the manufacture of a medicament for the treatment or prevention of cataract in a mammal.

28. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 25 in admixture with a pharmaceutically acceptable diluent or carrier.

29. A method for enhancing the activity of glutathione reductase in a mammal comprising administering to said mammal an effective amount of a compound according to any one of Claims 1 to -511 A method for the treatment or prevention of cataract in a mammal comprising administering to said mammal an effective amount of a compound according to any one of Claims 1 to Dated this 20th day of October 2000 Sankyo Company Limited By Its Patent Attorneys DAVIES COLLISON CAVE So S. **S «*09 *9*